Alon D. Levin

Functional Defecation Disorders in Children: Comparing the Rome II with the Rome III Criteria

OBJECTIVES To evaluate the prevalence of pediatric functional defecation disorders (FDD) using the Rome III criteria and to compare these data with those obtained using Rome II criteria. STUDY DESIGN A chart review was performed in patients referred to a tertiary outpatient clinic with symptoms of constipation and/or fecal incontinence. All patients received a standardized bowel questionnaire and physical examination, including rectal examination. The prevalence of pediatric FDD according to both Rome criteria sets was assessed. RESULTS Patients with FDD (n = 336; 61% boys, mean age 6.3 ± 3.5 SD) were studied: 39% had a defecation frequency ≤ 2/wk, 75% had fecal incontinence, 75% displayed retentive posturing, 60% had pain during defecation, 49% passed large diameter stools, and 49% had a palpable rectal fecal mass. According to the Rome III criteria, 87% had functional constipation (FC) compared with only 34% fulfilling criteria for either FC or functional fecal retention based on the Rome II definitions (P < .001). Of the patients with a rectal fecal mass, 95% would also have been correctly identified as having FC without a rectal examination. Twenty-nine patients (11%) fulfilled the criteria for functional nonretentive fecal incontinence according to both the Rome II and Rome III criteria. CONCLUSION The pediatric Rome III criteria for FC are less restrictive than the Rome II criteria. The Rome III criteria are an important step forward in the definition and recognition of FDD in children.

Selective inhibition of mucosal serotonin as treatment for IBD

Serotonin (5-HT) has extensively been studied in the central and enteric nervous system. Altered levels of 5-HT play a role in many central nervous system (CNS) disorders and can be treated with specific 5-HT receptor agonists and antagonists. Interestingly, 95% of the bodies 5-HT is located outside central neuronal regions and in the intestine. The discovery of 5-HT secreting cells in the intestinal epithelium has resulted in a fruitful area of research that is focused on the function of intestinal epithelium-derived 5-HT.1 The subsequent discovery that 5-HT may play an important role in driving intestinal inflammation has generated interest in the potential of 5-HT antagonists for treatment of inflammatory bowel disease (IBD). However, side effects related to the important role of 5-HT in the enteric and central nervous system have precluded drug development in this field. In this issue of Gut , Margolis et al 2 use mouse models to demonstrate that it may be possible to selectively inhibit intestinal mucosal 5-HT signalling and suppress intestinal inflammation without such side effects. In the intestine, 5-HT is produced by a subset of enteroendrocrine cells called enterochromaffin (EC) …

Autophagy Contributes to the Induction of Anti-TNF Induced Macrophages

BACKGROUND AND AIMS Anti-tumour necrosis factor [TNF] antibodies induce regulatory macrophages which display a phenotype resembling M2 type macrophages. Anti-TNF induced macrophages [Mϕind] have immunosuppressive and wound healing properties. The factors that contribute to the induction of Mϕind remain to be explored. Autophagy has been described as a factor that is important for the induction and function of M2 type macrophages. We studied the contribution of autophagy to the induction of Mϕind. METHODS We studied the effect of autophagy on Mϕind in vitro using peripheral blood mononuclear cells. Interferon gamma [IFN-γ] induced macrophages [Mφ1] were generated by culturing monocytes in the presence of IFN-γ. Mϕind were generated by performing mixed lymphocyte reactions [MLR] in the presence of anti-TNF antibodies; 28 healthy donors were genotyped for rs_2241880 [ATG16L1]. Cells were analysed by autophagy gene array, immunofluorescence, western blot, flowcytometry, 3H-thymidine incorporation and MTS assay. RESULTS Mϕind had a different expression profile of autophagy related transcripts with increased expression of 33/40 altered genes compared with Mφ1. In addition, autophagic activity was increased in Mϕind compared with Mφ1. Induction of Mϕind was positively correlated to the number of wild-type alleles for the ATG16L1 T300A risk allele present in the culture. Finally, the autophagy-related protein cathepsin S was highly expressed in Mφind and inhibition resulted in decreased viability as well as decreased expression of CD206. CONCLUSIONS Mϕind have increased levels of autophagy compared with inflammatory Mφ1, and the induction of these macrophages is impaired in donors carrying the T300A risk allele for the ATG16L1. Given the association between Mϕind and clinical response, this suggests that an intact autophagy pathway may be important for an optimal response to anti-TNF therapy in inflammatory bowel disease.