Shoko Edogawa

Potential predictors of disease progression for main‐duct intraductal papillary mucinous neoplasms of the pancreas

The evidence for main pancreatic duct intraductal papillary mucinous neoplasms (MPD‐IPMN) malignancy is based predominantly on investigation of resected cases, and the natural history is still unclear. The aim of the present study is to investigate the natural history of MPD‐IPMN and examine potential predictors of disease progression in MPD‐IPMN patients who conformed to “high‐risk stigmata” criteria.

Autophagy Deficiency Diminishes Indomethacin-Induced Intestinal Epithelial Cell Damage through Activation of the ERK/Nrf2/HO-1 Pathway

Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause epithelial cell damage in the stomach, intestine, and colon. NSAIDs are reported to induce autophagy and apoptosis in intestinal epithelial cells; however, their role in cell damage is poorly understood. To examine the role of autophagy in cell damage, we used autophagy-related gene Atg5-conditional knockout mice, in which the Atg5 gene is only knocked out in intestinal epithelial cells. In an indomethacin (IM)–induced gastrointestinal ulcer mouse model, intestinal epithelium damage was reduced in Atg5-conditional knockout mice compared with wild-type mice. IM-induced damage in IEC6 rat intestinal epithelial cells was reduced when Atg5 was silenced (IEC6shAtg5 cells). Western blot analyses indicated that IM-induced apoptosis decreased, and the potent, oxidative stress–related extracellular signal–regulated kinase (ERK)/nuclear factor-erythroid2-like2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway was upregulated in IEC6shAtg5 cells. An experiment using a reactive oxygen species (ROS)-sensitive fluorescent dye in IEC6shAtg5 cells revealed that the amount of ROS at the baseline and the rate of increase after IM treatment were lower than in intact IEC6 cells. The mitochondrial membrane potential at the baseline and the reduction rate in IM-treated IEC6shAtg5 cells were lower than in intact IEC6 cells, indicating that autophagy deficiency increased ROS production caused by mitochondrial disturbance. Furthermore, MnTMPyP, a manganese–superoxide dismutase mimetic, significantly inhibited IM-induced autophagy and subsequent apoptosis as well as activation of the ERK/Nrf2/HO-1 pathway. These data suggest that autophagy deficiency and subsequent activation of the ERK/Nrf2/HO-1 pathway diminished IM-induced, apoptosis-mediated intestinal epithelial cell damage, and genetic analyses of single nucleotide polymorphisms in autophagy-related genes could predict NSAID-induced intestinal injury.

A novel endoscopic submucosal dissection technique for proton pump inhibitor-refractory gastroesophageal reflux disease

Abstract Objectives: Although drug treatment is the usual first-line therapy for gastroesophageal reflux disease (GERD), not all patients receive satisfactory relief from drug therapy, alone. We developed an endoscopic fundoplication technique using endoscopic submucosal dissection (ESD); the technique is referred to as ESD for GERD (ESD-G). This study investigated the safety and efficacy of this novel technique in patients with drug-refractory GERD. Patients and methods: ESD-G narrows the hiatal opening through ESD of the esophagogastric junction (EGJ) mucosa. For safety reasons, the range of mucosal resection was limited to half (1/2 or 1/4 +1/4) of the circumference of the EGJ lumen. ESD-G was performed on 13 patients with proton pump inhibitor (PPI)-refractory GERD. GERD symptoms, PPI dose, and 24-h esophageal pH monitoring results were compared before and 6 months after the procedure. Results. In 12 cases, symptoms significantly improved after ESD-G. Five patients demonstrated improved esophagitis, three were able to discontinue PPI therapy, and three were able to reduce their PPI dosage following surgery. The esophageal pH <4 holding time ratio was also decreased after ESD-G. Conclusions. ESD-G may be useful for PPI-refractory GERD patients.

Down-regulation of collagen I biosynthesis in intestinal epithelial cells exposed to indomethacin: a comparative proteome analysis.

