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Inter-subject variability in human milk microbiome is well known, however, its origins and possible relationship to the mother&rsquo, s diet are still debated. We investigated associations between maternal nutrition, milk fatty acids composition and microbiomes in mother&ndash, infant dyads. Breast milk and infant fecal samples were collected across three time points (one week, one month and three months postpartum) from 22 mother&ndash, infant pairs. Food frequency questionnaires for the months of pregnancy and three months postpartum were collected. Milk fatty acids were analyzed by GC&ndash, MS and the microbiome in breast milk and infant feces was determined by 16S rRNA sequencing. Statistical interactions were computed using Spearman&rsquo, s method and corrected for multiple comparisons. We found significant negative correlation between Streptococcus relative abundance in maternal milk and intake of unsaturated fatty acids and folic acid at one month postpartum. At three months postpartum, vitamin B-12 consumption was significantly associated with a single operational taxonomic unit belonging to Streptococcus. Comparison between milk microbiome and lipid composition showed, one-month postpartum, significant negative correlation between Streptococcus relative abundance and the abundance of oleic acid. Additional correlations were detected between Staphylococcus hominis and two medium-chain saturated fatty acids. Our results reinforce the hypothesis that maternal nutrition may affect milk microbiome.

Background: The clinical, histological, and serological spectrum of celiac disease (CD) vary widely. We aimed to examine relationships between symptoms, serum anti-tissue transglutaminase antibodies (tTG) levels, mucosal damage, and mucosal anti-tTG deposits in pediatric CD. Methods: A retrospective single-center, cohort study of children referred for endoscopy with suspected CD during 2011–2014. We retrieved the clinical data, blindly reviewed duodenal biopsies, and performed immunohistochemical staining for anti-tTG deposits. Patients were classified as monosymptomatic or polysymptomatic. Mucosal anti-tTG deposits were classified according to the location of deposits, dominant intensity, maximal intensity, and percentage of stained area. Results: Of 252 patients with confirmed CD, complete data were available for 100: 37 males in the age range 1.3–16.7 with median 4.0 years. Monosymptomatic patients (n = 54) presented at an older age than polysymptomatic patients (1.3–15.5, median 8.1 vs. 1.3–16.7, median 6.3 years, p = 0.026). Marsh 2–3c was more prevalent in polysymptomatic patients (93 vs. 78%, p = 0.028). The intensity of mucosal anti-tTG deposits correlated with serum anti-tTG levels but not with the clinical presentation. Conclusions: Multiple symptoms and high serum anti-tTG antibody levels correlated with mucosal damage in children with CD. The role of immunohistochemical staining for intestinal anti-tTG mucosal deposits in the diagnosis of borderline CD is not yet established.

ObjectiveWhile extensive research revealed that interleukin (IL)-1β contributes to insulin resistance (IR) development, the role of IL-1α in obesity and IR was scarcely studied. Using control, whole body IL-1α knockout (KO) or myeloid-cell-specific IL-1α-deficient mice, we tested the hypothesis that IL-1α deficiency would protect against high-fat diet (HFD)-induced obesity and its metabolic consequences.Research design and methodsTo induce obesity and IR, control and IL-1α KO mice were given either chow or HFD for 16 weeks. Glucose tolerance test was performed at 10 and 15 weeks, representing early and progressive stages of glucose intolerance, respectively. Liver and epididymal white adipose tissue (eWAT) samples were analyzed for general morphology and adipocyte size. Plasma levels of adiponectin, insulin, total cholesterol and triglyceride (TG), lipoprotein profile as well as hepatic lipids were analyzed. Expression of lipid and inflammation-related genes in liver and eWAT was analyzed. Primary mouse hepatocytes isolated from control mice were treated either with dimethyl sulfoxide (DMSO) (control) or 20 ng/mL recombinant IL-1α for 24 hours and subjected to gene expression analysis.ResultsAlthough total body weight gain was similar, IL-1α KO mice showed reduced adiposity and were completely protected from HFD-induced glucose intolerance. In addition, plasma total cholesterol and TG levels were lower and HFD-induced accumulation of liver TGs was completely inhibited in IL-1α KO compared with control mice. Expression of stearoyl-CoA desaturase1 (SCD1), fatty acid synthase (FASN), elongation of long-chain fatty acids family member 6 (ELOVL6), acetyl-CoA carboxylase (ACC), key enzymes that promote de-novo lipogenesis, was lower in livers of IL-1α KO mice. Treatment with recombinant IL-1α elevated the expression of ELOVL6 and FASN in mouse primary hepatocytes. Finally, mice with myeloid-cell-specific deletion of IL-1α did not show reduced adiposity and improved glucose tolerance.ConclusionsWe demonstrate a novel role of IL-1α in promoting adiposity, obesity-induced glucose intolerance and liver TG accumulation and suggest that IL-1α blockade could be used for treatment of obesity and its metabolic consequences.

Anti tumor necrosis factor alpha (TNFα) agents have become widely used in pediatric inflammatory bowel disease (IBD). So far, only few studies examined the long-term results of anti-TNFα treatment in children with IBD.The long-term outcome of pediatric patients with IBD was assessed retrospectively in a multicenter cohort of children treated with anti-TNFα beyond induction treatment. Short- and long-term response rates, predictors for loss of response, data on growth and laboratory parameters were assessed.120 patients [101 crohn's disease (CD), 19 ulcerative colitis (UC) or indeterminate colitis (IC)] received either infliximab or adalimumab. The mean age at initiation of anti-TNFα was 13.4 ± 3.9 years and the median duration of anti-TNFα treatment was 15 months (range: 2-90). Overall, 89% of the cohort experienced short-term response following induction. Response was associated with improvement in weight and BMI Z-scores (p0.001) but not with linear growth. Responders experienced a significant decrease in erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) during treatment (p0.001). Albumin and hemoglobin both improved but only albumin increased significantly (p0.001). The cumulative probability of losing response to anti-TNFα treatment was 17%, 38%, and 49% after 1, 3, and 5 years, respectively. Responders had a significantly lower weight and BMI Z-scores at initiation of anti-TNFα treatment in compared to non-responders (p=0.04 and 0.02 respectively).Our long term cohort supports the current evidence on the effectiveness and safety of anti-TNFα treatment in children with IBD. Response to treatment was interestingly associated with lower weight and BMI.

Objective Familial Mediterranean fever (FMF) and Crohn's disease are autoinflammatory disorders, associated with genes (MEFV and NOD2/CARD15, respectively) encoding for regulatory proteins, important in innate immunity, apoptosis, cytokine processing, and inflammation. Although mutations in the MEFV gene were shown to modify Crohn's disease, the role of NOD2/CARD15 gene mutations in the FMF disease phenotype was never studied before. Patients and methods The cohort consisted of 103 consecutive children with FMF, followed in a single referral center. NOD2/CARD15 genotypes were analyzed in all patients and 299 ethnically matched unaffected controls. Demographic data, clinical characteristics, and disease course of FMF patients with and without NOD2/CARD15 mutation were compared. Results A single NOD2/CARD15 mutation was detected in 10 (9.7%) FMF patients and 26 (8.7%) controls. No homozygous or compound heterozygous subjects were discovered in the 2 groups. FMF patients carrying a NOD2/CARD15 mutation had a higher rate of erysipelas-like erythema and acute scrotum attacks, a trend for a higher rate of colchicine resistance and a more severe disease as compared with patients without mutations. Conclusions NOD2/CARD15 mutations are not associated with an increased susceptibility to develop FMF. Nevertheless, the presence of these mutations in FMF patients appears to be associated with a trend to a more severe disease.

