The low-FODMAP diet in the management of functional dyspepsia in East and Southeast Asia.

Functional dyspepsia (FD) is a common disorder in East and Southeast Asia where subjects experience post prandial fullness/bloating, early satiety, belching, epigastric pain, and/or burning. A subset of patients with FD experience triggers exclusively related to meals, defined as the post prandial distress syndrome in the Rome IV guidelines. There is significant overlap of symptoms and implicated pathogenic factors with another common functional gastrointestinal disorder, irritable bowel syndrome (IBS) and in fact, a significant proportion of subjects have FD/IBS overlap. The introduction of the low-FODMAP diet has changed the paradigm of treatment for IBS. Like IBS, dietary management appears to be important to patients with FD and clinicians treating the condition. This review aims to examine the current role of diet in the management of FD in East and Southeast Asia, with an exploration of the likely efficacy and mechanisms of action of the low-FODMAP diet in this region.

Venous and arterial disease in inflammatory bowel disease.

Awareness is increasing that risk of venous thromboembolism and development of atherosclerosis is elevated in patients with some chronic inflammatory diseases. This review aimed to examine the risk of vascular disease in patients with inflammatory bowel disease (IBD) and to identify potential pathogenic mechanisms and therapeutic approaches. An extensive literature search was conducted using MEDLINE database, Cochrane Library and international conference abstracts for studies pertaining to venous and arterial thromboembolism in adult IBD patients. There is a 1.1-3.6 fold risk of venothromboembolism in IBD, affecting 0.55-6.15% of patients. Risks are increased during a flare or with chronically active inflammation. Evidence is building that there may be a modestly increased risk of arterial disease overall, despite evidence that traditional risk factors may be reduced. Multiple pathogenic factors have been identified including endothelial dysfunction, inflammation-mediated calcium deposition in the media of arteries, hyperhomocysteinemia, platelet activation, and altered coagulation and fibrinolysis. The key to active and preventive therapy is to effectively treat inflammation. Recommendations for prophylaxis of venothromboembolism have followed guidelines where they exist and have been extrapolated from studies of other at-risk conditions, as have those for arterial disease, where screening for risk factors and actively treating abnormalities is encouraged. In conclusion, patients with IBD are at considerably increased risk of venothromboembolism and probably of arterial disease, in particular mesenteric ischemia and ischemic heart disease. Increased penetration of gaps between this knowledge and clinical therapeutic action to prevent thromboembolic events into IBD clinical practice is needed.

XIAP-associated factor 1 (XAF1), a novel target of p53, enhances p53-mediated apoptosis via post-translational modification.

The role of X chromosome-linked inhibitor of apoptosis protein (XIAP)-associated factor 1 (XAF1) in mediating apoptosis has been reported but the underlying mechanism remains unclear. The present study was designed to examine the putative interaction between XAF1 and p53 and the functional importance of this interaction in regulation of apoptosis in human gastric and colon cancer cells. We first identified XAF1 as a novel target gene of p53 by the chromatin immunoprecipitation (CHIP) assay and demonstrated that wild-type p53, but not mutant p53, down-regulated XAF1 at both mRNA and protein levels, which acted mostly under the condition of high expression of XAF1 and was associated with the physical interaction between p53 and the XAF1 promoter. We also found that the over-expression of XAF1 led to activation of wild-type p53 via post-translational modification in cells with or without DNA damage, which resulting in p53 nuclear accumulation and its increased transcriptional activity and enhancing p53-dependent apoptosis. These findings suggest that a potential novel feedback loop exists between XAF1 and wild-type p53.

Asian-Pacific consensus on small intestinal bacterial overgrowth in gastrointestinal disorders: An initiative of the Indian Neurogastroenterology and Motility Association.

In the clinical setting, small intestinal bacterial overgrowth (SIBO) is a frequent, but under-diagnosed entity. SIBO is linked to various gastrointestinal (GI) and non-GI disorders with potentially significant morbidity. The optimal management of SIBO is undefined while there is a lack of published consensus guidelines. Against this background, under the auspices of the Indian Neurogastroenterology and Motility Association (INMA), formerly known as the Indian Motility and Functional Diseases Association (IMFDA), experts from the Asian-Pacific region with extensive research and clinical experience in the field of gut dysbiosis including SIBO developed this evidence-based practice guideline for the management of SIBO utilizing a modified Delphi process based upon 37 consensus statements, involving an electronic voting process as well as face-to-face meetings and review of relevant supporting literature. These statements include 6 statements on definition and epidemiology; 11 on etiopathogenesis and pathophysiology; 5 on clinical manifestations, differential diagnosis, and predictors; and 15 on investigations and treatment. When the proportion of those who voted either to accept completely or with minor reservations was 80% or higher, the statement was regarded as accepted. The members of the consensus team consider that this guideline would be valuable to inform clinical practice, teaching, and research on SIBO in the Asian-Pacific region as well as in other countries.

