Herbert M. van Wering

Novel interaction at the Cdx-2 binding sites of the lactase-phlorizin hydrolase promoter

Cdx-2 is an intestine-specific homeodomain-containing transcription factor that activates the promoters of intestinal genes through specific interactions with the consensus, TTTAT/C. Here, we demonstrate that Cdx-2 interacts with the lactase-phlorizin hydrolase (LPH) promoter at cis-element (CE)-LPH1a (-54 to -40 bp) as well as the LPH TATA-box. Affinity comparisons between SIF-1, CE-LPH1a, and the LPH TATA-box revealed that the TATA-box has the lowest affinity for Cdx-2. Characterization of CE-LPH1a using EMSAs revealed binding of a novel, non-Cdx-2 complex in multiple cell lines that bind to sequence that is different from that of the Cdx-2 binding site. Heterologous promoter analysis in transient transfection assays revealed a repressor function for this protein, and thus, it was designated as nuclear factor-LPH1/repressor (NF-LPH1/R). These data are consistent with the hypothesis that NF-LPH1/R represses LPH gene expression in non-Cdx-2-producing cells, and that this repression is released in cells that synthesize Cdx-2, such as those in the intestinal epithelium.

Adalimumab therapy in children with Crohn disease previously treated with infliximab

Objectives: Adalimumab, a humanised anti-tumour necrosis factor antibody, is an effective treatment in adult patients with refractory Crohn disease (CD). The available literature on its efficacy in children remains limited. We aimed to evaluate the real-world efficacy in paediatric patients with CD and compare the efficacy between infliximab (IFX) nonresponders and patients who lost response to IFX. Methods: All Dutch patients with CD receiving adalimumab before the age of 18 years after previous IFX therapy were identified. We analysed longitudinal disease activity, assessed by the mathematically weighted Pediatric Crohns Disease Activity Index (wPCDAI) or the physician global assessment (PGA), and adverse events (AEs). Results: Fifty-three patients with CD were included. Twelve patients received monotherapy and the others received combination treatment with thiopurines (n = 21), methotrexate (n = 11), steroids (n = 7), or exclusive enteral nutrition (n = 2). Median follow-up was 12 months (interquartile range 5–23). Remission was reached in 34 patients (64%, wPCDAI < 12.5 or PGA = 0) after a median of 3.3 months, and maintained by 50% for 2 years. Eleven patients (21%) reached response but not remission (decrease in wPCDAI ≥ 17.5 or decrease in PGA). Eighteen patients (34%) failed adalimumab treatment because of nonresponse (n = 4), lost response (n = 11), or AEs (n = 3). More IFX nonresponders failed adalimumab treatment than patients who lost response to IFX (2/3 vs 8/34, hazard ratio 18.8, 95% confidence interval 1.1–303.6). Only 1 patient encountered a serious AE, a severe but nonfatal infection. Conclusions: In clinical practice, adalimumab induces remission in two-thirds of children with IFX refractory CD.

Home-Based Hypnotherapy Self-exercises vs Individual Hypnotherapy With a Therapist for Treatment of Pediatric Irritable Bowel Syndrome, Functional Abdominal Pain, or Functional Abdominal Pain Syndrome: A Randomized Clinical Trial

