中村 正克

This study investigated the trends in idiopathic peptic ulcers, examined the characteristics of refractory idiopathic peptic ulcer, and identified the optimal treatment. The characteristics of 309 patients with idiopathic peptic ulcer were examined. We allocated idiopathic peptic ulcers that did not heal after 8 weeks' treatment (6 weeks for duodenal ulcers) to the refractory group and those that healed within this period to the healed group. The typical risk factors for idiopathic peptic ulcer (atherosclerosis-related underlying disease or liver cirrhosis complications) were absent in 46.6% of patients. Absence of gastric mucosal atrophy (refractory group: 51.4%, healed group: 28.4%; p = 0.016), and gastric fundic gland polyps (refractory group: 17.6%, healed group: 5.9%; p = 0.045) were significantly more common in the refractory group compared to the healed group. A history of H. pylori eradication (refractory group: 85.3%, healed group: 66.0%; p = 0.016), previous H. pylori infection (i.e., gastric mucosal atrophy or history of H. pylori eradication) (refractory group: 48.5%, healed group: 80.0%; p = 0.001), and potassium-competitive acid blocker treatment (refractory group: 28.6%, healed group, 64.1%; p = 0.001) were significantly more frequent in the healed group compared to the refractory group. Thus, acid hypersecretion may be a major factor underlying the refractoriness of idiopathic peptic ulcer.

Objective In general, surface ulceration in gastric gastrointestinal stromal tumor (GIST) is considered a malignant feature; however, the mechanism underlying its formation has not been evaluated in detail. In this study, we analyzed the factors involved in ulceration using resected specimens of gastric GIST. Methods A total of 48 samples were retrospectively analyzed. We examined the association of surface ulceration of gastric GIST with the MIB-1 labeling index, mitotic number, tumor size, endoscopic ultrasound (EUS) findings and growth pattern on computed tomography (CT). Results The proportion of men was significantly higher in the ulceration group than in the non-ulceration group (p=0.04146), whereas age was not significantly different between the groups. Tumor was significantly larger in the ulceration group than in the non-ulceration group (p=0.0048). There was no correlation between tumor size and ulcer number. The MIB-1 index was not related to ulceration, nor were EUS findings. The number of mitotic cells tended to be higher in the ulceration group than in the non-ulceration group (p=0.05988). Intraluminal growth pattern was strongly associated with ulceration (p=0.00019). After a multivariate analysis, the growth pattern was the only factor associated with ulceration of gastric GIST. Conclusion Although formation of surface ulceration in gastric GIST was partially associated with the degree of malignancy, the growth pattern was the most important factor associated with ulceration in gastric GIST.

We encountered three cases with incidental penetration of a straight Amsterdam-type bile duct plastic stent into the duodenal papilla. All patients had undergone insertion of a biliary plastic stent due to common bile duct stones. However, in all three cases, we observed penetration of the biliary plastic stent into the duodenal papilla just before the elective surgery or at the time of plastic stent replacement. We, therefore, performed stent dissection using a bipolar snare and were able to safely remove the plastic stents in all three cases. We believe that this is the first report of plastic stent dissection using a bipolar snare.

We herein report the case of a 79-year-old patient with unresectable stage III non-small cell lung cancer who developed immune-related hepatitis caused by durvalumab administration. Durvalumab was administered at 10 mg/kg every two weeks after the treatment with carboplatin (AUC2), paclitaxel (35 mg/m2), and 60 Gy radiation. At the day 208 in which the 14th durvalumab administration was scheduled, the patient was urgently hospitalized due to CTCAE Grade 4 hepatic dysfunction detected during the an outpatient blood sampling test. He was diagnosed with immune-related hepatitis and started on methylprednisolone 60 mg/day. After 51 days, his liver dysfunction improved and he was discharged.

BACKGROUND: CpG methylation of tumor suppressor genes occurs in the early stage of carcinogenesis. Detecting risk factors for aberrant CpG methylation is clinically important for predicting cancer development. DNA methyltransferase (DNMT) 3a is considered to play critical roles in the DNA methylation process during pathogenesis. In this study, we evaluated the association between DNMT3A polymorphisms (rs6733868 and rs13428812) and CpG methylation status in non-cancerous gastric mucosa. METHODS: We determined the DNMT3A genotype and CpG methylation status of 4 genes (p14ARF, p16INK4a, DAPK, and CDH1) in 510 subjects without gastric cancer. Helicobacter pylori (HP) infection status was determined by the rapid urease test, urea breath test, speculum examination, or serum antibody test. We determined the DNMT3A genotype using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP). CpG methylation status was determined by methylation-specific polymerase chain reaction (MSP). When the methylated band was stronger than 10 ng/μL according to the DNA marker, we judged CpG island hypermethylation (CIHM) to be present. Associations between genotypes and susceptibilities were assessed by logistic regression analysis. RESULTS: The minor allele frequencies of both polymorphisms (rs6733868 and rs13428812) were lower in the CpG methylated groups of each of the 4 genes (p14ARF, p16INK4a, DAPK, and CDH1). Using a dominant genetic model, rs6733868 was significantly associated with the hypermethylation of each gene, whereas rs13428812 was associated with the methylation of 3 genes (all except p14ARF). When low-CIHM was defined as 1 or 2 CpG islands methylated and high-CIHM was defined as 3 or more CpG islands methylated, carrying the minor allele of rs6733868 was associated with both decreased low- and high-CIHM, and that of rs13428812 also was associated with a decrease. Comparing low-CIHM with high-CIHM, carrying the minor alleles of rs6733868 or rs13428812 was related to decreased susceptibility to high-CIHM. In HP-infected subjects, carrying the minor alleles of rs6733868 or rs13428812 had a significantly greater association with decreased susceptibility to high-CIHM. CONCLUSIONS: Our study indicates that polymorphisms of DNMT3A are associated with the accumulation of gene methylation in gastric mucosa. Carrying the minor alleles of rs6733868 or rs13428812 inhibits aberrant gene methylations, which are typically enhanced by HP infection.

