The Variable Response to Teduglutide in Pediatric Short Bowel Syndrome: A Single Country Real-Life Experience.

OBJECTIVES: The glucagon-like peptide-2 analog Teduglutide has been shown to enhance intestinal absorption and decrease parenteral nutrition (PN) requirements in short bowel syndrome (SBS). As data in children is limited, we evaluated nationwide real-life experience and treatment outcome in children with SBS. METHODS: Longitudinal data of children treated with Teduglutide for ≥3 months was collected. Data included demographic and medical background, anthropometrics, laboratory assessments and PN requirements. Treatment response was defined as >20% reduction in PN requirement. RESULTS: The study included 13 patients [54% males, median (interquartile range {IQR}) age of 6 (4.7-7) years]. The most common SBS etiology was necrotizing enterocolitis (38%), and median (IQR) small bowel length was 20 (15-40) cm. Teduglutide treatment ranged between 3 and 51 months [median (IQR) of 18 (12-30) months], with 10 patients (77%) treated >1 year. Response to treatment was observed in 8 patients (62%), with a mean [±standard deviation (SD)] treatment duration of 5.9 (±3.2) months. Among responders, 2 patients were weaned off PN and additional 4 decreased PN needs by >40%. There was a median (IQR) reduction in PN volume/kg of 36% (15%-55%) and in PN energy/kg of 27% (6%-58%). Response was not associated with patients' background, and no correlation was found with bowel length or PN dependency at baseline. CONCLUSIONS: Real-life response to Teduglutide is highly variable among children with SBS. While most patients did reach 20% reduction in PN, less achieved further significant reduction or enteral autonomy. No predictive factors of response to treatment were identified, and large multicenter studies are needed to elucidate predictive factors and long-term outcome.

Monitoring Enables Progress: A Nationwide Quality Improvement Program in Children With Crohn Disease.

OBJECTIVES: In this quality improvement program, named quality in pediatric inflammatory bowel disease, we constructed a nation-wide platform that prospectively recorded clinically important quality indicators in pediatric inflammatory bowel diseases (PIBD), aiming at improving clinical management across the country. METHODS: Representatives of all 21 PIBD facilities in Israel formed a Delphi group to select quality indicators (process and outcomes), recorded prospectively over 2 years in children with Crohn's disease 2-18 years of age seen in the outpatient clinics. Monthly anonymized reports were distributed to all centers, allowing comparison and improvement. Trends were analyzed using the Mann-Kendall test, reporting τ (tau) values. RESULTS: The indicators of 3254 visits from 1709 patients were recorded from September 2017 to September 2019 (mean age 14.7 ±â€Š3.1 years, median disease duration 1.8 years (interquartile range 0.69-4.02)). An increase in three of five process indicators was demonstrated: obtaining drug levels of anti-tumor necrosis factor (TNF) (τ = 0.4; P = 0.005), utilization of fecal calprotectin (τ = 0.38; P = 0.008) and bone density testing (τ = 0.45; P = 0.002). Among outcome indicators, three of nine improved as measured during the preceding year: calprotectin <300 µg/mg (τ = 0.35; P = 0.015), and "resolution of inflammation" defined as a composite of endoscopy, imaging and fecal calprotectin (τ = 0.39; P = 0.007). Endoscopic healing reached borderline significance (τ = 0.28; P = 0.055). An increase in the use of biologics throughout the study was observed (τ = 0.47; P = 0.001) with a concurrent decrease in the use of immunomodulators (τ = -0.47; P = 0.001). CONCLUSIONS: Quality improvement nationwide programs can be implemented with limited resources while facilitating standardization of care, and may be associated with improvements in measured indicators.

The association between semaphorin 3A levels and gluten-free diet in patients with celiac disease.