Background: Further understanding of the clinical manifestations, hospital course and treatment options of the 2009 pandemic H1N1 influenza virus (H1N1) is needed in preparation for future outbreaks. Methods: Seventy-three children with polymerase-chain-reaction-confirmed infections with H1N1 treated in a tertiary care medical center in Israel were included in the study. Clinical data were extracted from medical records, and analyzed by hospitalization status or the presence of underlying chronic medical conditions. Results: Prevalent symptoms were fever, cough and shortness of breath, with additional findings of conjunctivitis, seizures, chills, dizziness, purpuric rash and chest pain. Hospitalized patients were more likely to have shortness of breath (OR 26.7, 95%CI: 3.5–1150), abnormal lung auscultation (OR 11.6, 95%CI: 2.8–67), abnormal X-ray (OR 3.3, 95%CI: 1.1–9.6), and a chronic illness (OR 5.4, 95%CI: 1.8–17), compared with non-hospitalized ones. Disease manifestations were similar between children with or without chronic diseases. Only two (2.7%) children required intensive care, and no deaths were recorded. A high rate (18%) of thrombocytopenia was found. One child had rapid symptom resolution after intravenous immunoglobulin treatment. Conclusion: H1N1 infection follows a mild course, even in the presence of severe underlying diseases. Abnormal respiratory findings and the presence of a chronic disease probably contributed to the decision to hospitalize patients. A rapid resolution of H1N1 symptoms after intravenous immunoglobulin treatment warrants further study, and could be a possible therapeutic option for severe cases.

Background There are no current recommendations for bowel cleansing before colonoscopy in children. The Israeli Society of Pediatric Gastroenterology and Nutrition (ISPGAN) established an iterative working group to formulate evidence-based guidelines for bowel cleansing in children prior to colonoscopy. Method Data were collected by systematic review of the literature and via a national-based survey of all endoscopy units in Israel. Based on the strength of evidence, the Committee reached consensus on six recommended protocols in children. Guidelines were finalized after an open audit of ISPGAN members. Results Data on 900 colonoscopies per year were accrued, which represents all annual pediatric colonoscopies performed in Israel. Based on the literature review, the national survey, and the open audit, several age-stratified pediatric cleansing protocols were proposed: two PEG-ELS protocols (polyethylene-glycol with electrolyte solution); Picolax-based protocol (sodium picosulphate with magnesium citrate); sodium phosphate protocol (only in children over the age of 12 years who are at low risk for renal damage); stimulant laxative-based protocol (e. g. bisacodyl); and a PEG 3350-based protocol. A population-based analysis estimated that the acute toxicity rate of oral sodium phosphate is at most 3/7320 colonoscopies (0.041 %). Recommendations on diet and enema use are provided in relation to each proposed protocol. Conclusion There is no ideal bowel cleansing regimen and, thus, various protocols are in use. We propose several evidence-based protocols to optimize bowel cleansing in children prior to colonoscopy and minimize adverse events.

Objective Probiotics reduce intestinal inflammation in, and Lactobacillus GG (LGG) reduces pulmonary exacerbation rate cystic fibrosis (CF) patients. We intended to determine the effect of a mixed probiotic preparation on pulmonary exacerbations and inflammatory characteristics of the sputum in CF patients. Study Design A prospective pilot study of 10 CF patients with mild–moderate lung disease and Pseudomonas aeruginosa colonization, treated with probiotics for 6 months. Pulmonary function tests (PFT's), sputum cultures with semi-quantitative bacterial analysis, and sputum neutrophil count and interleukin-8 (IL-8) levels were compared to pre-treatment and post-treatment values. The rate of pulmonary exacerbations was compared to 2 years prior to the study. Results The exacerbation rate was significantly reduced in comparison to the previous 2 years and to 6 months post-treatment (P = 0.002). PFT's have not changed at the end of treatment and during 6 months post-treatment. No change in sputum bacteria, neutrophil count, and IL-8 levels was observed. Conclusion Probiotics reduce pulmonary exacerbations rate in patients with CF. Probiotics may have a preventive potential for pulmonary deterioration in CF patients. Pediatr Pulmonol. 2010; 45:536–540. © 2010 Wiley-Liss, Inc.

Progressive familial intrahepatic cholestasis (PFIC) is a group of rare heterogeneous autosomal recessive disorders characterized by metabolic defects in biliary proteins involved in the formation and transfer of bile acids in the liver. The genotype-phenotype correlation is not always clear. Mutations in the ATP8B1, BSEP and MDR3 genes have been associated with PFIC1, PFIC2 and PFIC3, respectively. This study sought to characterize the molecular genetic basis for PFIC subtypes in Israel. It was conducted on 14 children with PFIC and their families; 10 with a PFIC1 or PFIC2 phenotype and 4 with a PFIC3 phenotype. Using denaturing high-performance liquid chromatography (DHPLC), five different mutations were identified in four affected families: three novel mutations in BSEP (G19R-g181c, S226L-c803t and G877R-g2755a), one novel mutation in MDR3 (IVS14+6 t/c) and one heterozygous mutation in ATP8B1 (R600W, in a family with the PFIC1/PFIC2 phenotype). The cause of PFIC was identified in 20% of the families tested. These findings indicate the probable involvement of additional genes in PFIC and the need for further studies to determine whether the abnormality lies on the RNA or protein level. A better understanding of the phenotype-genotype correlation in PFIC will lead to improved diagnoses and treatments.

Aims: Pediatric onset of Crohn disease (CD) is characterized by male sex predominance while adult-onset disease demonstrates female sex predominance. It has been postulated that this phenomenon may be genetically determined or due to an effect of estrogen on age of onset. Interleukin (IL)-6 modulates the TH17 pathway, and the IL-6 promoter is modulated by estrogen, possibly linking genetically determined inflammation and the presence of estrogen. The aim of our study was to investigate whether differences in IL-6 promoter genotype could explain male sex in earlier disease onset. Patients and Methods: We genotyped 333 patients with CD and 100 controls, 162 pediatric-onset patients (age of onset 18 years and younger) for the IL-6-174 polymorphic site. Genotype, sex, and age of onset were compared. Results: Males with IL-6-174GG genotype (the wild-type allele) had an increased risk for a younger age of onset compared to males with IL-6-174GC or CC genotype (G → C genotype), hazard ratio (HR) 1.49, P = 0.02, 95% confidence interval (CI) 1.07–2.09. Females with GG genotype were not found to have an increased risk for a younger age of onset compared with females with G → C genotype, HR 1.01, P = 0.96, 95% CI 0.72–1.41. Conclusions: Males with IL-6-174GG genotype are prone to develop CD at a younger age than males with the IL-6-174G → C genotype. Our study suggests that age of onset may be modified by the IL-6-174GG genotype and this modification is sex dependent. This may be due to increased transcription of IL-6, an effect that may be repressed by estrogen in females.

