We reviewed articles on the epidemiology and clinical characteristics of gastroesophageal reflux disease (GERD) in Japan to clarify these features of GERD in this country. Although the definition of ...GERD depends on the individual study, the prevalence of GERD has been increasing since the end of the 1990s. The reasons for the increase in the prevalence of GERD may be due to increases in gastric acid secretion, a decrease in the Helicobacter pylori infection rate, more attention being paid to GERD, and advances in the concept of GERD. More than half of GERD patients had non-erosive reflux disease, and the majority (87%) of erosive esophagitis was mild type, such as Los Angeles classification grade A and grade B. There were several identified risk factors, such as older age, obesity, and hiatal hernia. In particular, mild gastric atrophy and absence of H. pylori infection influence the characteristics of GERD in the Japanese population. We also discuss GERD in the elderly; asymptomatic GERD; the natural history of GERD; and associations between GERD and peptic ulcer disease and H. pylori eradication. We examined the prevalence of GERD in patients with specific diseases, and found a higher prevalence of GERD, compared with that in the general population, in patients with diabetes mellitus, those with obstructive sleep apnea syndrome, and those with bronchial asthma. We provide a comprehensive review of GERD in the Japanese population and raise several clinical issues.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Non-steroidal anti-inflammatory drugs (NSAIDs) are well known to cause gastroduodenal mucosal lesions as an adverse effect. Recently, the serious problem of NSAID-induced small intestinal damage has ...become a topic of great interest to gastroenterologists, since capsule endoscopy and balloon enteroscopy are available for the detection of small intestinal lesions. Such lesions have been of great concern in clinical settings, and their treatment and prevention must be devised as soon as possible. The prevalence of NSAIDs-induced small intestinal injury is higher than had been expected. Recent studies show that more than 50% of patients taking NSAIDs have some mucosal damage in the small intestine. The gross appearance of NSAID-induced enteropathy varies, appearing variously as diaphragm-like strictures, ulcers, erosions, and mucosal redness. To investigate NSAID-induced enteropathy, and to rule out other specific enteropathies, other useful methods (in addition to capsule endoscopy and balloon enteroscopy) include such modalities as radiological examination of the small intestine, the permeability test, scintigraphy or the fecal excretion test using
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Indium-labeled white blood cells, and measurement of the fecal calprotectin concentration. Diaphragm-like strictures and bleeding from mucosal breaks may be treatable with interventional enteroscopy. Misoprostol, metronidazole, and sulfasalazine are frequently used to treat NSAID-induced enteropathy, but have undesirable effects in some cases. In the experimental model, we confirmed that several existing drugs for gastroduodenal ulcers prevented indomethacin-induced small intestinal injury. Such drugs may be useful for preventing the adverse effects of NSAIDs not only in the stomach but also in the small intestine. We hope to examine these drugs in future clinical studies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Nighttime reflux during sleep plays a crucial role in several conditions associated with gastroesophageal reflux disease (GERD). Reflux patterns during arousal and sleep are different because of ...delayed gastric emptying, reduced esophageal peristalsis, decreases in swallowing and salivary secretion, and prolonged esophageal clearance during sleep. Clinical evidence strongly suggests that GERD is associated with sleep disturbances such as shorter sleep duration, difficulty falling asleep, arousals during sleep, poor sleep quality, and awakening early in the morning. New mechanisms on how GERD affects sleep have been recently identified by using actigraphy, and sleep deprivation was found to induce esophageal hyperalgesia to acid perfusion. Thus, the relationship between GERD and sleep disturbances is bidirectional. Among lifestyle modifications, avoidance of a late night meal plays a role in prevention of nighttime reflux. Treatment with a proton pump inhibitor (PPI) improves both nighttime symptoms and subjective sleep parameters, but its effects on objective sleep parameters remain unclear. Better control of nighttime acid secretion by administering a PPI at different times or by providing a double-dose PPI, adding H
2
receptor antagonists, or other new agents is proposed. The effects of such treatments on sleep disturbances remain to be elucidated. GERD patients with sleep disturbances report more severe symptoms and poorer quality of life as compared to those without sleep disturbances. Consequently, GERD should also be classified as GERD with sleep disturbance and GERD without sleep disturbance.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Treatment with kampo, the Japanese traditional medicine, is a form of pharmacological therapy that combines modern Western and traditional Asian medical practices. In Japan, various traditional ...medicines are often combined with Western medicines and prescribed for patients with diseases such as gastroesophageal reflux disease, functional dyspepsia, chronic gastritis, irritable bowel syndrome, and post-operative ileus. Based on numerous past observations, Japanese traditional medicines are thought to be particularly useful in the treatment of medically unexplained physical symptoms such as nausea, abdominal discomfort, and anorexia. However, the detailed mechanism by which they mediate their pharmacological action is yet unknown. In addition, the clinical evidence to support their use is insufficient. This review focuses on the basic evidence of the pharmacological action and the clinical efficacies of kampo medicines accumulated over several past decades. In addition, we introduce both the current novel insights into kampo medicines and the therapeutic approach employed when they are used to treat various disorders of the gastrointestinal tract.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
To seek a promising therapeutic regimen for proton pump inhibitor (PPI)-refractory patients with gastroesophageal reflux disease (GERD) after the standard PPI treatment, we compared the ...efficacies of rikkunshito (a Japanese traditional medication) combined with rabeprazole (RPZ) and a double dose of RPZ in a prospective randomized multicenter trial in Japanese PPI-refractory GERD patients.
