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Key Clinical Message: Pericarditis is a known complication of mesalazine in the treatment of ulcerative colitis. This case study illustrates that after diagnostic work‐up, pericarditis should not always be attributed to the use of mesalazine. It may be the presentation of an extra‐intestinal manifestation of ulcerative colitis. Restarting of mesalazine should be considered. [ABSTRACT FROM AUTHOR]

Background: Nutrilon Omneo (new formula; NF) contains high concentration of sn-2 palmitic acid, a mixture of prebiotic oligosaccharides and partially hydrolyzed whey protein. It is hypothesized that NF positively affects stool characteristics in constipated infants. Methods: Thirty-eight constipated infants, aged 3-20 weeks, were included and randomized to NF (n = 20) or a standard formula (SF; n = 18) in period 1 and crossed-over after 3 weeks to treatment period 2. Constipation was defined by at least one of the following symptoms: 1) defecation frequency < 3/week; 2) painful defecation; 3) abdominal or rectal palpable mass. Results: Period 1 was completed by 35 infants. A significant increase in defecation frequency (NF: 3.5 pre versus 5.6/week post treatment; SF 3.6 pre versus 4.9/week post treatment) was found in both groups, but was not significantly different between the two formulas (p = 0.36). Improvement of hard stool consistency to soft stool consistency was found more often with NF than SF, but did not reach statistical significance (90% versus 50%; RR, 1.8; 95% CI, 0.9-3.5; p = 0.14). No difference was found in painful defecation or the presence of an abdominal or rectal mass between the two groups. Twenty-four infants completed period 2. Only stool consistency was significantly different between the two formulas (17% had soft stools on NF and hard stools on SF; no infants had soft stools on SF and hard stools on NF, McNemar test p = 0.046). Conclusion: The addition of a high concentration sn-2 palmitic acid, prebiotic oligosaccharides and partially hydrolyzed whey protein resulted in a strong tendency of softer stools in constipated infants, but not in a difference in defecation frequency. Formula transition to NF may be considered as treatment in constipated infants with hard stools. [ABSTRACT FROM AUTHOR]

Stunted children with cystic fibrosis (CF) have less net protein anabolism than do children without CF, and the result is retarded growth in the CF patients. It is not known whether protein intake above that recommended by the Cystic Fibrosis Foundation would further stimulate whole-body protein synthesis. Objective: We studied the effects of 3 amounts of protein intake on whole-body protein synthesis and breakdown by using isotopic infusion of [1-13C]valine and [15N2]urea in children with stable CF who required tube feeding. Design: In 8 pediatric CF patients, we administered 3 randomly allocated isocaloric diets with normal (NP), intermediate (IP), and high (HP) amounts of protein (1.5, 3, and 5 g · kg-1 · d-1, respectively) by continuous drip feeding during a 4-d period at 6-wk intervals. Each patient acted as his or her own control. On the fourth day of feeding, whole-body protein synthesis and breakdown were measured. Results: Protein synthesis was significantly higher in the HP group (x ± SEM: 1.78 ± 0.07 μmol · kg-1 · min-1) than in the IP (1.57 ± 0.08 μmol · kg -1 · min-1; P < 0.001) and NP (1.37 ± 0.07 ±mol ± kg-1 · min -1; P< 0.001) groups. There were no significant differences in protein breakdown. Net retention of nitrogen was significantly higher in the HP group (12.93 ± 1.42 μmol · kg-1 · min-1) than in the IP (7.61 < 1.40 μmol · kg-1 min-1; P=0.01) and HP (2.48 - 0.20 μmol · kg-1 · min-1; P = 0.001) groups. Conclusion: In stunted children with CF requiring tube feeding, the highest stimulation of whole-body protein synthesis was achieved with a short-term dietary protein intake of 5 g · kg-1 · d-1. [ABSTRACT FROM AUTHOR]

