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Both clinical and X-ray findings have been used for postoperative assessment of the donor site following secondary alveolar bone grafting in our department. However, this approach requires that patients be exposed to X-ray irradiation several times at the donor site and the cleft site. Furthermore, the findings do not depict bone healing status in detail and thus offer little information to help in deciding the required duration of postoperative movement restriction. Therefore, we sought to determine the utility of ultrasound in addition to X-ray for evaluating bone surface healing at the donor site.

We evaluated maxillary growth outcomes of our modification of a two-stage palatoplasty algorithm (the Zurich University protocol) for the treatment of complete unilateral cleft lip, alveolus, and palate (UCLP) that allows for maxillary growth by delaying alveolar and hard palate closure with bone grafting until age 8 years or older.

It has been reported that two-stage palatoplasty is excellent in terms of maxillary growth but poor in terms of speech outcomes. We modified the two-stage Zurich approach in two aspects. First, the speech plate is placed immediately after soft palatoplasty using Perko’s technique to prevent air leakage through the nose in all cases. The other is that simultaneous closure of the alveolar and hard palate cleft with bone grafting is delayed until age ≥8 years to allow maxillary growth. In this paper we report on postoperative velopharyngeal function and role of the speech plate.

OBJECTIVES:The objective of this study was to assess prospectively the diagnostic accuracy of computer-assisted computed tomographic colonography (CTC) in the detection of polypoid (pedunculated or sessile) and nonpolypoid neoplasms and compare the accuracy between gastroenterologists and radiologists.METHODS:This nationwide multicenter prospective controlled trial recruited 1,257 participants with average or high risk of colorectal cancer at 14 Japanese institutions. Participants had CTC and colonoscopy on the same day. CTC images were interpreted independently by trained gastroenterologists and radiologists. The main outcome was the accuracy of CTC in the detection of neoplasms ≥6 mm in diameter, with colonoscopy results as the reference standard. Detection sensitivities of polypoid vs. nonpolypoid lesions were also evaluated.RESULTS:Of the 1,257 participants, 1,177 were included in the final analysis: 42 (3.6%) were at average risk of colorectal cancer, 456 (38.7%) were at elevated risk, and 679 (57.7%) had recent positive immunochemical fecal occult blood tests. The overall per-participant sensitivity, specificity, and positive and negative predictive values for neoplasms ≥6 mm in diameter were 0.90, 0.93, 0.83, and 0.96, respectively, among gastroenterologists and 0.86, 0.90, 0.76, and 0.95 among radiologists (P<0.05 for gastroenterologists vs. radiologists). The sensitivity and specificity for neoplasms ≥10 mm in diameter were 0.93 and 0.99 among gastroenterologists and 0.91 and 0.98 among radiologists (not significant for gastroenterologists vs. radiologists). The CTC interpretation time by radiologists was shorter than that by gastroenterologists (9.97 vs. 15.8 min, P<0.05). Sensitivities for pedunculated and sessile lesions exceeded those for flat elevated lesions ≥10 mm in diameter in both groups (gastroenterologists 0.95, 0.92, and 0.68; radiologists: 0.94, 0.87, and 0.61; P<0.05 for polypoid vs. nonpolypoid), although not significant (P>0.05) for gastroenterologists vs. radiologists.CONCLUSIONS:CTC interpretation by gastroenterologists and radiologists was accurate for detection of polypoid neoplasms, but less so for nonpolypoid neoplasms. Gastroenterologists had a higher accuracy in the detection of neoplasms ≥6 mm than did radiologists, although their interpretation time was longer than that of radiologists.

Many patients with Helicobacter pylori infection may have different cure rates depending on genetic differences in the enzyme S-mephenytoin 4'-hydroxylase (CYP2C19). This liver enzyme metabolizes the drug omeprazole, which is used to treat Helicobacter pylori infection. Helicobacter pylori infection has been linked to peptic ulcer. In a study of 62 Japanese patients with Helicobacter pylori infection, those who metabolized omeprazole quickly had a 28% cure rate, those who metabolized the drug more slowly had a 60% cure rate and those who metabolized the drug the slowest had a 100% cure rate. Their ulcers healed at similar rates.