Diagnosis of celiac disease frequently depends upon serology assays. We set out to prospectively assess the diagnostic value of five serology tests: an enzyme-linked immunosorbent assay (ELISA) for tissue transglutaminase (tTG)-immunoglobulin A (IgA) and tTG-IgG, a chemiluminescence assay for tTG-IgA, an ELISA for deamidated gliadin peptide (DGP) IgG and IgA screening, and detection of endomysial antibodies (Abs) by indirect immunofluorescence. One hundred sixteen children at high risk for developing celiac disease were evaluated clinically and underwent small bowel biopsies and blood serology tests. We examined differences between younger and older children in terms of clinical presentation, test performance, and the ability of high Ab levels to correctly predict diagnosis of celiac disease. Celiac disease was diagnosed for 85 (73%) children. No significant clinical differences were observed between the biopsy-positive and biopsy-negative groups. Children ≤3 years of age revealed higher concentrations of tTG-IgA and DGP Abs than children >3 years old ( P = 0.017 and 0.007, respectively). High Ab concentrations were predictive of villous atrophies, with sensitivities ranging from 92.8% to 97.9%, depending on the assay and the cutoff points applied. Sensitivities, specificities, positive predictive values, and negative predictive values varied among assays and improved after correction for best cutoff points. Assay specificities obtained in the clinical setting were lower than expected. The new tTG-IgA chemiluminescence assay demonstrated high throughput but low specificity (74.2%). The tTG-IgA ELISA exhibited the highest test efficiency, and the tTG-IgA chemiluminescence assay was suitable for large-scale screening, with reduced specificity. High concentrations of celiac disease-specific Abs bring into question the need for performance of biopsies on children at high risk.

Background: Oral budesonide has been found to be comparable to systemic corticosteroids in mild to moderately active Crohn's disease (CD). Remission rates in pediatric studies to date have been suboptimal (47%–55%), even though patients with colonic involvement were excluded in some studies. In addition, the optimal pediatric dosing regimen has never been evaluated before. Methods: This was a randomized, controlled, double-blind study in 70 children with mild or moderately active CD randomized to 1 of 2 groups: Group 1: Standard dose budesonide (9 mg/day) for 7 weeks followed by 6 mg budesonide daily for an additional 3 weeks. Group 2: Induction with 12 mg/day for the first month followed by the same regimen as Group 1. Outcome measures included a decrease in Pediatric Crohn's Disease Activity Index and remission rates. Patients with colonic disease were not excluded. Results: At week 7 a clinical response was obtained in 51.4% in Group 1 versus 74.3% in Group 2. A significant decrease in C-reactive protein was seen only in Group 2. At the end of treatment, remission was obtained in 42.9% in Group 1 versus 65.7% in Group 2 (P = 0.054). There was no significant difference in adverse events or serum cortisol. Conclusions: Use of an induction dose of budesonide followed by a budesonide taper resulted in a trend to higher rates of clinical remission and a decrease in inflammation, without an increase in steroid-associated side effects. Budesonide was also useful for patients with ileocolonic disease. (Inflamm Bowel Dis 2009)

Background Immunomodulatory drugs play a major role in maintaining remission and steroid sparing in children with Crohn disease. Although thiopurine agents are commonly used, unresponsiveness or intolerance to these drugs is common. The efficacy of methotrexate in maintenance of remission has been shown in adult Crohn disease; however, pediatric data are limited. Our goal was to evaluate the efficacy and safety of methotrexate in induction and maintenance of clinical remission in children with active Crohn disease who failed thiopurine treatment. Patients and methods In a retrospective multicenter study, efficacy of methotrexate in inducing and maintaining remission or response was assessed by Harvey-Bradshaw activity index, paediatric Crohn disease activity index and steroid use, in 25 children with Crohn disease, refractory or intolerant to thiopurine analogues. Results Crohn disease was diagnosed at a mean age of 11.1 +/- 3.1 years and methotrexate was initiated at age 14.5 +/- 3.1 years. The median methotrexate dose was 12.5 mg/m2. Remission was achieved in 16 patients (64%), and response in 6 patients (24%). Out of 18 patients treated for longer than 6 months, 83% were in remission or response after 12 months of treatment. The mean duration of remission and response was 10.8 +/- 8.8 months. Steroid withdrawal was possible in 12/16 patients (75%) receiving steroids at methotrexate introduction. Adverse effects were observed in 6 patients (24%) including nausea and vomiting in 3, elevation of liver enzymes in 2 and pancreatitis in 1 patient. Conclusions Methotrexate is beneficial in maintaining remission and steroid-sparing treatment in children with Crohn disease following failure of thiopurine therapy.

OBJECTIVES Short stature is one of the presenting symptoms of celiac disease (CD), and growth acceleration can be achieved with gluten-free diet (GFD). However, the data regarding final adult height of CD patients are scarce and inconclusive. Our aim was to evaluate the adult height of CD patients in relation to the age at diagnosis: 18 yr. METHODS Questionnaires were sent to CD patients > or =18 yr of age, who were either members of the Israeli Celiac Association or patients followed by the pediatric gastroenterology unit, including questions about height, weight, gender, age at diagnosis, and GFD adherence. The height Z scores were calculated for each patient. RESULTS In total, 290 patients (M/F = 83/207), age 38.9 +/- 15.5 yr (range 18-76), were included: 113 were diagnosed before and 177 after 18 yr of age (groups 1 and 2, respectively). The mean adult height was: 178.4 +/- 6.6 cm and 176.2 +/- 8.6 cm for men (P= 0.22), and 163.0 +/- 6.6 cm and 162.6 +/- 6.5 cm for women (P= 0.68) in groups 1 and 2, respectively. The height Z scores were 0.230 +/- 0.931 and -0.07 +/- 1.19 for men (P= 0.22), and -0.05 +/- 1.02 and -0.101 +/- 0.990 for women (P= 0.68) in groups 1 and 2, respectively. The final height inversely correlated with age at diagnosis in men (R =-0.275, P= 0.012) but not in women (R =-1.0, P= not significant [NS]). CONCLUSIONS The final height of patients with CD is similar to the general population. The adult height of male patients with CD is inversely related to the age at diagnosis. Delayed diagnosis of CD may lead to a shorter adult height in men but not in women.