BACKGROUND: CDKN2A hypermethylation is among the major events associated with carcinogenesis and is also observed in non-neoplastic colonic mucosa in patients with ulcerative colitis (UC). Macrophage migration inhibitory factor (MIF) plays a crucial role in promoting gastrointestinal inflammation characteristic of UC. The aim of this study is to explore associations between CDKN2A methylation status and MIF polymorphisms (rs755622 and rs5844572). METHODS: One hundred and fifty-nine patients diagnosed with UC were enrolled in this study. The methylation status of p14ARF and p16INK4a was determined by MSP; MIF genotypes were identified by PCR-SSCP. RESULTS: We found no differences with respect to mean age, gender, clinical type (chronic continuous or relapse/remitting), or extent of disease among the patients with methylated and unmethylated p14ARF or p16INK4a. Carrying the rs755622 C allele indicated a significantly higher risk for p14ARF methylation (odds ratio (OR), 2.16; 95% confidence interval (CI), 1.08-4.32; p = 0.030); similarly, carrying the rs5844572 7-repeat allele indicated a significantly higher risk for p16INK4a methylation (OR, 2.57; 95% CI, 1.26-5.24; p = 0.0094) after an adjusted regression analysis. The carriers of the rs755662 C allele or the rs5844572 7-repeat allele were both at a significantly higher risk for methylation of both p14ARF and p16INK4a when compared to the cohort in which neither of the genes were methylated (OR, 2.70; 95% CI, 1.22-6.01; p = 0.015 and OR, 2.87; 95% CI, 1.25-6.62; p = 0.013, respectively). Additionally, carrying rs755622 C allele was significantly associated with CIHM in chronic continuous of clinical type and total colitis (OR, 25.9; 95% CI, 2.55-262.6; p = 0.0059 and OR, 4.38; 95% CI, 1.12-17.2; p = 0.034, respectively), and carrying 7-repeat allele of rs5844572 was significantly associated in chronic continuous type (OR, 14.5; 95%CI, 1.46-144.3; p = 0.022). CONCLUSIONS: Taken together, our findings suggest that MIF genotypes associated with inflammation may also be involved in promoting carcinogenesis via CDKN2A hypermethylation in patients diagnosed with UC.

65歳男性、38年前に大腸憩室膿瘍で小腸結腸側端吻合を施行、今回高熱と右下腹部痛で入院となった。造影CTでアメーバ性肝膿瘍と腸管アメーバ症を疑ったため、下部消化管内視鏡を行った。小腸結腸側端吻合の回腸盲端内に不整形潰瘍と偽膜を認め、迅速検鏡で栄養型アメーバ虫体を認めた。非常にまれな回腸盲端内が主病巣である、腸管アメーバ症より発症をした肝膿瘍の1例を経験したので報告をする。(著者抄録)

症例は79歳男性。高度貧血を主訴に近医を受診し小腸腫瘍が疑われたため当院紹介となった。造影CT、PET-CTで空腸に腫瘤性病変を認めたため、経口シングルバルーン小腸内視鏡検査と小腸カプセル内視鏡検査を行った。2型病変を空腸に認める以外に十二指腸水平部にも0-IIc病変を認め、いずれの病変も腺癌の病理結果であった。リスク因子となる炎症性腸疾患や遺伝性疾患(FAP、Lynch syndrome、Peutz-Jeghers syndrome)を認めない、非常に稀な原発性同時多発小腸癌を経験したため報告をする。(著者抄録)

The aim of the present study was to investigate whether single nucleotide polymorphisms in the DNMT3A gene are associated with susceptibility to gastric cancer in the Japanese population. The present case-control study examined the associations between single nucleotide polymorphisms (rs6733868 and rs13428812) in DNMT3A and cancer susceptibility in 343 patients with gastric cancer and 708 subjects without gastric malignancies on upper gastro-duodenal endoscopy. Of 708 controls, 409 were classified into two groups histologically: 99 cases with and 310 cases without gastric mucosal atrophy. Overall, homozygosity for the DNMT3A rs6733868 minor allele was significantly associated with a reduced risk of gastric cancer (odds ratio [OR], 0.621; 95% confidence interval [CI], 0.402-0.958; P=0.031), especially of the intestinal type (OR, 0.494; 95% CI, 0.274-0.890; P=0.019). In subjects >60 years, rs6733868 minor allele homozygosity was significantly associated with gastric cancer susceptibility. Carriers of the rs6733868 minor allele had a reduced risk of severe gastric mucosal atrophy (OR, 0.495; 95% CI, 0.299-0.826; P=0.0069). In addition, the number of minor alleles of both rs6733868 and rs13428812 was significantly correlated with the risk of Helicobacter pylori (HP) infection (P=0.0070 and P=0.0050, respectively). However, rs13428812 was not associated with severe gastric mucosal atrophy or gastric carcinogenesis. The present results suggest that DNMT3A polymorphisms serve roles in the progression from HP infection to gastric mucosal atrophy and gastric carcinogenesis in terms of degree and manner.

A 79-year-old male with severe anemia was referred to our hospital for a suspected tumor in the small intestine. Contrast computed tomography (CT) and positron emission tomography (PET)-CT showed a tumor lesion in the jejunum. Oral single-balloon enteroscopy and small bowel capsule endoscopy revealed a Type 2 lesion in the jejunum and a Type 0-IIc lesion in the third portion of the duodenum. Histopathological examination of biopsy specimens showed that both lesions were adenocarcinomas. Here, we report a very rare case of simultaneous multiple primary small bowel cancers in a patient without known risk factors such as inflammatory bowel disease or hereditary condition (e.g., familial adenomatous polyposis, Lynch syndrome, Peutz-Jeghers syndrome).

A 65-year-old man was admitted complaining of high fever and pain in the right lower abdomen. An ileocolonic side-to-end anastomosis had been performed 38 years previously for an abscess in a colonic diverticulum. On the current admission, findings on contrast-enhanced computed tomography suggested an amebic liver abscess and intestinal amebiasis. Colonoscopy revealed an irregularly shaped ulcer and false membrane in the ileal blind end of the ileocolonic anastomosis. Amebic trophozoites were seen by rapid microscopy. Amebiasis in the blind end of the ileum has rarely been reported. This case is of particular interest because the intestinal amebiasis also led to a liver abscess.

