A Prospective Study of Eosinophilic Esophagitis and the Expression of Tight Junction Proteins in Patients with Gastroesophageal Reflux Disease Symptoms.

BACKGROUND/AIMS: Eosinophilic esophagitis (EoE) is often erroneously diagnosed as gastroesophageal reflux disease (GERD). The aim of this study is to investigate the prevalence of EoE and the expression of tight junction (TJ) proteins in patients with GERD symptoms. METHODS: One hundred patients with GERD symptoms and 10 healthy controls were prospectively studied. Sixty-two patients had symptoms refractory to proton pump inhibitors (PPI). All patients underwent esophageal biopsy. Patients were diagnosed with EoE if the number of eosinophil granulocytes per high-power field was ≥15. Immunohistochemical analysis of TJ proteins (claudin-1, claudin-4, occludin, and zonula occludin-1 [ZO-1]) was performed. RESULTS: EoE was diagnosed in six of 100 patients (6%) with GERD symptoms and in six patients (9.7%) of 62 patients with PPI-refractory GERD. Only one had typical EoE endoscopic findings. The proportion of ZO-1-positive cells was significantly lower in the lower than in the middle esophagus (56.0%±14.0% vs 66.0%±11.5%, p＜0.05). There were no significant correlations between TJ protein expression and GERD symptoms. CONCLUSIONS: The prevalence of EoE among patients with PPI-refractory GERD is approximately 10%. Regardless of endoscopic findings, esophageal biopsy is crucial in diagnosing EoE. The disruption of ZO-1 expression in the lower esophagus is significantly associated with GERD symptoms.

Endoscopy-Guided Evaluation of Duodenal Mucosal Permeability in Functional Dyspepsia.

OBJECTIVES: The pathophysiology of functional dyspepsia (FD) is not fully understood. Impaired duodenal mucosal integrity characterized by increased mucosal permeability and/or low-grade inflammation was reported as potentially important etiologies. We aimed to determine the utility of a recently developed simple catheterization method to measure mucosal admittance (MA), the inverse of mucosal impedance, for evaluation of duodenal mucosal permeability in patients with FD. METHODS: We conducted two prospective studies. In the first study, duodenal MA of 23 subjects was determined by catheterization during upper endoscopy, and transepithelial electrical resistance (TEER) of duodenal biopsy samples in Ussing chambers was measured to assess the correlation between MA and TEER. In the second study, duodenal MA of 21 patients with FD fulfilling the Rome III criteria was compared with that of 23 healthy subjects. RESULTS: The mean MA and TEER values were 367.5±134.7 and 24.5±3.7 Ω cm2, respectively. There was a significant negative correlation between MA and TEER (r=-0.67, P=0.0004, Pearson's correlation coefficient). The mean MA in patients with FD was significantly higher than that in healthy subjects (455.7±137.3 vs. 352.1±66.9, P=0.002, unpaired t-test). No procedure-related complications were present. CONCLUSIONS: We demonstrated the presence of increased duodenal mucosal permeability in patients with FD by MA measurement using a simple catheterization method during upper endoscopy.

Heparin-bridging therapy is associated with a high risk of post-polypectomy bleeding regardless of polyp size.

BACKGROUND AND AIM: Evidence regarding safety and efficacy of heparin-bridging therapy for colonoscopic polypectomy remains scarce. The aim of the present study was to evaluate the risk of post-polypectomy bleeding (PPB) in patients receiving heparin-bridging therapy. METHODS: We retrospectively reviewed the database of patients who underwent colonoscopic polypectomy with prophylactic clip closure between January 2007 and December 2014 at our institution. We evaluated patients receiving heparin-bridging therapy (HB group) compared with those who did not receive antithrombotic therapy (No-HB group). RESULTS: A total of 1421 polypectomies were carried out on 773 patients; 45 patients were in the HB group and 728 patients were in the No-HB group. The incidence of PPB per patient was significantly higher in the HB group (22.2% vs 1.9%, P < 0.0001), and multivariate analysis showed that heparin-bridging therapy was an independent risk factor for PPB (OR 9.80, 95% CI 4.23-22.3, P < 0.0001). In the HB group, the polyp size was not a risk factor for PPB (OR 0.67, 95% CI 0.19-2.26, P = 0.55); the incidence of PPB in lesions of <10 mm and ≥10 mm in size was 14.6% and 10.2% respectively. In contrast, that was a significant risk factor in the No-HB group (OR 4.71, 95% CI 1.41-21.3, P = 0.011). Activated partial thromboplastin time and international normalized ratio were in or under the therapeutic range in the HB group when PPB occurred. CONCLUSIONS: Heparin-bridging therapy is associated with a high risk of PPB regardless of polyp size.