UNLABELLED In contrast to accumulated knowledge about gastroduodenal injury associated with nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin, small intestinal mucosal injuries have been noticed only recently, and the precise mechanism remains to be elucidated. To clarify the mechanism, we performed 2-DE on IEC-6 rat normal intestinal cells that were treated with indomethacin (200μΜ, 24h) or a vehicle control and identified 18 up-regulated and 8 down-regulated proteins through MALDI-TOF/TOF mass spectrometry. Among these proteins, collagen I and proteins involved in collagen I biosynthesis and maturation, including prolyl 4-hydroxylase subunit α1, protein disulfide isomerase A3 (PDIA3), calreticulin, and endoplasmin, were all down-regulated by indomethacin. Immunohistochemical staining of the intestinal mucosa of indomethacin-administered rats showed a decrease of collagen I on the apical surface of intestinal cells. Cell death induced by indomethacin was prominently suppressed when IEC-6 cells were grown on collagen I-coated plates. cis-4-Hydroxy-l-proline, a proline analog that inhibits collagen synthesis, depressed IEC-6 cell viability in a concentration-dependent manner. Cell death was also induced by short interfering RNA knockdown of endogenous collagen I in IEC-6 cells. In conclusion, by comparative proteome analysis, we identified down-regulation of collagen I as an important mechanism in NSAID-induced intestinal injury. BIOLOGICAL SIGNIFICANCE Small intestinal lesions induced by NSAIDs are of great concern in clinical settings. Various hypotheses have been proposed for the origin of these inflammatory responses, such as reduction in the blood flow, intestinal hypermotility, abnormal intestinal mucosal permeability, mitochondrial dysfunction, and reactive oxygen species, many of which are related to the inhibition of prostaglandin synthesis. However, the precise mechanism is yet to be known. The cellular process of the lesions must involve up- and down-regulations of a large number of proteins and complex interactions between them. To elucidate it, global and systematic identification of the proteins in intestinal cells affected by NSAIDs is essential. We found that the proteins exhibiting reduced expression by indomethacin treatment are collagen I and the proteins involved in collagen I synthesis and maturation. Consistent with this, immunohistochemical analysis showed that the indomethacin-treated rat intestinal mucosal cells exhibits decreased collagen I expression on its apical surface. Furthermore, the cell-protective effect of collagen on intestinal mucosal cells was demonstrated by the use of a collagen-synthesis inhibitor, short interfering RNA (siRNA) knockdown of endogenous collagen I, and cell cultivation on collagen I-coated plates versus uncoated plates. These results give important information on the role of the collagen synthesis in intestinal mucosa in the mechanism of NSAID-induced small intestinal lesions.

Effect of long-term proton pump inhibitor therapy and healing effect of irsogladine on nonsteroidal anti-inflammatory drug-induced small-intestinal lesions in healthy volunteers.

This study assessed time-course changes of the small intestinal lesions during long-term treatment with diclofenac sodium plus omeprazole and the effects of irsogladine on such lesions. Thirty two healthy volunteers were treated with diclofenac sodium (75 mg/day) plus omeprazole (10 mg/day) for 6 weeks, with irsogladine (4 mg/day) added from weeks 6 to 10 (Group A) or with diclofenac sodium plus irsogladine for 6 weeks (Group B). Five volunteers received diclofenac sodium plus omeprazole for 10 weeks (Group C). Subjects underwent capsule endoscopy at each time. In Group A, the number of lesions remarkably increased at week 2, but the worse was not found at week 6 compared with week 2, whereas no exacerbation of lesions was observed in Group B. Additional treatment with irsogladine from weeks 6 to 10 in Group A significantly decreased the number of lesions at weeks 10 compared with Group C. In Group C, no significant change in lesions was observed since weeks 2. In conclusions, a PPI did not prevent the occurrence of small intestinal damage. However such lesions were not aggravated since weeks 2. These suggested mucosal adaptation may occur in the small intestine. Irsogladine was effective in both preventing and healing such lesions.

Exploratory Research on Latent Esophageal Motility Disorders in Dysphagia Patients

Background/Aims: High-resolution manometry (HRM) has been applied to assess esophageal motility disorders. However, the frequency and types of motility disorders in patients with dysphagia, which are frequently seen in clinical practice, are not clear. We evaluated latent esophageal motility disorders associated with dysphagia. Methods: The study included patients without erosive esophageal mucosal damage and with dysphagia symptoms refractory to at least 8 weeks of standard-dose proton pump inhibitors. After enrolment, HRM was used to evaluate for esophageal motility disorder based on the Chicago classification. Results: Esophageal motility disorder was found in 58 of 100 patients and was classified based on the causes: achalasia (13%), esophagogastric junction outflow obstruction (16%), distal esophageal spasms (3%), weak peristalsis (14%), frequently failed peristalsis (5%), and hypertensive peristalsis (7%). Conclusion: Primary esophageal motility disorder was found in approximately 50% of cases in dysphagia patients. Therefore, esophageal motility disorder is not an uncommon condition and should be sought for in order to elucidate precisely the cause of dysphagia.

