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  • 1.
    Dahlbom, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Korponay-Szabó, Ilma R
    Kovács, Judit B
    Szalai, Zsuzsanna
    Mäki, Markku
    Hansson, Tony
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Prediction of clinical and mucosal severity of celiac disease and dermatitis herpetiformis by quantification of IgA/IgG serum antibodies to tissue transglutaminase2010In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 50, no 2, p. 140-146Article in journal (Refereed)
    Abstract [en]

    Objectives: We analysed whether the quantification of autoantibodies against tissue transglutaminase could be used to predict mucosal destruction and disease severity in patients with gluten sensitivity. Patients and Methods: One hundred seventy patients with coeliac disease (CD), comprising 52 children with severe malabsorption (group 1), 59 children with mild symptoms (group II), 59 adults (group III), 134 patients with dermatitis herpetiformis (DH), and 131 disease controls, were studied. Serial serum samples of patients in groups I and II on a gluten-free diet were also included. Serum levels of antibodies against recombinant tissue transglutaminase were determined with ELISA using standard curves for quantification of antibodies. Results: Immunoglobulin (Ig)A antibodies against tissue transglutaminase (IgA-TGA) were detected in all of the patients with CD and in 95% of the DH patients. The IgA-TGA and IgG-TGA levels were higher in group I (P < 0.001). The IgG-TGA levels and positivity rate in group I (100%)were higher than in group II (81%), group III (73%), and the DH group (67%). Elevated IgA-TGA and IgG-TGA levels in combination predicted a more severe small intestinal atrophy (P < 0.0001) with a specificity of 99% for Marsh IIIb-IIIc (flat) lesions. The kinetics of the IgA-TGA decrease during diet differed between groups I and II. Conclusions: High levels of IgA-TGA and IgG-TGA antibodies were associated with the grade of mucosal villous atrophy and a more severe clinical presentation. The combined measurement of IgA-TGA and IgG-TGA enables a noninvasive prediction of small intestinal villous atrophy with high accuracy, and may reduce the need for a biopsy in patients with suspected CD.

  • 2. Degraeuwe, Pieter L J
    et al.
    Beld, Monique P A
    Ashorn, Merja
    Canani, Roberto Berni
    Day, Andrew S
    Diamanti, Antonella
    Fagerberg, Ulrika L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Henderson, Paul
    Kolho, Kaija-Leena
    Van de Vijver, Els
    van Rheenen, Patrick F
    Wilson, David C
    Kessels, Alfons G H
    Faecal calprotectin in suspected paediatric inflammatory bowel disease.2015In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 60, no 3, p. 339-346Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The diagnostic accuracy of faecal calprotectin (FC) concentration for paediatric inflammatory bowel disease (IBD) is well described at the population level, but not at the individual level. We reassessed the diagnostic accuracy of FC in children with suspected IBD and developed an individual risk prediction rule using individual patient data.

    METHODS: MEDLINE, EMBASE, DARE, and MEDION databases were searched to identify cohort studies evaluating the diagnostic performance of FC in paediatric patients suspected of having IBD. A standard study-level meta-analysis was performed. In an individual patient data meta-analysis, we reanalysed the diagnostic accuracy on a merged patient dataset. Using logistic regression analysis we investigated whether and how the FC value and patient characteristics influence the diagnostic precision. A prediction rule was derived for use in clinical practice and implemented in a spreadsheet calculator.

    RESULTS: According to the study-level meta-analysis (9 studies, describing 853 patients), FC has a high overall sensitivity of 0.97 (95% confidence interval [CI] 0.92-0.99) and a specificity of 0.70 (0.59-0.79) for diagnosing IBD. In the patient-level pooled analysis of 742 patients from 8 diagnostic accuracy studies, we calculated that at an FC cutoff level of 50 μg/g there would be 17% (95% CI 15-20) false-positive and 2% (1-3) false-negative results. The final logistic regression model was based on individual data of 545 patients and included both FC level and age. The area under the receiver operating characteristic curve of this derived prediction model was 0.92 (95% CI 0.89-0.94).

    CONCLUSIONS: In high-prevalence circumstances, FC can be used as a noninvasive biomarker of paediatric IBD with only a small risk of missing cases. To quantify the individual patients' risk, we developed a simple prediction model based on FC concentration and age. Although the derived prediction rule cannot substitute the clinical diagnostic process, it can help in selecting patients for endoscopic evaluation.

