Joseph Y. Chang

Phospholipase A2 enzymes : regulation and inhibition

The phospholipase A2 enzymes are important components of the cellular machinery that responds to inflammatory stimuli and maintains cell homeostasis by membrane remodelling. Their role as the rate-limiting step in the production of pro-inflammatory lipid mediators makes these enzymes an important therapeutic target for the treatment of inflammatory disorders. Keith Glaser and colleagues explain how the two major groups of phospholipase A2, the secretory and cytosolic forms, are very different both structurally and enzymatically. Understanding the relative contributions of these different forms of phospholipase A2 to physiological and pathological conditions requires greater insight into their cellular regulation and the development of selective inhibitors.

Impact of Functional Gastrointestinal Disorders on Survival in the Community

OBJECTIVES:Functional gastrointestinal disorders (FGIDs) comprise a constellation of symptoms that have no identifiable structural or biochemical abnormality. In view of the lack of data from large-scale population-based studies evaluating the effects of these disorders on survival, we aimed to examine whether FGIDs are associated with impaired survival.METHODS:Between 1988 and 1993, valid self-report questionnaires that recorded gastrointestinal symptoms required for the diagnosis of irritable bowel syndrome (IBS), chronic constipation, chronic diarrhea, dyspepsia, and abdominal pain were mailed to randomly selected cohorts of Olmsted County, Minnesota residents. Minnesota administrative death records were used to identify which of the survey respondents had died over the follow-up period (through April 2008). The association between survival and each FGID was assessed using proportional hazards regression models with univariate and adjusted hazard ratios (HRs, 95% confidence intervals (CIs)), adjusting for age at time of survey, gender, smoking, alcohol, marital status, and Charlson Comorbidity Index (CCI).RESULTS:Of the 5,262 randomly selected eligible subjects who received a questionnaire, a total of 4,176 responded to the surveys (overall response rate 79%). From these respondents, 243 subjects were excluded because of lack of research authorization (or were registered solely at a different medical institution in Olmsted County, MN), resulting in 3,933 eligible subjects for analysis (eligible response rate 75%); 10% reported symptoms of IBS; 16% chronic constipation; 18% chronic diarrhea; 2% dyspepsia; and 15% abdominal pain. At baseline, the mean (s.d.) age was 54 (18) years, and 52% were female. No association with overall survival was detected for IBS (HR=1.06 (95% CI: 0.86–1.32)), chronic diarrhea (HR=1.03 (95% CI: 0.90–1.19)), abdominal pain (HR=1.09 (95% CI: 0.92–1.30)), or dyspepsia (HR=1.08 (95% CI: 0.58–2.02)). Reporting symptoms of chronic constipation was associated with poorer survival (HR=1.23 (95% CI: 1.07–1.42)). This association remained significant after adjusting for the CCI (HR=1.19 (95% CI: 1.03–1.37)).CONCLUSIONS:In this large population-based cohort study with over 30,000 person-years of follow-up, no significant association was observed between survival and IBS, chronic diarrhea, dyspepsia, or abdominal pain. Furthermore, no association was found between increasing burden of FGIDs and survival. However, in contrast to these other FGIDs, subjects with symptoms of chronic constipation were found to be at increased risk of poorer survival. Further investigation is required to determine the cause of this observed association.

A shift in the clinical spectrum of eosinophilic gastroenteritis toward the mucosal disease type

BACKGROUND & AIMS Eosinophilic gastroenteritis (EG) is a rare disorder characterized by eosinophilic infiltration of the gastrointestinal (GI) tract. Despite the increasing prevalence of eosinophilic GI disorders, the epidemiology of EG has not been well studied. We evaluated the clinical spectrum of EG. METHODS We reviewed data from patients diagnosed with EG, allergic gastroenteropathy, or eosinophilia and referred to gastroenterologists from 1987 to 2007 (n = 59; 52 with mucosal, 3 with muscularis, and 4 with subserosal disease). The study included subjects diagnosed with EG and those with a history that suggested EG, defined by GI symptoms; eosinophilic infiltration of the GI tract, eosinophilic ascites, or characteristic radiographic findings with eosinophilia; and no parasitic or extraintestinal disease. Findings were compared with those from patients with unexplained GI symptoms and peripheral eosinophilia (n = 11). RESULTS Associations between clinical variables and EG subgroups did not differ between patients with EG and peripheral eosinophilia. Fifty percent of patients with EG who underwent food allergy testing had a positive test result; only 32% of those with EG who underwent radiographic imaging had positive test results. Patients with EG received steroid therapy; 75% with mucosal, 67% with muscle, and 100% with subserosal disease received prednisone. Eighty-eight percent of patients who received only steroids (mean follow-up period, 7 mo) and 94% of patients who received steroids in combination with another therapy (mean follow-up period, 4 mo) had improved or resolved disease. CONCLUSIONS Unlike eosinophilic esophagitis, EG is rare. Results from this large study suggest that EG disease type has shifted toward that of the mucosal layer.