The aim of the present study was to investigate an association of genetic polymorphism (rs7521584) located in miR‑200a‑200b‑429 cluster, which has tumor suppressor and pro‑inflammatory function, with the development of gastric mucosal atrophy and metaplasia as a pre‑malignant condition. Gastric mucosa samples were obtained from the antrum of 393 patients with no malignancies. The rs7521584 genotype was determined using the polymerase chain reaction‑single‑strand conformation polymorphism analysis method. The degree of gastritis was assessed histologically in all subjects and serum levels of pepsinogen (PG) I/II were quantified in 123 out of 393 patients. Patients with an atrophy score ≥1 and metaplasia score ≥1 were classified into the atrophic gastritis group (AG group). The rs7521584 TT genotype was significantly associated with the development of atrophic gastritis [odds ratio (OR), 2.41; 95% confidence interval (CI), 1.10‑5.25; P=0.027), particularly in patients with H. pylori infection (OR, 3.31; 95% CI, 1.35‑8.12; P=0.0089). In addition, in patients younger than 60 years of age, this genotype was associated with atrophic gastritis (OR, 3.15; 95% CI 1.03‑9.61; P=0.044)]. In patients with H. pylori infection, the metaplasia score was significantly higher in the TT homozygote compared with the GG+GT genotype. In the rs7521584 TT homozygote, serum PG I/II ratio was significantly reduced with increasing age (P=0.0084). No significant trend was identified between the GG+GT genotype and age. The results of the current study indicated that the rs7521584 minor allele homozygote was associated with the development of chronic gastritis under the influence of H. pylori‑induced inflammation, particularly with the severity of metaplastic alterations.

The present study aimed to investigate whether single nucleotide polymorphisms in receptor interacting serine/threonine kinase 2 (RIPK2), which encodes a component of the nucleotide binding oligomerization domain containing 2-RIP2 pathway, may compromise the innate immune response to Helicobacter pylori infection, leading to increased susceptibility to gastric cancer in the Japanese population. The present case control study investigated the associations between RIPK2 single nucleotide polymorphisms and gastric mucosal inflammation, atrophy and cancer susceptibility in 528 patients with gastric cancer and 697 patients without gastric malignancies on upper gastro-duodenal endoscopy. Overall, the RIPK2 rs16900627 minor allele was significantly associated with the susceptibility to gastric cancer [OR, 1.37; 95% confidence interval (CI), 1.06-1.77; P=0.016], particularly of the intestinal type (OR, 1.53; 95% CI, 1.13-2.07; P=0.0062). It was also significantly associated with gastric mucosal atrophy (OR, 1.83; 95% CI, 1.14-2.93; P=0.011). When assessing the severity of chronic gastritis using the updated Sydney system, the activity and inflammation scores, as well as atrophy and metaplasia scores, were significantly higher in rs16900627 minor allele carriers compared with wild-type homozygotes. In patients younger than 60 years old, the pepsinogen I/II ratio was significantly lower in rs16900627 minor allele carriers compared with wild-type homozygotes (P=0.037). The rs16900627 minor allele is associated with the severity of gastric mucosal inflammation and the development of gastric mucosal atrophy. Carriers of this allele may have an increased risk for the development of gastric cancer, particularly of the intestinal type.

AIM: To investigate whether single nucleotide polymorphisms in maf protein K (MAFK), which encodes the MAFK, lead to increased susceptibility to ulcerative colitis in the Japanese population. METHODS: This case control study examined the associations between MAFK single nucleotide polymorphisms (rs4268033 G>A, rs3735656 T>C and rs10226620 C>T) and ulcerative colitis susceptibility in 174 patients with ulcerative colitis (UC) cases, and 748 subjects without no lower abdominal symptoms, diarrhea or hematochezia (controls). In addition, as the second controls, we set 360 subjects, who have an irregular bowel movement without abnormal lower endoscopic findings (IBM controls). RESULTS: The genotype frequency of rs4268033 AA and allelic frequency of the rs4268033A allele were significantly higher in the UC cases than in both controls (P = 0.0005 and < 0.0001, P = 0.015 and 0.0027 vs controls and IBM controls, respectively). Logistic regression analysis after adjustment for age and gender showed that the rs4268033 AA and rs3735656 CC genotypes were significantly associated with susceptibility to UC development (OR = 2.63, 95%CI: 1.61-4.30, P = 0.0001 and OR = 1.81; 95%CI: 1.12-2.94, P = 0.015, respectively). Similar findings were observed by the comparison with IBM controls. In addition, the rs4268033 AA genotype was significantly associated with all phenotypes of UC except early onset. There was no significant association between rs10226620 and ulcerative colitis. CONCLUSION: Our results provide the first evidence that MAFK genetic polymorphisms are significantly associated with susceptibility to UC development. In particular, rs4268033 is closely associated with an increased risk for the development of UC.

Telomere shortening occurs with human aging in many organs and tissues and is accelerated by rapid cell turnover and oxidative injury. To clarify the clinical importance of telomere shortening in colonic mucosa in ulcerative colitis (UC), we measured average telomere length using quantitative real-time PCR in non-neoplastic colonic mucosa in UC patients and assessed its relationship to various clinical subtypes. Relative telomere length in genomic DNA was measured in colonic biopsies obtained from rectal inflammatory mucosa from 86 UC patients as well as paired non-inflammatory proximal colonic mucosae from 10 patients. Data were correlated with various clinical phenotypes. In paired samples, average relative telomere length of rectal inflammatory mucosa was shortened compared to normal appearing proximal colon in eight out of ten cases (p = 0.01). Telomere length shortening was significantly associated with more severe Mayo endoscopic subscore (p < 0.0001) and cases needing surgery due to toxic megacolon or cancer occurrence (p = 0.043). When the severe clinical phenotype was defined as having at least one of following phenotypes, more than two times of hospitalization, highest Mayo endoscopic subscore, steroid dependent, refractory, or needing operation, average relative telomere length was significantly shortened in the same phenotypes than the others (p = 0.003). Telomere shortening is associated with more severe clinical phenotypes of UC, reflecting severe inflammatory state in the colonic mucosa.