  • 3.
    Earp, Justin C.
    et al.
    US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 3154, Silver Spring, MD 20993 USA..
    Mehrotra, Nitin
    US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 3154, Silver Spring, MD 20993 USA..
    Peters, Kristina E.
    US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 3154, Silver Spring, MD 20993 USA..
    Fiorentino, Robert P.
    US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 3154, Silver Spring, MD 20993 USA..
    Griebel, Donna
    US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 3154, Silver Spring, MD 20993 USA..
    Lee, Sue C.
    US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 3154, Silver Spring, MD 20993 USA..
    Mulberg, Andrew
    US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 3154, Silver Spring, MD 20993 USA..
    Rohss, Kerstin
    Former Employee AstraZeneca R&D Molndal, Molndal, Sweden..
    Sandstrom, Marie
    Former Employee AstraZeneca R&D Molndal, Molndal, Sweden..
    Taylor, Amy
    US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 3154, Silver Spring, MD 20993 USA..
    Tornoe, Christoffer W.
    US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 3154, Silver Spring, MD 20993 USA.;Novo Nordisc, Aalborg, Denmark..
    Wynn, Erica L.
    US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 3154, Silver Spring, MD 20993 USA..
    van der Walt, Jan-Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Astellas Pharma Europe BV, Global Clin Pharmacol & Exploratory Dev, Leiden, Netherlands..
    Garnett, Christine
    US FDA, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave,Bldg 51,Rm 3154, Silver Spring, MD 20993 USA..
    Esomeprazole FDA Approval in Children With GERD: Exposure-Matching and Exposure-Response2017In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 65, no 3, p. 272-277Article in journal (Refereed)
    Abstract [en]

    Objectives: Food and Drug Administration approval of proton-pump inhibitors for infantile gastroesophageal reflux disease has been limited by intrapatient variability in the clinical assessment of gastroesophageal reflux disease. For children 1 to 17 years old, extrapolating efficacy from adults for IV esomeprazole was accepted. The oral formulation was previously approved in children. Exposure-response and exposure matching analyses were sought to identify approvable pediatric doses. Methods: Intragastric pH biomarker comparisons between children and adults were conducted. Pediatric doses were selected to match exposures in adults and were based on population pharmacokinetic (PK) modeling and simulations with pediatric esomeprazole data. Observed IV or oral esomeprazole PK data were available from 50 and 117 children, between birth and 17 years, respectively, and from 65 adults, between 20 and 48 years. A population PK model developed using these data was used to simulate steady-state esomeprazole exposures for children at different doses to match the observed exposures in adults. Results: Exposure-response relationships of intragastric pH measures were similar between children and adults. The PK simulations identified a dosing regimen for children that results in comparable steady-state area under the curve to that observed after 20 mg in adults. For IV esomeprazole, increasing the infusion duration to 10 to 30 minutes in children achieves matching C-max values with adults. Conclusions: The exposure-matching analysis permitted approval of an esomeprazole regimen not studied directly in clinical trials. Exposureresponse for intragastric pH-permitted approval for the treatment of gastroesophageal reflux disease in children in whom it was not possible to evaluate the adult primary endpoint, mucosal healing assessed by endoscopy.

  • 4. Hossain, Md Iqbal
    et al.
    Nahar, Baitun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Hamadani, Jena D.
    Ahmed, Tahmeed
    Brown, Kenneth H.
    Effects of Community-based Follow-up Care in Managing Severely Underweight Children2011In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 53, no 3, p. 310-319Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of the present study was to assess the effects of community-based follow-up care, food supplementation, and/or psychosocial stimulation on the recovery of severely underweight children.

    Patients and Methods: A total of 507 severely underweight children (weight-for-age z score <-3) ages 6 to 24 months hospitalized at the International Center for Diarrheal Disease Research, Bangladesh, were randomly assigned to 1 of the following regimens for 3 months once they recovered from diarrhea: fortnightly follow-up care at the International Center for Diarrheal Disease Research, Bangladesh Hospital, including growth monitoring, health education, and micronutrient supplementation (group H-C, n = 102); fortnightly follow-up at community clinics, using the same treatment regimen as group H-C (group C-C, n = 99); community-based follow-up as per group C-C plus cereal-based supplementary food (SF) (group C-SF, n = 101); follow-up as per group C-C plus psychosocial stimulation (PS) (group C-PS, n - 102); or follow-up as per group C-C plus both SF and PS (group C-SF + PS, n = 103).

    Results: There were no significant differences in baseline characteristics by treatment group. Attendance at scheduled follow-up visits was greater in groups C-SF, C-SF + PS, and C-PS than in C-C and H-C; P<0.05. Rates of weight gain were greater in groups C-SF + PS, C-SF, and C-PS (0.88-1.01 kg) compared with groups C-C and H-C (0.63-0.76 kg), P<0.05. Three-factor analysis of covariance of the effects of treatment components indicated that weight gain and change in weight-for-age z score and weightfor- length z score were greater in groups that received SF (P< 0.05) and linear growth was greater among children managed in the community (P = 0.002).

