Escher, J.C.

Self-efficacy in adolescents with inflammatory bowel disease: A pilot study of the "IBD-yourself", a disease-specific questionnaire (Article)

2013-03-26T00:00:00Z

Background and aims: Successful transfer of adolescent IBD patients to an adult gastroenterologist requires anticipation of a changing role for patients and their parents. Self-efficacy has been demonstrated to be important for transfer readiness. We therefore developed an IBD-specific questionnaire (the "IBD-yourself") to assess self-efficacy in adolescent IBD patients visiting a transition clinic. Our aim was to evaluate the reliability of this questionnaire, and to describe the self-efficacy level of adolescent IBD patients, and the perceived self-efficacy level according to their parents. Methods: In a cross-sectional design, 50 IBD patients (aged 14-18 years) and 40 parents completed the "IBD-yourself" questionnaire. Internal reliability was assessed by standardised Cronbach's α. Median self-efficacy scores per domain were calculated. Results: The domains of the questionnaire for adolescents showed good to excellent internal consistency, with Cronbach's α ranging from 0.64 to 0.93. The domains of the parental questionnaire had Cronbach's α ranging from 0.47 to 0.93. Median self-efficacy scores of adolescents varied from 70 to 100%. In comparison with patient's self-assessment, parents thought that their child was more self-efficacious in knowledge of IBD and diagnostic tests, self-management of medication use, and transfer readiness. Length of time since first visit to the transition clinic was positively correlated with several domains of the questionnaire, such as independent behaviour at the outpatient clinic, and transfer readiness. Conclusion: The "IBD-yourself" questionnaire is a first step toward evaluating quality and efficacy of IBD transition programmes. Paediatric gastroenterologists should be aware that parents do not always accurately assess the self-efficacy of their child.

Long-term impact of infantile short bowel syndrome on nutritional status and growth. (Article)

2012-05-01T00:00:00Z

Short-term bowel adaptation has been documented, but data on long-term effects are scarce. The aim of the present study was to evaluate the long-term consequences of infantile short bowel syndrome (SBS). A cross-sectional assessment (2005-7) of growth, nutritional status, defecation pattern and health status in individuals with a history of infantile SBS, born between 1975 and 2002, were performed. Data were compared with reference values of healthy controls and presented as means and standard deviations or median and ranges. A total of forty subjects (sixteen male and twenty-four female; mean age 14·8 (SD 6·8) years) had received parenteral nutrition during a median of 110 (range 43-2345) d, following small bowel resection. The mean standard deviation scores (SDS) for weight for height and target height (TH) of the children were normal; mean SDS for height for age was - 0·9 (SD 1·3). The median BMI adults was 19·9 (range 17-26) kg/m2; mean SDS for height for age was - 1·0 (range - 2·5 to 1·5). Height in general was significantly shorter than TH, and 53 % of children and 78 % of adults were below TH range. Most subjects had normal body fat percentage (%BF). SDS for total body bone mineral density were generally normal. The SDS for bone mineral content (BMC) of the children were - 1·0 (SD 1·1). Mean energy intake was 91 % of the estimated average requirements. The frequencies of defecation and bowel complaints of the subjects were significantly higher than in healthy controls. In conclusion, infantile SBS results in shorter stature than was expected from their calculated TH. BMC was lower than reference values, but the subjects had normal weight for height and %BF.

Single-balloon enteroscopy, magnetic resonance enterography, and abdominal US useful for evaluation of small-bowel disease in children with (suspected) Crohn's disease (Article)

2012-01-01T00:00:00Z

The usefulness of single-balloon enteroscopy (SBE) has not been evaluated in children with known or suspected Crohn's disease (CD). The objectives of this study are to evaluate the diagnostic yield of SBE for pediatric CD by comparing it with US and magnetic resonance enterography (MRE). Single-center prospective study. Tertiary-care referral hospital. Between February 2009 and April 2010, 20 pediatric patients (ages 8-18 years) with suspected inflammatory bowel disease (IBD) or with a previous diagnosis of CD with suspected persistent small-bowel disease were enrolled. All patients underwent proximal and distal SBE, 17 patients also underwent US combined with Doppler flow measurements, and 18 underwent MRE. The findings of US with Doppler flow measurements and MRE were compared with those with SBE. The mean patient age was 15.0 years (range 11.3-18 years, 70% male). Of 14 patients with suspected IBD, 8 had a diagnosis of CD made after SBE. Activity in the small bowel was found in 14 patients (70%) with both suspected and previously diagnosed CD. Twelve patients (60%) had small-bowel disease that was out of reach of conventional endoscopy. Three patients (15%) had small-bowel activity solely in the jejunum, which was not detected by either MRE or US. Single-center study with small sample size. SBE can be used in children to accurately assess small-bowel disease and CD. Small-bowel activity may be identified by SBE in some patients in whom it may not be apparent despite use of conventional upper endoscopy, ileocolonoscopy, US with Doppler flow measurements, or MRE.