A randomized controlled trial comparing water exchange and air insufflation during colonoscopy without sedation.

OBJECTIVES: Previous studies have shown that water exchange is superior to air insufflation in attenuating insertion pain during colonoscopy. We conducted a randomized controlled trial with head-to-head comparison of these methods to assess their effectiveness in colonoscopy without sedation. METHODS: A total of 447 outpatients were randomized to either water exchange (WE) or the standard air (CO2) insufflation (AI). The primary outcome was the improvement of patient intraprocedural pain (pain score), evaluated using a questionnaire (scores 1 to 5). RESULTS: After exclusion of 44 patients from further analysis, 403 patients were analyzed. There was no difference in clinical background between the WE and AI groups. Patients in the WE group reported less intraprocedural pain than those in the AI group (2.17 ± 1.06 vs. 2.42 ± 1.03; unpaired t test, p = 0.021). We divided the cases into two groups, more or less painful colonoscopy, based on age, body mass index, use of anti-peristaltic drugs or not, and physician's experience. In less painful colonoscopy, the WE method could reduce pain effectively but its effect was limited in the more painful group. CONCLUSION: WE is superior to AI for attenuating insertion pain during colonoscopy without sedation, but its efficacy is limited in more painful endoscopy.

[A case of Kaposi's sarcoma of the rectum presenting with hematochezia and rectal pain].

A man in his 20s was referred to our hospital with hematochezia and rectal pain. Total colonoscopy revealed a reddish, protruding, ulcerated lesion occupying approximately half of the luminal circumference of the rectum. Examination of biopsy specimens showed proliferating spindle cells infiltrating the lamina propria, a finding consistent with Kaposi's sarcoma. The patient was also found to be anti-human immunodeficiency virus (HIV) antibody positive;therefore, we diagnosed acquired immunodeficiency syndrome (AIDS). The lesions of Kaposi's sarcoma were also seen in the skin, lung, and lymph nodes, but there were no lesions elsewhere in the gastrointestinal tract other than the rectum. We started anti-HIV therapy and chemotherapy against these lesions, and the lesions subsequently reduced in size. We present a rare case of a man with Kaposi's sarcoma presenting with a rectal lesion.

Gene expression profiling of laterally spreading tumors.

BACKGROUND: Laterally spreading tumors (LSTs) are generally defined as lesions >10 mm in diameter, are characterized by lateral expansion along the luminal wall with a low vertical axis. In contrast to other forms of tumor, LSTs are generally considered to have a superficial growth pattern and the potential for malignancy. We focused on this morphological character of LSTs, and analyzed the gene expression profile of LSTs. METHODS: The expression of 168 genes in 41 colorectal tumor samples (17 LST-adenoma, 12 LST-carcinoma, 12 Ip [pedunculated type of the Paris classification)-adenoma, all of which were 10 mm or more in diameter] was analyzed by PCR array. Based on the results, we investigated the expression levels of genes up-regulated in LST-adenoma, compared to Ip-adenoma, by hierarchical and K-means clustering. To confirm the results of the array analysis, using an additional 60 samples (38 LST-adenoma, 22 Ip-adenoma), we determined the localization of the gene product by immunohistochemical staining. RESULT: The expression of 129 genes differed in colorectal tumors from normal mucosa by PCR array analysis. As a result of K-means clustering, the expression levels of five genes, AKT1, BCL2L1, ERBB2, MTA2 and TNFRSF25, were found to be significantly up-regulated (p < 0.05) in LST-adenoma, compared to Ip-adenoma. Immunohistochemical analysis showed that the BCL2L1 protein was significantly and meaningfully up-regulated in LST-adenoma compared to Ip-adenoma (p = 0.010). With respect to apoptosis status in LST-Adenoma, it assumes that BCL2L1 is anti-apoptotic protein, the samples such as BCL2L1 positive and TUNEL negative, or BCL2L1 negative and TUNEL positive are consistent with the assumption. 63.2 % LST-adenoma samples were consistent with the assumption. CONCLUSIONS: LSTs have an unusual profile of gene expression compared to other tumors and BCL2L1 might be concerned in the organization of LSTs.