    Conclusions: Positioning follow-up services in the community increases follow-up visits and promotes greater linear growth; providing SF, with or without PS, increases clinic attendance and enhances nutritional recovery. Community-based service delivery, especially including SF, permits better rehabilitation of greater numbers of severely underweight children.

  • 5. Hossain, Md Iqbal
    et al.
    Nahar, Baitun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hamadani, Jena D.
    Ahmed, Tahmeed
    Roy, Anjan Kumar
    Brown, Kenneth H.
    Intestinal Mucosal Permeability of Severely Underweight and Nonmalnourished Bangladeshi Children and Effects of Nutritional Rehabilitation2010In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 51, no 5, p. 638-644Article in journal (Refereed)
    Abstract [en]

    Objective: Lactulose/mannitol (L/M) intestinal permeability tests were completed to compare the intestinal function of severely underweight children recovering from diarrhea and other illnesses and of nonmalnourished children from the same communities, and to evaluate the effects of food supplementation, with or without psychosocial stimulation, on the changes in intestinal function among the underweight children. Patients and Methods: Seventy-seven malnourished children completed intestinal permeability studies at baseline and 3 months after receiving 1 of the following randomly assigned treatment regimens: group-C-fortnightly follow-up at community-based follow-up units, including growth monitoring and promotion, health education, and micronutrient supplementation, n = 17; group-SF-same as group-C plus supplementary food (SF) to provide 150 to 300 kcal/day, n = 23; group-PS-same as group-C plus psychosocial stimulation (PS), n = 17; or group-SF+PS-same as group-C plus SF and PS, n = 20. Seventeen nonmalnourished children were included as comparison subjects. Results: The malnourished children's mean +/- SD initial age was 13.1 +/- 4.0 months, their mean weight-for-age z score was -3.82 +/- 0.61, and their median (interquartile range) urinary L/M recovery ratio was 0.16 (0.10-0.28). Eighty-four percent of the children had L/M >= 0.07, suggestive of impaired intestinal function. The median L/M of the malnourished children was significantly greater than that of 17 relatively well-nourished children (median 0.09; interquartile range 0.05-0.12; P = 0.001). There were no significant differences in baseline characteristics of the severely malnourished children by treatment group. Following treatment, the L/M ratio improved in all of the groups (P < 0.001), but there were no significant differences in these changes by treatment group. There was a significant positive association between weight gain and the magnitude of improvement in L/M ratio (r = 0.30, P = 0.012). Conclusions: Intestinal mucosal function, as measured by sugar permeability, is impaired among severely underweight children. Intestinal permeability improves in relation to weight gain, but intestinal mucosal recovery is not specifically related to the types or amount of food supplementation or PS provided in this trial.

  • 6. Keen, Christina
    et al.
    Olin, Anna-Carin
    Eriksson, Susanne
    Ekman, Anna
    Lindblad, Anders
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Beermann, Christopher
    Strandvik, Birgitta
    Supplementation With Fatty Acids Influences the Airway Nitric Oxide and Inflammatory Markers in Patients With Cystic Fibrosis2010In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 50, no 5, p. 537-544Article in journal (Refereed)
    Abstract [en]

    Objectives: To obtain a balance in the fatty acid (FA) metabolism is important for the inflammatory response and of special importance in cystic fibrosis (CF), which is characterized by impaired FA metabolism, chronic inflammation, and infection in the airways. Nitric oxide (NO) has antimicrobial properties and low nasal (nNO) and exhaled NO (FENO), commonly reported in CF that may affect bacterial status. The present study investigates the effect of different FA blends on nNO and FENO and immunological markers in patients with CF. Patients and Methods: Forty-three patients with CF and "severe" mutations were consecutively enrolled in a randomized double-blind placebo-controlled study with 3 FA blends containing mainly n-3 or n-6 FA or saturated FA acting as placebo. FENO, nNO, serum phospholipid concentrations of FA, and biomarkers of inflammation were measured before and after 3 months of supplementation. Results: Thirty-five patients in clinically stable condition completed the study. The serum phospholipid FA pattern changed significantly in all 3 groups. An increase of the n-6FA, arachidonic acid, was associated with a decrease of FENO and nNO. The inflammatory biomarkers, erythrocyte sedimentation rate, and interleukin-8 decreased after supplementation with n-3 FA and erythrocyte sedimentation rate increased after supplementation with n-6 FA. Conclusions: This small pilot study indicated that the composition of dietary n-3 and n-6 FA influenced the inflammatory markers in CF. FENO and nNO were influenced by changes in the arachidonic acid concentration, supporting previous studies suggesting that both the lipid abnormality and the colonization with Pseudomonas influenced NO in the airways.