Methods
One hundred and four patients with GERD symptoms remaining after 4-week treatment with RPZ (10 mg/day) were randomly assigned to 4 weeks of either combination therapy rikkunshito (7.5 g/day) with a standard dose of RPZ (10 mg/day) or a double dose of RPZ (20 mg/day). The primary endpoint was the improvement rate, calculated based on the frequency scale for the symptoms of GERD (FSSG) before and after treatment. Subgroup analysis was also performed with respect to each subject’s background factors such as reflux esophagitis (RE)/non-erosive GERD (NERD), age, gender, and body mass index (BMI).
Results
Four-week treatment with rikkunshito combined with RPZ significantly decreased the FSSG score from 17.6 ± 6.5 to 12.0 ± 6.9, similar to the decrease seen on treatment with a double dose of RPZ. Regarding the therapeutic improvement rate, there were also significant effects in both groups. However, in the subgroup analysis based on RE/NERD, the improvement rate of male NERD patients in the rikkunshito group was significantly greater than that of such patients in the other group (
P
< 0.05). In the rikkunshito group, the treatment was more effective in NERD patients with a low BMI than in those with a high BMI (
P
< 0.05).
Conclusion
Rikkunshito combined with standard-dose RPZ therapy may be a useful new strategy for PPI-refractory GERD patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
New strategies for the care of irritable bowel syndrome (IBS) are developing and several novel treatments have been globally produced. New methods of care should be customized geographically because ...each country has a specific medical system, life style, eating habit, gut microbiota, genes and so on. Several clinical guidelines for IBS have been proposed and the Japanese Society of Gastroenterology (JSGE) subsequently developed evidence-based clinical practice guidelines for IBS. Sixty-two clinical questions (CQs) comprising 1 definition, 6 epidemiology, 6 pathophysiology, 10 diagnosis, 30 treatment, 4 prognosis, and 5 complications were proposed and statements were made to answer to CQs. A diagnosis algorithm and a three-step treatment was provided for patients with chronic abdominal pain or abdominal discomfort and/or abnormal bowel movement. If more than one alarm symptom/sign, risk factor and/or routine examination is positive, colonoscopy is indicated. If all of them, or the subsequent colonoscopy, are/is negative, Rome III or compatible criteria is applied. After IBS diagnosis, step 1 therapy consisting of diet therapy, behavioral modification and gut-targeted pharmacotherapy is indicated for four weeks. Non-responders to step 1 therapy proceed to the second step that includes psychopharmacological agents and simple psychotherapy for four weeks. In the third step, for patients non-responsive to step 2 therapy, a combination of gut-targeted pharmacotherapy, psychopharmacological treatments and/or specific psychotherapy is/are indicated. Clinical guidelines and consensus for IBS treatment in Japan are well suited for Japanese IBS patients; as such, they may provide useful insight for IBS treatment in other countries around the world.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In this paper, we review the concept of quality of ulcer healing （QOUH） in the gastrointestinal tract and its role in the ulcer recurrence. In the past, peptic ulcer disease （PUD） has been a chronic ...disease with a cycle of repeated healing/remission and recurrence. The main etiological factor of PUD is Helicobacter pylori （H. pylorl~, which is also the cause of ulcer recur- rence. However, H. pylori-negative ulcers are pres- ent in 12%-20% of patients; they also recur and are on occasion intractable. QOUH focuses on the fact that mucosal and submucosal structures within ulcer scars are incompletely regenerated. Within the scars of healed ulcers, regenerated tissue is immature and with distorted architecture, suggesting poor QOUH. The abnormalities in mucosal regeneration can be the basis for ulcer recurrence. Our studies have shown that persistence of macrophages in the regenerated area plays a key role in ulcer recurrence. Our studies in a rat model of ulcer recurrence have indicated that proinflammatory cytokines trigger activation of macro- phages, which in turn produce increased amounts of cytokines and chemokines, which attract neutrophils to the regenerated area. Neutrophils release proteolytic enzymes that destroy the tissue, resulting in ulcer re- currence. Another important factor in poor QOUH can be deficiency of endogenous prostaglandins and a defi- ciency and/or an imbalance of endogenous growth fac- tors. Topically active mucosal protective and antiulcer drugs promote high QOUH and reduce inflammatory cell infiltration in the ulcer scar. In addition to PUD, the concept of QOUH is likely applicable to inflammatory bowel diseases including Crohn＇s disease and ulcer- ative colitis.