Inflammatory bowel disease (IBD) is a chronic relapsing-remitting condition that afflicts millions of people throughout the world and impairs their daily functions and quality of life. While the aetiology of IBD is not understood well, it appears to be driven by inflammatory cytokines such as tumor necrosis factor (TNF)-α. Hence, there is a strong interest in agents that can block the generation or actions of inflammatory cytokines. Curcumin is a bioactive substance present in the rhizomes of the herb “Curcuma longa” which has been used for centuries in Asia, both in traditional medicine and in cooking as turmeric which gives food an exotic natural yellow color. Further, in recent years, a large number of research papers have reported intriguing pharmacologic effects associated with curcumin. These include inhibitory effects on cyclooxygenases 1, 2 (COX-1, COX-2), lipoxygenase (LOX), TNF-α, interferon γ (IFN-γ), inducible nitric oxide synthase (iNOS), and the transcriptional nuclear factor kappa B (NF-κB), in addition to a strong anti-oxidant effect. NF-κB is a key factor in the upregulation of inflammatory cytokines that have a high profile in inflammatory diseases, suggesting that curcumin could be a novel therapeutic agent for patients with IBD. Therefore, in recent years, the efficacy of curcumin has been investigated in several experimental models of IBD. The results indicate striking suppression of induced IBD colitis and changes in cytokine profiles, from the pro-inflammatory Th1 to the anti-inflammatory Th2 type. In human IBD, up to now, only one open study has achieved encouraging results. In this study, patients were given curcumin (360mg/dose) 3 or 4 times/day for three months. Further, curcumin significantly reduced clinical relapse in patients with quiescent IBD. The inhibitory effects of curcumin on major inflammatory mechanisms like COX-2, LOX, TNF-α, IFN-γ, NF-κB and its unrivalled safety profile suggest that it has bright prospects in the treatment of IBD. However, randomized controlled clinical investigations in large cohorts of patients are needed to fully evaluate the clinical potential of curcumin.

Active ulcerative colitis (UC) is associated with elevated granulocytes and monocytes/macrophages (GM) which show activation behavior and increased survival time. Further, fecal calprotectin (a stable neutrophil protein) level parallels intestinal inflammation and can predict UC relapse. Since GM are major sources of inflammatory cytokines and chemokines, they are suspected to have roles in the initiation and perpetuation of UC. Our objective was to investigated relationships between peripheral blood (PB) neutrophils, calprotectin, and UC disease activity. Full PB and calprotectin were determined in 69 healthy controls and 31 patients with UC, then 7 randomly selected patients received GM adsorptive apheresis (GMA) with Adacolumn, 10 sessions of 60-min duration each. Patients with UC had higher neutrophil counts (P<0.001), but lower lymphocyte counts (P<0.001) compared with controls. Further, fecal calprotectin levels showed a correlation with UC clinical activity index (CAI; P<0.001) and mucosal inflammation (P<0.001). Following GMA, there were falls in neutrophils (P<0.02), CAI (P<0.02) and calprotectin (P<0.02). In conclusion, GM appear to contribute to intestinal inflammation and UC activity and reduction of these cells by GMA should benefit patients with active UC. Further, the correlations among calprotectin, UC activities, and PB neutrophils should serve as the basis for preemptive actions to control this disease.

Evidence suggests that the erythropoietin‐producing hepatocellular (EPH) receptor tyrosine kinases (RTKs) and their ephrin (EFN) ligands are involved in human carcinogenesis. Expression of two of them, EFNA1 ligand and its receptor, EPHA2, has been proposed to contribute to tumor‐induced neovascularization. Colorectal cancers were examined for expressions of EPHA2 and its ligand EFNA1 by semi‐quantitative RT‐PCR, and double‐immunostained for EPHA2 and CD34. Microvessels in the tumors were counted. Double‐staining was also performed in 25 cases of adenoma with focal cancer for comparison. Trends of overexpression of both EPHA2 and EFNA1 was found in tumor tissue compared to the corresponding normal tissue in the same specimen [22/37 (59.5%) and 25/37 (67.5%), respectively; P=0.100 for EPHA2 and P=0.009 for EFNA1]. Overexpression of EPHA2 and EFNA1 was noted more frequently in the early stage than in the late stage [EPHA2, 15/21 (71.4%) vs. 7/16 (43.8%), P=0.007; EFNA1, 15/21 (71.4%) vs. 10/16 (62.5%), P=0.007]. Both EPHA2 and EFNA1 were more frequently overexpressed in smaller tumors (less than 5 cm) than in larger tumors [EPHA2, 15/21 (71.4%) vs. 7/16 (43.8%), P=0.017; EFNA1, 16/21 (76.2%) vs. 8/16 (50%), P=0.001]. Tumors less than 5 cm in diameter and in stages I and II were significantly more likely to overexpress EPHA2 and EFNA1 (P=0.001 for EPHA2, P=0.001 for EFNA1). Microvessel counts (MVCs) after immuno‐staining for CD34 were significantly correlated (r=0.343, P=0.037) with overexpression of EPHA2. EPHA2‐expressing focal cancer also surrounded microvessels in adenomas with focal cancers. These findings suggest an involvement of EPHA2 in colon carcinogenesis, mainly in stages I and II, and probably through their effect on microvessel induction.

Background & Aims:Curcumin is known to have a variety of pharmacologic effects, including antitumor, anti-inflammatory, and anti-infectious activities. The pleiotropic effects of curcumin are attributable at least in part to inhibition of transcriptional factor nuclear factor κB (NF-κB). However, the effect of curcumin on intestinal inflammation has hitherto not been evaluated. The aim of this study was to determine whether treatment with curcumin prevents and ameliorates colonic inflammation in a mouse model of inflammatory bowel disease. Methods:Mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis were treated with 0.5%, 2.0%, or 5.0% curcumin in the diet, and changes in body weight together with histologic scores were evaluated. Colonic T-cell subsets were characterized, and NF-κB in colonic mucosa was detected by immunohistochemistry. NF-κB activity in the colonic mucosa was evaluated using electrophoretic mobility shift assay. Cytokine messenger RNA expression in colonic tissue was assessed by semiquantitative reverse-transcription polymerase chain reaction. Results:Treatment of mice with curcumin prevented and improved both wasting and histopathologic signs of TNBS-induced colonic inflammation. Consistent with these findings, CD4+T-cell infiltration and NF-κB activation in colonic mucosa were suppressed in the curcumin-treated group. Suppression of proinflammatory cytokine messenger RNA expression in colonic mucosa was also observed. Conclusions:This study has shown for the first time that treatment with curcumin can prevent and improve murine experimental colitis. This finding suggests that curcumin could be a potential therapeutic agent for the treatment of patients with inflammatory bowel disease.