Background and aims. To gain insight in intestinal epithelial proliferation, cell death, and gene expression during experimental colitis rats were treated with dextran sulfate sodium (DSS) for 7 days. Materials and methods. Proximal and distal colonic segments were excised on days 2, 5, 7, and 28. Epithelial proliferation, cell death, enterocyte gene expression (carbonic anhydrase I (CA I) and goblet cell gene expression (mucin, MUC2; trefoil factor 3, TFF3) were studied immunohistochemically and biochemically. Results. Proliferative activity was decreased in the proximal and distal colon at the onset of disease (day 2). However, during active disease (days 5–7) epithelial proliferation was increased in the entire proximal colon and in the proximity of ulcerations in the distal colon. During DSS treatment the number of apoptotic cells in the epithelium of both colonic segments was increased. In the entire colon surface enterocytes became flattened and CA I negative during active disease (day 5–7). Additionally, CA I levels in the distal colon significantly decreased during this phase. In contrast, during the regenerative phase (day 28) CA I levels were restored in the distal colon and up-regulated in the proximal colon. During all disease phases increased numbers of goblet cells were observed in the surface epithelium of the entire colon. In the distal colon TFF3 expression extended to the bottom of the crypts during active disease. Finally, MUC2 and TFF3 expression was increased in the proximal colon during disease. Conclusion. DSS affected the epithelium by inhibiting proliferation and inducing apoptosis. DSS-induced inhibition of CA I expression indicates down-regulation of specific enterocyte functions. Accumulation of goblet cells in the surface epithelium and up-regulation of MUC2 and TFF3 expression in the proximal colon underline the importance of goblet cells in epithelial protection and repair, respectively. [ABSTRACT FROM AUTHOR]

With the development of new drugs that directly affect CFTR protein function, clinical trials are being designed or initiated for a growing number of patients with cystic fibrosis. The currently available and accepted clinical endpoints, FEV1 and BMI, have limitations. The aim of this report is to draw attention to the need and the ample possibilities for the development and validation of relevant gastrointestinal clinical endpoints for scientific evaluation of CFTR modulation treatment, particularly in young children and infants. The gastrointestinal tract offers very good opportunities to measure CFTR protein function and systematically evaluate CF related clinical outcomes based on the principal clinical gastrointestinal manifestations of CF: intestinal pH, intestinal transit time, intestinal bile salt malabsorption, intestinal inflammation, exocrine pancreatic function and intestinal fat malabsorption. We present a descriptive analysis of a variety of gastrointestinal outcome measures for clinical relevance, reliability, validity, responsiveness to interventions, feasibility in particular in young children and the availability of reference values., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Childhood cancer survivors (CCS) are a growing group of young individuals with a high risk of morbidity and mortality. We evaluated the prevalence and risk factors of hepatic late adverse effects, defined as elevated liver enzymes, in a large cohort of CCS., Methods: The cohort consisted of all five-year CCS treated in the EKZ/AMC between 1966 and 2003, without hepatitis virus infection and history of veno-occlusive disease (VOD). Liver enzyme tests included serum levels of alanine aminotransferase (ALT) for hepatocellular injury and gamma-glutamyltransferase (γGT) for biliary tract injury. We performed multivariable linear and logistic regression analyses., Results: The study population consisted of 1404 of 1795 eligible CCS, of whom 1362 performed liver enzyme tests at a median follow-up of 12 years after diagnosis. In total, 118 (8.7%) of 1362 CCS had hepatic late adverse effects defined as ALT or γGT above the upper limit of normal. Abnormal ALT and γGT levels were found in 5.8% and 5.3%, respectively. In multivariable regression analyses treatment with radiotherapy involving the liver, higher body mass index, higher alcohol intake and longer follow-up time were significantly associated with elevated ALT and γGT levels; older age at diagnosis was only significantly associated with elevated γGT levels (all p<0.05)., Conclusion: One in twelve CCS showed signs of hepatic late adverse effects after a median follow-up of 12 years. Several risk factors have been identified. Future studies should focus on the course of long-term liver related outcomes and on the influence of radiotherapy and chemotherapy dose., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: In this retrospective study, 28 years of surgical treatment of children and young adults with familial adenomatous polyposis (FAP) was analyzed., Methods: Forty-three patients were operated on before the age of 26 years. Endoscopic aspects, operative data, and complications were analyzed, and the resection specimens were reevaluated. Functional outcome was assessed by telephone questionnaire., Results: Primary ileorectal anastomosis (IRA) was performed in 34 patients with a mean age of 16 years (range, 7-25 years). Primary ileal-pouch anal anastomosis (IPAA) was performed in 9 patients at a mean age of 19 years (range, 15-24 years). Secondary excision of the rectum was performed in 7 patients. Overall, rectal carcinoma was present in 4 patients, at the age of 35, 36, 37, and 38 years. Two patients, aged 39 and 40 years, died because of invasive carcinoma with distant metastasis. The functional outcome and postoperative complications after both procedures were similar to those described in literature for children with FAP. Most patients did not experience alterations in lifestyle, and there was no urinary incontinence., Conclusions: In this retrospective study, both IRA and IPAA showed to be feasible techniques in young patients with FAP. A prospective study with a sufficient follow-up is needed to compare both techniques in this specific group of patients.