Sporadic nonampullary duodenal adenoma/carcinoma is associated with not only colon adenoma/carcinoma but also gastric cancer: association of location of duodenal lesions with comorbid diseases.

BACKGROUND: It is well known that in patients with sporadic nonampullary duodenal adenoma/carcinoma (SNADA) with no polyposis syndrome, including familial adenomataous polyposis, the rates of colorectal adenoma/carcinoma are high. However, the prevalence rates of other tumor types, for example, gastric cancer, in SNADA patients remain unknown. In this study, we aimed to analyze the prevalence rate of comorbid diseases in SNADA patients. METHODS: We retrospectively analyzed 78 patients with SNADA treated by endoscopic resection between May 2005 and September 2014 at our institution. RESULTS: Overall, 51 of the 78 (65.4%) SNADA patients had comorbid colorectal adenoma/carcinoma. Further, 10 of the 78 (12.8%) SNADA patients had comorbid gastric cancer, and all of them were positive for Helicobacter pylori infection. SNADA lesions were located significantly more frequently at the oral side of the major papilla in patients with H. pylori infection than in those without H. pylori infection (27 of 36 [75.0%] vs. 19 of 42 [45.2%], p = 0.008, chi-square test). In contrast, SNADA lesions were located significantly more frequently at the anal side of the major papilla in patients with colorectal adenoma/carcinoma than in those without colorectal adenoma/carcinoma (27 of 51 [52.9%] vs. 5 of 27 [18.5%], p = 0.003, chi-square test). CONCLUSION: SNADA patients showed comorbidity with not only colorectal adenoma/carcinoma but also gastric cancer. H. pylori infection is known to cause gastric cancer and may influence tumorigenesis of SNADA lesions at the oral side of the major papilla.

Mosapride citrate increases postprandial glucagon-like peptide-1, insulin, and gene expression of sweet taste receptors.

BACKGROUND AND AIM: Mosapride citrate-a prokinetic agent-improves hemoglobin A1c levels in diabetic patients; however, the underlying mechanism is unclear. We aimed to clarify this mechanism. METHODS: Preprandial and postprandial (90 min after a meal) blood was obtained from 12 healthy men, and serum insulin and plasma active glucagon-like peptide-1 concentrations were measured. Measurements were also taken after the administration of 5 mg of mosapride citrate three times per day after every meal for 14 days. In addition, C57BL/6 mice were permitted free access to water containing 0.04 % domperidone (D group) or 0.02 % mosapride citrate (M group) for 2 weeks (four mice per group). T1r2 (taste receptor, type 1, member 2), T1r3, and Gnat3 (guanine nucleotide-binding protein, alpha transducing 3) mRNA expression levels of the stomach, duodenum, and proximal and mid-jejunum were evaluated. RESULTS: In human subjects, postprandial plasma active glucagon-like peptide-1 and serum insulin concentrations after administration of mosapride citrate were significantly higher than those pre-administration (4.8 ± 2.2 pmol/L, 45.6 ± 41.6 µIU/mL, and 3.7 ± 1.2 pmol/L, 34.1 ± 28.4 µIU/mL, respectively). The mouse expression levels of T1r2 and Gnat3 in the proximal jejunum and mid-jejunum in the M group (4.1 ± 1.8-fold, 3.1 ± 1.6-fold, and 4.6 ± 0.8-fold, 3.1 ± 0.9-fold increases, respectively), were significantly higher than those of the control group. CONCLUSIONS: The administration of mosapride citrate for 2 weeks enhanced postprandial plasma active glucagon-like peptide-1 and serum insulin concentration and increased the expression of sweet taste receptors in the upper intestine.