CD62Lneg CD38+ expression on circulating CD4 + T cells identifies mucosally differentiated cells in protein fed mice and in human celiac disease patients and controls (Article)

2011-06-01T00:00:00Z

Objectives: The aim of this study was to identify new markers of mucosal T cells to monitor ongoing intestinal immune responses in peripheral blood. Methods: Expression of cell-surface markers was studied in mice on ovalbumin (OVA)-specific T cells in the gut-draining mesenteric lymph nodes (MLN) after OVA feed. The effect of the local mucosal mediators retinoic acid (RA) and transforming growth factor-Β (TGF-Β) on the induction of a mucosal phenotype was determined in in vitro T-cell differentiation assays with murine and human T cells. Tetramer stainings were performed to study gluten-specific T cells in the circulation of patients with celiac disease, a chronic small-intestinal inflammation. Results: In mice, proliferating T cells in MLN were CD62LnegCD38 during both tolerance induction and abrogation of intestinal homeostasis. This mucosal CD62LnegCD38 T-cell phenotype was efficiently induced by RA and TGF-Β in mice, whereas for human CD4 T cells RA alone was sufficient. The CD4 CD62LnegCD38 T-cell phenotype could be used to identify T cells with mucosal origin in human peripheral blood, as expression of the gut-homing chemokine receptor CCR9 and Β 7 integrin were highly enriched in this subset whereas expression of cutaneous leukocyte-associated antigen was almost absent. Tetramer staining revealed that gluten-specific T cells appearing in blood of treated celiac disease patients after oral gluten challenge were predominantly CD4 CD62LnegCD38 . The total percentage of circulating CD62LnegCD38 of CD4 T cells was not an indicator of intestinal inflammation as percentages did not differ between pediatric celiac disease patients, inflammatory bowel disease patients and respective controls. However, the phenotypic selection of mucosal T cells allowed cytokine profiling as upon restimulation of CD62LnegCD38 cells interleukin-10 (IL-10) and interferon-γ (IFN-γ) transcripts were readily detected in circulating mucosal T cells. Conclusions: By selecting for CD62LnegCD38 expression that comprises 5-10% of the cells within the total CD4 T-cell pool we are able to highly enrich for effector T cells with specificity for mucosal antigens. This is of pivotal importance for functional studies as this purification enhances the sensitivity of cytokine detection and cellular activation.

Cortisol diurnal rhythm and stress reactivity in constipation and abdominal pain: The generation R study (Article)

2011-04-16T00:00:00Z

OBJECTIVES: The aim of this study was to assess whether diurnal cortisol rhythm and cortisol stress reactivity were associated with functional constipation and abdominal pain in infancy. METHODS: This study was embedded in a subset of the Generation R Study, a prospective cohort study from fetal life onwards in Rotterdam, The Netherlands. Data of infants between 14 and 24 months of age (N = 483) were used. Salivary cortisol diurnal rhythm and salivary cortisol stress reactivity after a Strange Situation Procedure were assessed at the age of 14 months. Data on functional constipation was available according to the ROME II criteria and data on abdominal pain on the basis of the Abdominal Pain Index were available from questionnaire data at 24 months. RESULTS: In the second year of life, 13% of the infants had functional constipation and 17% had abdominal pain. Only 4% had symptoms of both functional constipation and abdominal pain. Diurnal cortisol rhythm did not differ significantly between children with and those without functional constipation and abdominal pain. Cortisol stress reactivity was slightly higher in infants with abdominal pain than those without it but this was not statistically significant (OR: 1.41; 95%CI: 0.46-4.31). No association was found between the cortisol stress reactivity and functional constipation. CONCLUSIONS: Our results suggest that cortisol as a marker for stress does not play a major role in functional constipation or abdominal pain in infancy.

Consensus for managing acute severe ulcerative colitis in children: A systematic review and joint statement from ECCO, ESPGHAN, and the porto IBD working group of ESPGHAN (Article)