Background and Objectives: The acid-inhibitory effect of lansoprazole depends on differences in cytochrome P450 (CYP) 2C19 genotypes. We assessed whether therapeutic effects of lansoprazole on gastroesophageal reflux disease (GERD) depended on the CYP2C19 genotype status in relation to the grade of GERD.Methods: A total of 65 patients with GERD (grades A-D) completed treatment with lansoprazole, by taking 30 mg orally once a day for 8 weeks. The CYP2C19 genotype status of patients was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. Before and after treatment, esophageal endoscopy was performed. GERD was considered to be cured on the basis of endoscopic findings at the end of treatment. Plasma lansoprazole levels could be determined at 3 hours after the last 30-mg dose of lansoprazole in the 27 genotyped patients.Results: Cure rates for GERD depended significantly on the CYP2C19 genotype status, as well as the grade of GERD before treatment. Cure rates in the homozygous extensive, heterozygous extensive, and poor metabolizer groups were 45.8%, 67.9%, and 84.6%, respectively. Cure rates in the groups with GERD grade A, grade B, and grade C or D were 85.0%, 60.0%, and 45.0%, respectively. The cure rate in patients with the homozygous extensive metabolizer genotype of CYP2C19 with a GERD grade of C or D was very low (16.7%). Plasma lansoprazole levels in patients with the homozygous extensive metabolizer genotype were the lowest of the 3 groups.Conclusions: CYP2C19 genotype status, as well as the grade of GERD before treatment, is one of the determinants for the success or failure of treatment of GERD with lansoprazole. The low cure rate in patients with the homozygous extensive metabolizer genotype appeared to be a result of these patients having the lowest plasma lansoprazole levels among the 3 genotype groups.Clinical Pharmacology & Therapeutics (2002) 72, 453–460; doi: 10.1067/mcp.2002.127637

This study investigated the performance status, mental status, and prognosis of 24 patients older than 80 years whose gastric cancer had been managed surgically during the past 6 years, and 21 patients who were observed conservatively. The advantages and disadvantages of surgery for elderly patients with gastric cancer is discussed. The 3-year survival rate for patients with advanced gastric cancer was 31 for those surgically treated and 0 for those observed conservatively. The difference is statistically significant. The survival rate for patients with early gastric cancer was 62.5 in the surgical treatment group and 33.3 in the conservative observation group, a difference that is not significant. Decline in performance status and deterioration of mental status after open surgery were slight, and the survival rate for patients treated surgically was significantly higher than for conservatively observed patients, regardless of performance status and whether mental status had deteriorated. On univariate and multivariate analyses, the presence or absence of open surgery and macroscopic classification were the only significant prognostic factors, whereas performance status and the presence or absence of mental deterioration were not significant prognostic factors. These results suggest that surgical treatment should not be discouraged even for patients older than 80 years.

Abstract Purpose. We have previously reported that EPHB2 is overexpressed in gastric cancer; however, the expression profiles of its ligands, EFNB1 and EFNB2, are unknown. This study was designed to investigate the expression of EPHB2 and its ligands, EFNB1 and EFNB2, in human gastric cancer. Methods. Semi-quantitative RT-PCR using ³²P was performed on human gastric cancer tissues and corresponding normal tissues (29 gastric cancer patients). Results. EPHB2 was more highly expressed in tumor tissues than in normal tissues in 21 out of 29 (72.4%), in gastric cancer patients (P = 0.01); EFNB1 and EFNB2 were highly expressed in 21 out of 29 (72.4%) (P = 0.037) and 14 out of 29 (48.3%) patients, respectively. The overexpression of EPHB2 was frequently detected in both well-differentiated adenocarcinoma and poorly differentiated adenocarcinoma [10/13 (76.9%) and 9/14 (64.3%), respectively]. On the other hand, the overexpression of EFNB1 was more frequently detected in poorly differentiated adenocarcinoma than in well-differentiated adenocarcinoma [12/14 (85.7%) and 7/13 (53.8%), respectively. P =0.027]. Elevated levels of EPHB2 and EFNB1 were detected in substantial subsets of early gastric cancers. Genomic alterations to these three genes in gastric cancer specimens were either not found or rarely found except for several rare variations of EPHB2. Conclusions. These findings suggest that not only the expression of EPHB2, but the expression of its ligand EFNB1 may have some relation with the oncogenesis of gastric cancer.