Leptin, adiponectin, and ghrelin have diverse roles in the control of inflammation and metabolism in a normal state as well as in a chronic disease state. The aim of this study was to evaluate their role in the extreme metabolic and proinflammatory state after burn injury and during the initial weeks of recovery.A prospective descriptive study in a tertiary care center was undertaken. Patients were comprised of 5 children aged 20-108 months with severe burn injury; burn size ranged from 15%-36% of total body surface area. Early enteral feeding, according to estimated energy expenditure, was initiated as 150% of the recommended dietary allowance and in accordance with the patients' nitrogen balance. Seven blood samples were collected sequentially, approximately 5 days apart, during the first 65 days after the burn injury. Samples were tested for leptin, ghrelin, and adiponectin.Leptin, ghrelin, and adiponectin had a similar trajectory of concentration over time: low levels at the beginning, increasing until 2-3 weeks post-burn, where they reached a plateau at 5 weeks post-injury. The typical inverse correlations of ghrelin and adiponectin with leptin were absent. Interleukin-6 was negatively associated with ghrelin and adiponectin and was not associated with leptin. Insulin-like growth factor-1 (IGF-1) had a positive association with the 3 hormones; however, their profiles differ in their relationship to the expected concentration based on a literature review. Ghrelin and adiponectin were higher, leptin and IGF-1 were lower than expected.In the early weeks after burn injury, the hypermetabolic state and inflammation have a major effect on leptin, ghrelin, and adiponectin. The concurrent and similar change of the 3 hormones serves the parallel anabolic and catabolic processes during the recovery from burn injury. .

Liver disease is the second cause of death in cystic fibrosis. The most deleterious complication of liver disease is portal hypertension, which has an estimated prevalence of up to 8%. Portal hypertension may manifest itself by splenomegaly, hypersplenism, gastro-oesophageal bleeding and ascites. The aim of our study was to determine the prevalence, risk factors and invasive management of portal hypertension at our centre.One hundred and fifty patients with cystic fibrosis were followed up between 1975 and 2000 in the national cystic fibrosis centre in Israel. Forty patients (27%) had liver disease. All underwent clinical evaluation and laboratory and imaging studies.Portal hypertension was diagnosed in 10 patients (7%), of whom eight were male. The mean age at diagnosis was 11 years (range, 4-17 years). All had severe mutations of the cystic fibrosis transmembrane conductance regulator gene (the CFTR gene), pancreatic insufficiency, meconium ileus or distal intestinal obstruction syndrome and variceal bleeding. Seven patients underwent sclerotherapy to control acute bleeding. Four underwent portosystemic shunting (functioning up to 37 years). Two patients with severe lung and liver disease underwent transjugular intrahepatic portosystemic shunting, which provided bleeding control, but both died while waiting for lung/liver transplantation. One patient underwent liver transplantation due to liver failure and still had good liver and lung function 10 years later.Portal hypertension is more common among Israeli patients with cystic fibrosis. The unique genetic composition of our population may explain this phenomenon. Risk factors include male gender, pancreatic insufficiency, severe CFTR mutations, meconium ileus and meconium ileus equivalent. Sclerotherapy is the main option to control oesophageal variceal bleeding, while portosystemic shunts offer a prolonged alternative treatment for refractory bleeding. A transjugular intrahepatic portosystemic shunt and liver transplantation may also be effective, but further research is required in order to establish their role.

Our objective was to investigate the relationship between demographic factors, nutrition, stool gas production, and the existence of infantile colic (IC) syndrome. Hydrogen and methane production from stool specimens of infants with and without infantile colic was quantified at two separate time points, the age at presentation of colic ( 2 ppm by 15.3% of the infants at age 6 months. The mean methane concentrations produced by stool increased with age (0.95 ± 0.58 ppm at 3 months of age vs 1.29 ± 0.65 ppm at 6 months of age. There was no difference in stool hydrogen concentration between infants with and without IC. In contrast, the mean methane level at 3 and 6 months of age was higher in infants without IC than with IC, but reached statistical significance only at 6 months of age (0.97 ± 0.68 vs 0.93 ± 0.46) (NS) at 3 months of age, and 1.56 ± 0.55 vs 0.93 ± 0.62 (P

OBJECTIVES Breath analysis and exhaled breath condensate (EBC) collection are simple and noninvasive processes whereby inflammatory mediators and other biomarkers can be assessed in diseases that affect the lung. It was hypothesised that markers of epithelial dysfunction and secretion, such as a low pH, 8-isoprostane, and release of epithelial factors such as trefoil factor 2 (TFF2) and mucin, would be elevated in the breath of those with inflammatory bowel disease (IBD). The aim was to compare the levels of these biomarkers in EBC and the fraction of expired nitric oxide (FENO) in children with Crohn disease (CD), in those with asthma, and in normal individuals in a pilot study. METHODS EBC was collected from patients in the 3 groups mentioned above in a cross-sectional design. pH, 8-isoprostane, TFF2, and mucin levels were measured in the EBC. Spirometry was performed in asthmatic patients and patients with IBD, whereas FENO and skin prick tests were performed in patients with IBD. RESULTS Breath samples including EBC were collected from 80 patients (30 CD, 30 asthma, 20 controls). Compared with controls, EBC pH was lower in children with IBD (P < 0.0001) or asthma (P = 0.0041). 8-Isoprostane levels differed between the 3 groups (P < 0.05). EBC TFF2 was mainly less than the limit of detection, whereas mucin levels did not differ significantly between the 3 groups. FENO was measurable in children with IBD, but did not correlate with disease activity or serum markers of inflammation. CONCLUSIONS A lower EBC pH may reflect inflammatory events either in the lung or systemically. 8-Isoprostane, FENO, and mucin were detected for the first time in the EBC of children with IBD. Further studies are required to assess the value of these assessments.

Background & Aims There is controversy about whether levels of anti–tumor necrosis factor (TNF) and antidrug antibodies (ADAs) are accurate determinants of loss of response to therapy. We analyzed the association between trough levels of anti-TNF agents or ADAs and outcomes of interventions for patients with loss of response to infliximab or adalimumab. Methods We performed a retrospective study of pediatric and adult patients with inflammatory bowel disease and suspected loss of response to anti-TNF agents treated at medical centers throughout Israel from October 2009 through February 2013. We examined the correlation between outcomes of different interventions and trough levels of drug or ADAs during loss of response. An additional subanalysis was performed including only patients with a definite inflammatory loss of response (clinical worsening associated with increased levels of C-reactive protein or fecal calprotectin, or detection of inflammation by endoscopy, fistula discharge, or imaging studies). Results Among 247 patients (42 with ulcerative colitis), there were 330 loss-of-response events (188 to infliximab and 142 to adalimumab). Trough levels of adalimumab greater than 4.5 mcg/mL and infliximab greater than 3.8 mcg/mL identified patients who failed to respond to an increase in drug dosage or a switch to another anti-TNF agent with 90% specificity; these were set as adequate trough levels. Adequate trough levels identified patients who responded to expectant management or out-of-class interventions with more than 75% specificity. Levels of antibodies against adalimumab >4 microgram per mL equivalent (mcg/mL-eq) or antibodies against infliximab >9 mcg/mL-eq identified patients who did not respond to an increased drug dosage with 90% specificity. Patients with high titers of ADAs had longer durations of response when anti-TNF agents were switched than when dosage was increased ( P = .03; log-rank test), although dosage increases were more effective for patients with no or low titers of ADAs ( P = .02). An analysis of definite inflammatory loss-of-response events (n = 244) produced similar results; patients with adequate trough levels had a longer duration of response when they switched to a different class of agent than when anti-TNF was optimized by either a dosage increase or by a switch within the anti-TNF class ( P = .002; log-rank test). Conclusions The results of this retrospective analysis suggest that trough levels of drug or ADAs may guide therapeutic decisions for more than two-thirds of inflammatory bowel disease patients with either clinically suspected or definite inflammatory loss of response to therapy.