  • 7.
    Korponay-Szabó, Ilma R.
    et al.
    Dept. of Pediatrics, Celiac Disease Center, Heim Pál Children´s Hospital, Budapest.
    Vecsei, Zsófia
    Király, Róbert
    Dahlbom, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Chirdo, Fernando
    Nemes, Eva
    Fésüs, László
    Mäki, Markku
    Deamidated gliadin peptides form epitopes that transglutaminase antibodies recognize2008In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 46, no 3, p. 253-261Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Deamidated gliadin peptides are efficient antigens in diagnostic tests for celiac disease, and results correlate better with transglutaminase 2-based assays than those with native gliadin. We investigated whether deamidated gliadin antigens are structurally similar to transglutaminase 2 or could mimic transglutaminase epitopes. PATIENTS AND METHODS: Serum samples from 74 celiac and 65 control patients, and 13 different transglutaminase 2-specific monoclonal mouse antibodies were investigated for their binding to commercially available deamidated gliadin peptides using enzyme-linked immunosorbent assay, competition studies, and molecular modelling. RESULTS: The enzyme-linked immunosorbent assay with deamidated gliadin peptides had 100% sensitivity and 98.5% specificity in patients. Deamidated gliadin epitopes also were recognized by 3 transglutaminase-specific monoclonal antibodies, and antibodies affinity-purified with deamidated gliadin peptides from celiac patient sera reacted with transglutaminase but did not show endomysial binding. The binding of the monoclonal antibodies to deamidated gliadin was inhibited dose dependently by full-length recombinant human transglutaminase, its fragments containing the binding sites of these monoclonal antibodies, or by celiac patient antibodies. Deamidated gliadin peptides decreased the binding of transglutaminase-specific monoclonal antibodies to transglutaminase. Three different cross-reacting transglutaminase epitopes were found, of which 2 are located in the C-terminal domain and 1 is conformational. The binding of celiac serum samples to deamidated gliadin peptides could not be abolished by transglutaminase or by any of the transglutaminase-specific monoclonals, indicating that celiac sera also contain additional antibodies to gliadin epitopes different from transglutaminase. CONCLUSIONS: Certain deamidated gliadin-derived peptides and transglutaminase 2 epitopes have similar 3-dimensional appearance. This homology may contribute to the induction of transglutaminase autoantibodies by molecular mimicry.

  • 8.
    Lagerqvist, Carina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Dahlbom, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hansson, Tony
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Jidell, Erik
    Juto, Per
    Olcén, Per
    Stenlund, Hans
    Hernell, Olle
    Ivarsson, Anneli
    Antigliadin immunoglobulin A best in finding celiac disease in children younger than 18 months of age2008In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 47, no 4, p. 428-35Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The aim was to investigate age-dependent serum levels and occurrence of elevated celiac disease (CD)-related antibodies in young children, to define the optimal serological procedure when selecting for small intestinal biopsy. PATIENTS AND METHODS: Included were 428 children with biopsy verified CD (median age 16 months; range 7.5 months-14 years) and 216 controls (median age 2.7 years; range 8.5 months-14.6 years). Immunoglobulin (Ig) A antibodies against gliadin (AGA-IgA), tissue transglutaminase (tTG-IgA), and endomysium (EMA-IgA) were analysed. RESULTS: Increased serum AGA-IgA levels were found in 411 of 428 CD cases, tTG-IgA in 385 of 428, and EMA-IgA in 383 of 428. In the control group, 11 of 216 had increased levels of AGA-IgA, 5 of 216 of tTG-IgA, and 8 of 216 of EMA-IgA. In CD children younger than 18 months, elevated AGA-IgA occurred in 97% and elevated tTG-IgA and EMA-IgA were found in 83% of the cases. Conversely, in CD children older than 18 months, elevated AGA-IgA occurred in 94%, and elevated tTG-IgA and EMA-IgA were found in 99% of the cases. CONCLUSIONS: In children older than 18 months, both tTG-IgA and EMA-IgA are sufficiently accurate to be used as a single antibody marker, whereas a large proportion of younger children with CD lack these antibodies. Therefore, when selecting children for small intestinal biopsy, the detection of a combination of AGA-IgA and tTG-IgA is optimal for identifying untreated CD in children younger than 18 months.