DNA methylation has been identified as a hallmark of gastric cancer (GC). Identifying genes that are repressed by DNA promoter methylation is essential in providing insights into the molecular ...pathogenesis of gastric cancer. Using genome-wide methylation studies, we identified that transcription factor forkhead box F2 (FOXF2) was preferentially methylated in gastric cancer. We then investigated the functional significance and clinical implication of FOXF2 in gastric cancer. FOXF2 was silenced in gastric cancer cell lines and cancer tissues by promoter methylation, which was negatively associated with mRNA expression. Ectopic expression of FOXF2 inhibited proliferation, colony formation, G
-S cell-cycle transition, induced apoptosis of gastric cancer cell lines, and suppressed growth of xenograft tumors in nude mice; knockdown of FOXF2 elicited opposing effects. FOXF2 inhibited Wnt signaling by inducing β-catenin protein ubiquitination and degradation independently of GSK-3β. FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation. Multivariate Cox regression analysis identified FOXF2 hypermethylation as an independent prognostic factor of poor survival in early-stage gastric cancer patients. In conclusion, FOXF2 is a critical tumor suppressor in gastric carcinogenesis whose methylation status serves as an independent prognostic factor for gastric cancer patients.
FOXF2-mediated upregulation of the E3 ligase IRF2BPL drives ubiquitylation and degradation of β-catenin in gastric cancer, blunting Wnt signaling and suppressing carcinogenesis.
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Objective: Gastroesophageal reflux disease (GERD), functional dyspepsia (FD), and irritable bowel syndrome (IBS) are common, and have negative impacts on health‐related quality of life (HR‐QOL). ...Several studies demonstrated a significant overlap between two of these three diseases. The purpose of this study was to examine the prevalence of GERD, FD, and IBS, their overlap rates, and HR‐QOL for each disease and each overlap compared with healthy controls in the Japanese general population.
Methods: We performed a cross‐sectional study of Japanese workers who visited a clinic for a routine health check‐up, and asked them to fill out a self‐report questionnaire. Prevalence and overlap rate of GERD defined as heartburn and/or acid regurgitation at least weekly, FD and IBS based on Rome III criteria, and HR‐QOL by SF‐8 were examined.
Results: Of the 2680 eligible subjects, 207 (7.7%) were diagnosed as having GERD, 269 (10.0%) as FD, and 381 (14.2%) as IBS. Overlaps were found in 46.9% in GERD, 47.6% in FD, and 34.4% in IBS. Prevalence of overlaps in subjects with IBS was significantly lower compared with those among GERD or FD. Sufferers from GERD, FD, or IBS reported significantly poorer HR‐QOL across all domains compared with controls. Overlaps significantly worsened HR‐QOL in most domains except in the ‘role emotional’ domain. HR‐QOL was particularly poor in the physical component summary for overlapping GERD and in the mental component summary for overlapping IBS.
Conclusion: Overlaps among GERD, FD and IBS were common and worsened HR‐QOL in Japanese general population.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background:In patients with chronic heart failure with reduced ejection fraction (HFrEF), cardiac resynchronization therapy (CRT) improves left ventricular ejection fraction (LVEF) and exercise-based ...cardiac rehabilitation (ECR) enhances exercise capacity. This study examined the relationship between the 2 responses.Methods and Results:Sixty-four consecutive HFrEF patients who participated in a 3-month ECR program after CRT were investigated. Patients were categorized according to a median improvement in peak oxygen uptake (PV̇O2) after ECR of 7% as either good (n=32; mean percentage change in PV̇O2%∆PV̇O2=23.2%) or poor (n=32; mean %∆PV̇O2=2.5%) responders. There was no significant difference in baseline characteristics between the good and poor responders, except for PV̇O2(51% vs. 59%, respectively; P=0.01). The proportion of good CRT responders was similar between the good and poor responders (%∆LVEF ≥10%; 53% vs. 47%, respectively; P=NS). Overall, there was no significant correlation between %∆LVEF after CRT and %∆PV̇O2after ECR. Notably, among poor CRT responders (n=32), the prevalence of atrial fibrillation (0% vs. 29%; P<0.03) and baseline PV̇O2(48% vs. 57%; P<0.05) were significantly lower among those with a good (n=15) than poor (n=17) response to ECR.Conclusions:In patients with HFrEF, good ECR and CRT responses are unrelated. A good PV̇O2response to ECR can be achieved even in poor CRT responders, particularly in those with a sinus rhythm or low baseline PV̇O2.
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