OBJECTIVE: Taste is an important element in food preferences. Gastroesophageal reflux disease (GERD) is related to lifestyles including eating habits. We aimed to investigate the relationship between responses to specific tastes and GERD. METHODS: Altogether 280 patients including 170 men with a mean age of 58.6 years were included in the study to determine the relationship between their liking for specific tastes and GERD using a new self-administered questionnaire (responses to various tastes and participants' sensitivity to taste and hot food and on the frequency of stomatitis). Another self-administrated questionnaire was administrated for a diagnosis of GERD (the frequency scale for the symptoms of GERD cut-off score of 10). Furthermore, 142 of 280 patients who had received esophagogastroduodenoscopy (EGD) were investigated on the association between endoscopic esophagitis and their favorite tastes. RESULTS: In the association analyses between responses to specific tastes and GERD, the group liking salty food and the group with a high frequency of stomatitis had a significantly higher incidence of GERD (salty food: odds ratio [OR] 2.059, 95% confidence interval [CI] 1.215-3.488, P = 0.0073; stomatitis: OR 2.861, 95% CI 1.558-5.253, P = 0.0007, respectively). In association analyses with endoscopic esophagitis, the groups liking salty and sour food had a significantly higher incidence rate of endoscopic esophagitis (salty: OR 2.718, 95% CI 1.330-5.555, P = 0.0061; sour: OR 3.267, 95% CI 1.491-7.160, P = 0.0031, respectively). CONCLUSIONS: Sensitivity and response to specific food taste were associated with GERD. The results of a preference to hot or salty food and endoscopic esophagitis suggest that physical stimuli are important for esophageal injuries.

Interleukin (IL)‑1β, and tumor necrosis factor (TNF)‑α have significant roles in the mediation of inflammatory immune responses and are also potent inhibitors of gastric acid secretion in the stomach. The present study aimed to investigate the associations between polymorphisms at position ‑31 (T>C) of the IL‑1β gene and ‑857 (C>T) of the TNF‑α gene with dyspeptic symptoms. Polymorphisms at position ‑31 (T>C) of the IL‑1β gene and ‑857 (C>T) of the TNF‑α gene were genotyped in 261 subjects, including 126 subjects without symptoms and 135 subjects exhibiting symptoms of dyspepsia. The IL‑1β ‑31 CC genotype was inversely associated with dyspeptic symptoms in all subjects, as determined by the Fisher's exact test [odds ratio (OR), 0.57; 95% confidence interval (CI), 0.34‑0.96; P=0.046]; however, this association was not detected following logistic regression analysis. Within the subgroups of symptoms, the CC genotype was also inversely associated with upper abdominal pain (OR, 0.28; 95% CI, 0.12‑0.67; P=0.003) and epigastric pain syndrome (EPS)‑like symptoms (OR, 0.14; 95% CI, 0.07‑0.28; P=0.003), according to the Rome III classifications. These associations were also found following logistic regression analysis (upper abdominal pain: OR, 0.34; 95% CI, 0.14‑0.80; P=0.014; and EPS‑like symptoms: OR, 0.41; 95% CI, 0.20‑0.84; P=0.015). No significant associations were identified between the TNF‑α ‑857 polymorphism and dyspeptic symptoms, including amongst the various subtypes analyzed. In conclusion, the IL‑1β ‑31 CC genotype was inversely associated with susceptibility to dyspeptic symptoms, in particular, upper abdominal pain and EPS‑like symptoms.

BACKGROUND AND AIMS: Fusobacterium species are part of the gut microbiome in humans, but some species have been recognized as opportunistic pathogens implicated in inflammatory diseases including inflammatory bowel diseases. Here, we performed prevalence screening of Fusobacterium in ulcerative colitis (UC) in Japanese patients. METHODS: We examined Fusobacterium nucleatum (F. nucleatum) and whole Fusobacterium species (Pan-fusobacterium) by quantitative real-time PCR in 163 inflamed mucosae from 152 UC patients. Data were correlated with clinical subtypes of UC. RESULTS: In an initial prevalence screen, F. nucleatum and Pan-fusobacterium were detected in 6.3 % (4/64) and 53.1 % (34/64). For all 163 mucosae, the prevalence of Pan-fusobacterium was 54.6 % (89/163). Pan-fusobacterium status was concordant in inflamed and normal adjacent samples, and the matched cases during 1-year follow-up colonoscopy. The higher amount of Pan-fusobacterium was observed in chronic continuous type compared to one attack and relapse/remitting type (p = 0.039). The higher amount of Pan-fusobacterium was also associated with rather mild clinical course of disease, such as non-steroid dependency (p = 0.015), non-refractory phenotype (p = 0.013), and non-severe phenotype (p = 0.04). Based on the distribution of Pan-fusobacterium measurable cases, we identified 10 cases as having a high amount of Pan-fusobacterium (FB-high). The clinicopathological features of FB-high UC cases were also highlighted by chronic continuous type and mild phenotypes of disease. CONCLUSION: Whole Fusobacterium species, but not F. nucleatum, are common in UC patients and have a role in persistence of colonic inflammation in UC. However, Fusobacterium infection is associated with rather mild clinical phenotypes of UC.

Previous studies have demonstrated the protective role of inducible heat-shock protein (HSP) 70 in intestinal cells. The HSP70-2 gene has a PstI site due to an A-G transition at the 1,267 position and different genotypes are associated with various levels of mRNA expression. The present study aimed to clarify the effect of the HSP70-2 polymorphism on the risk of ulcerative colitis (UC), including its clinical phenotypes. A total of 121 patients with UC and 500 healthy control (HC) subjects participated in the study. To assess the polymorphisms at the 1,267 position of the HSP70-2 gene, restriction fragment length polymorphism analysis was performed. The subjects in the study were classified by disease behavior, severity and extent of disease. Although no significant difference of the HSP70-2 genotype distribution was identified between the HC and UC groups, the BB genotype exhibited a lower risk of the steroid-dependent phenotype [odds ratio (OR), 0.12; 95% confidence interval (CI), 0.02-0.95; P=0.02]. The same genotype was also associated with a lower risk of the refractory phenotype (OR, 0.16; 95% CI, 0.04-0.73; P=0.01). There was no direct correlation between the polymorphism of the HSP70-2 gene and UC susceptibility. However, there was an association between a reduced risk of the steroid-dependent and refractory phenotypes of UC and the BB genotype.