Intestinal dysmotility and neurogenic bladder have been described as part of two autosomal-recessive mitochondrial disorders assumed to be due to a defect in communication between the nuclear and mitochondrial genomes: myoneurogastrointestinal encephalopathy (MNGIE) and diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome). Partial cytochrome c oxidase deficiency has been described in both. We describe three Ashkenazi Jewish siblings with progressive intestinal dysmotility, neurogenic bladder, and autonomic manifestations but no central nervous system involvement. Cytochrome c oxidase deficiency was demonstrated in peripheral and multiple intestinal muscle biopsies. Mitochondrial DNA analysis of an intestinal biopsy of patient 1 showed heteroplasmy consisting of a normal 16.5-kb band and an approximately 28-kb band, suggestive of a duplication. Mitochondrial DNA analysis of a muscle biopsy of patient 2 showed multiple deletions, mainly 10- and 11-kb bands. We suggest that this unique combination of intestinal pseudo-obstruction and neurogenic bladder could comprise a new autosomal-recessive mitochondrial disorder. ( J Child Neurol 2000;15:386-389).

Iron supplementation is one of the principal therapies in inflammatory bowel disease. Iron is a major prooxidative agent; therefore therapeutic iron as well as heme iron from chronic mucosal bleeding can increase the iron-mediated oxidative stress in colitis by facilitating the Fenton reaction, namely production of hydroxyl radicals. In the present study colitis was induced in the iodoacetamide rat model. Forty male Whistar rats were divided into four groups, each group receiving a different diet regimen in parallel with colitis induction: Malondialdehyde was measured to assess the degree of tissue oxidative stress. There were microscopic changes, and significantly more severe colitis was seen in colonic biopsies when iron was supplemented. It was concluded that iron supplementation can amplify the inflammatory response and enhance the subsequent mucosal damage in a rat model of colitis. We suggest that the resultant oxidative stress generated by iron supplementation leads to the extension and propagation of crypt abscesses.

Glucose galactose malabsorption (GGM) is a rare autosomal recessive disorder characterized by life-threatening osmotic diarrhea at infancy. When the intake of the offending sugars (namely, glucose, galactose and lactose) is ceased, the diarrhea promptly stops. Mutations in the SLC5A1 gene, encoding the sodium-glucose co-transporter located in the brush border of enterocytes, have been shown to cause the disease. More than 300 subjects of diverse origin have been reported worldwide, most of whom are a result of a consanguineous union. We examined 6 patients from 4 families presenting with complaints consistent with GGM and responsive to the appropriate fructose-based diet. Genomic DNA of the patients was polymerase chain reaction amplified for each of the 15 exons of the SLC5A1 gene and analyzed by nucleotide sequencing. The analysis lead to the identification of 2 novel mutations: a 1915 del C mutation, a frameshift mutation leading to a premature stop at codon 645; and a substitution missense mutation of T to C on nucleotide 947 (exon 9) causing a L316P substitution. In addition, G426R and C255W mutations previously described were identified; in both cases, the patients were shown to be homozygous and their parents heterozygous for the mutation. Of note, additional patients who underwent a similar evaluation at our center for suspected GGM did not show mutations in the SLC5A1 gene. Because the latter did not previously undergo a diagnostic algorithm in full, for instance, one that may consist of a glucose breath hydrogen test and an empiric attempt of a dietary switch to galactomin, we suggest that molecular genotyping of such patients should only follow such appropriate clinical evaluation.

OBJECTIVE: The main objective is to study whether the month of birth is associated with the development of Crohn's disease (CD) in the Israeli Jewish population. BACKGROUND: It was suggested that perinatal exposure to infectious agents may have a role in the pathogenesis of CD. Due to the seasonal nature of some infections, a linkage between birth dates and a risk to develop CD would support such a hypothesis. Previous studies that addressed this question were conducted in Europe and differed in their findings. METHODS: Birth dates of 844 Jewish ulcerative colitis (UC) and CD patients from three medical centers representing the north, central, and the south of Israel were compared with the monthly rates of birth during the same period of time. The standard incidence ratio was used to define the risk to develop either disease according to the month of birth. The Score method was used for the evaluation of seasonality trends. RESULTS: Birth during the winter period in Israel was associated with increased risk to develop CD, whereas birth during the spring was associated with a reduced risk. The Score method for seasonality showed a significant peak during winter time in these patients (z = 2.02, p = 0.021). No such seasonal variation was noted for UC patients. CONCLUSIONS: A seasonal pattern was observed in the risk to develop CD but not UC. The findings may support the involvement of environmental factors in the pathogenesis of CD.

Assessment of fecal calprotectin, a surrogate marker of mucosal inflammation, is a promising means to monitor therapeutic response in pediatric inflammatory bowel disease, especially if the result is readily available. We tested the performance of a novel calprotectin rapid test, Quantum Blue, versus the conventional enzyme-linked immunosorbent assay in 134 stool samples from 56 pediatric patients with Crohn disease. The intraclass correlation coefficient analysis reflected good agreement (intraclass correlation coefficient 0.97 [95% confidence interval 0.95-0.98]) but agreement was better in lower values, where dilutions were not required. Using a cutoff of 100 μg/g for normal values, the percentage agreement between the 2 tests was 87%. The optimal cutoff values to guide clinical decisions in the therapy of inflammatory bowel disease have yet to be determined.

Low vitamin B-6 status, based on plasma concentrations of pyridoxal-5-phosphate (PLP), has been identified in inflammatory diseases, including cardiovascular disease, rheumatoid arthritis, inflammatory bowel disease, and diabetes. Our objective was to examine the association between plasma PLP and multiple markers of inflammation in a community-based cohort [n = 2229 participants (55% women, mean age 61 ± 9 y)]. We created an overall inflammation score (IS) as the sum of standardized values of 13 individual inflammatory markers. Multivariable-adjusted regression analysis was used to assess the associations between the IS and plasma PLP. Geometric mean plasma PLP concentrations were lower in the highest tertile category of IS relative to the lowest (61 vs. 80 nmol/L; P-trend < 0.0001). Similarly, the prevalence of PLP insufficiency was significantly higher for participants in the highest compared with the lowest tertiles for IS categories. These relationships persisted after accounting for vitamin B-6 intake. Also, there were significant inverse relationships between plasma PLP and 4 IS based on functionally related markers, including acute phase reactants, cytokines, adhesion molecules, and oxidative stress. In addition, secondary analyses revealed that many of the individual inflammatory markers were inversely associated with plasma PLP after adjusting for plasma C-reactive protein concentration. This study, in combination with past findings, further supports our hypothesis that inflammation is associated with a functional deficiency of vitamin B-6. We discuss 2 possible roles for PLP in the inflammatory process, including tryptophan metabolism and serine hydroxymethyltransferase activity.