2011-04-01T00:00:00Z

OBJECTIVES: Acute severe ulcerative colitis (ASC) is a potentially life-threatening disease. We aimed to formulate guidelines for managing ASC in children based on systematic review of the literature and robust consensus process. This manuscript is a product of a joint effort of the ECCO (European Crohn's and Colitis Organization), the Pediatric Porto Inflammatory Bowel Disease (IBD) Working group of ESPGHAN (European Society of Pediatric Gastroenterology, Hepatology, and Nutrition) and ESPGHAN.METHODS: A group of 19 experts in pediatric IBD participated in an iterative consensus process including two face-to-face meetings. A total of 17 predefined questions were addressed by working subgroups based on a systematic review of the literature.RESULTS: The recommendations and practice points were eventually endorsed with a consensus rate of at least 95% regarding: definitions, initial evaluation, standard therapy, timing of second-line therapy, the role of endoscopic evaluation and heparin prophylaxis, how to administer second-line medical therapy, how to assess response, surgical considerations, and discharge recommendations. A management flowchart is presented based on daily scoring of the Pediatric Ulcerative Colitis Activity Index (PUCAI), along with 28 formal recommendations and 34 practice points.CONCLUSIONS: These guidelines provide clinically useful points to guide the management of ASC in children. Taken together, the recommendations offer a standardized protocol that allows effective monitoring of disease progress and timely treatment escalation when needed.

The duration of effect of infliximab maintenance treatment in paediatric Crohn's disease is limited (Article)

2011-01-01T00:00:00Z

Background Infliximab is effective for induction and maintenance of remission in children with moderately to severely active Crohn's disease (CD). Aim To evaluate the long-term efficacy of infliximab treatment in paediatric CD. Methods In this observational, multicentre study, all paediatric CD patients in The Netherlands treated with infliximab from October 1992 to November 2009 and with minimal follow-up of 3 months since start of infliximab, were studied. Results One hundred and fifty-two CD patients [81M; median age at start of infliximab 15.0 years (IQR 13.1-16.4)] received a median number of 10.5 infliximab infusions (IQR 6-21). Median follow-up after start of infliximab was 25 months (IQR 13-40). Kaplan-Meier analysis showed that the cumulative probability of losing response to infliximab in patients who initially required repeated infusions was 13%, 40% and 50% after 1, 3 and 5 years, respectively. Seventy-four patients (49%) needed dose adjustments, with a median time to any adjustment of 6 months. Conclusions Duration of effect of infliximab is limited as 50% of patients on infliximab maintenance treatment lose their therapeutic response after 5 years. Dose adjustments after start of infliximab are frequently needed to regain therapeutic benefit. These findings emphasise the need for effective, long-term treatment strategies for paediatric CD.

Overlap, common features, and essential differences in pediatric granulomatous inflammatory bowel disease (Article)

2010-12-01T00:00:00Z

Overlap in the clinical presentation of pediatric granulomatous inflammatory bowel disease may be substantial, depending on the mode of presentation. Chronic granulomatous disease (CGD) may present with granulomatous colitis, perianal abscesses, hepatic abscesses or granulomas, failure to thrive, and obstruction of the gastrointestinal tract (including esophageal strictures and dysmotility, delayed gastric emptying, and small bowel obstruction). Anemia, thrombocytosis, elevated C-reactive protein and erythrocyte sedimentation rate, and hypoalbuminemia are nonspecific and may occur in any of the granulomatous inflammatory bowel diseases. In histology, macrophages with cytoplasmic inclusions will be rather specific for CGD. Sarcoidosis may present with abdominal pain or discomfort, diarrhea, weight loss, growth failure, delayed puberty, erythema nodosum, arthritis, uveitis, and hepatic granulomata. Only in 55% of the patients will angiotensin-converting enzyme be elevated. The noncaseating epithelioid granulomata will be unspecific. Bronchoalveolar lymphocytosis and abnormalities in pulmonary function are reported in sarcoidosis and in Crohn disease (CD) and CGD. Importantly, patients with CD may present with granulomatous lung disease, fibrosing alveolitis, and drug-induced pneumonitis. Sarcoidosis and concomitant gastrointestinal CD have been reported in patients, as well as coexistence of CD and sarcoidosis in siblings. Common susceptibility loci have been identified in CD and sarcoidosis. CD and CGD share defects in the defense mechanisms against different microbes. In the present review, common features and essential differences are discussed in clinical presentation and diagnostics-including histology-in CGD, sarcoidosis, and CD, together with 2 other granulomatous inflammatory bowel diseases, namely abdominal tuberculosis and Hermansky-Pudlak syndrome. Instructions for specific diagnosis and respective treatments are provided. Copyright

Association of Linear Growth Impairment in Pediatric Crohn's Disease and a Known Height Locus: A Pilot Study (Article)