  • 9.
    Lorentzon Fagerberg, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Lööf, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Lindholm, Johan
    Hansson, Lars-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Finkel, Yigael
    Fecal calprotectin: a quantitative marker of colonic inflammation in children with inflammatory bowel disease2007In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 45, no 4, p. 414-420Article in journal (Refereed)
    Abstract [en]

    Objectives: The protein calprotectin (S100 A8/A9) is present in neutrophils, monocytes, and macrophages. Colorectal inflammation can be detected by increased excretion of fecal calprotectin (FC). The aim of this study was to evaluate FC as a quantitative marker of inflammatory activity in children with inflammatory bowel disease (IBD). Patients and Methods: Thirty-nine children with IBD delivered a fecal spot sample and underwent colonoscopy. The samples were examined with an enzyme-linked immunosorbent assay for FC (Calprest, Eurospital, Trieste, Italy). The concentrations were correlated to macroscopic and microscopic assessments of extent and severity of inflammation in 8 colonic segments for each patient. Results: FC correlated significantly to the macroscopic extent (Spearman p=0.61) and the severity (Spearman p=0.52) of colonic inflammation and to a macroscopic, combined extent and severity score (Spearman p = 0.65). Significant correlations also were found to the microscopic extent (Spearman p=0.71) and severity (Spearman p = 0.72) of colonic inflammation and to a microscopic, combined extent and severity score (Spearman p=0.75). The median FC was 392 μg/g (95% confidence interval [CI], 278-440) in children with clinical IBD symptoms (n=23) and 32.9 μg/g (95% CI, 9.4-237) in asymptomatic IBD patients (n= 16). Of the asymptomatic children, 56% had a complete microscopic mucosal healing, and their median FC was 9.9 μg/g (95% CI, 5.9-41.9). Conclusions: FC can be used as a surrogate marker for estimation of colonic inflammation in pediatric IBD. Normalized FC concentration seems to indicate complete mucosal healing. FC is simple to obtain and analyze; this should facilitate objective assessment and monitoring of IBD activity.

  • 10.
    Mårtensson, Thomas
    et al.
    Karolinska Institutet, Department of Clinical Science, Intervention and Technology (CLINTEC), Stockholm, Sweden.
    Szakos, Attila
    Karolinska University Hospital, Department of Clinical Pathology and Cytology, Stockholm, Sweden.
    Mellgren, Karin
    University of Gothenburg, Department of Pediatrics, Institute of Clinical Sciences Sahlgrenska Academy, Sweden.
    Toporski, Jacek
    Skåne University Hospital, Department of Pediatrics, Lund, Sweden.
    Arvidson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Casswall, Thomas H
    Karolinska Institutet, Department of Clinical Science, Intervention and Technology (CLINTEC), Stockholm, Sweden.
    Gustafsson, Britt
    Karolinska Institutet, Department of Clinical Science, Intervention and Technology (CLINTEC), Stockholm, Sweden.
    Choice of Endoscopic Procedure in Children With Clinically Suspected Gastrointestinal Graft-Versus-Host Disease.2018In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 66, no 5, p. 744-750Article in journal (Refereed)
    Abstract [en]

    Objectives: Gastrointestinal graft-versus-host disease (GI-GVHD) is a potentially life-threatening complication after hematopoietic stem cell transplantation. Symptoms indicating GI-GVHD motivates endoscopy with biopsy sampling and histopathological confirmation. Optimal extent of endoscopy in children is, however, presently unknown. Therefore, we aimed to evaluate whether biopsies from the rectosigmoid area versus the rest of the colon/ileocolon with or without biopsies from simultaneous upper endoscopy, were equally reliable for detection of GI-GVHD and relevant differential diagnoses.

    Methods: Retrospective multicenter study based on histopathological re-evaluation of biopsies and hospital record data, collected from children with suspected GI-GVHD.

    Results: Forty-four children with 51 endoscopic occasions (81 procedures) were included. Thirty-nine of 51 (76.5%) were diagnosed as GI-GVHD, 14 (27.4%) received a differential diagnosis and 7 (13.7%) had normal histology findings. Comorbidity, that is, simultaneous detection of a differential diagnosis and GI-GVHD, was observed in 9 (23.1%) cases. Cytomegalovirus infection was the most frequent differential diagnosis, 6 of 7 were detected in biopsies from rectosigmoid and esophagogastroduodenal areas. Sensitivity for detection of GI-GVHD in biopsies collected from rectosigmoid-ileocolonic-, rectosigmoid-, or esophagogastroduodenal areas were 97.4%, 84.6%, 83.3%, respectively, and 97.4% when the latter 2 were merged. The difference, nondetected GI-GVHD in the rectosigmoid area versus detected elsewhere in the GI tract, was statistically significant (P = 0.03).