Background: Vincristine (VCR) and actinomycin D (ACD) form the backbone of chemotherapeutic regimens of Wilms tumor treatment. Veno-occlusive disease (VOD) is a potentially life-threatening complication of ACD., Objectives: To investigate the incidence of VOD after preoperative chemotherapy and assess the effect of dose and frequency of administrating ACD on the occurrence of VOD., Methods: A single-center retrospective study of patients where liver biopsies were performed after 4 or 8 weeks of preoperative chemotherapy. Patients had localized or metastatic Wilms tumor and were treated according to SIOP 9, 93-1, or 2001 protocol. A correlation was analyzed between histologically confirmed VOD, laboratory parameters, and mode and frequency of ACD administration. Long-term hepatic toxicity was assessed 5 years after the end of therapy., Results: Ninety-one patients were included in this analysis. Forty-one patients (45.1%) had histological evidence of VOD. The incidence of histologically proven VOD was significantly correlated with single administration of 45 microg/kg ACD (SIOP 2001 protocol) as compared to repeated dosing of l5 microg/kg (P = 0.003). Fifty-two percent of all patients had mild-to-severe abnormal liver enzymes 5 years after accomplishing therapy., Conclusion: Despite short-course preoperative chemotherapy regimen, patients are at risk of developing histological VOD. This risk is higher when ACD is administered in a 1-day 45 microg/kg regimen as compared to 3 days l5 microg/kg.

Background: Genetic susceptibility may play a more important role in the etiology of early-onset inflammatory bowel disease (IBD) than in late-onset IBD, and therefore pediatric-onset IBD patients can be expected to have a higher frequency of gene mutations. We aimed to determine genotypes and phenotypes of patients with pediatric-onset IBD, to compare them with those of patients with adult-onset IBD and with controls, and to identify genotype-phenotype associations., Methods: Polymorphisms R702W, G908R, and 3020insC of CARD15 (caspase activating recruitment domain 15); Asp299Gly and Thr399Ile of TLR4; -207G-->C, 1672C-->T (L503F), rs3792876, rs274551, rs272893, and rs273900 of SLC22A4/5; and 113G-->A as well as rs2289311, rs1270912, and rs2165047 of DLG5 (Drosophila discs large homologue 5) were assessed in 103 pediatric-onset and 696 adult-onset IBD patients. Phenotypic classification was based on disease localization and behavior., Results: Homozygosity for 3020insC in CARD15 was significantly higher in patients with pediatric-onset Crohn's disease (CD) than in patients with adult-onset CD (4.2% versus 0.6%, 95% confidence interval [CI] 1.2-42.0). Homozygosity for single-nucleotide polymorphism (SNP) rs3792876 in SLC22A4/5 was significantly higher in patients with pediatric-onset CD than in patients with adult-onset CD (6.1% versus 1.1%, P=0.02). Polymorphism 3020insC in CARD15 was associated with ileal involvement (1.9% versus 13.3%, CI 1.0-53.8) and a positive family history (6.1% versus 20%, CI 1.2-9.0). DLG5 SNP rs2165047 was significantly associated with perianal disease (50% versus 21.2%, CI 1.4-4)., Conclusions: Polymorphisms 3020insC in CARD15 and SNP rs3792876 in SLC22A4/5 occurred statistically significantly more often in patients with pediatric-onset CD than in patients with adult-onset CD. Polymorphisms 3020insC in CARD15 and SNP rs2165047 in DLG5 were associated with specific phenotypes in this pediatric-onset CD cohort.