2010-11-01T00:00:00Z

The etiology of growth impairment in Crohn's disease (CD) has been inadequately explained by nutritional, hormonal, and/or disease-related factors, suggesting that genetics may be an additional contributor. The aim of this cross-sectional study was to investigate genetic variants associated with linear growth in pediatric-onset CD. We genotyped 951 subjects (317 CD patient-parent trios) for 64 polymorphisms within 14 CD-susceptibility and 23 stature-associated loci. Patient height-for-age Z-score < -1.64 was used to dichotomize probands into growth-impaired and nongrowth-impaired groups. The transmission disequilibrium test (TDT) was used to study association to growth impairment. There was a significant association between growth impairment in CD (height-for-age Z-score < -1.64) and a stature-related polymorphism in the dymeclin gene DYM (rs8099594) (OR = 3.2, CI [1.57-6.51], p = 0.0007). In addition, there was nominal over-transmission of two CD-susceptibility alleles, 10q21.1 intergenic region (rs10761659) and ATG16L1 (rs10210302), in growth-impaired CD children (OR = 2.36, CI [1.26-4.41] p = 0.0056 and OR = 2.45, CI [1.22-4.95] p = 0.0094, respectively). Our data indicate that genetic influences due to stature-associated and possibly CD risk alleles may predispose CD patients to alterations in linear growth. This is the first report of a link between a stature-associated locus and growth impairment in CD. © 2010 The Authors Annals of Human Genetics

Final adult height of children with inflammatory bowel disease is predicted by parental height and patient minimum height Z-score (Article)

2010-10-01T00:00:00Z

Background: This study was designed to elucidate the contribution of parental height to the stature of children with inflammatory bowel disease (IBD), who often exhibit growth impairment. Accordingly, we compared patients' final adult heights and target heights based on measured parental heights and examined predictors of final adult height in pediatric IBD patients. Methods: We prospectively analyzed the growth of 295 patients diagnosed between ages 1 and 18 (211 Crohn's disease [CD], 84 ulcerative colitis [UC]) and their family members (283 mothers, 231 fathers, 55 siblings). Results: Twenty-two percent had growth impairment (height for age Z-score <-1.64, equivalent to <5th percentile on growth curve) in more than 1 measurement since diagnosis; most growth-impaired patients had CD (88% CD versus 12% UC). Parents of the growth-impaired group had lower mean height Z-scores compared to parents of nongrowth-impaired patients (-0.67 versus 0.02 for mothers [P < 0.001]; -0.31 versus 0.22 for fathers [P = 0.002]). For 108 patients who reached adult heights and had available parental heights, the growth-impaired group continued to demonstrate lower adult height Z-scores (-1.38 versus 0.07; P < 0.001). Adult heights were within 1 SD of target heights even for the growth-impaired group. Only 11.3% remained persistently growth-impaired in adulthood. Multivariate regression analysis demonstrated lower parental height and minimum patient height Z-score as significant predictors of lower final adult height in IBD. Conclusions: Parental height is a powerful determinant of linear growth even in the presence of chronic inflammation, and should be an integral part of the evaluation of growth in IBD children.

Human astrovirus infection in a patient with new-onset celiac disease (Article)

2010-09-01T00:00:00Z

Many diseases with unknown etiology may be caused by unidentified viruses. Sequence-independent amplification revealed a new astrovirus, similar to VA1, in a 4-year-old male diagnosed with celiac disease. This expands the geographic range of this virus to include Europe and may associate astrovirus infection with the onset of celiac disease. Copyright

Infant Nutritional Factors and Functional Constipation in Childhood: The Generation R Study (Article)

2010-04-01T00:00:00Z

OBJECTIVES:Food allergy and celiac disease may lead to childhood constipation. Early introduction of food allergens and gluten in the first year of life has been suggested to have a function in these food intolerances, but it is unclear whether this also holds true for development of childhood constipation. The aim of this study was to assess the association between the timing of introduction of food allergens and gluten early in life and functional constipation in childhood.METHODS:This study was embedded in the Generation R study, a population-based prospective cohort study from fetal life until young adulthood. Functional constipation at 24 months of age was defined in 4,651 children according to the Rome II criteria of defecation frequency <3 times a week or the presence of mainly hard feces for at least 2 weeks.RESULTS:At the age of 24 months, 12% of the children had functional constipation. Children with functional constipation got introduced to gluten more often before or at the age of 6 months than children without functional constipation (37% and 27%, respectively). After adjustment for birth weight, gestational age, gender, ethnicity, maternal education, and family history of atopy and chronic intestinal disorders, functional constipation was significantly associated with early gluten introduction (odds ratio (OR): 1.35; 95% confidence interval (CI): 1.10-1.65). No association was found between timing of introduction of cow's milk, hen's egg, soy, peanuts, and tree nuts with functional constipation. A history of cow's milk allergy in the first year of life was significantly associated with functional constipation in childhood (OR: 1.57; 95% CI: 1.04-2.36).CONCLUSIONS:These results suggest that early gluten introduction in the first year of life provide a trigger for functional constipation in a subset of children. In case of functional constipation, there also might be a role for cow's milk allergy initiated in the first year of life.Am J Gastroenterol advance online publication, 2 March 2010; doi:10.1038/ajg.2010.96.