    Conclusions: Biopsies collected from the rectosigmoid area solely were not optimal for detection of pediatric GI-GVHD. When biopsy sampling from rectosigmoid and upper GI tract areas was combined, the sensitivity for GI-GVHD was, however, equally high as for ileocolonoscopy or full upper and lower endoscopy.

  • 11.
    Rolandsdotter, Helena
    et al.
    Södersjukhuset, Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden; Södersjukhuset, Sachs Children & Youth Hosp, Dept Gastroenterol, Stockholm, Sweden.
    Eberhardson, Michael
    Södersjukhuset, Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden; Danderyd Hosp, Dept Gastroenterol, Stockholm, Sweden.
    Fagerberg, Ulrika L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.
    Finkel, Yigael
    Södersjukhuset, Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden; Södersjukhuset, Sachs Children & Youth Hosp, Dept Gastroenterol, Stockholm, Sweden.
    Granulocyte and Monocyte Apheresis for Induction of Remission in Children With New-Onset Inflammatory Bowel Colitis2018In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 66, no 1, p. 84-89Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of the study was to analyze the effect of granulocyte and monocyte apheresis (GMA) with mesalazine for induction of remission in pediatric patients with newly onset chronic inflammatory bowel disease (IBD) colitis.

    Methods: Thirteen pediatric patients with newly onset extensive IBD colitis were investigated per the ECCO/ESPGHAN IBD protocol. Of these 13, 12 received 10 treatments with Adacolumn (ADA) during a median of 6.25 weeks in combination with low-to-moderate doses of mesalazine, which was continued after apheresis. A control colonoscopy was performed 12 to 16 weeks after GMA treatment. Primary outcomes were mucosal healing (Mayo endoscopic score) and histopathologic grading of biopsies. A secondary outcome was disease activity as measured by the Pediatric Ulcerative Colitis Activity Index.

    Results: Twelve children (6 girls) with a median age of 14.6 years and a median duration of symptoms at diagnosis of 3.2 months received all planned 10 treatment sessions with ADA. Ten of 12 patients had pancolitis and 2 of 12 extensive colitis. A final diagnosis, however, indicated ulcerative colitis in 10 children and Crohn disease in 2 children. At control colonoscopy, 8 of 12 children were in clinical remission and the Mayo endoscopic score showed significant improvement in 9 of 12 patients (P = 0.006). Complete microscopic remission, according to the Geboes score, was observed in 2 patients.

    Conclusions: In this small study GMA for induction of remission of newly onset pediatric IBD colitis was effective in 8 of 12 patients. Further controlled studies are warranted to confirm the efficacy of this treatment model.

  • 12.
    Rolandsdotter, Helena
    et al.
    Karolinska Inst, Sodersjukhuset, Dept Clin Sci & Educ, Huddinge, Sweden.;Karolinska Inst, Sodersjukhuset, Sachs Children & Youth Hosp, Dept Gastroenterol, Huddinge, Sweden..
    Jonsson-Videsater, Kerstin
    Karolinska Inst, Dept Med, Huddinge, Sweden.;Karolinska Univ Hosp, Clin Immunol & Transfus Med, Stockholm, Sweden..
    Fagerberg, Ulrika L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.
    Eberhardson, Michael
    Karolinska Inst, Sodersjukhuset, Dept Clin Sci & Educ, Huddinge, Sweden.;Danderyd Hosp, Dept Gastroenterol, Stockholm, Sweden..
    Finkel, Yigael
    Karolinska Inst, Sodersjukhuset, Dept Clin Sci & Educ, Huddinge, Sweden.;Karolinska Inst, Sodersjukhuset, Sachs Children & Youth Hosp, Dept Gastroenterol, Huddinge, Sweden..
    Mucosal Cytokine Profiles After Induction Therapy With Granulocyte/Monocyte Apheresis in New-onset Inflammatory Colitis2018In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 66, no 4, p. E103-E107Article in journal (Refereed)
    Abstract [en]