Variability in response to clopidogrel: how important are pharmacogenetics and drug interactions?

Clopidogrel is a pro-drug which is converted to an active metabolite that selectively blocks ADP-dependent platelet activation and aggregation. The main enzyme responsible for activating clopidogrel is the cytochrome P450 (CYP) isoenzyme CYP2C19, which is polymorphic. There is a growing body of literature showing that carriers of variant CYP2C19 alleles have impaired ability to metabolize clopidogrel (i.e. poor metabolizers), which is associated with decreased inhibition of platelet aggregation and increased cardiovascular risk. Some proton pump inhibitors are also metabolized by the CYP2C19 enzyme and often given together with clopidogrel to reduce gastrointestinal side effects. In particular, omeprazole has been shown to inhibit the CYP-mediated metabolism of clopidogrel, and some studies have shown that the combination was associated with a higher incidence of cardiovascular adverse reactions than clopidogrel given alone. However, a recent randomized controlled trial demonstrated no significant difference in adverse cardiovascular events for patients on the combination of clopidogrel and omeprazole compared with clopidogrel alone. This current review aims to summarize the role of pharmacogenetics and drug interactions in determining variability in response to clopidogrel.

Helicobacter pylori and gastritis: Untangling a complex relationship 27 years on.

Since its' introduction by Warren and Marshall 27 years ago, Helicobacter pylori (HP) has become the linchpin in our understanding of important gastric conditions including gastritis, intestinal metaplasia (IM), gastric/duodenal ulcers (GU/DU), Mucosal Associated Lymphoid Tumour (MALToma) and gastric cancer. Initially named Campylobacter pyloridis, it was re-named HP when biochemical and genetic characterization of the organism showed that it was not a member of the Campylobacter genus. The finding in 1983 was seminal. It is now recognized that HP is the most common chronic human bacterial infection and it is the most common cause of gastritis. It is strongly implicated in the development of peptic ulcer disease and gastric neoplasms. In the years since its' discovery, much headway has been made in the understanding of this ubiquitous organism that had remained elusive, with much work focused on eradication, in part driven by pharmaceutical research and development. Standard triple therapy emerged to eradicate HP. However, with the emergence of HP resistance, newer regimes have been put forth that include quadruple therapy, sequential therapy and a dizzying array of other combinations bent on eradicating HP. Much less is known about the natural history of HP, the different faces of HP internationally, HP eradication and its effect on gastritis, IM, GU/DU and gastric cancer. This review will address the changing face of HP in 2011.

Rabeprazole is effective in treating laryngopharyngeal reflux in a randomized placebo-controlled trial.

BACKGROUND & AIMS: There is controversy about the efficacy of treating patients with laryngopharyngeal reflux (LPR) using proton pump inhibitors (PPIs). We assessed the effects of high doses of the PPI rabeprazole in patients with LPR. METHODS: Patients with LPR symptoms were assigned randomly to receive rabeprazole (20 mg, twice daily, n = 42) or placebo (n = 40) for 12 weeks. All patients completed symptom questionnaires; these provided demographic information and the reflux symptom index before, during, and 6 weeks after cessation of treatment. Videolaryngostroboscopy was used to document the laryngeal findings and determine the reflux finding score. RESULTS: Twenty-four patients (57.1%) in the rabeprazole group and 27 patients (67.5%) in the placebo group had pH-documented LPR. The total reflux symptom index score decreased significantly in the group given rabeprazole, compared with patients given placebo, at weeks 6 and 12, but not at week 18. However, there were no significant differences in reflux finding scores between the rabeprazole and placebo groups at any of the time points. CONCLUSIONS: Twelve weeks of treatment with rabeprazole (20 mg, twice daily) significantly improved reflux symptoms, compared with placebo, in patients with LPR. Relapse of symptoms was observed 6 weeks after stopping PPI therapy, indicating the requirement for longer treatment duration in patients with LPR.