Enteral Nutrition in Children with Short-Bowel Syndrome: Current Evidence and Recommendations for the Clinician (Article)

2010-03-01T00:00:00Z

The optimal enteral feeding regimen in children with short-bowel syndrome (SBS) is debated by clinicians. The purpose of this article is to present an overview of published data on feeding strategies in children with SBS. A structured literature search (years 1966 through 2007) was done to identify human studies in children directly addressing nutrition (or specified nutrients) in relation to SBS. Eight relevant studies retrieved were graded by seven experts according to the Scottish Intercollegiate Guidelines Network criteria. This grading system is based on the study design and methodological quality of individual studies. Recommendations were made based on the outcome according to the Scottish Intercollegiate Guidelines Network if appropriate and on expert opinion otherwise. The most important recommendations are:•Enteral nutrition should be initiated as soon as possible after bowel resection to promote intestinal adaptation.•Enteral nutrition should be administered in a continuous fashion.•Breast milk or standard polymeric formula (depending on the child's age) is recommended as preferred type of nutrition.•Bottle-feeding (small volumes) should be started as soon as possible in neonates to stimulate the suck and swallow reflexes. Solid food can be introduced at the age of 4 to 6 months (corrected for gestational age if necessary) to stimulate oral motor activity and to avoid feeding aversion behavior. The team of experts concluded that high-quality research on the preferred types of enteral and oral nutrition in children with SBS is scarce. Multicenter prospective studies on the effects of feeding strategies on bowel adaptation, fecal production, linear growth, and clinical outcome are required to find the optimal feeding regimen in children with SBS.

Interdisciplinary management of infantile short bowel syndrome: resource consumption, growth, and nutrition (Article)

2010-03-01T00:00:00Z

Background/Purpose: To date, there are hardly any data on the treatment costs of infantile short bowel syndrome (SBS), despite growing interest in evidence-based and cost-effective medicine. Therefore, the aim of the study was to evaluate resource consumption and costs, next to studying nutritional and growth outcomes, in children with SBS who were treated by an interdisciplinary short bowel team. Methods: Data were collected for 10 children with infantile SBS (≤1 year of age) born between 2002 and 2007. Data included demographic and medical data of the first admission and data on resource consumption, growth, and type of nutrition for the total follow-up period. Real economic costs were calculated in Euro (€) and US dollar ($). Results: Seven of the 10 patients were discharged with home parenteral nutrition. Total follow-up varied between 9 months and 5.5 years (median, 1.5 years). Six patients could be weaned off parenteral nutrition and 5 patients off enteral tube feeding, resulting in full oral intake. Seven patients had normal growth. Median duration of initial hospital admission was 174 days, and average costs of initial admission amounted to €166,045 ($218,681). Average total costs were €269,700 ($355,195), reaching to a maximum of €455,400 ($599,762). These costs mainly comprised hospital admissions (82%), followed by nutrition (12%), surgical interventions (5%), and outpatient visits (1%). Conclusions: This study is among the first to describe resource consumption and costs in infants with SBS, examining real economic costs and extending beyond the initial hospitalization. Treatment of SBS requires considerable resource consumption, especially when patients depend on parenteral nutrition. Because the costs mainly comprise those of hospital admissions, early home parenteral nutrition could contribute to costs reduction. Interdisciplinary teams have the potential to facilitate early home parenteral nutrition and thus may reduce health care costs.

T-cell regulation of neutrophil infiltrate at the early stages of a murine colitis model (Article)

2010-02-26T00:00:00Z

Background: T-cells are a main target for antiinflammatory drugs in inflammatory bowel disease. As the innate immune system is also implicated in the pathogenesis of these diseases, T-cell suppressors may not only inhibit T-cell-dependent production of proinflammatory mediators but also affect innate immune cell function. Specifically, these drugs may impair innate immune cell recruitment and activation through inhibition of T-cells or act independent of T-cell modulation. We explored the extent of immune modulation by the T-cell inhibitor tacrolimus in a murine colitis model. Methods: We assessed the effects of tacrolimus on trinitro-benzene sulphonic acid (TNBS) colitis in wildtype and Rag2-deficient mice. The severity of colitis was assessed by means of histological scores and weight loss. We further characterized the inflammation using immunohistochemistry and by analysis of isolated intestinal leukocytes at various stages of disease. Results: Tacrolimus-treated wildtype mice were less sensitive to colitis and had fewer activated T-cells. Inhibition of T-cell function was associated with strongly diminished recruitment of infiltrating neutrophils in the colon at the early stages of this model. In agreement, immunohistochemistry demonstrated that tacrolimus inhibited production of the neutrophil chemoattractants CXCL1 and CXCL2. Rag2-deficient mice displayed an enhanced baseline level of lamina propria neutrophils that was moderately increased in TNBS colitis and remained unaffected by tacrolimus. Conclusions: Both the innate and the adaptive mucosal immune system contribute to TNBS colitis. Tacrolimus suppresses colitis directly through inhibition of T-cell activation and by suppression of T-cell-mediated recruitment of neutrophils.