ABSTRACTBenzo[a]pyrene [B(a)P], a potent procarcinogen found in combustion products such as diesel exhaust and cigarette smoke, has been recently shown to activate the c-Jun NH2-terminal kinase 1 (JNK1) and induce caspase-3-mediated apoptosis in Hepa1c1c7 cells. However, the molecules of the signaling pathway that control the mitogen-activated protein kinase cascades induced by B(a)P and the interaction between those and apoptosis by B(a)P have not been well defined. We report here that B(a)P promoted Cdc42/Rac1, p21-activated kinase 1 (PAK1), and JNK1 activities in 293T and HeLa cells. Moreover, alpha-PAK-interacting exchange factor (α PIX) mRNA and its protein expression were upregulated by B(a)P. While overexpression of an active mutant of α PIX (ΔCH) facilitated B(a)P-induced activation of Cdc42/Rac1, PAK1, and JNK1, overexpression of mutated αPIX (L383R, L384S), which lacks guanine nucleotide exchange factor activity, SH3 domain-deleted αPIX (Δ SH3), which lacks the ability to bind PAK, kinase-negative PAK1 (K299R), and kinase-negative SEK1 (K220A, K224L) inhibited B(a)P-triggered JNK1 activation. Interestingly, overexpression of αPIX (Δ CH) and a catalytically active mutant PAK1 (T423E) accelerated B(a)P-induced apoptosis in HeLa cells, whereas αPIX (Δ SH3), PAK1 (K299R), and SEK 1 (K220A, K224L) inhibited B(a)P-initiated apoptosis. Finally, a preferential caspase inhibitor, Z-Asp-CH2-DCB, strongly blocked the αPIX (Δ CH)-enhanced apoptosis in cells treated with B(a)P but did not block PAK1/JNK1 activation. Taken together, these results indicate that αPIX plays a crucial role in B(a)P-induced apoptosis through activation of the JNK1 pathway kinases.

Rabeprazole is a potent proton pump inhibitor and is mainly reduced to thioether rabeprazole by a non-enzymatic pathway and partially metabolized to demethylated rabeprazole by CYP2C19 in the liver. We intended to determine a cure rate for Helicobacter pyloriinfection by dual rabeprazole/amoxicillin therapy in relation to CYP2C19 genotype status prospectively. Ninety-seven patients with gastritis andH. pyloriinfection completed the dual therapy with 10 mg of rabeprazole bid and 500 mg of amoxicillin tid for 2 weeks. At 1 month after treatment, cure of H. pyloriinfection was assessed on the basis of histology, a rapid urease test, culture, polymerase chain reaction (PCR), and 13C-urea breath test. CYP2C19 genotype status was determined by a PCR-restriction fragment length polymorphism method. Of the 97 patients, 33 were homozygous extensive metabolizers (homEM), 48 were heterozygous extensive metabolizers (hetEM), and 16 were poor metabolizers (PM). Cure ofH. pyloriinfection was achieved in 79 of the 97 patients (81.4, 95CI 71.9–88.7). Significant differences in cure rates among the homEM, hetEM, and PM groups were observed; 60.6 (95CI 42.1–77.3), 91.7 (95CI 80.0–97.7), and 93.8 (95CI 69.8–99.8), respectively (P0.0007). Twelve patients without cure after initial treatment (10 homEMs and 2 hetEMs) were successfully retreated with rabeprazole 10 mg q.i.d. and amoxicillin 500 mg q.i.d. for 2 weeks. The cure rates forH. pyloriinfection by dual rabeprazole/amoxicillin therapy depended on the CYP2C19 genotype status. This dual therapy appears to be effective for hetEM and PM patients. However, high dose dual rabeprazole/amoxicillin therapy was effective even for homEM patients. Therefore, the genotyping test of CYP2C19 appears to be a clinically useful tool for the optimal dual treatment with rabeprazole plus amoxicillin.

Background: Proton pump inhibitors such as omeprazole and lansoprazole are mainly metabolized by CYP2C19 in the liver. The therapeutic effects of proton pump inhibitors are assumed to depend on CYP2C19 genotype status.Objective: We investigated whether CYP2C19 genotype status was related to eradication rates of H pylori by triple proton pump inhibitor–clarithromycin–amoxicillin (INN, amoxicilline) therapy and attempted to establish a strategy for treatment after failure to eradicate H pylori.Methods: A total of 261 patients infected with H pylori completed initial treatment with 20 mg of omeprazole or 30 mg of lansoprazole twice a day, 200 mg of clarithromycin three times a day, and 500 mg of amoxicillin three times a day for 1 week. CYP2C19 genotypes of patients were determined with polymerase chain reaction–restriction fragment length polymorphism analysis. Patients without eradication after initial treatment were retreated with 30 mg of lansoprazole four times daily and 500 mg of amoxicillin four times daily for 2 weeks.Results: Eradication rates for H pylori were 72.7% (95% confidence interval, 64.4%-81.8%), 92.1% (confidence interval, 86.4%-97.3%), and 97.8% (confidence interval, 88.5%-99.9%) in the homozygous extensive, heterozygous extensive, and poor metabolizer groups, respectively. Thirty-four of 35 patients without eradication had an extensive metabolizer genotype of CYP2C19. Nineteen of those patients were infected with clarithromycin-resistant strains of H pylori. However, there were no amoxicillin-resistant strains of H pylori. Re-treatment of H pylori infection with dual high-dose lansoprazole-amoxicillin therapy succeeded in 30 of 31 patients with extensive metabolizer genotype of CYP2C19.Conclusion: The majority of patients without initial eradication of H pylori had an extensive metabolizer CYP2C19 genotype but were successfully re-treated with high doses of lansoprazole and an antibiotic to which H pylori was sensitive, such as amoxicillin, even when the patients were infected with clarithromycin-resistant strains of H pylori.