Proton pump inhibitor and clopidogrel interaction: the case for watchful waiting.

Clopidogrel is an integral part of the management of several important vascular diseases. However the medium to long term clinical outcomes are poorer for these patients if they experience gastro-intestinal bleeding, hence patients with risk factors for gastro-intestinal bleeding are frequently prescribed proton pump inhibitors. Conflicting evidence exists as to the existence of an adverse interaction between clopidogrel and proton pump. This review examines the original studies, which suggested the adverse interaction, the subsequent and most recent studies, the pharmaco-dynamics of the two drugs and suggests an algorithm for the use of clopidogrel with proton pump inhibitors.

Trend of colorectal cancer in Hong Kong: 1983-2006.

BACKGROUND AND AIM: The incidence of colorectal cancer (CC) is increasing in many Asian countries, but decreasing in western countries. The present study examined the local incidence of CC in the past few decades. METHODS: A population based study, using data from Hong Kong (HK) Cancer Registry, was carried out to examine the trends of CC in different age groups in HK. Comparison with other countries was made. RESULTS: The crude rate of CC in HK increased from 29.6/100,000 in 1983 to 57.1/100,000 in 2006. Age standardized rate (ASR) increased by less than 20%. It was markedly smaller than the 190% increase in crude rate. ASR progressively increased in males. In females, ASR peaked in 1994 and declined in the last decade. In most countries, the risk of CC was higher and increasing in males, but stable or decreasing in females. With respect to age, increasing risk was noted in males above 60 years old and females above 70 years old. However, a declining rate was noted in those below 50 years old. The decrease was over 40% in the 30-34 years group over the past two decades. CONCLUSIONS: Increasing incidence of CC in HK was mostly in the older and male population, but not in the younger age group.

Epidemiology of colorectal cancer in Asia.

The prevalence of colorectal cancer is increasing in Asia. However, the age-standardized rate has reached a plateau in some countries. Some studies have shown a male predominance difference and increasing risk in the elderly, but not in the younger population. 'Right shifting' of colorectal cancer, not accountable by difference in age or the indications for endoscopic examination, has also been noted. Westernized diet is associated with colorectal cancer, but controversy remains on how it causes colorectal cancer. Alcohol consumption, obesity, diabetes mellitus, consumption of red and processed meat and cigarette smoking are linked to bowel cancer epidemiologically. Only high dietary calcium has a consistent negative (or 'protective') effect. The efficacy of fish oil, vitamin D, soy, phytoestrogens, folate, methionine, riboflavin and vitamin B6 has not been established. Aspirin and non-steroidal anti-inflammatory drugs use decrease risk of colorectal cancer after 5-10 years of use. There is no evidence for a detrimental effect of proton pump inhibitors or benefit of statins in colorectal cancer. In conclusion, there is a rising trend and prevalence of colorectal cancer in Asia. Dietary modification or supplementation may not be effective in preventing colorectal cancer. Surveillance of colorectal cancer in high-risk groups, according to current recommendation, is probably most effective.

pink1, atp13a2 and uchl1 expressions are affected by inflammation in the brain.

In Parkinson's disease (PD), several genes have been identified as the PD-related genes, however, the regulatory mechanisms of these gene expressions have not been fully identified. In this study, we investigated the effect of inflammation, one of the major risk factors in PD on expressions of the PD-related genes. Lipopolysaccharide (LPS) was intraperitoneally administered to mature male zebrafish and gene expressions in the brains were examined by real-time PCR. In the inflammation-related genes, expressions of tnfb, il1b and il6 were increased at 2 days post administration in the 10 µg group, and tnfb expression was also increased at 4 days post administration in the 1 µg and 10 µg group. In the PD-related genes, pink1 expression was significantly decreased at 4 days, atp13a2 expression was significantly increased at 7 days, and uchl1 expression was significantly decreased at 7 days. This suggests that pink1, atp13a2 and uchl1 expressions are regulated by inflammation, and this regulatory mechanism might be involved in the progress of PD.

Gastric cancer chemoprevention: the current evidence.

Chemoprevention may form the cornerstone in the management of gastric adenocarcinoma of the future. Helicobacter pylori eradication and aspirin and/or nonsteroidal anti-inflammatory drug therapy have emerged as front-runner chemotherapeutic agents due to the putative pathogenic mechanisms that they address. Before a population-based chemopreventive strategy can be recommended on a large scale, randomized controlled trials with follow-up of more than 10 years of these 2 agents in populations at high gastric adenocarcinoma risk is urgently awaited.