Celiac disease (CD) is an inflammatory disease affecting the small intestine. We aim to assess serum level and expression of semaphorin 3A (Sema3A) on T regulatory (Treg) cells in CD patients. Twenty-six newly diagnosed celiac patients, 13 celiac patients on a gluten-free diet and 16 healthy controls included in the study. Sema3A protein level in the serum of celiac patients was significantly higher compared to healthy group (7.17±1.8ng/ml vs. 5.67±1.5ng/ml, p=0.012). Sema3A expression on Treg cells was statistically lower in celiac patients compared to healthy subjects (p=0.009) and significantly lower in celiac patients compared to celiac patients on gluten free diet (p=0.04). Negative correlation was found between Sema3A on Teg cells and the level of IgA anti-tTG antibodies (r=-0.346, p<0.01) and anti-DGP (r=-0.448, p<0.01). This study suggests involvement of the Sema3A in the pathogenesis of CD.

Activated Notch signaling cascade is correlated with stem cell differentiation toward absorptive progenitors after massive small bowel resection in a rat.

Notch signaling is thought to act to drive cell versification in the lining of the small intestine. The purpose of the present study was to evaluate the role of the Notch signaling pathway in stem cell differentiation in the late stages of intestinal adaptation after massive small bowel resection in a rat. Male Sprague-Dawley rats were randomly assigned to one of two experimental groups of eight rats each: Sham rats underwent bowel transection and reanastomosis, while SBS rats underwent 75% small bowel resection. Rats were euthanized on day 14 Illumina's Digital Gene Expression (DGE) analysis was used to determine Notch signaling gene expression profiling. Notch-related gene and protein expression was determined using real-time PCR, Western blot analysis, and immunohistochemistry. From seven investigated Notch-related (by DGE analysis) genes, six genes were upregulated in SBS vs. control animals with a relative change in gene expression level of 20% or more. A significant upregulation of Notch signaling-related genes in resected animals was accompanied by a significant increase in Notch-1 protein levels (Western blot analysis) and a significant increase in the number of Notch1 and Hes1 (target gene)-positive cells (immunohistochemistry) compared with sham animals. Evaluation of cell differentiation has shown a strong increase in total number of absorptive cells (unchanged secretory cells) compared with control rats. In conclusion, 2 wk after bowel resection in rats, stimulated Notch signaling directs the crypt cell population toward absorptive progenitors.NEW & NOTEWORTHY This study provides novel insight into the mechanisms of cell proliferation following massive small bowel resection. We show that 2 wk after bowel resection in rats, enhanced stem cell activity was associated with stimulated Notch signaling pathway. We demonstrate that activated Notch signaling cascade directs the crypt cell population toward absorptive progenitors.

The significance of allergic contact urticaria to milk in children with cow's milk allergy.

BACKGROUND: Cow's milk allergy (CMA) is the most common food allergy in infancy. Food allergy is generally triggered through ingestion, but can also be triggered through skin contact. We investigated the incidence and the clinical significance of cow's milk protein (CMP)-induced contact urticaria in individuals with CMA with and without atopic dermatitis (AD). METHODS: A total of 157 children of whom 133 were diagnosed with CMA were participated. The study was based on observational data gathered in the course of patient care, including a skin prick test and a 'finger test', in which cow's milk is applied on the cheek by a physician's finger to detect contact urticaria. RESULTS: Eighty nine of 133 patients (66.9%) had IgE-mediated CMA. Forty of these 89 (44.9%) tested positive in the finger test. Family atopy was higher in those with positive contact urticaria [21/40 (52.5%) vs. 14/49 (28.5%), p = 0.029]. Patients with positive vs. negative CMP contact urticaria had higher incidence of multiple food allergies [20 of 40 (50%) vs. 7/49 (14.3%), p < 0.004]. IgE-mediated CMA patients with AD had statistically higher CMP allergic contact urticaria compared to patients without AD [71% (15/21) vs. 37% (25/68), p = 0.0064]. Children with non-IgE milk allergy and healthy control group did not have contact urticaria to CMP. CONCLUSION: CMP contact urticaria exists only in patients with IgE-mediated CMA. A 'finger test' to CMP should be part of the evaluation of CMA patients, and positivity suggests the potential for multiple food allergies, especially to sesame and egg.