Importance Individual gut-directed hypnotherapy (HT) is effective in pediatric irritable bowel syndrome (IBS) and functional abdominal pain or functional abdominal pain syndrome (FAP[S]). It is, however, unavailable to many children. Objective To compare the effectiveness of HT by means of home-based self-exercises using a CD with that of individual HT (iHT) performed by qualified therapists. Design, Setting, and Participants This noninferiority randomized clinical trial with a follow-up of 1 year after the end of treatment was conducted from July 15, 2011, through June 24, 2013, at 9 secondary and tertiary care centers throughout the Netherlands. A total of 303 children were eligible to participate. Of those, 260 children (aged 8-18 years) with IBS or FAP(S) were included in this study. Children were randomized (1:1 ratio) to home-based HT with a CD (CD group) or iHT performed by qualified therapists (iHT group). No children withdrew from the study because of adverse effects. Interventions The CD group was instructed to perform exercises 5 times per week or more for 3 months. The iHT group consisted of 6 sessions during 3 months. Main Outcomes and Measures Primary outcomes were treatment success directly after treatment and after 1-year follow-up. Treatment success was defined as a 50% or greater reduction in pain frequency and intensity scores. The noninferiority limit was set at 50% treatment success in the CD group, with a maximum of 25% difference in treatment success with the iHT group after 1-year follow-up. Modified intention-to-treat analyses were performed. Results A total of 132 children were assigned to the CD group and 128 to the iHT group; 250 children were analyzed (126 in the CD group and 124 in the iHT group) (mean [SD] age, 13.4 [2.9] years in the CD group and 13.3 [2.8] years in the iHT group; 94 female [74.6%] in the CD group and 85 [68.5%] in the iHT group). Directly after treatment, 46 children (36.8%) in the CD group and 62 (50.1%) in the iHT group were successfully treated. After 1-year follow-up, the 62.1% treatment success in the CD group was noninferior to the 71.0% in the iHT group (difference, −8.9%; 90% CI, −18.9% to 0.7%; P = .002). Conclusions and Relevance Long-term effectiveness of home-based HT with a CD is noninferior to iHT performed by therapists in pediatric IBS or FAP(S). Treatment with hypnosis using a CD provides an attractive treatment option for these children. Trial Registration trialregister.nl Identifier: NTR2725

Glucose hydrogen breath test for small intestinal bacterial overgrowth in children with abdominal pain-related functional gastrointestinal disorders.

Objectives: A potential link between small intestinal bacterial overgrowth (SIBO) and abdominal pain–related functional gastrointestinal disorders (AP-FGID) has been suggested by symptom similarities and by the reported prevalence of SIBO in children with irritable bowel syndrome (IBS) and functional AP. The aim of this study is to evaluate the prevalence of SIBO using the glucose hydrogen breath test (GHBT), in a cohort of Dutch children with AP-FGID fulfilling the Rome III criteria, and to identify potential predictors. Methods: Children ages 6 to 18 years with AP-FGID fulfilling the Rome III criteria were included. All of the children underwent a GHBT. SIBO was diagnosed if the fasting breath hydrogen concentration was ≥20 ppm or an increase in H2 levels of ≥12 ppm above the baseline value was measured after ingestion of glucose. Gastrointestinal symptoms were collected using a standardised AP questionnaire. Results: A total of 161 Dutch children with AP-FGID were enrolled. Twenty-three patients (14.3%) were diagnosed as having SIBO, as assessed by GHBT; 78% of the children diagnosed as having SIBO had fasting hydrogen levels ≥20 ppm. IBS was significantly more found in children with SIBO compared with children without SIBO (P = 0.001). An altered defecation pattern (ie, change in frequency or form of stool) (P = 0.013), loss of appetite (P = 0.007), and belching (P = 0.023) were significantly more found in children with SIBO compared with those without SIBO. Conclusions: SIBO is present in 14.3% of children presenting with AP-FGID. IBS, altered defecation pattern, loss of appetite, and belching were predictors for SIBO in children with AP-FGID.

Are constipation drugs effective and safe to be used in children?: a review of the literature

Introduction: Functional constipation is a common and often enduring problem in childhood. Although functional constipation is well defined by the Rome III criteria, these criteria have not always been integrated in general practice. Early diagnosis and treatment are key factors with respect to successful long-term outcome, as chronic constipation has a negative effect on the quality of life and is a burden for the public healthcare system. The safety of laxatives used for paediatric-functional constipation is based on well-designed trials carried out mostly in adults. Therefore, we conducted a review of the literature outlining the evidence for the efficacy and safety of laxatives used in chronic paediatric-functional constipation. Areas covered: This review clearly shows a lack of large well-designed placebo-controlled trials in children with constipation. Therefore, any interpretation with regards to the evidence for the effectiveness or safety of laxatives used in children is difficult and we extended the search for side effects to the adult literature. Expert opinion: In adults, new promising drugs are on the virtue of breaking through in the treatment of chronic constipation. Carrying out well-defined placebo-controlled trials in children should be the next step before using these drugs.