Familial adenomatous polyposis coli in childhood [Familiaire adenomateuze polyposis coli op de kinderleeftijd] (Article)

2010-01-01T00:00:00Z

Familial adenomatous polyposis coli (FAP) is an inherited predisposition to develop hundreds to thousands adenomatous colorectal polyps leading to colorectal cancer, and is caused by germline mutations in the APC-gene. Polyps generally develop in childhood and are often asymptomatic or give aspecific symptoms. However, other extra-intestinal manifestations of FAP may well become manifest in childhood. Here we present a child with hepatoblastoma as the first manifestation of FAP and describe the genetic testing and counseling of him and his brother. An overview of the medical, genetic and psychosocial aspects of FAP in childhood is given. The genetic testing and counseling for FAP in children requires specific expertise and should be provided in a multidisciplinary setting.

Transition from pediatric to adult health care in inflammatory bowel disease (Article)

2009-10-19T00:00:00Z

Inflammatory bowel disease (IBD) is a lifelong disease that has great psychosocial impact on the adolescent patient and his/her family. Starting around age 12-14 years, many changes take place related to school, work, and sexual development. At some point, usually around the age of 16-18 years, these patients need to move from the pediatric clinic to the adult caregivers. A stepwise program for transition of care, aimed at coaching the adolescent patient into self-management will benefit patients, parents, and the 'adult gastroenterologist' who will take over the care from the pediatric gastroenterologist. Differences in pediatric and adult health care, transition goals, tips and tools for successful transition will be discussed. Copyright

Activation of Intestinal Cl- Secretion by Lubiprostone Requires the Cystic Fibrosis Transmembrane Conductance Regulator (Article)

2009-09-01T00:00:00Z

Background & Aims: Lubiprostone alleviates constipation by stimulating intestinal fluid secretion, purportedly through activation of ClC-2-type Cl-channels. Intestinal obstruction is also a recurrent cause of distress in cystic fibrosis (CF) patients, caused by loss of CF transmembrane conductance regulator (CFTR) Cl-channel activity. Because ClC-2 recruitment might be beneficial to CF patients, we investigated lubiprostone's mode of action. Methods: Cl-transport was measured in an Ussing chamber, in 3 model systems: (1) T84 colonocytes, (2) intestinal epithelium of wild-type and CF mice, and (3) intestinal epithelium of CF patients and controls. Results: In T84 monolayers, lubiprostone induced a robust secretory response. Selective permeabilization of the basolateral plasma membrane revealed that lubiprostone activated an apical Cl-conductance. The lubiprostone response was attenuated by H89, an inhibitor of the cAMP-dependent protein kinase, and lubiprostone precluded responsiveness to the cAMP agonist forskolin. CFTR blockage by CFTRinh172, but not ClC-2 blockage by CdCl2, inhibited the lubiprostone response. Lubiprostone induced a CdCl2-insensitive secretory response in mouse intestine, but failed to induce intestinal Cl-secretion in Cftr-null mice. Correspondingly, lubiprostone induced a secretory response in human intestinal epithelium, but not in tissue of CF patients. The EP4-type prostanoid receptor antagonist L-161,982 blocked the lubiprostone response in all 3 models studied. In T84 cells, lubiprostone induced a rise in cAMP levels that was sensitive to EP4-receptor blockage. Conclusions: Lubiprostone enhances intestinal Cl-and fluid secretion via prostanoid receptor signaling, triggering activation of CFTR. Therefore, it is of limited use for treatment of CF-related intestinal disease.

Percutaneous endoscopic gastrostomy (PEG) in children is not a minor procedure: risk factors for major complications (Article)

2009-05-01T00:00:00Z

Percutaneous endoscopic gastrostomy (PEG) provides for enteral nutrition in children with feeding problems. PEG, however, is not without complications. The present study has a twofold aim: (1) comparing our incidence of major complications after PEG with the incidence in other centers, and (2) identifying risk factors for major complications. All patients receiving a PEG or laparoscopic-assisted PEG (lap PEG) in the period 1992-2008 were reviewed. Primary outcome was the occurrence of major complications, defined as the need for surgery, nonprophylactic antibiotics, or blood transfusion, and procedure-related death. Potential risk factors, eg, age under 1 year, mental retardation, scoliosis, constipation, hepatomegaly, upper abdominal surgery, ventriculoperitoneal shunt, peritoneal dialysis, esophageal stenosis, and coagulopathy, were analyzed. Of the 467 patients (448 PEG, 19 lap PEG), 12.6% developed major complications. The complication rate significantly decreased (P = 0.003) over the years. A significantly higher complication rate of 32% (P = 0.02) occurred in children with a ventriculoperitoneal shunt. None of the lap PEG procedures was associated with a major complication, but the difference was not significant, perhaps because of the small numbers in the latter group. The major complication rate after PEG in children is high. Preexisting ventriculoperitoneal shunt is a significant risk factor. Laparoscopically assisted PEG procedures seem to be associated with a lesser major complication rate.