Determination of the adequate dosage of rebamipide, a gastric mucoprotective drug, to prevent low-dose aspirin-induced gastrointestinal mucosal injury

Small intestinal mucosal injury caused by low-dose aspirin is a common cause of obscure gastrointestinal bleeding. We aimed to investigate the protective effects and optimal dose of rebamipide for low-dose aspirin-induced gastrointestinal mucosal injury. In this prospective randomized trial, 45 healthy volunteers (aged 20–65 years) were included and divided into three groups. The groups received enteric-coated aspirin 100 mg (low-dose aspirin) plus omeprazole 10 mg (Group A: proton pump inhibitor group), low-dose aspirin plus rebamipide 300 mg (Group B: standard-dose group), or low-dose aspirin plus rebamipide 900 mg (Group C: high-dose group). Esophagogastroduodenoscopy and video capsule endoscopy were performed, and the fecal occult blood reaction and fecal calprotectin levels were measured before and two weeks after drug administration. Although the fecal calprotectin levels increased significantly in Group A, they did not increase in Groups B and C. The esophagogastroduodenoscopic and video capsule endoscopic findings and the fecal occult blood test findings did not differ significantly among the three groups. In conclusion, standard-dose rebamipide is sufficient for preventing mucosal injury of the small intestine induced by low-dose aspirin, indicating that high-dose rebamipide is not necessary.

Characteristics of refractory gastroesophageal reflux disease (GERD) symptoms -is switching proton pump inhibitors based on the patient's CYP2C19 genotype an effective management strategy?

OBJECTIVE We investigated factors related to proton pump inhibitor (PPI) -refractory gastroesophageal reflux disease (GERD) symptoms, particularly with respect to acid, the CYP2C19 genotype and psychological aspects. METHODS Patients with an Frequency Scale for the Symptoms of GERD (FSSG) score of ≥8 after the initial treatment were switched to therapy with rabeprazole at a dose of 20 mg once daily for eight weeks. We investigated the rate of improvement in PPI-refractory GERD symptoms, background factors, the Hospital Anxiety and Depression Scale (HADS) score and the CYP2C19 genotype. Patients Sixty patients endoscopically diagnosed with reflux esophagitis within the past six months who had received omeprazole at a dose of 20 mg once daily for eight weeks or longer were enrolled. RESULTS In 71.6% of the patients, the FSSG score decreased to <8 after treatment with omeprazole at a dose of 20 mg once daily for ≥8 weeks, resulting in improvements in their GERD symptoms. Significant factors related to omeprazole-refractory GERD symptoms included a longer disease duration (p=0.0004) and higher HADS score (p=0.01). Among the omeprazole-refractory cases, only 23.5% of the patients showed symptom improvement after switching to rabeprazole. There were no significant differences in the average scores for FSSG (p=0.089) or HADS (p=0.182), before or after the drug change. A total of 92% of the rabeprazole poor responders were homo/hetero extensive metabolizers for the CYP2C19 genotype. CONCLUSION Our findings suggest that switching the PPI from omeprazole (20 mg once daily) to rabeprazole (20 mg once daily) is not a significant effective therapeutic strategy for improving PPI-refractory GERD symptoms, taking into consideration possible psychometric factors and patients who require stronger acid suppression than that achieved with a double dose of PPIs for PPI-refractory GERD symptoms.

Current Topics of Strategy of NSAID-Induced Small Intestinal Lesions

Small intestinal mucosal injuries have been recently recognized as common complications associated with non-steroidal anti-inflammatory drugs (NSAIDs) because video capsule endoscopy and balloon enteroscopy are now available for the detection of small intestinal lesions. Small intestinal injury occurs not in an acid-dependent mechanism but by various factors such as enteric bacteria, bile acids, prostaglandin (PG) deficiency and topical factors (abnormal intestinal mucosal permeability, mitochondrial dysfunction, reactive oxygen species, endoplasmic reticulum stress and so on), and there is no well-established prophylactic approach. Several experimental and clinical studies found the effectiveness of some of the mucoprotective drugs, PG analogs, but not that of acid suppressants. Considering the effect of proton pump inhibitors (PPIs) for upper gastrointestinal (GI) disease and in the small intestine, the following 2 kinds of strategies against NSAID-induced GI injuries may be recommended. In patients with a high risk of upper GI disease (peptic ulcer etc.), simultaneous administration of a PPI (for upper GI disease) and a mucoprotective drug (for small intestine) is needed to prevent NSAID-induced GI injury. In other cases, an effective mucoprotective drug is enough for the protection of the entire digestive tract, that is, starting from the esophagus to the small intestine. These strategies may fulfill both economical and curative effects.

A novel method for treating bilious vomiting following endoscopic ultrasound-guided hepaticogastrostomy.

A Novel Method for Treating Bilious Vomiting Following Endoscopic Ultrasound-Guided Hepaticogastrostomy