Bronchial reactivity and fractional exhaled NO in Crohn's disease in the era of immunomodulating treatment.

AIM: Our aim was to determine bronchial hyper-responsiveness (BHR) and fractional exhaled NO (FeNO) in a cohort followed and treated for Crohn's disease (CD) in a Pediatric Gastroenterology Unit. METHODS: Consecutive children with CD were referred to the Pediatric Pulmonary Unit. Each patient completed a questionnaire, followed by spirometry, methacholine challenge test (MCT) and determination of FeNO. The control group included patients evaluated for functional cough who had negative MCT. RESULTS: Twenty-three children and young adults (mean age, 17.39 ± 2.96 years) with CD were compared to 24 healthy controls. 20/23 patients received immunomodulating treatment. Forced expiratory volume in 1 sec (FEV1) was significantly lower prior to (93.74 ± 10.81%, p = 0.009) and at the end of (78.91 ± 18.39%, p = 0.001) the MCT in the CD group compared with the control group (102.2 ± 10.477% and 95.33 ± 11.075%, respectively). Bronchial hyper-responsiveness was observed in 30.4% of patients with CD. FeNO levels were 15.37 ± 24.17 in CD and 11.38 ± 5.42 in the control group (p = 0.21). Neither the response to MCT nor FeNO levels were affected by the disease duration or activity index. CONCLUSION: In our series, BHR is less frequent than previously described in children with CD. We hypothesize that our finding could result from immunomodulating treatments or lower disease activity.

Hypothyroidism and dyshormonogenesis induced by D-penicillamine in children with Wilson's disease and healthy infants born to a mother with Wilson's disease.

Two siblings born to a mother with Wilson's disease, who was taking D-penicillamine, developed transient goitrous hypothyroidism. A prospective evaluation of 5 patients with Wilson's disease taking and not taking D-penicillamine for as long as 9.5 years showed subclinical hypothyroidism. D-penicillamine probably inhibited thyroperoxidase activity in utero in healthy infants and during childhood in patients with Wilson's disease.

Early performance of voiding cystourethrogram after urinary tract infection in children.

BACKGROUND: Voiding cystourethrogram is performed 3-6 weeks after urinary tract infection. This prolongs the interval of prophylactics, reducing the likelihood of having to perform the procedure. OBJECTIVES: To investigate the yield and potential risks/benefits of early compared to late performance of VCUG after UTI. METHODS: We conducted a prospective study of 84 previously healthy children < 5 years old admitted from October 2001 to November 2002 with first documented UTI. We then divided the 78 patients who had VCUG into two groups and compared them to a control group: group A--49 children in whom VCUG was performed within 10 days, group B--29 children in whom VCUG was performed > 10 days after UTI, and a historical control group C--82 children in whom VCUG was performed > 4 weeks following UTI. RESULTS: VCUG was performed in 48/48 (100%), 6/35 patients (17.1%) and 34/116 patients (29.3%), and vesicoureteral reflux was demonstrated in 38.8%, 37.9% and 39% in groups A, B and C respectively. No significant difference was found between these groups in terms of incidence of VUR and severity and grading of reflux within each group. One case of UTI secondary to VCUG occurred in a patient in whom the procedure was performed 4 months after the diagnosis. CONCLUSIONS: Performing VCUG early does not influence the detection rate, severity of the VUR, or risk of secondary infection; it shortens the period of prophylactic use and increases performance rate of VCUG, thereby minimizing the risk of failure to detect VUR. The traditional recommendation of performing VCUG 3-6 weeks after the diagnosis of UTI should be reevaluated.

Nutritional supplementation with polymeric diet enriched with transforming growth factor-beta 2 for children with Crohn's disease.