We investigated possible impairment of the signal transduction system in gastric myocytes of streptozotocin-induced diabetic (STZ) and spontaneous diabetic WBN/Kob (WBN/Kob) rats. Gastric motility 10 weeks after the onset of diabetes mellitus was significantly reduced in both diabetic rats compared with control, and the decreased motility was not recovered by the administration of insulin to maintain normal blood glucose levels. There was no significant difference between both types of diabetic rats and control rats in total number of [3H]quinuclidinyl benzilate ([3H]QNB) binding sites (Bmax: 545–587 fmol/mg protein) on gastric smooth muscle cell membranes or in the affinity of [3H]QNB for the binding sites(Kd: 0.06–0.07nM). Immunoblot analysis using polyclonal anti-G-protein antibodies indicated increased expression of Gsαin gastric smooth muscle cell membranes, but no significant change in Giαor Gq/11αexpression in STZ rats, and decreased expression of Gq/11αwith no significant change in Gsαand Giαin WBN/Kob rats. The cAMP production in gastric smooth muscle cell membranes was augmented in the absence and presence of 100 μM isoproterenol, and 100 μM forskolin in STZ rats, whereas no significant change of cAMP production was observed in WBN/Kob rats irrespective of the presence of the stimulants. These findings suggest that long-standing diabetes may induce alterations in signal transduction at downstream receptors in gastric myocytes, resulting in the impairment of gastric motility, although the mechanism of reduced contractile activity may differ between STZ and WBN/Kob rats.

A 53-year old female patient with duodenal ulcer and Helicobacter pylori infection was treated three times with a proton pump inhibitor–based triple therapy, such as lansoprazole-clarithromycin-amoxicillin (INN, amoxicilline) and lansoprazole-minocycline-cefaclor. However, the H pylori infection was not cured. A culture test revealed that her infection was a clarithromycin-resistant but amoxicillin-sensitive strain of H pylori. Moreover, a polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) analysis revealed that she was a homozygous extensive metabolizer of cytochrome P450 (CYP) 2C19 (wt/wt). The usual dose of the proton pump inhibitor was therefore assumed to be insufficient for her and then she was treated with a high dose of omeprazole (120 mg/day) and amoxicillin (2250 mg/day) for 2 weeks. The H pylori infection and the ulcer lesion were then cured. One of the factors associated with success or failure of cure of H pylori infection by the proton pump inhibitor–based triple therapy appeared to be CYP2C19 genotype status. Dual treatment with a sufficient dose of a proton pump inhibitor plus amoxicillin could cure H pylori infection even after the failure to cure H pylori infection by a usual proton pump inhibitor–based triple therapy in patients with the wt/wt homozygous extensive metabolizer genotype of CYP2C19.Clinical Pharmacology & Therapeutics (2000) 67, 684–689; doi: 10.1067/mcp.2000.106826

A 64-year-old man presented with leg edema and hypoproteinemia. His alpha-1 antitrypsin clearance rate of 174 mL/day indicated the presence of protein-losing enteropathy (PLE). Computed tomographic scans demonstrated thickened ileal wall and mesenteric edema. Angiography revealed occlusion in a peripheral branch of the superior mesenteric vein. Furthermore, both the patient and his son had low protein C levels. The patient was treated successfully with partial resection of the ileum. Histologic examination of the resected ileum revealed multiple erosions and submucosal fibrosis with organized venous thrombi in the mesenteric veins. This is the first case report of PLE caused by mesenteric venous thrombosis, and our findings suggest that serum protein was lost through erosion of the ileum caused by ischemia due to mesenteric venous thrombosis.

Objective: Omeprazole is metabolized by genetically determined S-mephenytoin 4′-hydroxylase (CYP2C19) in the liver. This study aimed to determine whether the effect of omeprazole on intragastric pH depends on CYP2C19 genotype status.Methods: CYP2C19 genotype status for 2 mutations associated with the poor metabolizer phenotype was determined by a polymerase chain reaction–restriction fragment length polymorphism method in 16 healthy volunteers. Helicobacter pylori status was determined by serology and the [13C]urea breath test. After a single oral administration of 20 mg omeprazole or a placebo, intragastric pH values were recorded for 24 hours. Plasma levels of omeprazole and its 2 metabolites and gastrin were measured before and 1, 2, 3, 5, 7, 10, and 24 hours after administration.Results: Fifteen of the 16 subjects were H pylori negative. Five of the 15 subjects were homozygous extensive metabolizers, 4 were heterozygous extensive metabolizers, and 6 were poor metabolizers. After omeprazole administration, significant differences in mean intragastric pH values and plasma levels of gastrin, omeprazole and its metabolites were observed among the 3 groups, whereas no significant differences in these parameters were observed with the placebo administration.Conclusions: The effect of omeprazole on intragastric pH significantly depends on CYP2C19 genotype status. The genotyping test of CYP2C19 may be useful for an optimal prescription of omeprazole.