A complex interaction of genetic and environmental factors is closely associated with the development of inflammatory bowel disease. Previous studies reported that the expression of the regulated upon activation, normal T-cell expressed and secreted (RANTES) gene is enhanced in the colonic mucosa of ulcerative colitis (UC). Quantitative differences in RANTES gene expression among numerous promoter genotypes have also been reported. The aim of the present study was to clarify the effect of RANTES promoter polymorphism on the risk of UC, including its clinical phenotypes. A total of 150 UC patients and 372 healthy control (HC) subjects participated in the study. The UC patients were classified by disease behavior, severity and extent of disease. Restriction fragment length polymorphism analysis was performed for polymorphisms at -28 C/G in the RANTES gene promoter region. Although no significant difference of the RANTES promoter genotype distribution was observed between the HC and UC groups, the G/G genotype was significantly higher among female (OR=3.95, 95% CI=1.22-12.82, P=0.03), non-steroid dependent (OR=3.37, 95% CI=1.16-9.85, P=0.03) and non-refractory (OR=3.76, 95% CI=1.29-10.98, P=0.02) UC patients. The G carrier was also found to be associated with an increased risk of rectal colitis (OR=2.21, 95% CI=1.12-4.39, P=0.03). The data indicate that the polymorphism of the RANTES promoter is not directly associated with the susceptibility to UC, but the -28 G allele is associated with female UC patients and mild clinical phenotypes of UC, including non-steroid dependency, non-refractory and rectal colitis.

Plummer-Vinson syndrome (PVS) is a rare entity characterized by upper esophageal webs and iron deficiency anemia. We report a case of PVS whose esophageal web was rapidly improved by iron therapy. A 77-year-old woman was admitted to our hospital with complaints of dysphagia, vomiting, shortness of breath and weight loss for 1 month. Physical examination revealed conjunctival pallor, koilonychia, angular cheilitis and smooth tongue, and laboratory findings were consistent with microcytic hypochromic anemia with iron deficiency. Gastrointestinal endoscopy and barium-swallow esophagography detected a web that prevented passage of the endoscope into the upper portion of the esophagus. The patient received oral iron therapy daily; the hemoglobin concentration rose to 8.9 g/dl and the complaints of dysphagia were dramatically improved after 2 weeks, with improvement of luminal stenosis confirmed by gastrointestinal endoscopy and barium-swallow esophagography. The PVS described in this report had a distinct clinical course, showing very rapid improvement of dysphagia and esophageal web after 2 weeks of oral iron therapy.

Toll‑like receptor activation intitially recruits the myeloid differentiation primary response gene (88) (MyD88) protein. A polymorphism *1244 A>G (rs7744) in the 3'‑untranslated region of MyD88 has been identified. In the present study, the association of this polymorphism with ulcerative colitis (UC) was investigated. The population studied comprised 922 individuals, including patients with UC (UC cases) and without (controls). Genotyping of rs7744 was performed by PCR single-strand conformation polymorphism and the rs7744 G allele frequencies in the controls and UC cases were 32.8 and 43.5%, respectively (P<0.0001). The results showed that the genotype frequency of the AA homozygote was significantly lower and that of the GG homozygote was significantly higher in the UC cases compared with those in the controls (P=0.0012 for both groups). The rs7744 minor allele variants were significantly associated with susceptibility to UC as indicated by dominant and recessive genetic models. The minor allele variants were associated with an increased risk for UC in the male individuals but not the female individuals. The rs7744 was also associated with a non‑continuous phenotype of UC and steroid unused/independent UC. This minor allele homozygote was associated with the disease severity of UC, hospitalization and response to steroid treatment. The results of the present study provided evidence that MyD88 polymorphism rs7744 was significantly associated with the development of UC and that this polymorphism may be associated with the response to treatment therapies for UC.

BACKGROUND: The neurochemical serotonin (5-HT) is an important signaling molecule in the gastrointestinal motor and sensory functions. A key regulator of 5-HT levels is the transmembrane serotonin transporter (5-HTT; SLC6A4) that governs the reuptake of 5-HT. Recent studies have indicated 5-HTT expression may be regulated by epigenetic mechanisms. We investigated DNA methylation status of SLC6A4 gene in the gastric mucosa from functional dyspepsia (FD) because of their potential role in dyspeptic symptoms. METHODS: Endoscopic gastric biopsies were obtained from 78 subjects with no upper abdominal symptoms and 79 patients with FD. Bisulfite Pyrosequencing was carried out to determine the methylation status of promoter CpG islands (PCGIs), promoter non-CpG islands (PNCGIs) and gene body non-CpG islands (NPNCGIs) in the SLC6A4 gene. Gene expression was examined by real-time PCR. RESULTS: In overall, methylation level of PCGIs was significantly lower in FD compared to control subjects (p = 0.04). On the other hand, methylation level of NPNCGIs was significantly higher in FD compared to control subjects (p = 0.03). Lower methylation level in PNCGIs was highlighted in the patients with PDS (p = 0.01), while higher methylation level in NPNCGIs was more prominent in the patients with EPS (p = 0.017). Methylation levels of PCGIs and PNCGIs were inversely correlated, while methylation levels of NPNCGIs was positively correlated with SLC6A4 mRNA levels in FD patients. CONCLUSIONS: Our data suggest that change in DNA methylation pattern of SLC6A4 in the gastric mucosa may have a role for developing FD. A role of epigenetics for developing FD needs to be further evaluated.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a phenomenon that allows the conversion of adherent epithelial cells to a mesenchymal cell phenotype, which enhances migratory capacity and invasiveness. Recent studies have suggested that EMT contributes to the pathogenesis of ulcerative colitis (UC). We investigated the promoter DNA methylation status of EMT-related genes in the colonic mucosa in UC. METHODS: Colonic biopsies were obtained from the rectal inflammatory mucosa of 86 UC patients and the non-inflammatory proximal colonic mucosa of 10 paired patients. Bisulfite pyrosequencing was used to quantify the methylation of 5 candidate CpG island promoters (NEUROG1, CDX1, miR-1247, CDH1, and CDH13) and LINE1. RESULTS: Using an unsupervised hierarchical clustering analysis, inflamed rectal mucosa was well separated from mucosa that appeared normal. The CDH1 and CDH13 promoters were significantly associated with patient age (p = 0.04, 0.03, respectively). A similar trend was found between those genes and the duration of disease (CDH1: p = 0.07, CDH13: p = 0.0002, mean of both: p<0.00001). Several positive associations were found between hypermethylation and severe clinical phenotypes (CDX1 and miR-1247 and a refractory phenotype: p = 0.04 and 0.006, respectively. miR-1247 and CDH1 hyper methylation and a more severe Mayo endoscopic subscore: miR-1247: p = 0.0008, CDH1: p = 0.03, mean of both: p = 0.003). When the severe clinical phenotype was defined as having any of five phenotypes (hospitalized more than twice, highest Mayo endoscopic subscore, steroid dependence, refractory, or a history of surgery) miR-1247 hypermethylation was associated with the same phenotype (p = 0.008). CONCLUSIONS: Our data suggest that variability in the methylation status of EMT-related genes is associated with more severe clinical phenotypes in UC.