Two-week treatment with proton pump inhibitor is sufficient for healing post endoscopic submucosal dissection ulcers.

AIM: To investigate the optimum period of treatment for post endoscopic submucosal dissection (ESD) ulcers. METHODS: Patients who underwent ESD for gastric cancer were randomized to two groups and treated with esomeprazole 20 mg per day for 4 wk (4W group) or 2 wk (2W group). At 4 wk after ESD, we measured the size of the artificial ulcers by endoscopy and determined the ulcer healing rate, compared with the size of the ESD specimens. This randomized controlled trial study was approved by our ethics committee and registered in the UMIN Clinical Trial Registry. RESULTS: A total of 60 consecutive patients were included in the study. All patients received rebamipide 300 mg per day for 4 wk. One patient in 2W group who showed bleeding within two weeks and received endoscopic treatment was excluded from further analysis. The numbers of patients with ulcers in the healing/scar stage in the 2W and 4W groups at 4 wk after ESD were 20/6 and 28/5, respectively, with no significant difference. The ulcer healing rate in the 2W and 4W groups were 96.1% [95% confidence interval (CI): 94.6%-97.55] vs 94.8% (95%CI: 92.6%-97.1%), respectively, with no statistical difference (UMIN000006951). CONCLUSION: Two-wk treatment with a proton pump inhibitor is as effective as four-week treatment for healing post ESD ulcers.

A Case of Blind Loop Syndrome Caused by Infection with Giardia duodenalis Diagnosed with Double Balloon Enteroscopy.

A 75-year-old man who had undergone partial gastrectomy was referred to our hospital due to worsening leg edema, loose stools and malnutrition. Double balloon enteroscopy followed by insertion of an indwelling ileus tube was performed to investigate the microbial flora and for washing inside the blind loop. Trophozoites of Giardia were detected in the sampled fluid from the blind loop and DNA analysis disclosed an assemblage of genotype A-II of Giardia duodenalis. Treatment with oral metronidazole was effective. This case emphasizes the importance of a correct diagnosis when treating patients with blind loop syndrome in the digestive tract.

Severe diffuse duodenitis successfully treated with intravenous tacrolimus after colectomy for ulcerative colitis.

We encountered a rare case of severe diffuse duodenitis associated with ulcerative colitis (UC). A 23-year-old man underwent total proctocolectomy with ileal J-pouch anal anastomosis for UC. He suffered from severe abdominal pain, fever and bloody diarrhea for six months after the surgery. Upper double-balloon enteroscopy disclosed severe diffuse duodenitis, of which the findings were endoscopically and histologically similar to those of colonic lesions of UC. Although the administration of prednisolone was ineffective, treatment with intravenous tacrolimus markedly improved the clinical findings. This is the first report of the successful treatment of severe UC-associated diffuse duodenitis with intravenous tacrolimus.

Risk factors for early and delayed post-operative bleeding after endoscopic submucosal dissection of gastric neoplasms, including patients with continued use of antithrombotic agents.

BACKGROUND: Endoscopic submucosal dissection (ESD) has become widely accepted as a standard treatment for gastric epithelial neoplasms. Antithrombotic agents are widely used to prevent thromboembolic disease. However, the feasibility of endoscopic procedures for patients using such agents has been rarely investigated. The aim of this study was to identify risk factors for post-operative bleeding after gastric ESD and to evaluate the relationship between the use of antithrombotic agents and post-operative bleeding. METHODS: From June 2005 to March 2014, 413 patients with 425 gastric neoplasms were treated by ESD. The demographic and clinical parameters associated with post-operative bleeding were investigated. 83 patients receiving antithrombotic agents were separately assessed using various methods of administration during the ESD procedure. Post-operative bleeding that occurred within 5 days of ESD was defined as early post-operative bleeding, whereas subsequent bleeding was defined as delayed bleeding. RESULTS: The overall post-operative bleeding rate was 4.7%. In patients with continued low-dose aspirin (LDA), heparin replacement (HR), or continued LDA along with HR, post-operative bleeding rates were 9.5%, 23.8%, and 25.0%, respectively. On multivariate analysis, a specimen size of ≥40 mm was a risk factor for early post-operative bleeding [odds ratio (OR) 6.08, 95% CI: 1.74-21.27], and HR and chronic kidney disease (CKD) requiring hemodialysis were risk factors for delayed bleeding (OR 12.23, 95% CI: 2.63-56.77 and OR 28.35, 95% CI: 4.67-172.11, respectively). Continued LDA was not a risk factor for post-operative bleeding. CONCLUSIONS: Large specimen size is a risk factor for early post-operative bleeding, and HR and CKD requiring hemodialysis are risk factors for delayed bleeding. Patients with risk factors should be carefully watched, allowing for the timing of post-operative bleeding after ESD.