    Granulocyte/monocyte apheresis (GMA) selectively removes circulating granulocytes and monocytes; important producers of proinflammatory cytokines. Seven children with new-onset inflammatory bowel disease (IBD) colitis were treated with GMA together with mesalazine, and had significant decreases in Pediatric UC Activity Index (P=0.018) and Mayo endoscopic score (P=0.013). We investigated the colonic mucosal cytokine profiles (analyzed with real-time polymerase chain reaction), before and after induction treatment, and in 6 non-IBD controls. Significant decreases were seen in Colony Stimulating Factor 2 (P=0.018), tumor necrosis factor- (P=0.028), interleukin (IL)-23 (P=0.043), IL-1 (P=0.028), IL-36 (P=0.018), IL-10 (P=0.028), and transforming growth factor beta 1 (P=0.043) after treatment. In 6 non-IBD controls there were significantly lower levels of IL-12 (P=0.023) and IL-23 (P=0.046) compared to the patients with IBD at onset, and IL-22 (P=0.088) and IL-36 (P=0.062) showed lower values without reaching significant differences. We speculate that the decreases in colonic mucosal cytokine profiles after treatment may explain the observed clinical efficacy in the GMA-treated children with IBD.

  • 13.
    Sjöström, Elisabeth Stoltz
    et al.
    Department of Clinical Sciences, Pediatrics, Umeå University.
    Öhlund, Inger
    Department of Clinical Sciences, Pediatrics, Umeå University.
    Ahlsson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Domellöf, Magnus
    Department of Clinical Sciences, Pediatrics, Umeå University.
    Intakes of Micronutrients are Associated with Early Growth in Extremely Preterm Infants - A Population-Based Study.2016In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 62, no 6, p. 885-892Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The aim of the study was to describe micronutrient intakes and explore possible correlations to growth during the first 70 days of life in extremely preterm infants.

    METHODS: Retrospective population-based study including extremely preterm infants (<27 weeks) born in Sweden during 2004-2007. Detailed nutritional and growth data were derived from hospital records.

    RESULTS: Included infants (n = 531), had a mean gestational age of 25 weeks+2 days and a mean birth weight of 765 g. Estimated and adjusted intakes of calcium, phosphorus magnesium, zinc, copper, selenium, vitamin D and folate were lower than estimated requirements while intakes of iron, vitamin K and several water-soluble vitamins were higher than estimated requirements. High iron intakes were explained by blood transfusions. During the first 70 days of life, taking macronutrient intakes and severity of illness into account, folate intakes were positively associated with weight (p = 0.001) and length gain (p = 0.003) and iron intake was negatively associated with length gain (p = 0.006).

    CONCLUSIONS: Intakes of several micronutrients were inconsistent with recommendations. Even when considering macronutrient intakes and severity of illness, several micronutrients were independent predictors of early growth. Low intake of folate was associated with poor growth of weight and length growth. Further, high iron supply was associated with poor length and head circumference growth. Optimized early micronutrient supply may improve early growth in extremely preterm infants.

  • 14.
    Stenberg, Reidun
    et al.
    Dept of Paediatrics, Centre for Rehabilitation Research, Örebro University Hospital, .
    Dahle, Charlotte
    Clinical Immunology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University.
    Magnuson, Anders
    Clinical Epidemiology and Biostatistic Unit, Örebro University Hospital, Sweden.
    Hellberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Tysk, Curt
    Department of Medicine, Division of Gastroenterology, Örebro University Hospital.
    Increased Prevalence of Antibodies Against Dietary Proteins In Children And Young Adults With Cerebral Palsy2013In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 56, no 2, p. 233-238Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    Undernourishment is common in children with cerebral palsy (CP) but the reasons are unknown. We previously reported elevated levels of immunoglobulin (Ig) A and IgG antibodies against gliadin (AGA) and tissue transglutaminase (tTG) in 99 children and young adults with CP without characteristic findings of gluten enteropathy in small bowel biopsies. Our aim was to perform a case-control study of IgG-antibodies against other dietary antigens, AGA, anti-tTG and IgE-antibodies against wheat and gluten.

    METHODS:

    Sera from 99 CP-cases and 99 healthy, age- and sex-matched controls were analysed with fluorescence enzyme-linked immunosorbent assay(FEIA) for detection of IgG-antibodies against beta-lactoglobulin, casein, egg white, IgG- and IgA-AGA, IgA-anti-tTG and IgE antibodies against gluten and wheat.

    RESULTS:

    Compared with controls, the odds ratio (OR) in CP cases for having elevated levels of IgG antibodies against beta-lactoglobulin was 17.0 (95% CI 2.3-128), against casein 11.0 (95% CI 2.6-46.8) and against egg white 7.0 (95% CI 1.6-30.8). The IgE-responses for wheat/gluten were generally low. The tetraplegic (TP) and dyskinetic (DK) CP-subtypes had significantly higher frequencies of elevated levels for all tested antibodies except IgG against egg white, and IgA-anti- tTG. A significantly lower weight was seen in CP-cases with positive versus negative serology.