In the present study, we report an association between gastric cancer and polymorphisms in NFKB1 (rs28362941 and rs78696119). We employed the PCR-SSCP method to detect gene polymorphisms in 479 gastric cancer cases and 880 controls. The rs28362941 del/del homozygote was significantly associated with gastric cancer development; in particular it was closely associated with diffuse type gastric cancer. The rs78696119 GG homozygote was also associated with the diffuse type of gastric cancer. In young subjects, both polymorphisms were significantly associated with the development of gastric cancer. In addition, both polymorphisms were related to tumor progression such as tumor invasion and lymph node metastasis. The inflammatory cell infiltration into non-cancerous gastric mucosa was greater in the subjects with the rs28362491 del/del or rs78696119 GG genotype when compared to those with the other genotypes. In conclusion, functional polymorphisms of NFKB1 are associated with an increased risk of gastric cancer; in particular they are closely associated with the development of diffuse type of gastric cancer via severe gastric inflammation. These polymorphisms also appear to be associated with gastric cancer progression.

Interleukin-17A plays a role in tissue inflammation by inducing release of proinflammatory and neutrophil-mobilizing cytokines. We investigated the association between ulcerative colitis (UC) and polymorphisms of IL17A, rs2275913 (-197 G > A), and rs3748067 (*1249 C > T). The study was performed in 475 healthy subjects (controls) and 202 with UC (UC cases), including 113 controls and 64 UC cases from previous study. We employed the multiplex PCR-SSCP method to detect gene polymorphisms. The minor allele frequency of rs2275913 was significantly higher but that of rs3748067 was significantly lower in UC cases than controls. The rs2275913 minor homozygote (AA) had an increased risk of the development of UC, whereas rs3748067 minor carrier (CT + TT) had decreased risks for the development of UC. When compared with LR group (rs2275913 GG + GA with rs3748067 CT + TT), HR group (rs2275913 AA with rs3748067 CC) had a more increased risk of the development of UC (OR, 3.38; p = 0.0007). The polymorphisms of IL17A were associated with the noncontinuous and pancolitis phenotypes of UC. Our results suggest that IL17A polymorphisms (both rs2275913 and rs3748067) influence the susceptibility to and pathophysiological features of UC, coordinately.

BACKGROUND: Aberrant methylation patterns in CpG island are known to be influential in gene silencing. Histamine plays important physiological roles in the upper gastrointestinal tract and acts via the H2 receptor. We report an investigation into the effect of HRH2 promoter polymorphism (rs2607474 G > A) on the methylation of DAPK and CDH1. METHODS: Non cancerous gastric mucosa samples were obtained from 115 subjects with gastric cancer (GC) and 412 non-cancer subjects (non-GC). Methylation status of genes was determined by MSP. The genotyping of rs2607474 was performed by PCR-SSCP. RESULTS: Methylation of DAPK and CDH1 was observed in 296 and 246 subjects, respectively. The frequency of CDH1 methylation in the subjects with GC was significantly lower in cancer lesion than in non cancerous mucosa, whereas that of DAPK methylation was not different. The allelic distribution of rs2607474 was 401GG, 119GA and 7AA. The GG homozygote was associated with a significantly increased risk for methylation of both DAPK and CDH1 (p < 0.0001 and p = 0.0009, respectively). In the non-GC subjects or more than 60 years of age, GG homozygote was more closely associated with both DAPK and CDH1 methylation. However, this genotype did not show an increased risk for the development of methylation of both genes in patients with GC. In H. pylori negative subjects, GG homozygote showed an increased risk for the methylation of both DAPK and CDH1 (p = 0.0074 and p = 0.0016, respectively), whereas this genotype was associated with an increased risk for the development of DAPK methylation in H. pylori positive subjects (p = 0.0018). In addition, in subjects older than 60 years of age, atrophy and metaplasia scores were significantly higher in the GG homozygote (p = 0.011 and p = 0.039, respectively) and a significant correlation was observed between age and atrophy or metaplasia. CONCLUSIONS: Our results suggest that rs2607474 GG homozygote confers a significantly increased risk for age- and inflammation-related DAPK and CDH1 methylation.

BACKGROUND: Visceral sensory impulses are transmitted via C-fibers from the gastrointestinal tract to the central nervous system. The tetrodotoxinresistant (TTX-r) sodium channel, Na(V) 1.8/SNS (sensory-neuron specific), encoded by SCN10A, has been identified on C-fibers. We attempted to clarify the association between functional dyspepsia (FD) and SCN10A non-synonymous polymorphisms (2884 A>G, 3218 C>T and 3275 T>C). METHODS: The study was performed in 642 subjects (345 with no symptoms and 297 with FD). We employed a multiplex polymerase chain reaction single-strand confirmation polymorphism (PCR-SSCP) method to detect the gene polymorphisms. RESULTS: The 3218 CC homozygotes had a reduced risk for the development of FD [odds ratio (OR) 0.589; 95 % confidence interval (CI) 0.402-0.864; p = 0.0067]. In addition, both 2884 A>G and 3275 T>C, which were in linkage disequilibrium, were also associated with the development of FD (p = 0.039 and 0.028, respectively). Each 2884 G carrier, 3218 CC homozygote, and 3275 C carrier had a reduced risk for the development of both epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS). The subjects with the 2884 G allele, 3275 C allele, and no 3218 T allele had a reduced risk for FD (OR 0.618; 95 % CI 0.448-0.853; p = 0.0034). This haplotype was associated with a reduced risk for both EPS and PDS (p = 0.0011 and 0.0056, respectively). In addition, there was a significant association between FD and this haplotype in Helicobacter pylori-negative subjects (OR 0.463; 95 % CI 0279-0.9768; p = 0.0029). CONCLUSION: We conclude that genetic polymorphisms of SCN10A are closely associated with FD (both EPS and PDS), especially in H. pylori-negative subjects, in Japanese.