BACKGROUND: A polymeric diet rich in transforming growth factor-beta 2 used as a single nutrient has been shown to induce remission in 79% of children with Crohn's disease. OBJECTIVES: To summarize the experience of several pediatric gastroenterology units in Israel using a TGFbeta2-enriched polymeric diet (Modulen IBD) supplementation in children and adolescents with Crohn's disease. METHODS: In a retrospective study we reviewed the charts of 28 children with Crohn's disease (10 girls, 18 boys) who received, in addition to conventional treatment, Modulen IBD as a supplement to their regular nutrition. These children were compared with 18 children supplemented with standard polymeric formula (Ensure Plus) and 18 children without formula supplementation. We recorded clinical manifestations, growth, and the Pediatric Crohn's Disease Activity Index before and after initiation of the polymeric diet. RESULTS: The Modulen-treated children showed a significant decrease in PCDAI from 34.3 to 15.7 (P< 0.0001). A significant decrease in PCDAI was recorded also in the Ensure Plus group, from 35 to 22 (P= 0.02) but not in the non-supplemented group. Significant improvements in body mass index (P = 0.01) and erythrocyte sedimentation rate (P= 0.03) were recorded at follow-up (median 3.4 months) only in the Modulen IBD group. CONCLUSIONS: In this cohort of children with Crohn's disease, supplementation of the diet with Modulen IBD as well as supplementation with Ensure Plus was associated with a decrease in PCDAI. The children supplemented with Modulen IBD also showed improvement in BMI, suggesting an additional advantage of nutritional therapy in children with this disease.

Impaired gastric myolectrical activity in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is frequently associated with gastrointestinal complaints that can be due to gastrointestinal dysmotility. Electrogastrography (EGG) is an attractive, non-invasive procedure to assess gastric electric activity. The aims of our study were to investigate EGG abnormalities in pancreatic sufficient and pancreatic insufficient CF patients, and to examine whether EGG correlates with gastric emptying as assessed by scintigraphy. METHODS: EGG was performed in 23 CF patients (12 pancreatic sufficient patients, 11 pancreatic insuffficient) by using cutaneous recording pre- and postprandialy. Pre- and postpostprandial EGG indexes were compared to 19 healthy control patients. Gastric emptying was assessed simultaneously by gastric scintigraphy in 11 of the 23 CF patients. Six patients underwent a repeated scintigraphy recording following a month of treatment with cisapride. RESULTS: Abnormal patterns of EGG were found in 78.3% of CF patients compared to 31.3% of controls during fasting (p

Long-term lamivudine therapy for chronic hepatitis B infection in children unresponsive to interferon.

OBJECTIVES: Prolonged lamivudine treatment in adults has been shown to improve hepatitis B e (HBe) seroconversion rates in patients with chronic hepatitis B. This prospective open study reports the results of prolonged lamivudine treatment in a group of children with chronic hepatitis B. PATIENTS AND METHODS: Twenty-two children and adolescents age 13.2 years (range, 9.5-18 years), who have been treated with lamivudine for 1 year, continued treatment with lamivudine (3 mg/kg/day, up to 100 mg/d) as long as there was evidence of continued biochemical and virological benefit compared with baseline. We evaluated virological and biochemical responses, the occurrence of YMDD mutants and adverse effects during 4 years of follow-up. RESULTS: After 4 years on lamivudine, only 4 patients (18%) underwent HBe seroconversion. In addition, in 3 patients (13%), the treatment was stopped when lamivudine's lack of efficacy became evident. During the 4-year study period, we recorded a continuing decline in the participants' number, mostly because of lack of compliance with treatment (9/22, 41%). Only 5 children were still receiving lamivudine and showing benefit after 4 years. In 2 children, treatment termination and YMDD mutant emergence were associated with hepatitis flare. Besides subclinical elevation of creatine phosphokinase, no other adverse events were recorded during the study period. CONCLUSIONS: Four years after starting lamivudine treatment, most children from this study were off lamivudine, mainly because of lack of compliance and poor HBe seroconversion. These findings suggest that continuing treatment with lamivudine for undefined periods is hard to implement and does not improve HBe seroconversion.