    CONCLUSION:

    Elevated levels of IgG against dietary antigens were more frequent in the CP-group compared with controls, and particularly in the TP and DK CP-subtypes with the most severe neurologic handicap and undernourishment. Hypothetically, malnourishment may cause increased intestinal permeability and thus immunization against dietary antigens.

  • 15. Stenberg, Reidun
    et al.
    Kaukinen, Katri
    Bengtsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lindberg, Eva
    Dahle, Charlotte
    Early Developing Celiac Disease in Children With Cerebral Palsy2011In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 53, no 6, p. 674-678Article in journal (Refereed)
    Abstract [en]

    Objectives: We have reported on increased levels of antibodies against gliadin and/or transglutaminase 2 (TG2) in children with cerebral palsy (CP) but without having increased prevalence of celiac disease (CD). The aim of the present study was to evaluate whether these children have mucosal signs of early developing CD, human leukocyte antigen (HLA)-DQ2/DQ8, and antibodies against deamidated gliadin peptides (DGP). Patients and Methods: Stored blood samples from 16 children with CP were analyzed regarding HLA-DQ2/DQ8 and anti-DGP antibodies. HLA-DQ2/DQ8 were analyzed by polymerase chain reaction sequence-specific oligonucleotide probes. Anti-DGP antibodies were analyzed with enzyme-linked immunosorbent assay. Small-bowel biopsies from 15 of these children were available for immunohistochemistry regarding IgA colocalized with TG2, densities of alpha/beta+ and gamma/delta+ intraepithelial lymphocytes. Results: Mucosal immunoglobulin A (IgA) deposits colocalized with TG2 were found in the small-bowel biopsy from 1 patient with serum IgA-class anti-TG2 antibodies, HLA-DQ2, and gastrointestinal complaints. Another 2 children had slightly increased numbers of mucosal alpha/beta+ and/or gamma/delta+ intraepithelial lymphocytes. In total, 10 of 16 children were HLA-DQ2 and/or DQ8-positive. Anti-DGP antibodies were detected in sera from 4 of 16 children. Conclusions: In the present study, 1 child with CP had IgA colocalizing with TG2 in the small-bowel mucosa, suggesting CD at an early stage. Although the majority of children with CP and elevated levels of CD-related seromarkers are HLA-DQ2 and/or DQ8-positive, they have neither classical nor early developing CD.

  • 16. Turner, Dan
    et al.
    Levine, Arie
    Escher, Johanna C
    Griffiths, Anne M
    Russell, Richard K
    Dignass, Axel
    Dias, Jorge Amil
    Bronsky, Jiri
    Braegger, Christian P
    Cucchiara, Salvatore
    de Ridder, Lissy
    Fagerberg, Ulrika L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Hussey, Séamus
    Hugot, Jean-Pierre
    Kolacek, Sanja
    Kolho, Kaija Leena
    Lionetti, Paolo
    Paerregaard, Anders
    Potapov, Alexander
    Rintala, Risto
    Serban, Daniela E
    Staiano, Annamaria
    Sweeny, Brian
    Veerman, Gigi
    Veres, Gabor
    Wilson, David C
    Ruemmele, Frank M
    Management of pediatric ulcerative colitis: joint ECCO and ESPGHAN evidence-based consensus guidelines.2012In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 55, no 3, p. 340-61Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Pediatric ulcerative colitis (UC) shares many features with adult-onset disease but there are some unique considerations; therefore, therapeutic approaches have to be adapted to these particular needs. We aimed to formulate guidelines for managing UC in children based on a systematic review (SR) of the literature and a robust consensus process. The present article is a product of a joint effort of the European Crohn's and Colitis Organization (ECCO) and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN).

    METHODS: A group of 27 experts in pediatric IBD participated in an iterative consensus process including 2 face-to-face meetings, following an open call to ESPGHAN and ECCO members. A list of 23 predefined questions were addressed by working subgroups based on a SR of the literature.

    RESULTS: A total of 40 formal recommendations and 68 practice points were endorsed with a consensus rate of at least 89% regarding initial evaluation, how to monitor disease activity, the role of endoscopic evaluation, medical and surgical therapy, timing and choice of each medication, the role of combined therapy, and when to stop medications. A management flowchart, based on the Pediatric Ulcerative Colitis Activity Index (PUCAI), is presented.

    CONCLUSIONS: These guidelines provide clinically useful points to guide the management of UC in children. Taken together, the recommendations offer a standardized protocol that allows effective, timely management and monitoring of the disease course, while acknowledging that each patient is unique.

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