AIM: To clarify the association between a polymorphism -449 C>G (rs72696119) in 5'-UTR of NFKB1 with ulcerative colitis (UC). METHODS: The studied population comprised 639 subjects, including patients with UC (UC cases, n = 174) and subjects without UC (controls, n = 465). We employed polymerase chain reaction-single strand conformation polymorphism to detect the gene polymorphism. RESULTS: The rs72696119 G allele frequencies in controls and UC cases were 33.4% and 38.5%, respectively (P = 0.10). Genotype frequency of the GG homozygote in UC cases was significantly higher than that in controls (P = 0.017), and the GG homozygote was significantly associated with susceptibility to UC [odds ratio (OR), 1.88; 95%CI, 1.13-3.14]. In male subjects, the GG homozygote was associated with an increased risk for UC (OR, 3.10; 95%CI, 1.47-6.54; P = 0.0053), whereas this association was not found in female subjects. In addition, the GG homozygote was significantly associated with the risk of non-continuous disease (OR, 2.06; 95%CI, 1.12-3.79; P = 0.029), not having total colitis (OR, 2.40; 95%CI, 1.09-3.80, P = 0.040), disease which developed before 20 years of age (OR, 2.80; 95%CI, 1.07-7.32, P = 0.041), no hospitalization (OR, 2.28; 95%CI, 1.29-4.05; P = 0.0090) and with a maximum of 8 or less on the UCDAI score (OR, 2.45; 95%CI, 1.23-4.93; P = 0.022). CONCLUSION: Our results provide evidence that NFKB1 polymorphism rs72696119 was significantly associated with the development of UC. This polymorphism influences the susceptibility to and pathophysiological features of UC.

BACKGROUND: The role of genetics in the susceptibility to functional dyspepsia (FD) remains unclear. We attempted to clarify the association between FD and polymorphisms in SLC6A4. In addition, rs5981521 (C>T) in the pri-microRNA 325 (pri-miR-325) coding region was also investigated. METHODS: The study was performed in 395 subjects (172 with no upper abdominal symptoms and 223 with FD, including medication-resistant FD). We employed a polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) method to detect gene polymorphisms. RESULTS: Neither SLC6A4 -185 A>C nor *463 G>T was associated with susceptibility to FD. The number of rs5981521 T alleles was significantly correlated with an increased risk for FD (odds ratio [OR] 1.45, 95 % confidence interval [CI] 1.05-1.98; p = 0.022) and the TT homozygote was more closely associated with the risk for FD (OR 3.01, 95 % CI 1.41-6.42; p = 0.0043). The TT homozygote also had significantly increased risks for both the epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS) subtypes of FD (OR 3.04, 95 % CI 1.25-7.42; p = 0.014 and OR 3.05, 95 % CI 1.14-8.13; p = 0.026, respectively). In addition, Helicobacter pylori-negative TT homozygotes had a greater risk for FD (OR 8.37, 95 % CI 1.78-39.5; p = 0.0072). In subjects with the SLC6A4 5'-untranslated region (UTR) wild homozygote, the number of rs5981521 T alleles was significantly correlated to an increased risk for FD (OR 1.45, 95 % CI 1.03-2.04, p = 0.033). Of note, in subjects who were SLC6A4 3'-UTR mutant carriers, the number of rs5981521 T alleles was also significantly correlated with an increased risk for FD (OR 2.07, 95 % CI 1.08-3.98; p = 0.029). CONCLUSIONS: Our results suggest that the genetic polymorphism pri-miR-325 is associated with FD and interacts with SLC6A4 polymorphisms in increasing susceptibility to FD in Japanese.

CpG island aberrant methylation is shown to be an important mechanism in gene silencing. The important role of NF-κB in the inflammatory response to H. pylori colonization has been indicated. We investigated the influence of NFKB1 polymorphisms, -94 ins/del (rs28362491) and -449 C>G (rs72696119), on the aberrant gene methylation under H. pylori infection. Gastric mucosal samples were obtained from sub-subjects without malignancies. Methylation status of genes (p14ARF, p16INK4a, DAPK and CDH1) was determined by methylation-specific PCR (MSP). The genotyping of NFKB1 was performed by PCR-SSCP. There was a strong allelic association between rs28362491 and rs72696119, and all H. pylori-infected -94 del/del homozygotes had a -449 GG genotype. The -94 del/del homozygosity was significantly associated with risk for development of CpG island high methylation (CIHM) (two or more gene methylations), especially DAPK and CDH1 methylations, and the number of methylated genes was significantly higher in -94 del/del homozygotes than in ins/del and ins/ins (ins carrier) H. pylori-infected elder subjects. In addition, this methylated gene number was significantly increased with age in H. pylori-infected del/del homozygotes, but not in infected ins carriers. Furthermore, the inflammation score was significantly higher in H. pylori-infected del/del homozygotes compared to ins carriers. NFKB1 -94 ins/del ATTG polymorphism (rs28362491) was significantly associated with the increased risk for the development of age-related gene methylation in non-cancerous gastric mucosa under H. pylori-induced inflammation.

Histamine plays important physiological roles in the upper gastrointestinal tract and acts via the H2 receptor. The -1018 G>A (rs2067474) in an enhancer element of the promoter and non-synonymous rs79385261 (Asn46Thr) were identified in HRH2. We attempted to clarify the associations of these polymorphisms with gastric carcinogenesis. The study was performed in 321 patients with gastric cancer and 599 subjects with no evidence of gastric malignancies on upper gastroduodenal endoscopy. The genotypes were determined using a one-tube multiplex PCR-SSCP method. The degree of gastritis was assessed in 496 subjects and serum pepsinogen (PG) I/II levels were measured in 124 subjects without gastric cancer. The minor allele of Asn46Thr could not be detected. The frequencies of the -1018 A allele in the non-GC and GC groups were 13.5% and 8.26%, respectively (p=0.00077). Overall, -1018 GG homozygotes had an increased risk for developing gastric cancer (OR 1.68; 95% CI 1.17-2.42; p=0.0052), especially intestinal type cancer (OR 1.94; 95% CI 1.23-3.08; p=0.0047). In subjects aged >60 years, the adjusted risk for gastric cancer among individuals who were -1018 GG homozygotes was 1.87 (range 1.19-2.93; p=0.0065) compared with A carriers. In the gastric cancer cases located in the antrum and at comparative advanced stage, -1018 GG homozygosity was a significantly increased risk factor. In subjects >60 years, the metaplasia score was significantly higher in -1018 GG homozygotes than A carriers. Both atrophy and metaplasia scores were significantly increased with age only in -1018 GG homozygotes. The PG I/II ratio was significantly decreased in H. pylori positive GG homozygotes than negative GG homozygotes and positive A carriers. Our results suggest that -1018 GG homozygosity of HRH2 may be associated with the severity of gastric mucosal atrophy. This genotype has an increased risk for the subsequent development of gastric cancer, especially intestinal type, at advanced age.