Intragastric hyperacidity occurs after abruptwithdrawal of histamine H2-receptorantagonists, and the prolonged administration of theseagents induces tachyphylaxis of the inhibitory effectson gastric acid secretion. We examined the effect of theprolonged administration of H2-receptorantagonists on the H2-receptor signalingsystem in parietal cells isolated from rabbits that hadreceived H2-receptor antagonists for 14 days.[125I]aminopotentidine (APT) binding sites toH2receptors in parietal cell membranes wereincreased without any significant change in the affinityfor [125I]APT. The expression of Gsα, guanosine triphosphate(GTP)-binding protein coupled to H2receptor,was slightly increased. Basal as well as GTP orhistamine-stimulated cAMP production was increased, butno significant change was observed in the presence of anH2-receptor antagonist. The up-regulation ofthe H2receptor and adenylate cyclaseappeared to cause hypersecretion of acid afterwithdrawal of H2receptor blockade.

Background and purpose: A triple therapy with omeprazole, amoxicillin (INN, amoxicilline), and clarithromycin is widely used for the eradication of Helicobacter pylori. Omeprazole and clarithromycin are metabolized by CYP2C19 and CYP3A4. This study aimed to elucidate whether clarithromycin affects the metabolism of omeprazole.Methods: After administration of placebo or 400 mg clarithromycin twice a day for 3 days, 20 mg omeprazole and placebo or 400 mg clarithromycin were administered to 21 healthy volunteers. Plasma concentrations of omeprazole and clarithromycin and their metabolites were determined before and 1, 2, 3, 5, 7, 10, and 24 hours after dosing. CYP2C19 genotype status was determined by a polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method.Results: Subjects were classified into three groups on the basis of PCR-RFLP analyses for CYP2C19: homozygous extensive metabolizer group (n = 6), heterozygous extensive metabolizer group (n = 11), and poor metabolizer group (n = 4). Mean area under the plasma concentration–time curves from 0 to 24 hours (AUC) of omeprazole in the homozygous extensive metabolizer, heterozygous extensive metabolizer, and poor metabolizer groups were significantly increased by clarithromycin from 383.9 to 813.1, from 1001.9 to 2110.4, and from 5589.7 to 13098.6 ng · h/mL, respectively. There were significant differences in the mean AUC values of clarithromycin among the three groups.Conclusion: Clarithromycin inhibits the metabolism of omeprazole. Drug interaction between clarithromycin and omeprazole may underlie high eradication rates achieved by triple therapy with omeprazole, amoxicillin, and clarithromycin.

We examined the effect of soluble corn bran hemicellulose (CBH, 10g/day) on glucose control and serum insulin in three groups: patients with impaired glucose tolerance (IGT) with (20 subjects) or without (8 subjects) obesity and with healthy non-obese controls (10 subjects). Long-term supplementation (6 months) with CBH decreased the post oGTT curve for patients with impaired mild Type II diabetes, but not that for the controls. Hemoglobin A1cdecreased significantly during CBH supplementation in the obese patients, while the fasting glucose level decreased in all three groups, although not significantly. A decreased serum insulin response by oGTT was found in those patients with IGT.The improved oGTT result was associated with improved insulin release and perhaps with peripheral insulin sensitivity. These findings suggest that CBH at a low dose might contribute to glycemic control and would play a useful role in treating Type II diabetes patients.

Calcium transport systems of isolated ileal epithelial cells were investigated. The concentration of cytosolic free calcium ions, [Ca2+]i, was monitored with a fluorescent Ca2+ dye, fura-2. The fluorescence intensity ratio (I340/I380) was used as an index of [Ca2+]i. [Ca2+]i of the cells suspended in the nominally Ca2+-free solution was estimated at 52±3 nM. Ca2+ uptake was followed for as long as 5 min in the presence of 100–1000 µM added CaCl2. Most of the experiments were performed at 200 µM CaCl2. The Ca2+ uptake was abolished by 0.8 mM Ni2+ and 50 µM Mn2+ and partitally antagonized by 50 µM verapamil and 50 µM diltiazem but not affected by 20 µM nifedipine. The Ca2+ entry was reduced by increasing concentrations of extracellular K+ in the presence of valinomycin, suggesting a voltage-dependent nature of the uptake. On the other hand, the Ca2+ transport doubled in the presence of Bay K8644 (8 µM), a Ca2+ channel agonist. The Bay-K-8644-induced uptake was inhibited by either 10 µM nifedipine, 10 µM verapamil or 10 µM diltiazem and was relatively independent of extracellular K+ concentration. These results suggest that there are at least two distinct Ca2+ transport systems in the rat ileal epithelial cells, one resistant to organic Ca2+ channel blockers but relatively sensitive to membrane potential (basal uptake) and another inducible by Bay K 8644 and sensitive to the channel blockers but relatively independent of membrane potential.