Adenosine bronchial provocation with computerized wheeze detection in young infants with prolonged cough: correlation with long-term follow-up.

BACKGROUND: Chronic cough in babies is often associated with bronchial hyperreactivity (BHR). The objective documentation of BHR in babies is difficult, and acoustic methods have been described (provocative concentration of a substance causing wheeze) for conducting bronchial provocation tests (BPTs). We conducted a study to evaluate automatic computerized wheeze detection (CWD) in determining BHR in young infants with prolonged cough, and its correlation with the subsequent development of wheezing. METHODS: Infants aged < 24 months with prolonged cough (ie, > 2 months) underwent acoustic BPTs with the response determined by CWD and auscultation by a physician. Telephone interviews with parents were conducted after 1 month and yearly for the next 3 years. RESULTS: A total of 28 infants who were 4 to 24 months old with prolonged cough were included in the study. Twenty of these infants (71.4%) had BHR as determined by a positive acoustic BPT result. In 11 of these 20 tests, the CWD occurred earlier, and in 9 tests it occurred at the same step as auscultation by a physician. Rhonchi or whistles often preceded wheezes. Seventeen of the 20 patients with BHR completed 3 years of follow-up. Of these, 14 had recurrent episodes of wheezing and shortness of breath, and 3 were well. Six of the eight adenosine-negative patients completed 3 years of follow-up and had no symptoms of BHR. CONCLUSIONS: Acoustic BPT is a technically feasible test for the detection of BHR in young infants. CWD provides an earlier detection of wheeze than stethoscope auscultation. In our group of infants, a positive acoustic BPT result had high correlation with symptoms compatible with BHR over the next 3 years.

Lamivudine treatment for chronic hepatitis B infection in children unresponsive to interferon.

BACKGROUND/AIMS: Lamivudine is a potent inhibitor of hepatitis B virus (HBV) replication. This prospective open study reports the results of lamivudine treatment in children with chronic hepatitis B infection who did not respond to previous interferon treatment. PATIENTS AND METHODS: Lamivudine, 3 mg/kg/day (maximum, 100 mg/day), was given for 52 weeks to 20 children and adolescents, ages 8.5 to 19 years, with chronic hepatitis B infection who had been treated with interferon 2 to 5 years earlier. We evaluated virologic and biochemical responses, the occurrence of YMDD mutants and adverse effects. RESULTS: All children were HBV DNA+, hepatitis B e antigen (HBeAg) /anti-hepatitis B e antibody- at start of treatment. At the end of 1 year, HBV DNA declined by 95% in all patients, and 8 of 18 (44%) had sustained undetectable HBV DNA by hybridization assay. Median pretreatment alanine aminotransferase (ALT) x1.5 upper limit of normal decreased to ALT x0.9 upper limit of normal after 1 year. One child became HBeAg-negative. YMDD mutants were detected in 11 of 17 (65%) children after 1 year of lamivudine treatment. Among children with YMDD mutant variants, 54% maintained normal ALT values and 45% had undetectable HBV DNA by hybridization assay. No adverse effects were observed. CONCLUSIONS: Children with chronic hepatitis B infection treated with lamivudine after failure of interferon therapy had decreased HBV replication and improved ALT values. However, lamivudine treatment resulted in an exceptionally high rate of lamivudine-resistant mutants and low HBeAg seroconversion rate.

Serum levels of bile salt-stimulated lipase and breast feeding.