Complications and Disease Recurrence After Primary Ileocecal Resection in Pediatric Crohn's Disease: A Multicenter Cohort Analysis

Background: Studies on the outcome of ileocecal resection in pediatric Crohns disease (CD) have a limited follow-up and fail to assign predictors of adverse outcomes. Therefore, we aimed to investigate (I) the complication and disease recurrence rates and (II) identify risk factors for these adverse outcomes after ileocecal resection for pediatric CD. Methods: This is a retrospective cohort analysis of all children (<18 years) that underwent ileocecal resection as first intestinal resection for CD derived from 7 tertiary hospitals in the Netherlands (1990–2015). Risk factors were identified using multivariable analysis. Results: In total, 122 children were included (52% male; median age 15.5 years [interquartile range 14.0–16.0]). Severe postoperative complications rate was 10%. Colonic disease (odds ratio: 5.6 [95% confidence interval {CI}: 1.3–26.3], P = 0.024), microscopically positive resection margins (odds ratio: 10.4 [95% CI: 1.1–100.8] P = 0.043), and emergency surgery (odds ratio: 6.8 [95% CI: 1.1–42.2], P = 0.038) were risk factors for severe complications. Clinical and surgical recurrence rates after 1, 5 and 10 years were 19%, 49%, 71% and 2%, 12%, 22%, respectively. Female sex (hazard ratio [HR]: 2.1 [95% CI: 1.1–3.8], P = 0.023) was a risk factor for clinical recurrence, whereas ileocecal disease (HR: 3.9 [95% CI: 1.2–12.5], P = 0.024) and microscopically positive resection margins (HR: 9.6 [95% CI: 1.2–74.5], P = 0.031) were risk factors for surgical recurrence. Immediate postoperative therapy reduced the risk of both clinical (HR: 0.3 [95% CI: 0.1–0.6], P = 0.001) and surgical (HR: 0.5 [95% CI: 0.1–0.9], P = 0.035) recurrence. Conclusions: Ileocecal resection is an effective and durable treatment of pediatric CD, although postoperative complications occur frequently. Postoperative therapy may be started immediately to prevent disease recurrence.

Histamine-2 Receptor Antagonist in the Treatment of Gastroesophageal Reflux Disease

In the stomach, gastric acid is secreted by the parietal cell. Several factors such as the presence of food, the smell, and/or taste of food and stress have influence on gastric acid secretion. Gastrin, histamine, acetylcholine, and prostaglandin regulate gastric acid secretion through the gastrin, the histamine, the muscarine, and the prostaglandin receptors, respectively (Fig. 88.1). In contrast, the prostaglandin receptor downregulates the gastric acid secretion and protects against the erosive irritation of gastric acid. The presence of food raises the pH in the stomach, which stimulates gastrin cells in the antrum of the stomach to produce gastrin. Subsequently, gastrin is then excreted into the bloodstream and stimulates the receptors at the parietal cell (the direct pathway) as well as the receptors at the adjacent endocrine cell (the histamine pathway). Acetylcholine (neurotransmitter) has a similar working mechanism and demonstrates the neural influence on gastric acid secretion. Histamine is produced by the endocrine cells and stimulates the histamine-2 receptor at the adjacent parietal cells. This stimulation results in an increase of intracellular cAMP, which in turn activates the H+/K+-ATPase. Also at the parietal cell, the acetylcholine binds and activates the acetylcholine receptor, which results in the opening of calcium channels. This leads to a calcium influx. In addition, gastrin binds and activates the gastrin receptors, which results in the mobilization of the intracellular calcium pool. These two additional mechanisms help the cAMP to activate the H+/K+-ATPase. This process will actively shift H+-ions into the lumen of the stomach in exchange to K+-ions (Fig. 88.1). The histamine, gastrin, acetylcholine, and prostaglandin receptors together form a mechanism to balance the gastric acid production for the digestion of food and the downregulation for the protection of the esophagus, stomach, and duodenum.