Telomerase activity is generally absent in primary cell cultures and normal tissues. Telomerase is known to be induced upon immortalization or malignant transformation of human cells. In the present study, we analyzed both telomere length and telomerase activity in biopsy samples from mucosa undergoing metaplasia, adenoma and cancer of the stomach. We attempted to estimate the correlation between telomerase activity and telomere length in these tissues. Telomerase activity was estimated using the telomeric repeat amplification protocol and telomere length by Southern blot analysis. Extracts were defined as telomerase-negative when the signals were less intense than those for 102KATO-III cells (positive control). We detected telomerase activity in 15%, 45% and 89% of the examined cases of intestinal metaplasia, adenoma and gastric cancer respectively. However, telomere length in the gastric mucosa became reduced as the mucosa underwent metaplasia and developed into adenoma. Gastric cancers showed a broad range of telomere length among cases. However, gastric adenomas showed the shortest telomere length. These results suggest that telomerase is expressed during the early phase (intestinal metaplasia through adenoma) of gastric carcinogenesis, although the activity at that stage is not high enough to fully restore the reduced telomeric DNA.

It is currently accepted that colorectal tumorigenesis results from accumulation of multiple mutations in certain genes. This concept prompted us to search for possible mutations in the APC, k-ras, and p53genes in an advanced cancer coexisting with a large villous adenoma of the rectum in a 54-year-old patient with no family history of colorectal cancer. Genomic DNA extracted from multiple subregions of the tumor and surrounding normal mucosa was studied by polymerase chain reaction (PCR) followed by single-strand conformation polymorphism (SSCP) analysis and direct sequencing. Both the adenoma and carcinoma had abnormal PCR-SSCP for APC(exon 11) and k-ras, irrespective of the location within the tumors. However, p53abnormality (exon 7) was detected only in samples taken from the carcinoma. Subsequent sequencing revealed a TTC to TAG mutation at codon 479 of APC, a GGT to GAT mutation at codon 12 of k-rasin both the adenoma and carcinoma, and a CGG to TGG mutation at codon 248 of p53(exon 7) in the carcinoma. These findings were in accord with the current concept of colorectal tumor progression whereby genetic alteration of APC and k-rasoccurs relatively early while that of p53is rather late and is possibly a decisive event in relation to malignancy.

Abstract. Recently, hypertension research has focused on altered cytosolic free Ca2+, [Ca2+]i, in cells of spontaneously hypertensive rats (SHR). In this work, a mechanism(s) responsible for regulating [Ca2+]i was studied with duodenal epithelial cells isolated from SHR and their control, normotensive Wistar-Kyoto rats (WKY). The equal specific activity of sucrase, an enzyme characteristic of microvilli, in both mucosal scrapings and isolated cells from SHR and WKY suggested that mucosal density of enterocytes was not largely different between the two strains. [Ca2+]i of the isolated cells was estimated with fura-2. Upon incubation in the presence of CaCl2, [Ca2+], increased to a larger extent in SHR than in WKY cells. Ca2+efflux based on measurements of [Ca2+]1 was decreased in SHR cells. Correspondingly, it was found that 45Ca efflux at 10 sec was lower for SHR cells than for WKY cells. Specific activities of Ca2+-stimulated and Ca2+/calmodulin-stimulated ATPases in basolateral plasma membrane preparations were reduced in SHR cells. These results indicated that Ca2+efflux was decreased by reduction in Ca2+-pumping ATPase activity in SHR enterocytes.

Familial adenomatous polyposis of the colon, or Gardner's syndrome, is often accompanied by adenomas of the stomach and duodenum. We experienced a rare case of Gardner's syndrome, with adenomas of the common bile duct, in a patient who presented with relapsing acute pancreatitis. Our findings indicate that adenoma in the common bile duct or pancreatic duct should be considered as a possible etiology when patients with familial polyposis or Gardner's syndrome present with pancreatitis, particularly relapsing acute pancreatitis.

Helicobacter pyloriis present in infected patients not only on the gastric epithelial cell surface but also in gastric mucus. We developed a competitive polymerase chain reaction (cPCR) method for quantitative measurement of H. pyloriin gastric mucus. The aim of this study was to determine the number of H. pyloriin gastric mucus before and after anti‐H. pyloritreatment. Patients with duodenal ulcer were treated with lansoprazole alone (n=11) or lansoprazole and amoxycillin (n=12). The amount of H, pyloriin gastric mucus was measured over time by a cPCR assay. Helicobacter pyloriinfection was also tested for using histology, culture, and the rapid urease test (RUT). Although most patients treated with lansoprazole alone had become H. pylori‐negative by the end of treatment when tested by histology, RUT, and culture, a large number of H. pyloriorganisms were found in the gastric mucus at that time by cPCR. These patients returned to being H. pyloripositive 1 to 12 months later on the basis of histology, RUT, and culture. However, cPCR results indicated eradication of H. pyloriby the end of treatment in eight of the 12 patients treated with lansoprazole and amoxicillin, and these patients remained H. pylorinegative on histology, RUT, culture, and cPCR 1 to 12 months later. Testing for H. pyloriin gastric mucus is thus useful for precise determination of the success or failure of H. pylorieradication therapy.