We report an association between gastric cancer (GC) and polymorphisms in IL17A, rs2275913 (-197 G > A), rs3748067 (*1249 C > T), and pri-miR-938, rs2505901 (T > C). We employed the multiplex PCR-SSCP method to detect gene polymorphisms in 337 GC cases and 587 controls. The minor allele frequency of rs2275913 was significantly higher, and those of rs3748067 and rs2505901 significantly lower, in GC cases than controls. The rs2275913 AA homozygote was associated with an increased risk (OR, 2.38; 95%CI, 1.63-3.46; p < 0.0001) for the development of both intestinal and diffuse types of GC. The rs3748067 T polymorphism was associated with a decreased risk for intestinal GC (OR, 0.511; 95%CI, 0.272-0.962; p = 0.037), whereas rs2505901 C locus carried a decreased risk overall for GC (OR, 0.733; 95%CI, 0.545-0.985; p = 0.039). In addition, rs3748067 T allele was inversely correlated with lymph node metastasis. Our results suggest that polymorphisms in both IL17A and pri-miR-938 contribute to cancer risk susceptibility and therefore can affect the development of gastric cancer.

BACKGROUND AND AIM: Histamine plays important physiological roles in upper gastrointestinal tract and acts via the H2 receptor. A polymorphism -1018 G>A (rs2067474) was identified in an enhancer element of the HRH2 promoter. We attempted to clarify the associations of this polymorphism with the progression of gastric mucosal atrophy. METHODS: Gastric mucosa samples were obtained from 398 subjects with no malignancies. The rs2067474 genotype was determined by PCR-SSCP method. The degree of gastritis was assessed in 366 subjects and serum pepsinogen (PG) I/II levels were measured in 108 subjects. The subjects with atrophy score higher or equal to 2 and metaplasia score higher or equal to1 were classified into the severe atrophic gastritis group (SA group). RESULTS: The -1018G>A minor allele frequencies in SA and non-SA groups were 8.02% and 13.3%, respectively (p=0.057). The -1018 GG homozygote had a significantly high risk for gastric mucosal atrophy (OR: 2.03, 95%CI: 1.03-4.01, p=0.042). In H. pylori positive subjects, GG homozygote was a more significant risk factor for gastric mucosal atrophy (OR: 2.32, 95%CI: 1.12-4.81, p=0.023). In addition, in the subjects older than 60 years, GG homozygote had also a significant risk for gastric mucosal atrophy (OR: 2.63, 95%CI: 1.15-6.00, p=0.022). In -1018 GG homozygote, PG I/II ratio was significantly lower in H. pylori positive than negative subjects and was significantly decreased with age (p=0.0032 by ANOVA), whereas it was not in the A carrier. CONCLUSIONS: Our results suggest that HRH2 -1018 GG homozygote is a risk factor for the severity of gastric mucosal atrophy under the influence of H. pylori infection, especially in older subjects.

INTRODUCTION: It is suggested that minimal change (grade M) esophagitis is a spectrum of gastric acid reflux disease. We evaluated the clinical significance of grade M esophagitis, including its subtypes (reddish change: MR and whitish change: MW), especially with attempt to pathological conditions in the stomach that relates to gastric acid secretion. MATERIALS AND METHODS: Using 241 subjects undergoing esophagogastroduodenoscopy for various indications, we investigated the association between grade M esophagitis with histological and serological severity of gastritis and endoscopic degree of atrophy. We also examined its association with ulcer diseases and various symptoms. RESULTS: When grade M cases were divided into MR and MW, all MR cases had MW in considerable degrees. Dyspeptic symptoms were more likely to be associated with H. pylori negative grade M cases, while presence of duodenal ulcer and its scar were associated with Helicobacter pylori-positive grade M cases. In all subjects, histological parameters, especially in the corpus, were lower in grade M cases compared to normal appearance. In grade M cases, degree of acute and chronic inflammation, and atrophy in corpus were lowest in cases that have grade MR. Grade M cases were also associated with higher pepsinogen I/II ratio and lower endoscopic atrophy. CONCLUSIONS: Pathological conditions of the stomach relate to higher gastric acid secretion correlates with grade M esophagitis. In grade M cases, appearance of MR may reflect higher gastric acid secretion or severe acid reflux than cases that have grade MW only.

Background/Aims: There have been reports showing the protective role of inducible Heat-shock protein (HSP) 70 in gastric epithelial cells. An A to G transition at the 1267 position HSP70-2 gene has been shown to be associated with a different level of HSP70 mRNA expression. We aimed to clarify the effect of HSP70-2 polymorphism on the risk of peptic ulcer diseases in a Japanese population. Methodology: A total of 519 subjects participated in this study. All subjects underwent upper gastroscopy. Restriction fragment length polymorphism analysis was performed for polymorphisms at 1267 of HSP70-2 gene in all the subjects. Results: After gastroscopy, 109, 53 and 357 subjects were diagnosed as gastric ulcer, duodenal ulcer and non-ulcer subjects, respectively. Although, there were no significant differences of HSP70-2 genotype distributions among non-ulcer subjects, overall ulcer, gastric and duodenal ulcers when the subjects were divided into two groups according to age distribution, logistic regression analysis showed that the BB genotype increased the risk of duodenal ulcer in subjects 60 years and older. (Gender, status of H. pylori infection and NSAID use adjusted OR=3.12, 95%CI=1.33-7.35, p=0.009). Conclusions: It appears that polymorphism of HSP70-2 gene is not directly associated with the susceptibility to peptic ulcer diseases but BB genotype is associated with an increased risk of duodenal ulcer in older subjects in the Japanese population. © H.G.E. Update Medical Publishing S.A.