BACKGROUND & AIMS: There are few data on risk of travel for patients with inflammatory bowel disease (IBD). We assessed rates of illness while traveling among patients with IBD. METHODS: We performed a retrospective, case-controlled study of illnesses among 222 patients with IBD and 224 healthy individuals (controls) during 1099 total trips. Data were retrieved by structured questionnaires, personal interviews, and chart review. RESULTS: Participants had 142 episodes of illness during the trips; 92% were enteric disease. An episode of illness occurred during 79/523 (15.1%) trips made by patients with IBD compared with 63/576 (10.9%) trips made by controls (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.01‐2.0; P .04). However, this difference was mostly attributable to the increased incidence of illness among IBD patients traveling in industrialized countries. In contrast, the rate of illness among travelers to developing countries was similar among patients with IBD and controls (34/200, 17% vs 52/243, 21% of trips, respectively; P .24). Moreover, numerically more controls that traveled to the tropics developed illness than travelers with IBD (43/135 vs 23/97, respectively; P .18). In multivariate analysis, factors that increased risk for travel illness included frequent flares of IBD (OR, 1.9; 95% CI, 1.1‐3.4; P .02) and prior IBD-related hospitalizations (OR, 3.5; 95% CI, 1.3‐9.3; P .01); remission within 3 months before traveling reduced the risk for illness (OR, 0.3; 95% CI, 0.16‐0.5; P .001). Use of immunomodulatory drugs was not independently associated with risk of illness during travel. CONCLUSIONS: Patients with IBD have a higher rate of illness compared with controls during trips to industrialized countries, but not to developing or tropical regions. These findings indicate that most travelassociated illnesses stem from sporadic IBD flares rather than increased susceptibility to enteric infections.

Laparoscopic cholecystectomy is rapidly replacing traditional cholecystectomy as the standard treatment for cholelithiasis and cholecystitis in adults. Over a period of 16 months, 14 children with a clinical diagnosis of cholelithiasis, ranging in age from 4 to 15 years (mean 12.2), were treated. All had symptoms of abdominal pain or vomiting; one had jaundice and recurrent cholecystitis. Five children (35%) had associated metabolic or hemolytic diseases. The 14 children were operated on using the laparoscopic cholecystectomy technique. No operation was converted to open cholecystectomy, but two patients required laparotomy: one because of suspected injury to the common duct, and the other because of nonvisualization of the gallbladder during laparoscopy. The mean post-operative hospital stay for the 11 children who underwent only laparoscopic cholecystectomy (one patient also had a simple mastectomy) was 50 hours (range 48-72 hours). All children resumed their normal activities almost immediately after discharge from hospital. No long-term biliary or other complications were seen in any patient throughout an average follow-up period of 6.2 months (range 3-16 months). The benefits of this operation in children are obvious: It is safe, effective, and well tolerated.

Further understanding of the clinical manifestations, hospital course and treatment options of the 2009 pandemic H1N1 influenza virus (H1N1) is needed in preparation for future outbreaks.Seventy-three children with polymerase-chain-reaction-confirmed infections with H1N1 treated in a tertiary care medical center in Israel were included in the study. Clinical data were extracted from medical records, and analyzed by hospitalization status or the presence of underlying chronic medical conditions.Prevalent symptoms were fever, cough and shortness of breath, with additional findings of conjunctivitis, seizures, chills, dizziness, purpuric rash and chest pain. Hospitalized patients were more likely to have shortness of breath (OR 26.7, 95%CI: 3.5-1150), abnormal lung auscultation (OR 11.6, 95%CI: 2.8-67), abnormal X-ray (OR 3.3, 95%CI: 1.1-9.6), and a chronic illness (OR 5.4, 95%CI: 1.8-17), compared with non-hospitalized ones. Disease manifestations were similar between children with or without chronic diseases. Only two (2.7%) children required intensive care, and no deaths were recorded. A high rate (18%) of thrombocytopenia was found. One child had rapid symptom resolution after intravenous immunoglobulin treatment.H1N1 infection follows a mild course, even in the presence of severe underlying diseases. Abnormal respiratory findings and the presence of a chronic disease probably contributed to the decision to hospitalize patients. A rapid resolution of H1N1 symptoms after intravenous immunoglobulin treatment warrants further study, and could be a possible therapeutic option for severe cases.

Probiotics reduce intestinal inflammation in, and Lactobacillus GG (LGG) reduces pulmonary exacerbation rate cystic fibrosis (CF) patients. We intended to determine the effect of a mixed probiotic preparation on pulmonary exacerbations and inflammatory characteristics of the sputum in CF patients.A prospective pilot study of 10 CF patients with mild-moderate lung disease and Pseudomonas aeruginosa colonization, treated with probiotics for 6 months. Pulmonary function tests (PFT's), sputum cultures with semi-quantitative bacterial analysis, and sputum neutrophil count and interleukin-8 (IL-8) levels were compared to pre-treatment and post-treatment values. The rate of pulmonary exacerbations was compared to 2 years prior to the study.The exacerbation rate was significantly reduced in comparison to the previous 2 years and to 6 months post-treatment (P = 0.002). PFT's have not changed at the end of treatment and during 6 months post-treatment. No change in sputum bacteria, neutrophil count, and IL-8 levels was observed.Probiotics reduce pulmonary exacerbations rate in patients with CF. Probiotics may have a preventive potential for pulmonary deterioration in CF patients.

Only a few studies have addressed the subject of physical manifestations in children with attention deficit hyperactivity disorder (ADHD) and gastrointestinal (GI) complaints, although pharmacological treatments for ADHD may have GI symptoms as a main side effect.The goal of this study was to assess whether children with ADHD have a higher frequency of GI symptoms compared with healthy children in the general population.The study group included 62 children with ADHD and 57 healthy children as a control group. The childrens' parents were asked to report on abdominal pain, diarrhea, constipation, encopresis, food intolerance or allergy. Height, weight and the medical data of the two groups were compared.A higher frequency of food allergies was found in the ADHD group, but the relationship was at near significant levels only (p = 0.06), and open to criticism.This study showed no obvious correlation between GI symptoms and ADHD in Israeli children.

The D-xylose absorption test has been used during the last four decades for evaluation of malabsorption in the small intestine. However, some disagreement still exists about the recommended method of performing this test: the 1-hr blood test, the 5-hr urine test, or both. We evaluated the test by performing 125 combined blood and urine tests in 111 patients. Normal xylose absorption was recorded in both blood and urine in 71 tests (group A, 56.8%). Abnormal test results in both blood and urine were recorded in 29 patients (group B, 23.2%). Only one patient had a pathological blood value and normal xylose excretion in the urine. Twenty-four patients (group D, 19.2%) had normal 1-hr blood xylose (greater than 25 mg/100 ml) with abnormal 5-hr urine xylose (less than 4.5 g/5 hr). Fat and/or bile salt malabsorption were documented in 21 patients (87.5%) of this group using stool fat analysis and the [14C]cholylglycine breath test. These data suggest that in adults the 5-hr urine collection more accurately reflects intestinal absorption in comparison with the 1-hr blood value.