Treatment of functional dyspepsia with sertraline: a double-blind randomized placebo-controlled pilot study.

AIM: To evaluate sertraline, a selective serotonin reuptake inhibitor in the treatment of patients with functional dyspepsia. METHODS: Consecutive tertiary hospital patients with a clinical diagnosis of functional dyspepsia (FD) according to the Rome II criteria with a Hong Kong dyspepsia index (HKDI) of greater than 16 were recruited. Patients commenced enrolment prior to the inception of the Rome III criteria for functional dyspepsia. All patients were ethnic Chinese, had a normal upper endoscopy and were Helicobacter pylori negative prior to enrolment. Study patients were randomized to receive sertraline 50 mg or placebo daily for 8 wk. HKDI symptom scores, quality of life, hospital anxiety and depression (HAD) scale and global symptom relief were evaluated before, during and after treatment. Adverse effects were monitored during and after treatment. RESULTS: A total of 193 patients were randomized in the intention to treat (ITT), and 150 patients were included in the per protocol (PP) analysis. In both the ITT and PP, there was no difference in the primary outcome of global dyspepsia symptoms between the sertraline and placebo groups at week 8. In the ITT analysis, 98 and 95 patients were randomized to the sertraline and placebo groups respectively. A total of 43 patients withdrew from the study (22.3%) by week 8, with 23 of the 24 drop-outs in the sertraline group occurring prior to week 4 (95.8%). In contrast, in the placebo arm, 11 of 19 patients dropped out by week 4 (57.9%). Utilizing the last response carried forward to account for the drop-outs, there were no differences between the sertraline and placebo groups at baseline in terms of the HKDI, HKDI 26.08 ± 6.19 vs 26.70 ± 5.89, P = 0.433; and at week 8, HKDI 22.41 ± 6.36 vs 23.25 ± 7.30, P = 0.352 respectively. In the PP analysis, 74 and 76 patients were randomized to the sertraline and placebo groups respectively. At baseline, there were no statistically significant differences between the sertraline and placebo groups, HKDI 25.83 ± 6.313 vs 27.19 ± 5.929 respectively, P = 0.233; however by week 8, patients in the sertraline group demonstrated a statistically significant difference in their Hong Kong Dyspepsia Index compared to placebo, HKDI 20.53 ± 6.917 vs 23.34 ± 7.199, P = 0.02, respectively). There was also no statistically significant difference in overall quality of life measures or the HAD scale related to treatment in either the ITT or PP analysis at week 8. CONCLUSION: This pilot study, the first to examine sertraline, a selective serotonin reuptake inhibitor, for the management of FD, did not find that it was superior to placebo.

Treatment of non-erosive reflux disease with a proton pump inhibitor in Chinese patients: a randomized controlled trial.

BACKGROUND: Evidence suggests that rates of gastroesophageal reflux disease are increasing in the Asia-Pacific region, where patients tend to have predominantly non-erosive reflux disease as opposed to erosive (reflux) esophagitis. At present, data for the responsiveness of non-erosive reflux disease to proton pump inhibition are scant. We aimed to study esomeprazole for the treatment of non-erosive reflux disease in Chinese patients. METHODS: Patients with a clinical diagnosis of gastroesophageal reflux, and a locally validated reflux index, the Chinese GerdQ, of equal to or greater than 12 were recruited and randomized to receive esomeprazole 20 mg daily or placebo for 8 weeks. Reflux index scores, quality of life (SF-36), and the hospital anxiety and depression (HAD) scale and symptom relief were evaluated before, during, and after treatment. RESULTS: A total of 175 patients were randomized. Patients in the esomeprazole group (n = 85) demonstrated statistically significant reductions in their GerdQ index, from 19.45 to 15.37 and to 14.32 (p = 0.013, p = 0.005) at weeks 4 and 8, respectively. Compared to placebo at week 8, 57.1% of patients on esomeprazole found that their symptoms had resolved or were acceptable compared with 37.2% in the placebo group (p = 0.001). There were no statistically significant differences in overall quality-of-life measures or the HAD scale related to treatment. CONCLUSIONS: This study suggests that esomeprazole is efficacious in treating Chinese patients with non-erosive reflux disease.