Predictive factor of re-bleeding after negative capsule endoscopy for obscure gastrointestinal bleeding: over 1-year follow-up study.

BACKGROUND AND AIM: Capsule endoscopy (CE) is now widely accepted as a first-line diagnostic modality for obscure gastrointestinal bleeding (OGIB), with a high diagnostic yield compared to other modalities. However, even after negative CE examination, re-bleeding is often known to occur. The aim of the present study was to identify predictive factors of re-bleeding after negative CE, and to clarify the clinical utility of double-balloon enteroscopy (DBE) after negative CE for OGIB. METHODS: Two hundred and sixty patients who underwent CE for OGIB between October 2007 and September 2012 were included, and followed up for at least 1 year after CE examination. Demographic and clinical parameters associated with re-bleeding after negative CE were investigated. RESULTS: A total of 154 patients (59.2%) had negative findings. Thirteen of those patients (8.4%) had one or more re-bleeding episodes during the follow-up period. In comparing patients with and without re-bleeding, Cox hazard regression analysis revealed that advanced age was a predictive factor for re-bleeding after negative CE (hazard ratio 1.05 [1.01-1.10], P = 0.03). Subsequent DBE for reasons other than re-bleeding was carried out in 51 patients (33.1%). Mucosal lesions (ulcer or multiple erosions) were subsequently detected in seven patients (13.7%), and endoscopic therapies were carried out in two patients (3.9%). CONCLUSIONS: In patients of advanced age, more extensive follow up is needed, even if the CE result is negative. In addition, DBE subsequent to negative CE may be useful to detect lesions that were overlooked on CE.

Expression level of sonic hedgehog correlated with the speed of gastric mucosa regeneration in artificial gastric ulcers.

BACKGROUND AND AIM: Gastric ulcer healing is a complex process involving cell proliferation and tissue remodeling. Sonic hedgehog (Shh) activates the Shh signaling pathway, which plays a key role in processes such as tissue repair. Shh and interleukin 1ß (IL1ß) have been reported to influence the proliferation of gastric mucosa. We evaluated the relationships between the speed of gastric ulcer healing and the levels of expression of Shh and IL1ß. METHODS: The study included 45 patients (mean age 71.9 ± 9.0 years; M/F, 30/15) who underwent endoscopic submucosal dissection (ESD) for gastric cancer, followed by standard dose of oral proton-pump inhibitor for 4 weeks. Subsequently, the size of ESD-induced artificial ulcers were measured to determine the speed of gastric ulcer healing, and regenerating mucosa around the ulcers and appropriately matched controls were collected from patients by endoscopic biopsy. Polymerase chain reaction (PCR) array analysis of genes in the Shh signaling pathway was performed, and quantitative reverse transcription (RT)-PCR was used to measure IL1ß mRNA. RESULTS: The levels of Shh and IL1ß mRNA were 3.0 ± 2.7-fold and 2.5 ± 2.5-fold higher, respectively, in regenerating mucosa of artificial ulcers than in appropriately matched controls, with the two being positively correlated (r = 0.9, P < 0.001). Shh (r = 0.8, P < 0.001) and IL1ß (r = 0.7, P < 0.005) expression was each positively correlated with the speed of gastric ulcer healing, but multivariate analysis showed that Shh expression was the only significant parameter (P = 0.045). CONCLUSIONS: Expression of Shh was correlated with the speed of gastric ulcer healing, promoting the regeneration of gastric mucosa.