Infliximab is a chimeric monoclonal antibody (75% human, 25% murine) against tumor necrosis factor-alpha, a cytokine with a central role in the pathogenesis of inflammatory bowel disease. Large randomized controlled trials have shown the efficacy and safety of infliximab for the induction and maintenance of remission in adult patients with active Crohn disease (CD). In children and adolescents, mostly small, nonrandomized, non-placebo-controlled studies have supported the notion that infliximab is a potent drug in a population that does not respond to standard therapies. The safety of infliximab is of major concern, and the most frequent severe adverse events are related to severe infections and reactivation of tuberculosis. Non-life-threatening infusion reactions occur rather frequently and seem to be related to the formation of antibodies. The indications for infliximab treatment are therapy-resistant luminal CD (no efficacy or insufficient efficacy of conventional treatment) and therapy-resistant fistulas. An efficient remission induction strategy consists of 3 initial infliximab infusions at 0, 2, and 6 weeks in a dosage of 5 mg/kg to sustain remission. Patients needing maintenance therapy are subsequently treated with an infliximab infusion every 8 weeks. There are indications that the early stages of CD may be more susceptible to immunomodulation, and the natural history of CD may be altered by the introduction of infliximab early in the disease process instead of waiting until conventional therapy has failed. Major points of discussion are whether infliximab maintenance treatment should be episodic (on demand) or scheduled and when infliximab therapy can be discontinued.

Objectives: Rectal bleeding is an alarming event both for the child and parents. It is hypothesized that colonoscopy instead of sigmoidoscopy and adding esophago-gastro-duodenoscopy in case of accompanying complaints, improves the diagnostic accuracy in children with prolonged rectal bleeding., Study Design: All pediatric patients undergoing colonoscopy because of prolonged rectal bleeding over an 8-year period at the Emma Children's Hospital/Academic Medical Centre were reviewed. Patient demographics, clinical features, number and extent of endoscopic examinations and the endoscopic and histopathological findings were assessed., Results: A total of 147 colonoscopies were performed in 137 pediatric patients (63 boys) because of prolonged rectal bleeding. Inflammatory bowel disease and polyp(s) were the most prevalent diagnoses. In 72% of patients diagnosed as Crohn's disease, focal, chronically active gastritis was seen on histology, giving support to the diagnosis Crohn's disease. In 22% of the cases polyps would have been missed in the case where only sigmoidoscopy was performed. No complications after endoscopic intervention were seen., Conclusions: Colonoscopy is the investigation of choice in children with prolonged rectal bleeding. In patients presenting with accompanying complaints such as abdominal pain or diarrhea, it is advisable to perform ileocolonoscopy combined with esophago-gastro-duodenoscopy. This combines a high diagnostic yield with a safe procedure.

6-Mercaptopurine (6-MP) maintains remission in pediatric Crohn's disease (CD). Azathioprine, a prodrug of 6-MP, is used for maintenance of remission of CD in Europe. We evaluated to what extent azathioprine is used in newly diagnosed pediatric CD patients and whether maintenance of remission differed between patients using azathioprine or not. Charts of children (diagnosed 1998-2003, follow-up > or = 18 mo) were reviewed. Active disease was defined as Pediatric Crohn's Disease Activity Index (PCDAI) greater than 10 or systemic corticosteroid use. Remission was defined as PCDAI 10 or less without use of corticosteroids. Eighty-eight children (55M/33F, age 12 +/- 3 yr) were included. Seventy-two (82%) patients received azathioprine during the follow-up period (38 +/- 17 mo). Patients diagnosed after 2000 received azathioprine significantly earlier during the course of disease compared with those diagnosed earlier (median, at 233 vs. 686 days; P < 0.05). At initial presentation, moderate-severe disease activity and prescription of corticosteroids were more prevalent in patients using azathioprine compared with nonazathioprine patients (75% vs. 52%; P < 0.05; and 89% vs. 58%; P < 0.005, respectively). Duration of corticosteroid use was longer in patients receiving azathioprine (232 vs. 168 days; P < 0.005). Median maintenance of first remission in patients who initially used corticosteroids, however, was longer in patients receiving azathioprine compared with nonazathioprine patients (PCDAI, 544 vs. 254 days, P = 0.08; corticosteroid free, 575 vs. 259 days, P < 0.05, respectively). We conclude that, since 2000, azathioprine is being introduced earlier in the treatment of newly diagnosed pediatric CD patients. The use of azathioprine is associated with prolonged maintenance of the first remission.