Expression of muscarinic receptor subtypes inrat gastric smooth muscle was examined with reversetranscriptase-polymerase chain reaction (RT-PCR). Underthe condition for detecting the messages of m1-m4 subtypes in brain, atrium, and gastric mucosa,only the fragments of m2 and m3 subtypes were amplifiedwith RNA prepared from rat gastric smooth muscles.Furthermore, the amplified fragments were digested by restriction enzymes, reconfirming that thepredicted size products of m2 and m3 contain the partialDNA sequences of m2 and m3 subtypes, respectively. Wemeasured gastric motility in rats with a pressure transducer system under the continuous venousinfusion of the muscarinic antagonists atropine andbutylscopolamine (nonselective), AF-DX 116 (M2),zamifenacine (M3), and glucagon. Heart rate wasmonitored simultaneously in the tail. Gastric motilitywas inhibited in the presence of glucagon andzamifenacine without alteration of heart rate, whereasthere was no inhibition in the presence of AF-DX 116even after the augmentation of heart rate wasobserved. Gastric emptying was also suppressed in thepresence of zamifenacine, which had an effect comparablewith that of atropine, butylscopolamine, and glucagon. These results indicate that the activation ofthe M3 subtype in gastric smooth muscle causes itscontraction, and the M3 selective antagonist could be apotentially useful drug without an adverse effect on the heart for radiological and endoscopicexamination in the upper gastrointestinaltract.

We have used modified unified velopharyngoplasty (mUVP) with mucosal palatal flaps for cleft palate and congenital velopharyngeal insufficiency (VPI) in 88 patients since 1996. This surgical method is reasonable from a functional point of view in that the levator veli palatini muscle is sutured to the pharyngeal constrictor muscle at both sides of the base of the pharyngeal flap. However, long-term outcomes remain inadequate because this is still a new surgical technique. We thus evaluated surgical complications and improvement in velopharyngeal closure (VPC) of our method.

Thiopurine S-methyltransferase (TPMT), which exhibits a genetic polymorphism, plays an important role in the metabolism of thiopurine drugs such as mercaptopurine, thioguanine, and azathioprine. To determine the frequency distribution of TPMT activity in 157 Japanese subjects with different TPMT genotypes, ie, TPMT1/1and TPMT1/3, the authors measured levels of 6-methylmercaptopurine formed from 6-mercaptopurine in red blood cells lysates by HPLC. The TPMT activities in our Japanese subjects ranged from 11.0 to 42.6 pmol/h/mgHb. Although the mean value of TPMT activities in 6 subjects with TPMT1/3C(20.3 ± 8.1 pmol/h/mgHb) was 25 lower than that in 151 subjects with TPMT1/1(27.0 ± 5.1 pmol/h/mgHb), there was overlap. The ranges of TPMT activity in subjects with TPMT1/1and those with TPMT1/3Cwere similar. The median values in TPMT1/3Cand TPMT1/1individuals were 20.1 (11.0–31.2) and 26.8 pmol/h/mgHb (15.7–42.7), respectively (Mann-Whitney U-test median difference 6.7 pmol/h/mgHb, 95 CI 0–25.5, P< 0.05). This observation may have relevance for the use of 6-mercaptopurine and azathioprine as therapeutic agents in Japanese patients.

The occurrence of tumor in the small intestine is relatively rare. It has been demonstrated that lipoma of the ileum is a cause of intussusception. We report a 59-year-old man admitted to our hospital for lower abdominal pain. Diagnosis of intussusception was made by abdominal x-ray and ultrasonography. Enema contrast studies revealed ileocolic intussusception. Colonoscopy revealed a tumor with an submucosal tumor (SMT)-like head and coil-spring appearance in the ascending colon. Endoscopic ultrasonography (EUS) revealed a hyperechoic submucosal lesion with features compatible with lipoma. Subsequently, this was confirmed histopathologically after resection. To our knowledge, this is the first report of preoperative diagnosis of ileal lipoma by EUS.

Biliobiliary fistula is thought to be a rare type of internal biliary fistula. A 68-year-old man presented to our hospital with complaints of jaundice and general malaise. Endoscopic retrograde cholangiography was performed, but the gallbladder was not imaged. Mirizzi's sign was observed in the common hepatic duct. During the course of evaluating this inpatient, imaging revealed that a gallstone was extruded to the right hepatic duct. After incision of the papilla, stones in the bile duct were subjected to mechanical lithotripsy and were extracted. As a result of bile duct decompression, the biliobiliary fistula was closed completely 2 months later.

Abstract: A case of congenital subclavian steal caused by a previously unreported aortic arch anomaly was demonstrated by angiography. The patient was shown to have a right aortic arch with a retroesophageal segment, a stenotic proximal portion of the left subclavian artery, and a left descending aorta.