Efficacy of Levofloxacin Based Triple and High-Dose PPI-Amoxicillin Dual Eradication Therapy for Helicobacter pylori after Failures of First- and Second-Line Therapies.

Objectives. The aim of this study was to investigate and compare the eradication rate of Helicobacter pylori as the third-line triple therapy with rabeprazole (RPZ) + amoxicillin (AMPC) + levofloxacin (LVFX) and high-dose RPZ + AMPC. Methods. 51 patients who failed Japanese first-line (proton pump inhibitor (PPI) + AMPC + clarithromycin) and second-line (PPI + AMPC + metronidazole) eradication therapy were randomly assigned at a 1 : 1 ratio to one of the following third-line eradication groups: (1) RAL group: RPZ 10 mg (b.i.d.), AMPC 750 mg (b.i.d.), and LVFX 500 mg (o.d.) for 10 days; (2) RA group: RPZ 10 mg (q.i.d.) and AMPC 500 mg (q.i.d.) for 14 days. Patients who failed to respond to third-line eradication therapy received salvage therapy. Results. The rates of eradication success, based on intention to treat (ITT) analysis, were 45.8% in the RAL group and 40.7% in the RA group. The overall eradication rates were 73.9% in the RAL group and 64.0% in the RA group. There was no significant difference between the two groups. Conclusions. The third-line triple therapy with RPZ, AMPC, and LVFX was as effective as that with high-dose RPZ and AMPC.

Acute liver failure associated with propylthiouracil in a pregnant 26-year-old woman.

It seems appropriate to use propylthiouracil to treat maternal hyperthyroidism during the first trimester of pregnancy. We present the case of a 26-year-old woman with acute liver failure associated with propylthiouracil during the first trimester of pregnancy. She was successfully treated without liver transplantation. Attention should be paid to the possible occurrence of propylthiouracil-induced hepatotoxicity even during the first trimester of pregnancy.

A primary arterio enteric fistula with Takayasu arteritis.

Arterio enteric fistulas (AEFs) are rare. We herein report a case of a primary arterio enteric fistula of the rectum associated with Takayasu arteritis. A 77-year-old woman presented with acute massive hematochezia and was taken to our hospital. Colonoscopy revealed pulsatile extrinsic rectal wall compression with an exposed blood vessel. Transvaginal ultrasonography and Doppler ultrasound revealed a localized vascular growth laying on the dorsal surface of the uterus that showed an arterial blood-flow signal. We diagnosed the patient to have a pelvic aneurism that had formed a fistula within the rectal wall. We eliminated the aneurysm by ligating the drainage and feeder arteries. Following surgery, the patient did not experience any relapses of hematochezia.

A case of hypokalemia-induced fatal arrhythmia caused by indapamide in an anorexic elderly patient.

An 84-year-old man was referred to our hospital for atrioventricular block and severe hypokalemia. He had been treated for hypertension since 2007 with indapamide, a thiazide-like diuretic. His laboratory data had not been tested for a long time. One week before his first visit, he suffered from a common cold and anorexia. He was admitted to our hospital because his electrocardiogram showed ventricular flutter, and pulmonary arrest occurred at the time of his visit. Cardiopulmonary resuscitation was successfully performed. Hypokalemia (K, 1.7 mEq/L) was considered as the cause of acute cardiopulmonary failure. His oral intake of potassium decreased, but potassium loss from the kidney persisted (urinary potassium, 14.0 mEq/L; transtubular potassium gradient, 5.00). These results suggested that although hypokalemia was suspected to have been present for a long time due to indapamide, severe hypokalemia was induced during the period of anorexia. After discontinuation of indapamide and intravenous administration of potassium L: -aspartate for potassium supplementation, the patient's serum potassium levels increased and his general condition improved. Although it is well known that hypokalemia is caused by indapamide, the incidence is not frequent and if observed is not severe. However, we experienced an unusual case of hypokalemia-induced fatal arrhythmia caused by indapamide. Hence, the serum potassium concentration of patients under the drug, especially anorexic elderly patients, should be monitored.