Cd1d-dependent regulation of bacterial colonization in the intestine of mice (Article)

2009-05-01T00:00:00Z

The accumulation of certain species of bacteria in the intestine is involved in both tissue homeostasis and immune-mediated pathologies. The host mechanisms involved in controlling intestinal colonization with commensal bacteria are poorly understood. We observed that under specific pathogen-free or germ-free conditions, intragastric administration of Pseudomonas aeruginosa, E. coli, Staphylococcus aureus, or Lactobacillus gasseri resulted in increased colonization of the small intestine and bacterial translocation in mice lacking Cd1d, an MHC class I-like molecule, compared with WT mice. In contrast, activation of Cd1d-restricted T cells (NKT cells) with α- galactosylceramide caused diminished intestinal colonization with the same bacterial strains. We also found prominent differences in the composition of intestinal microbiota, including increased adherent bacteria, in Cd1d-/-mice in comparison to WT mice under specific pathogen-free conditions. Germ-free Cd1d-/-mice exhibited a defect in Paneth cell granule ultrastructure and ability to degranulate after bacterial colonization. In vitro, NKT cells were shown to induce the release of lysozyme from intestinal crypts. Together, these data support a role for Cd1d in regulating intestinal colonization through mechanisms that include the control of Paneth cell function.

Pediatric inflammatory bowel diseases and the risk of lymphoma: Should we revise our treatment strategies? (Article)

2009-03-01T00:00:00Z

Inflammatory bowel diseases (IBDs) are lifelong inflammatory gastrointestinal diseases starting in about one third of patients during childhood. Treatment strategies aim to control this chronic inflammatory process. Owing to recent advances in the understanding of IBD, immunosuppressive agents (mainly against TNFα directed) as well as biological drugs are more and more often used. This therapeutic approach clearly improved the clinical condition of the majority of patients with IBD. However, with this more aggressive treatment strategy, safety concerns clearly arise. Recently, the description of a series of a particularly severe form of T cell lymphoma in pediatric and young adult patients with IBD under immunomodulator and biological combination therapy raised the question of the risks of treatment-induced side effects or complications. As reviewed in the present article, there is a slightly increased risk of not only lymphoma development in IBD patients, potentially related to the inflammatory process, but also to the use of immunosuppressive therapies. On the basis of the literature data, we reanalyzed current treatment strategies for children with moderate-to-severe IBD, who are candidates to receive immunomodulator and/or biological agents potentially accelerating the risk of lymphoma development. Comparative clinical studies in IBD are still missing; however, it is prudent to think about adapting immunosuppressive therapies to the inflammatory process of the underlying disorder and if possible to reduce them to monotherapy. Alternative treatment strategies for heavy immunosuppression exist (eg, enteral nutrition in Crohn disease or colectomy in patients with ulcerative colitis) and should be considered whenever appropriate. There is a major need for comparative studies before evidence-based guidelines can be established for safest and best treatment strategies of pediatric patients with IBD.

Role of the innate immune system in the pathogenesis of inflammatory bowel disease (Article)

2009-02-01T00:00:00Z

Crohn disease and ulcerative colitis are chronic inflammatory diseases of the intestinal tract commonly denoted as inflammatory bowel diseases. It has been proposed that these diseases result from aberrant mucosal immune responses to nonpathogenic microbial residents of the intestines. Recently, it was established that continuous interactions between the innate and the adaptive intestinal immune cells and the microbiota are directly involved in maintaining the physiological noninflammatory state of the intestinal mucosa. In light of the complexity of this mucosal homeostasis, it is astonishing that the inflammatory bowel diseases are relatively rare. Recently, altered functions of the innate immune system have been identified. As such, both hyperresponsiveness and hyporesponsiveness of innate cells have been implicated in the pathogenesis of inflammatory bowel diseases.