Asialoglycoprotem receptor is an abundant protein localized in the sinusoidal domain of the hepatocyte plasma membrane. Its principle function is the clearance of serum glycoproteins which include several acute phase reactant proteins that have lost their terminal sialic acid residue. It has been reported that asialoglycoprotem receptor is nearly absent in mammalian fetal liver but rises to adult levels during the early postpartum period. The hypothesis to be tested was to determine whether defective glycoproteins, those lacking terminal sialic acid residues, are accumulated in fetal serum as a result of reduced receptor content. It was found that low levels of asialoglycoprotem receptor in 18-day-old fetal liver correlated to a threefold higher level of total asialoglycoproteins in fetal serum than adult serum as determined by a modified Western blot protocol employing radioiodinated ricinus communis agglutinin, a galactose-binding lectin. As hepatic asialoglycoprotem receptor accumulated at the time of birth, the elevated level of serum asialoglycoproteins decreased to adult values in an opposite manner. This study indicates that the hepatic asialoglycoprotem receptor plays an important role in reducing the amount of circulating defective glycoproteins at the time of birth.

Behcet disease (BD) is an inflammatory disorder of unknown origin. We present here an unusual case of juvenile Behcet with hemoptysis due to large pulmonary artery aneurysms (PAA), large intra-cardiac thrombus and prolonged fever, which posed several therapeutic challenges. In this case, a 14-year-old boy was admitted with a 3-month history of fever, painful oral ulcers, skin rash and intermittent hemoptysis. A high resolution helical computed tomography angiogram demonstrated thrombi in the right ventricle, two large aneurysms located in the right lung and two smaller ones in the left. The patient was successfully treated with colchicine, prednisone, cyclophosphamide and enoxaparine. A discussion about PAA and intracardiac thrombi and their role in BD is provided in this case.

This article presents the case of an infant who on routine physical examination at the age of 5 months was found to have hepatomegaly. The initial investigation revealed borderline liver function tests, and ultrasonography showed multiple space-occupying lesions. Further workup using different imaging techniques, urinary vanillylmandelic acid, serum catecholamines, and liver biopsy led to the diagnosis of stage IV-S neuroblastoma. No primary site outside of the liver could be demonstrated. The tumor regressed spontaneously.

Summary Numerous reports have established the association of Helicobacter pylori and peptic ulcer disease in adults. Recently, this association has also been demonstrated in children. We investigated 14 children and adolescents with recurrent abdominal pain. In six patients, endoscopy revealed gastritis and Helicobacter pylori was identified. Giemsa stain was more sensitive than culture or urease testing in identifying the bacteria. In four of the six, a nodular appearance of the antral mucosa was observed. The histological examination suggests lymphoid hyperplasia as the cause of the nodularity. All of the patients became symptomless after combined treatment with amoxicillin and bismuth subsalicylate. We conclude that nodular gastritis is a peculiar type of gastritis in children. It is frequently found in association with Helico-bacter pylori infection.

The expression of four integral membrane glycoproteins was examined in detail utilizing monospecific antibodies during liver development. These included asialoglycoprotein receptor, a hepatocyte glycoprotein residing in the sinusoidal domain, and three bile canalicular glycoproteins, leucine aminopeptidase, dipeptidyl peptidase IV, and a Mr 110,000 glycoprotein denoted GP 110. It was observed that asialoglycoprotein receptor, GP 110, and dipeptidyl peptidase IV were present in low amounts in fetal liver and reached adult levels between 1 to 3 weeks. In contrast, leucine aminopeptidase was present in nearly adult amounts in 18-day-old fetal livers. These observations were qualitatively confirmed by indirect immunofluorescent staining of frozen thin liver sections obtained from fetal and adult rats. Further, in fetal livers it was found that leucine aminopeptidase was not localized to typical bile canalicular areas. Immunoprecipitation studies performed in the presence of proteolytic inhibitors using detergent-solubilized extracts of metabolically labeled liver minces revealed that GP 110 was present in low amounts as Mr 110,000 and Mr 105,000 polypeptides in 17-day fetal livers but by 21 days of gestation the larger polypeptide was the major synthesis product. Conversely, the apparent molecular weights of leucine aminopeptidase and dipeptidyl peptidase IV were not altered during development. Experiments determining relative rates of synthesis using excess amounts of antibodies showed that the concentrations of the three bile canalicular glycoproteins in liver during ontogeny reflect their rates of synthesis. These results underscore that plasma membrane constituents of the hepatocyte undergo dramatic changes in expression and localization as the liver changes its physiological role at birth.

The Fibrotest-Actitest is a six-parameter scoring system that allows quantification of liver fibrosis and inflammation. This test has been validated by several studies in hepatitis B and C viruses and alcoholic liver disease, with a high correlation between the liver biopsy and the results of the FT-AT (AUROC between 0.78 and 0.95). The FT-AT was introduced in Israel (Rambam Laboratory) in March 2005.To assess the results of HCV patients who underwent the test during the period March 2005 to February 2006.Serum was taken and brought to the central laboratory performing the tests within 4 hours. Six parameters were evaluated using commercial kits approved by the designer of the test (Biopredictive): total bilirubin, gamma-glutamyltransferase, alpha-2 macroglobulin, haptoglobin, alanine aminotransferase, and apolipoprotein-A1. The results were sent to the website of Biopredictive (France), which provided the FT-AT score online using a patented formula.Of the 325 patients tested, only 4 were not interpretable because of hemolysis. Patients' age ranged from 7 to 72 years (median 42); 54% were female. Liver biopsy was performed in 81 patients and was compared with the results of the Fibrotest. Findings were as follows: 27% of the patients were F0, 19% F1, 20% F2, 17% F3 and 17% F4; 18% were A0, 32% A1, 28% A2 and 22% A3. The AUROC curve comparing the Fibrotest with liver biopsy with a cutoff point at F2 and A2 for significant fibrosis and inflammation was 0.85 and 0.79 respectively.Fibrotest is a simple and effective method to assess liver fibrosis and inflammation and can be considered an alternative to liver biopsy in most patients with HCV.