Risk factors for chronic constipation and a possible role of analgesics

Abstract  Constipation has an estimated prevalence of 15% in the general population. However, the etiopathogenesis of this condition remains relatively obscure. This study sought to identify potentially novel risk factors for chronic constipation. A valid self‐report questionnaire was mailed to an age‐ and gender‐stratified random sample of Olmsted County, Minnesota residents aged 30–64 years. A logistic regression model that adjusted for age, gender and somatic symptom score (SSC) was used to identify factors associated with chronic constipation. People reporting symptoms of irritable bowel syndrome (IBS) were excluded. Of the 892 eligible subjects, 653 (73%) returned the survey. Among the 523 subjects not reporting IBS symptoms, chronic constipation was reported by 93 (18%) of the respondents. Chronic constipation was significantly associated with use of acetaminophen [≥7 tablets per week, OR = 2.7 (1.1–6.6)]; aspirin [OR = 1.7 (1.0–2.7)]; non‐steroidal anti‐inflammatory drugs [OR = 1.8 (1.1–3.0)]; and SSC. No association was detected for age, gender, body mass index, marital status, smoking, alcohol, coffee, education level, food allergy, exposure to pets, stress, emotional support, or water supply. Chronic constipation is associated with use of acetaminophen, aspirin and non‐steroidal anti‐inflammatory drugs. The explanation of these associations requires further investigation.

Current and emerging therapies in irritable bowel syndrome: from pathophysiology to treatment

Irritable bowel syndrome is a common functional gastrointestinal disorder with characteristic symptoms of abdominal pain/discomfort with a concurrent disturbance in defecation. It accounts for a significant healthcare burden, and symptoms may be debilitating for some patients. Traditional symptom-based therapies have been found to be ineffective in the treatment of the entire syndrome complex, and do not modify the natural history of the disorder. Although the exact etiopathogenesis of IBS is incompletely understood, recent advances in the elucidation of the pathophysiology and molecular mechanisms of IBS have resulted in the development of novel therapies, as well as potential future therapeutic targets. This article reviews current and emerging therapies in IBS based upon: IBS as a serotonergic disorder; stimulating intestinal chloride channels; modulation of visceral hypersensitivity; altering low-grade intestinal inflammation; and modulation of the gut microbiota.

An update on irritable bowel syndrome: from diagnosis to emerging therapies.

Purpose of review Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by abdominal discomfort or pain that is accompanied by a disturbance in defecation. Although the exact etiopathogenesis is not completely understood, recent advances in the understanding of the biochemical, physiologic, and biopsychosocial mechanisms of IBS have resulted in exciting new insights as well as therapies. This article will review the recent developments in pathogenesis, diagnosis, and treatment. Recent findings IBS may be the product of various pathogenic mechanisms which include IBS as a serotonergic disorder; the role of genetics; IBS as an inflammatory state and the potential role of mast cells; IBS as a result of bacterial overgrowth and altered gastrointestinal microbiome; and abnormal pain processing and pain memory. Emerging therapies have developed targeting these mechanisms. Summary IBS remains a symptom-based diagnosis that can usually be made comfortably based on clinical history without testing in the absence of alarm features. Novel and emerging therapies that are based upon the evolving understanding of the pathophysiology of IBS hold significant promise and for the first time there are potential therapies that may alter the natural history of this disorder.

Population screening for barrett esophagus: a prospective randomized pilot study.

OBJECTIVE To assess the feasibility of unsedated transnasal endoscopy (uTNE) and video capsule endoscopy (VCE) as alternatives to sedated endoscopy (sEGD) as screening tools for Barrett esophagus (BE) and to obtain preliminary estimates of participation rates for sEGD, uTNE, and VCE when used for community BE screening in a population cohort. PATIENTS AND METHODS From February 1, 2009, to May 31, 2010, patients from Olmsted County, Minnesota, who were older than 50 years and had no history of known BE were randomized (stratified by age, sex, reflux symptoms noted in a validated questionnaire) into 3 groups for esophageal evaluation with sEGD, uTNE, or VCE. Participation rates and safety profiles were estimated. RESULTS We contacted 127 patients to recruit 20 for each procedure arm (60 total). The probability of participation was 38% (95% confidence interval [CI], 26%-51%) for sEGD, 50% (95% CI, 35%-65%) for uTNE, and 59% (95% CI, 42%-74%) for VCE. Both uTNE and VCE were well tolerated without adverse effects. BE was identified in 3 patients and esophagitis in 8. CONCLUSION Unsedated techniques may be acceptable, feasible, and safe alternatives to sEGD to screen for BE in the community. TRIAL REGISTRATION clinicaltrials.gov identifier: NCT00943280.