OBJECTIVES: Bile salt-stimulated lipase (BSSL) is present in the sera of healthy humans, may affect lipoprotein structure and composition, and reduce atherogenicity of oxidized LDL-cholesterol. Our aims were to examine serum levels of BSSL in breast- and formula-fed infants, and explore the influence of BSSL on serum lipid profile and oxidative status. METHODS: Infants (2-8 weeks old) were prospectively enrolled. Blood was drawn for serum levels of BSSL, total antioxidant status (TAS), and lipid profile. RESULTS: Serum levels of BSSL were similar in breast-fed (0.28 +/- 0.15 microg/l, n = 18) and formula-fed (0.31 +/- 0.09 microg/l, n = 15) infants, and were much lower than reported levels for adults. In breast-fed infants only, BSSL levels were correlated with LDL-cholesterol serum levels (r = -0.53, p = 0.04). Total cholesterol (119.2 +/- 34.3 mg/dl vs 97 +/- 27.2, and p = 0.05) and LDL-cholesterol serum levels (50.5 +/- 26.1 mg/dl vs 33.3 +/- 20.3, p = 0.05), were elevated in breast-fed compared with formula-fed infants, but TAS was similar in both groups (1.02 +/- 0.18 mmol/l and 0.98 +/- 0.12 mmol/l, respectively). CONCLUSIONS: Lack of difference in BSSL serum levels between formula- and breast-feeding, and lower BSSL levels in infants compared to adults, suggest that human milk does not contribute to BSSL serum levels.

Interferon treatment in children with chronic hepatitis B: an Israeli experience.

OBJECTIVE: To summarize the experience of two pediatric gastroenterology centers in northern Israel using interferon alpha to treat children with chronic hepatitis B. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 59 children with chronic HBV. Forty-nine children were treated with subcutaneous IFN alpha at dosages of 10 MU/m (n = 12) or 5 MU/m (n = 37) three times a week for 6 months. Children treated with 5 MU/m IFN alpha were a heterogeneous group with regard to their alanine aminotransferases levels: 11/37 (group 1) had ALT twice above the upper limit of normal and 26/37 (group 2) had normal or less than twice ULN elevations of ALT. Ten children were observed without treatment. RESULTS: Sustained biochemical and virologic response occurred in 9/12 children (75%) treated with 10 MU/m IFN alpha, 3/11 (27%) in group 1 given 5 MU/m (P = 0.0315) and 4% (1/26) in group 2 treated with 5 MU/m. After 4 years follow-up, similar seroconversion rates were present in children who had baseline ALT higher than twice ULN, whether they were treated with 10 or 5 MU/m IFN alpha (83 vs. 73%). Children with normal or slightly abnormal baseline ALT also had a similar anti-hepatitis B e antigen seroconversion rate at the end of follow-up, whether they had been treated with IFN alpha or not (2/26, 8%, in group 2 and 4/10, 40%, in the untreated children, not significantly different). CONCLUSIONS: The results of IFN alpha treatment in this group of Israeli children are similar to these reported in the literature and reinforce the current consensus, which recommends INF alpha only for children with chronic HBV and significantly elevated liver enzymes.

The role of Wnt/ß-catenin signaling in enterocyte turnover during methotrexate-induced intestinal mucositis in a rat.

BACKGROUND/AIMS: Intestinal mucositis is a common side-effect in patients who receive aggressive chemotherapy. The Wnt signaling pathway is critical for establishing and maintaining the proliferative compartment of the intestine. In the present study, we tested whether Wnt/ß-catenin signaling is involved in methotrexate (MTX)-induced intestinal damage in a rat model. METHODS: Non-pretreated and pretreated with MTX Caco-2 cells were evaluated for cell proliferation and apoptosis using FACS analysis. Adult rats were divided into three experimental groups: Control rats; MTX-2 animals were treated with a single dose of MTX given IP and were sacrificed on day 2, and MTX-4 rats were treated with MTX similar to group B and were sacrificed on day 4. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation, and enterocyte apoptosis were measured at sacrifice. Real Time PCR and Western blot was used to determine the level of Wnt/ß-catenin related genes and protein expression. RESULTS: In the vitro experiment, treatment with MTX resulted in marked decrease in early cell proliferation rates following by a 17-fold increase in late cell proliferation rates compared to early proliferation. Treatment with MTX resulted in a significant increase in early and late apoptosis compared to Caco-2 untreated cells. In the vivo experiment, MTX-2 and MTX-4 rats demonstrated intestinal mucosal hypoplasia. MTX-2 rats demonstrated a significant decrease in FRZ-2, Wnt 3A Wnt 5A, ß-catenin, c-myc mRNA expression and a significant decrease in ß-catenin and Akt protein levels compared to control animals. Four days following MTX administration, rats demonstrated a trend toward a restoration of Wnt/ß-catenin signaling especially in ileum. CONCLUSIONS: Wnt/ß-catenin signaling is involved in enterocyte turnover during MTX-induced intestinal mucositis in a rat.