Four and a half LIM protein 2 (FHL2) negatively regulates the transcription of E-cadherin through interaction with Snail1.

E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT), which plays a crucial role in cancer metastasis. We previously demonstrated that four and a half LIM protein 2 (FHL2) inhibited E-cadherin expression and promoted invasive potential and EMT in colon cancer. Here, we aim to further define the mechanism underlying the inhibition of E-cadherin by FHL2 in colon cancer. The expression profiles of FHL2 and Snail1 were first observed by Western blot, immunofluorescence and immunohistochemistry. We found that both the protein level and the cellular localisation of Snail1 were quite similar to FHL2 in colon cancer; reciprocal co-immunoprecipitation assay showed that FHL2 was able to bind Snail1 and its intact structure was required. The expression of FHL2 was positively correlated to Snail1 while negatively to E-cadherin and phospho-Snail1. FHL2 over-expression induced the accumulation of Snail1 in the nucleus. Moreover, dual luciferase assay revealed that FHL2 over-expression decreased while FHL2 siRNA increased the transcriptional activities of two E-cadherin promoter constructs which contained E-box sites (Snail1-binding elements). Mutation of E-boxes increased the transcriptional activities and FHL2 expression was involved in the function of mutation. These results suggested that FHL2 negatively regulated E-cadherin transcriptional activity through interaction with Snail1. Our study established a novel regulatory function of FHL2 and revealed a potential mechanism on promoting the process of EMT.

Chemoprophylaxis in colorectal cancer: current concepts and a practical algorithm for use.

Colorectal cancer (CRC) is the second most common lethal cancer in the Western world. There is a 10 to 20 years lead time from normal mucosa to carcinoma which offers a window of opportunity to modify and prevent the outcome of CRC, with its incipient morbidity and mortality. The objective of this paper is to review the evidence for chemoprophylaxis in CRC, identify currently used agents and determine their role in the current management algorithm of CRC. Large cohort-control and randomised controlled trials in the most studied chemoprophylaxis agents are reviewed. Currently, the role for chemoprophylaxis in CRC remains a niche area, with celecoxib the only recommended agent for use in patients with familial polyposis syndromes. However, the role of chemoprophylaxis is likely to grow significantly in the next decade as understanding of the stepwise tumorigenesis cascade becomes better understood and current clinical trials are completed.

Impact of genetic and acquired alteration in cytochrome P450 system on pharmacologic and clinical response to clopidogrel.

Dual antiplatelet therapy with aspirin and clopidogrel has been shown to reduce subsequent cardiac events in patients with acute coronary syndrome or coronary artery stenting. Clopidogrel, a thienopyridine, is a prodrug that is transformed in vivo to an active metabolite by the cytochrome P450 (CYP) enzyme system. The genes encoding CYP enzymes are polymorphic. Recent data demonstrated patients carrying a genetic variant of CYP enzymes (e.g. CYP2C19) would have a higher rate of ischemic events than non-carriers due to an attenuation of the pharmacokinetic and pharmacodynamic responses to clopidogrel. Furthermore, concomitant gastrointestinal ulcer prophylaxis with a proton pump inhibitor (PPI) is commonly prescribed to patients because of the increased risk of bleeding with dual antiplatelet therapy. PPIs are extensively metabolized by the cytochrome P450 system and have been associated with decreased antiplatelet activity of clopidogrel. In this review, we will discuss the impact of CYP450 enzymes genetic variation and CYP450 pathway drug-drug interactions in pharmacological and clinical response to clopidogrel.

A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer.

Recent evidence suggests that a subpopulation of cancer cells, cancer stem cells (CSCs), is responsible for tumor growth in colorectal cancer. However, the role of CSCs in colorectal cancer metastasis is unclear. Here, we identified a subpopulation of CD26(+) cells uniformly present in both the primary and metastatic tumors in colorectal cancer patients with liver metastasis. Furthermore, in patients without distant metastasis at the time of presentation, the presence of CD26(+) cells in their primary tumors predicted distant metastasis on follow-up. Isolated CD26(+) cells, but not CD26(-) cells, led to development of distant metastasis when injected into the mouse cecal wall. CD26(+) cells were also associated with enhanced invasiveness and chemoresistance. Our findings have uncovered a critical role of CSCs in metastatic progression of cancer. Furthermore, the ability to predict metastasis based on analysis of CSC subsets in the primary tumor may have important clinical implication as a selection criterion for adjuvant therapy.