Objective: To evaluate rectal sensitivity in patients with pediatric constipation (PC) and nonretentive fecal soiling (FNRFS) using pressure-controlled distention (barostat)., Study Design: Thresholds for rectal sensitivity (first sensation, urge to defecate, and pain), and rectal compliance were determined using a barostat., Results: A total of 69 patients with PC (50 males; mean age, 10.9 +/- 2.2 years) and 19 patients with FNRFS (15 males; mean age, 10.0 +/- 1.9 years) were compared with 22 healthy volunteers (HVs) (11 males; mean age, 12.7 +/- 2.6 years). Sensitivity thresholds were not significantly different among the 3 groups. Rectal compliance was increased in 58% of the patients with PC (P < .0001 vs HVs). Rectal compliance did not differ between patients with FNRFS and HVs. Children with PC with abnormal rectal function required significantly larger rectal volumes at urge to defecate., Conclusions: Increased compliance is the most prominent feature in patients with PC. Because of higher compliance in these children, larger stool volumes are required to reach the intrarectal pressure of the urge to defecate. Children with FNRFS have normal rectal function.

Background & Aims: Functional nonretentive fecal incontinence (FNRFI), incontinence in the absence of signs of fecal retention, is a frustrating phenomenon in children. No data on long-term outcome are available. The aim was to investigate the long-term outcome of FNRFI patients after intensive medical treatment., Methods: Between 1990 and 1999, 119 patients (96 boys) with FNRFI were enrolled in 2 prospective, randomized trials investigating the effect of biofeedback training and/or laxative treatment. Follow-up (FU) was performed at 6 months, 1 year, and thereafter annually until September 2004. A standardized questionnaire was used to evaluate symptoms. Success was defined as a fecal incontinence frequency <1 per 2 weeks., Results: Median age (25th-75th percentiles) was 9.2 years (range, 7.9-11.6 years). A 90% FU was achieved at all stages of the study. After 2 years of intensive therapy, 33 of 112 (29.5%) patients were successfully treated. The cumulative success percentage after 7 years of FU was 80%. At the biologic ages of 12 and 18 years, 49.4% (40/81) and 15.5% (9/58), respectively, of the patients still had fecal incontinence. Duration of fecal incontinence, with 4 years of age as the starting age for fecal incontinence (when a child should be toilet trained), was not related to successful outcome or relapse. Relapse occurred in 37% of patients., Conclusions: Only 29% of the patients with FNRFI were successfully treated after 2 years of intensive treatment. Despite recovery in the majority of patients beyond puberty, at age 18 years, 15% continued to have fecal incontinence.

Background: Gastroesophageal reflux is a frequent problem after esophageal atresia (EA) repair. Our aim was to determine the prevalence of esophagitis and Barrett esophagus more than 10 years after repair of EA., Methods: Ninety-two patients treated between 1973 and 1985 were included in this prospective study. A questionnaire was completed by 86 patients; esophagogastroscopy was performed in 49 patients., Results: Only 36 patients had no complaints at all. Thirty-one patients complained of difficulties swallowing solid food; 23 complained of heartburn. Esophagogastroscopy revealed grade 3 esophagitis in 2 patients and a macroscopic image of Barrett esophagus in 2. Histology showed esophagitis in 30 patients, gastric metaplasia in 3, and no intestinal metaplasia (Barrett esophagus)., Conclusions: For epidemiologic reasons, that is, the short interval of follow-up (10 years) and the low compliance of the study group, larger numbers are needed to decide if routine long-term endoscopic screening after repair of EA is necessary. For now, it cannot yet be recommended. The prevalence of symptoms of gastroesophageal reflux disease in this study group is higher than that in the general population, but we found no severe complications of gastroesophageal reflux in the pediatric age group.