Risk factors for chronic diarrhoea in the community in the absence of irritable bowel syndrome.

Abstract  In contrast to irritable bowel syndrome (IBS), the prevalence and risk factors for diarrhoea in the absence of IBS in the community are unknown. We aimed to evaluate potential risk factors for chronic diarrhoea (non‐IBS). A valid questionnaire that recorded gastrointestinal symptoms required for a diagnosis of chronic diarrhoea, self‐reported measures of potential risk factors, and a somatic symptom checklist was mailed to an age‐ and gender‐stratified random sample of Olmsted County, Minnesota residents (30–64 year). Chronic diarrhoea was defined as reporting one or more of the following symptoms more than 25% of the time in the past 3 months: ≥3 bowel movements a day, loose or watery stools, or faecal urgency. Subjects with IBS (Rome III) were excluded. Of 892 eligible subjects, 653 (73%) responded. Among 523 respondents not reporting IBS, chronic diarrhoea was reported by 148 (28%); 90 (61%) had chronic painless diarrhoea. Chronic diarrhoea was significantly associated with self‐reported food sensitivity (OR = 2.05 [1.31–3.20]) and stress (OR = 1.99 [1.03–3.85]). Both remained significant in the adjusted variable models that excluded subjects with any abdominal pain. Female gender (OR = 0.67 [0.45–0.98]) and higher education level (OR = 0.60 [0.39–0.92]) had smaller odds for chronic diarrhoea. No association was detected for age, marital status, body mass index, cigarette or alcohol use, coffee, analgesics, emotional support, pets or water source. Chronic diarrhoea in the absence of IBS is common; self‐reported food sensitivity, male gender and a lower level of education are risk factors.

Ulcerative colitis, infliximab, and hepatic epithelioid hemangioendothelioma: Who is to blame? Case report

Epithelioid hemangioendothelioma (EH) is a rare vascular neoplasm that was first described by Weiss and Enzinger [1982]. The natural history and clinical course of EH is largely unknown given its rarity, but its malignant potential is thought to range between that of a benign hemangioma to a malignant angiosarcoma [Woodall et al. 2008; Mehrabi et al. 2006; Uchimura et al. 2001]. Primary disease can involve soft tissue and visceral organs to include heart, spleen, lung, bone, and lymph nodes [Woodall et al. 2008; Mehrabi et al. 2006]. Primary malignant hepatic epithelioid hemangioendothelioma (HEH) is an exceptionally rare tumor with a reported incidence of less than 0.1 per 100,000, with less than 440 published reports in the literature [Mehrabi et al. 2006]. The exact etiopathogenesis of HEH is unknown but possible etiologic factors have been described to include oral contraceptives, vinyl chloride, asbestos, hepatic trauma, viral hepatitis, primary biliary cirrhosis, and alcohol consumption [Mehrabi et al. 2006].

The Natural History of Functional Gastrointestinal Disorders Over 20 Years: A Population Based Study

G A A b st ra ct s The 16519T SNP, but not 3010A, was associated with IBS, and was significantly increased in those with maternal inheritance (Table). IBS patients with PMI were significantly more likely to have the 16519T SNP than controls (66.7% vs 26.3%; OR=5.6 95%CI=1.6-19.2). Conclusions: A significant minority (1/6) of IBS patients have pedigrees that are highly suggestive of maternal inheritance. The mtDNA polymorphism 16519T, which has been previously implicated in other functional disorders, is also associated with IBS, especially in the sub-group displaying maternal inheritance. These findings suggest that mtDNA-related mitochondrial dysfunction constitutes a sub-group within the entity known as IBS. This may have consequences for treatment of these patients. Mitochondrial-targeted treatments like supplementation with co-enzyme Q10 seem to reduce symptoms in patients with other functional disorders such as migraines and cycl ic vomiting (PMID 15728298; PMID20109321) and should be tested in IBS patients withmaternal inheritance. [This study is funded by a grant from the International Foundation of Functional Gastrointestinal Disorders]