Glutamine attenuates the inhibitory effect of methotrexate on TLR signaling during intestinal chemotherapy-induced mucositis in a rat.

Toll-like receptor 4 (TLR-4) is crucial in maintaining intestinal epithelial homeostasis, participates in a vigorous signaling process and heightens inflammatory cytokine output. The objective of this study was to determine the effects of glutamine (GLN) on TLR-4 signaling in intestinal mucosa during methotrexate (MTX)-induced mucositis in a rat. Male Sprague-Dawley rats were randomly assigned to one of four experimental groups of 8 rats each: 1) control rats; 2) CONTR-GLN animals were treated with oral glutamine given in drinking water (2%) 48 hours before and 72 hours following vehicle injection; 3) MTX-rats were treated with a single IP injection of MTX (20 mg/kg); and 4) MTX-GLN rats were pre-treated with oral glutamine similar to group B, 48 hours before and 72 hours after MTX injection. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation and enterocyte apoptosis were determined 72 hours following MTX injection. The expression of TLR-4, MyD88 and TRAF6 in the intestinal mucosa was determined using real time PCR, Western blot and immunohistochemistry. MTX-GLN rats demonstrated a greater jejunal and ileal mucosal weight and mucosal DNA, greater villus height in ileum and crypt depth and index of proliferation in jejunum and ileum, compared to MTX animals. The expression of TLR-4 and MyD88 mRNA and protein in the mucosa was significantly lower in MTX rats versus controls animals. The administration of GLN increased significantly the expression of TLR-4 and MyD88 (vs the MTX group). In conclusion, treatment with glutamine was associated with up-regulation of TLR-4 and MyD88 expression and a concomitant decrease in intestinal mucosal injury caused by MTX-induced mucositis in a rat.

Increased Toll-like receptor 9 expression by B cells from inflammatory bowel disease patients.

BACKGROUND: Toll-like receptors (TLRs) are important mediators of the innate immune response. Our aim was to evaluate TLR9 expression in peripheral B cells, taken from inflammatory bowel disease (IBD) patients before and after anti-inflammatory treatment. Nineteen patients with IBD (12-crohn's disease, 7-ulcerative colitis) and 18 healthy controls were included in the study. Disease severity was assessed using the Pediatric/Adults crohn's disease activity index and the ulcerative colitis activity index as needed. Accordingly, patients were classified as mild, moderate or severe disease. Peripheral B cells isolated from IBD patients, before and after anti-inflammatory treatment, and from the control group, were cultured for 24 h with and without CpG oligodeoxynucleotides (ODN-CpG) 0.5 µM. TLR9 expression by memory B cells (CD19+CD27+) was assessed by flow cytometry. RESULTS: We found that TLR9 expression by peripheral B cells was significantly higher in IBD patients than that in healthy controls (12.42 ± 9.5 MFI vs. 6.0 ± 2.6 MFI p = 0.02). The addition of ODN-CpG to B cells resulted in a significantly increase of TLR9 expression in B cells from healthy controls (6.5 ± 3.2 MFI vs. 8.8 ± 4.2 MFI p = 0.007). On the contrary, B cells from IBD patients only partly respond to the addition of ODN-CpG after anti-inflammatory treatment (6.3 ± 3.8 vs. 7.3 ± 3.7, p = 0.1). TLR9 expression was positively correlated with IBD disease severity (r = 0.681, p < 0.0001). CONCLUSIONS: TLR9 expression in memory B from IBD patients is elevated and associated with disease severity.