Several studies have shown a linear correlation between nutritional status and pulmonary function in patients with cystic fibrosis. Our study aims were: 1) To evaluate the effect of nutritional supplementation via gastrostomy on nutritional, clinical, and pulmonary parameters, and 2) To identify predicting factors for success of long-term nutritional rehabilitation.Twenty-one Israeli patients, aged 8 months to 20 years, underwent gastrostomy insertion from 1992 to 2001. All patients were pancreatic insufficient, and all carried severe mutations (W1282X in 62% of the patients). Anthropometric and clinical data were obtained for each patient: 0-12 months before and 6-12 months and 18-24 months after gastrostomy placement. Standard deviation scores (SDS) for height, weight, and body mass index as well as percent of height-appropriate body weight were calculated.The mean percent-of-predicted forced expiratory volume in 1 second (FEV1) decreased significantly during the first year of gastrostomy feeding (n = 16), from 44.2% +/- 13.9 to 41% +/- 13.3 (P = 0.05). However, during the second year of therapy (n = 10), a trend toward improvement was observed (from 39.4 +/- 12.1 to 41.4 +/- 16.1). Weight, and BMI z-scores as well as weight percent-of ideal body weight increased significantly. Height z-score for age decreased during the first year (from -1.9 +/- 1.3 to -2.1 +/- 1.4), However, a trend toward improvement was observed during the second year. A significant correlation was found between the change in weight z-score and height z-score during the first (r = 0.488, P = 0.016) and the second (r = 0.825, P0.001) years. There was no difference between compliers and noncompliers regarding height, weight, and BMI either before or after gastrostomy placement. A significant correlation between age at insertion of gastrostomy and improvement in height z-score (r = 0.52, P = 0.016) was observed. Cystic fibrosis related diabetes (n = 8) did not affect the response to supplemental feeding.We observed a trend toward improvement of pulmonary disease during the second year, and a significant improvement in weight, height, and BMI z-scores. Compliance, diabetes, and young age prior to tube insertion did not predict success of nutritional rehabilitation.

Ulcerative colitis and Crohn disease may present before the age of 20 years in 25% to 30% of all patients with inflammatory bowel disease. Reported incidence figures vary considerably depending on the collection of data. Multicenter, multinational collaboration is needed when studying pediatric inflammatory bowel disease. The essential first step is uniformity in the work-up and criteria used for diagnosis. The Porto diagnostic criteria presented here provide the tool that is needed. These criteria are the result of consensus reached by the ESPGHAN inflammatory bowel disease working group. Diagnosis of Crohn disease, ulcerative colitis and indeterminate colitis is based on clinical signs and symptoms, endoscopy and histology and radiology. Every child suspected of inflammatory bowel disease should undergo a complete diagnostic program consisting of colonoscopy with ileal intubation, upper gastrointestinal endoscopy and (in all cases except in definite ulcerative colitis) radiologic contrast imaging of the small bowel. Multiple biopsies from all segments of the gastrointestinal tract are needed for a complete histologic evaluation. A diagnosis of indeterminate colitis cannot be made unless a full diagnostic program has been performed.

Obesity is a serious health problem, and is becoming increasingly common in affluent societies. In 1998, an Expert Committee published guidelines regarding obesity evaluation and treatment. The purpose of this study was to assess the attitude of primary care physicians in Israel toward diagnosis and treatment of childhood obesity, as related to the recommended guidelines. Primary physicians caring for children and adolescents were asked to complete an anonymous questionnaire including personal and professional details, methods of diagnosis, documentation and treatment of childhood obesity, and familiarity with and implemention of the Expert Committee recommendations. One hundred forty-four physicians, treating approximately 100,000 children monthly, completed the questionnaire. Ninety-four percent were considered to have diagnosed obesity properly. Furthermore, only 19% reported weighing all children examined, while 99% of the physicians suggested some treatment for obesity. The most frequent recommendations for managing obesity were referral to a dietitian (92%), physical exercise (85%), and group treatment (27%). The majority of physicians (78%) were not familiar with the new Expert Committee recommendations regarding obesity treatment. This study suggests that the majority of primary physicians diagnose obesity properly and recommend accepted modalities to manage obesity. A comprehensive program to prevent and treat obesity is recommended to improve the health status of the population.

Objectives The allelic variants in the NOD2/CARD15 gene G908R, R702W, and 1007fs are strongly and independently associated with susceptibility to Crohn's disease (CD). Our aim was to compare the NOD2/CARD15 genotype and the genotype-phenotype correlation in Jewish pediatric patients with CD (≤16 years of age) with older patients with CD. Study design Carrier frequencies of the three variants were determined in 67 children and 144 adults with CD. Variants were detected by using allele-specific polymerase chain reaction and restriction enzyme digestion assay. Demographic and phenotypic characterizations of the patients were determined. Results The carrier rate of the three NOD2/CARD15-associated variants was 51.5% in children and 37.5% in adults ( P = .07). The most prevalent allele variant was G908R (allele frequency 18% in children, 11% in adults; P = .063). Young Ashkenazi patients had the highest allele frequency of G908R, and higher than Ashkenazi adults: 25% and 9%, respectively ( P = .003). Children had more family history of inflammatory bowel disease and more inflammatory-type disease, with no relation to variant allele carriage. Conclusions G908R allele-variant of the NOD2/CARD15 gene is closely related with the appearance of CD at a young age in Jewish Ashkenazi patients.

We prospectively evaluated a 13 C urea breath test (UBT) that involves passive continuous sampling for diagnosis of Helicobacter pylori in 72 children. Results were obtained within 10 minutes in 96% of patients. The test is rapid, user-friendly, and has 100% concordance with conventional diagnostic methods.

Screening for celiac disease is based on the sequential evaluation of serologic tests and intestinal biopsy; an optimal screening protocol is still under investigation. The screening policy of one of the main healthcare providers in Israel (Maccabi) consists of measuring total immunoglobulin A and tissue transglutaminase IgA antibodies and confirming positive results by endomysial antibodies. For IgA-deficient patients antigliadin IgG is measured.To evaluate the use of tTGA as a first-level screening test in patients suspected of having celiac diseaseThe results of tTGA and EMA tests over a 3 month period were obtained from the laboratory computer. Letters were sent to the referring physicians of patients with positive tests, requesting clinical information and small intestinal biopsy results. tTGA was performed using an anti-guinea pig tTG-IgA enzyme-linked immunosorbent assay kit.Overall, 2,505 tTGA tests were performed: 216 (8.6%) were tTGA-positive of which 162 (75%) were EMA-negative (group 1) and 54 (25%) EMA-positive (group 2.) Clinical information was obtained for 91 patients in group 1 and 32 in group 2. Small intestinal biopsy was performed in 33 (36%) and 27 patients (84%) in groups 1 and 2, respectively. Celiac disease was diagnosed in 4 biopsies (12%) in group 1 and 23 (85%) in group 2 (P0.0001). The positive predictive value was 45% for tTGA and 85% for EMA.Symptomatic patients with positive tTGA and negative EMA have a low rate of celiac disease compared to those who are tTGA-positive and EMA-positive. Confirmation with EMA is advised when tTGA is performed as a first-level screening for suspected celiac disease.

We investigated whether there are independent intradaily changes in bilirubin levels in neonates. Healthy term newborn infants (n = 124) with neonatal jaundice bilirubin >/t171 mmol/L (10mg/dl) were studied for at least 3 consecutive days. Starting from the second day of life, consistent intradaily changes were observed in bilirubin levels (morning levels were greater than evening levels; p < 0.001), and body weight steadily increased. This diurnal variation in bilirubin levels should be considered in the follow-up and treatment of neonatal jaundice.