Objective: To compare the diagnostic accuracy of contrast enema (CE), anorectal manometry (ARM), and rectal suction biopsy (RSB) for the detection of Hirschsprung's disease (HD)., Study Design: Following a prospective protocol, infants suspected of HD underwent all 3 index tests. Children with positive results on 2 or more index tests or who continued to have severe bowel problems underwent a full thickness biopsy as reference standard. Clinical follow-up was the reference standard in all other children., Results: Between 2000 and 2003, 111 consecutive patients (67 boys; median age, 5.3 months) in whom HD was suspected were enrolled. HD was found in 28 patients. RSB had the highest sensitivity (93%) and specificity (100%) rates, but values were not significantly different from CE (sensitivity, 76%; specificity, 97%) or from ARM (sensitivity, 83%; specificity, 93%). Inconclusive test results occurred in 8 infants with CE, in 15 infants with ARM because of agitation, and in 2 infants with RSB., Conclusion: RSB is the most accurate test for diagnosing HD, and it has the lowest rate of inconclusive test results.

Objective: The purpose of this study was to describe the clinical experience with the anti-tumor necrosis factor chimeric monoclonal antibody, infliximab, in pediatric patients with Crohn disease in The Netherlands., Design: Descriptive., Methods: Clinical response and adverse effects of infliximab were recorded for pediatric patients with Crohn disease treated from October 1992 to January 2003., Results: Thirty patients (aged 7-18 years) with refractory Crohn disease (with or without severe fistulas) were treated with infliximab. Patients were treated with up to 30 infusions. Mean follow-up was 25.3 months. A total of 212 infusions were administered. Thirteen patients had refractory Crohn disease without fistulas. Six patients showed good long-term response to infliximab treatment (defined as clinical index < or =10 points). Sixteen patients had refractory Crohn disease with draining fistulas. Nine showed good long-term response (closure or nonproductiveness of fistulas). One patient with metastatic Crohn disease in the skin had a good long-term response. Six patients developed an allergic reaction during infusion. In one patient, the allergic reaction occurred after an infliximab-free interval of 9 years. One patient died of sepsis., Conclusions: Infliximab was an effective therapy in 53% of patients with refractory pediatric Crohn disease, with or without fistulas. Approximately half of the patients become unresponsive to infliximab therapy. Randomized controlled studies are mandatory to assess long-term efficacy and safety to define the optimal therapeutic strategy of infliximab therapy in children with Crohn disease.

Background & Aims: Sparse data exist about the prognosis of childhood constipation and its possible persistence into adulthood., Methods: A total of 418 constipated patients older than 5 years at intake (279 boys; median age, 8.0 yr) participated in studies evaluating therapeutic modalities for constipation. All children subsequently were enrolled in this follow-up study with prospective data collection after an initial 6-week intensive treatment protocol, at 6 months, and thereafter annually, using a standardized questionnaire., Results: Follow-up was obtained in more than 95% of the children. The median duration of the follow-up period was 5 years (range, 1-8 yr). The cumulative percentage of children who were treated successfully during follow-up was 60% at 1 year, increasing to 80% at 8 years. Successful treatment was more frequent in children without encopresis and in children with an age of onset of defecation difficulty older than 4 years. In the group of children treated successfully, 50% experienced at least one period of relapse. Relapses occurred more frequently in boys than in girls (relative risk 1.73; 95% confidence interval, 1.15-2.62). In the subset of children aged 16 years and older, constipation still was present in 30%., Conclusions: After intensive initial medical and behavioral treatment, 60% of all children referred to a tertiary medical center for chronic constipation were treated successfully at 1 year of follow-up. One third of the children followed-up beyond puberty continued to have severe complaints of constipation. This finding contradicts the general belief that childhood constipation gradually disappears before or during puberty.