Chronic hereditary pancreatitis in a girl with a serine protease inhibitor kazal type i (SPINK-1) gene mutation and a coxsackie type B5 infection (Article)

2009-02-01T00:00:00Z

Refractory inflammatory bowel disease in children (Article)

2008-08-01T00:00:00Z

Third party mesenchymal stromal cell infusions fail to induce tissue repair despite successful control of severe grade IV acute graft-versus-host disease in a child with juvenile myelo-monocytic leukemia (Article)

2008-06-01T00:00:00Z

20 Years of scientific training of dutch medical students in an american academic division for pediatric gastroenterology and nutrition: Impact on career development (Article)

2008-04-01T00:00:00Z

OBJECTIVES: To evaluate the impact on career development of a program for scientific training of Dutch medical students in an American academic division for pediatric gastroenterology and nutrition. MATERIALS AND METHODS: A survey was undertaken of medical students who were trained in the division of pediatric gastroenterology and nutrition at Tufts University and later at Children's Hospital, Harvard Medical School, Boston, MA. Characteristics of the students, the training period, the scientific output, and their career development were evaluated. RESULTS: A questionnaire was sent to 54 students, of which 39 (72%) responded. The mean time of their rotation was 12.2 ± 12.1 months. Twenty-five students published 33 scientific manuscripts. Fifteen students obtained a doctorate degree and 4 are involved in a doctorate program. Six theses were directly related to the scientific content of the rotation and were performed under the supervision of American mentors. A total of 59% of the students hold a position as medical specialist, which is a substantially higher percentage than the national average of all graduated medical doctors. Thirty-five percent of them practice pediatrics (of whom 38% practice pediatric gastroenterology) and 22% practice gastroenterology. Seventy-eight percent of the medical specialists hold an academic position. CONCLUSIONS: Dutch medical students who are scientifically trained in a US academic division for pediatric gastroenterology and nutrition-where specialists approached all of the students with a special program to involve them in biomedical research-have a great chance to establish a scientific career track and to become a medical specialist.

Infliximab dependency in pediatric Crohn's disease: Long-term follow-up of an unselected cohort (Article)

2008-03-01T00:00:00Z

Background: Infliximab is effective for induction and maintenance of remission in Crohn's disease. It is unknown how long patients should be kept on infliximab therapy. The primary aim of this study was to assess duration of effective maintenance therapy and infliximab dependency in pediatric CD patients initially responding to infliximab therapy. Methods: All pediatric patients treated with infliximab by pediatric gastroenterologists in the Netherlands because of severe luminal or fistulizing CD with initial response to infliximab therapy were reviewed. Duration of therapy, clinical response and adverse events were recorded. Results: Sixty-six CD patients (37 boys) in 10 hospitals were initially responding to infliximab therapy. Mean age at the start of infliximab therapy was 14.5 years (range, 8.1-18.5 years). Mean follow-up since infliximab was started was 41.3 months (range 12-165). In total, 991 infusions were administered. Analysis demonstrates that 15.2% of patients had prolonged response, while 56.1% were infliximab dependent and 28.8% lost response. In total, 10 patients (15.2%) developed an infection during infliximab therapy and 8 (12.1%) had an immediate allergic reaction. Conclusions: Good clinical response to maintenance infliximab therapy was seen in 70% of patients. Infliximab maintenance therapy seems very effective and safe in pediatric CD. However, more than half of the patients in this cohort is dependent on repeated infliximab infusions. The number of infliximab infusions received when patients lost response to infliximab was diverse. There was no statistical difference regarding response to infliximab therapy when started early as compared to later in the course of Crohn's disease. Copyright

Early onset IBD: What's the difference? (Article)

2008-01-01T00:00:00Z

In this paper we describe an array of differences between paediatric and adult inflammatory bowel diseases. Specifically, patient specifics such as genetics, disease location, immune responses and drug responsiveness are addressed. Given the distinct disease phenotype in children, it seems warranted that early onset inflammatory bowel diseases will be denoted as a specific disease entity.

Roles of CD1d-restricted NKT cells in the intestine (Article)

2007-09-01T00:00:00Z

Natural killer T (NKT) cells are a subset of lymphocytes that express cell surface molecules of both conventional T cells and natural killer cells and share the features of both innate and adaptive immune cells. NKT cells have been proposed to make both protective and pathogenic contributions to inflammatory bowel diseases (IBD). On the one hand, recent studies have shown that these cells are involved in the maintenance of mucosal homeostasis. On the other, NKT cells were shown to play a pathogenic role in human ulcerative colitis. Similar contrasting data have been generated in murine models of IBD. Whether the apparent differences in NKT response patterns depend on variations in NKT antigens and/or on the presence of specific subsets of mucosal NKT cells remains to be elucidated. In this article we review the current literature on intestinal NKT cells and their roles in IBD pathogenesis. Specifically, the nomenclature, NKT antigens, and immune mechanisms of NKT cells within the intestinal mucosa are discussed. Copyright

Look before you leap (Article)

2007-09-01T00:00:00Z