Dietary glutamine supplementation prevents mucosal injury and modulates intestinal epithelial restitution following acetic acid induced intestinal injury in rats.

Beneficial effects of glutamine (GLN) have been described in many gastrointestinal disorders. The aim of the present study was to evaluate the preventative effect of oral GLN supplementation against acetic acid (AA) induced intestinal injury in a rat. Male Sprague-Dawley rats were divided into four experimental groups: control (CONTR) rats underwent laparotomy, control-glutamine (CONTR-GLN) rats were treated with enteral glutamine given in drinking water (2%) 48 hours before and five days following laparotomy, AA rats underwent laparotomy and injection of AA into an isolated jejunal loop, and acetic acid-glutamine (AA-GLN) rats underwent AA-induced injury and were treated with enteral GLN 48 hours before and 5 days following laparotomy. Intestinal mucosal damage (Park's injury score), mucosal structural changes, enterocyte proliferation and enterocyte apoptosis were determined five days following intestinal injury. Western blotting was used to determine p-ERK and bax protein levels. AA-induced intestinal injury resulted in a significantly increased intestinal injury score with concomitant inhibition of cell turnover (reduced proliferation and enhanced apoptosis). Treatment with dietary GLN supplementation resulted in a decreased intestinal injury score with concomitant stimulation of cell turnover (enhanced proliferation and reduced apoptosis). In conclusion, pre-treatment with oral GLN prevents mucosal injury and improves intestinal recovery following AA-induced intestinal injury in rats.

Etiology and long-term outcome of extrahepatic portal vein obstruction in children.

AIM: To study the management and outcome of children with extrahepatic portal vein obstruction (EHPVO) in a whole country population. METHODS: A nationwide multicenter retrospective case series of children with EHPVO was conducted. Data on demographics, radiographic studies, laboratory workup, endoscopic and surgical procedures, growth and development, were extracted from the patients' charts. Characteristics of clinical presentation, etiology of EHPVO, management and outcome were analyzed. RESULTS: Thirty patients, 13 males and 17 females, 19 (63.3%) Israeli and 11 (36.7%) Palestinians, were included in the analysis. Age at presentation was 4.8 ± 4.6 years, and mean follow-up was 4.9 ± 4.3 years. Associated anomalies were found in 4 patients. The incidence of EHPVO in Israeli children aged 0-14 years was 0.72/million. Risk factors for EHPVO were detected in 13 (43.3%) patients, including 9 patients (30%) with perinatal risk factors, and 4 patients (13.3%) with prothrombotic states: two had low levels of protein S and C, one had lupus anticoagulant, and one was homozygous for methyltetrahydrofolate reductase mutations. In 56.6% of patients, no predisposing factors were found. The most common presenting symptoms were an incidental finding of splenomegaly (43.3%), and upper gastrointestinal bleeding (40%). No differences were found between Israeli and Palestinian children with regard to age at presentation, etiology and clinical symptoms. Bleeding occurred in 18 patients (60%), at a median age of 3 years. Sclerotherapy or esophageal banding was performed in 20 patients. No sclerotherapy complications were reported. Portosystemic shunts were performed in 11 patients (36.6%), at a median age of 11 (range 3-17) years: splenorenal in 9, mesocaval in 1, and a meso-Rex shunt in 1 patient. One patient underwent splenectomy due to severe pancytopenia. Patients were followed up for a median of 3 (range 0.5-15) years. One patient died aged 3 years due to mucopolysaccharidase deficiency type III. None of the patients died due to gastrointestinal bleeding. CONCLUSION: EHPVO is a rare disorder. The etiological factors are still mostly unknown, and the endoscopic and surgical treatment options ensure a good long-term prognosis.