Publications by authors named "Carsten Posovszky"

39 Publications

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Dtsch Arztebl Int 2021 02;118(8):134

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http://dx.doi.org/10.3238/arztebl.m2021.0032DOI Listing
February 2021

Do Children With Functional Abdominal Pain Benefit More From a Pain-Specific Cognitive-Behavioral Intervention Than From an Unspecific Attention Control Intervention? Results of a Randomized Controlled Trial.

Am J Gastroenterol 2021 Mar 5. Epub 2021 Mar 5.

Department of Psychology, University of Potsdam, Potsdam, Germany; Department of Child and Adolescent Psychiatry, Charité-Universitätsmedizin Berlin, Berlin, Germany; Department of Pediatric Gastroenterology, Princess Margaret Children's Hospital Darmstadt, Darmstadt, Germany; Klinik für Kinder- und Jugendmedizin, St. Vincenz-Krankenhaus GmbH Paderborn, Paderborn, Germany; Department of Pediatric Gastroenterology, Nephrology, and Metabolic Diseases, Charité-Universitätsmedizin Berlin, Berlin, Germany; Katholisches Kinderkrankenhaus Wilhelmstift GmbH, Hamburg, Germany; Department of Pediatrics and Adolescent Medicine, University Ulm Medical Centre, Ulm, Germany; Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Introduction: We aimed to compare the efficacy of cognitive-behavioral therapy (CBT) among children with functional abdominal pain with an attention control (AC), hypothesizing the superiority of CBT group intervention regarding pain intensity (primary outcome), pain duration and frequency (further primary outcomes), functional disability, and quality of life and coping strategies (key secondary outcomes).

Methods: We conducted a prospective, multicenter, randomized controlled efficacy trial (RCT) with 4 time points (before intervention, after intervention, 3-month follow-up, and 12-month follow-up). One hundred twenty-seven children aged 7-12 years were randomized to either the CBT (n = 63; 55.6% girls) or the AC (n = 64; 57.8% girls).

Results: Primary endpoint analysis of the logarithmized area under the pain intensity curve showed no significant difference between groups (mean reduction = 49.04%, 95% confidence interval [CI] -19.98%-78.36%). Treatment success rates were comparable (adjusted odds ratio = 0.53, 95% CI 0.21-1.34, number needed to treat = 16). However, time trend analyses over the course of 1 year revealed a significantly greater reduction in pain intensity (40.9%, 95% CI 2.7%-64.1%) and pain duration (43.6%, 95% CI 6.2%-66.1%) in the CBT compared with the AC, but not in pain frequency per day (1.2, 95% CI -2.7 to 5.2). In the long term, children in the CBT benefitted slightly more than those in the AC with respect to functional disability, quality of life, and coping strategies.

Discussion: Both interventions were effective, which underlines the role of time and attention for treatment efficacy. However, in the longer term, CBT yielded more favorable results.
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http://dx.doi.org/10.14309/ajg.0000000000001191DOI Listing
March 2021

Congenital Diarrhea and Cholestatic Liver Disease: Phenotypic Spectrum Associated with MYO5B Mutations.

J Clin Med 2021 01 28;10(3). Epub 2021 Jan 28.

Emma Children's Hospital/AMC, 1105 Amsterdam, The Netherlands.

Myosin Vb (MYO5B) is a motor protein that facilitates protein trafficking and recycling in polarized cells by RAB11- and RAB8-dependent mechanisms. Biallelic MYO5B mutations are identified in the majority of patients with microvillus inclusion disease (MVID). MVID is an intractable diarrhea of infantile onset with characteristic histopathologic findings that requires life-long parenteral nutrition or intestinal transplantation. A large number of such patients eventually develop cholestatic liver disease. Bi-allelic MYO5B mutations are also identified in a subset of patients with predominant early-onset cholestatic liver disease. We present here the compilation of 114 patients with disease-causing MYO5B genotypes, including 44 novel patients as well as 35 novel MYO5B mutations, and an analysis of MYO5B mutations with regard to functional consequences. Our data support the concept that (1) a complete lack of MYO5B protein or early MYO5B truncation causes predominant intestinal disease (MYO5B-MVID), (2) the expression of full-length mutant MYO5B proteins with residual function causes predominant cholestatic liver disease (MYO5B-PFIC), and (3) the expression of mutant MYO5B proteins without residual function causes both intestinal and hepatic disease (MYO5B-MIXED). Genotype-phenotype data are deposited in the existing open MYO5B database in order to improve disease diagnosis, prognosis, and genetic counseling.
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http://dx.doi.org/10.3390/jcm10030481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865828PMC
January 2021

Increase in foreign body and harmful substance ingestion and associated complications in children: a retrospective study of 1199 cases from 2005 to 2017.

BMC Pediatr 2020 12 18;20(1):560. Epub 2020 Dec 18.

Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Eythstr. 24, 89075, Ulm, Germany.

Background: Children with a history of caustic or foreign body ingestion (FBI) seem to be presenting more frequently to emergency departments. This study aims to elucidate the clinical presentation, diagnostic procedures, and complications associated with the ingestion of different object categories over a 13-year time period.

Methods: A structured retrospective data analysis of patients who presented between January 2005 and December 2017 to the University Medical Centre Ulm was performed. Patients up to 17 years of age with food impaction or foreign body or harmful substance ingestion were included by selection of the corresponding International Statistical Classification of Diseases and Related Health Problems (ICD10-GM) codes. Descriptive statistics, parametric or non-parametric tests, and linear regression analysis were performed.

Result: In total, 1199 patients were analysed; the mean age was 3.3 years (SD 3.12; range 7 days to 16 years), the male to female ratio was 1.15:1, and 194 (16.2%) were hospitalized. The number of patients seen annually increased from 66 in 2005 to 119 in 2017, with a rise in percentage of all emergency patients from 0.82% in 2010 to 1.34% in 2017. The majority of patients (n = 619) had no symptoms, and 244 out of 580 symptomatic patients complained of retching or vomiting. Most frequently, ingested objects were coins (18.8%). Radiopaque objects accounted for 47.6%, and sharp objects accounted for 10.5% of the ingested foreign bodies, both of which were significantly more often ingested by girls (p < 0.001 for both). Button battery ingestion was recorded for 63 patients with a significant annual increase (R2 = 0.57; β = 0.753; p = 0.003). The annual rate of complications also increased significantly (R2 = 0.42; β = 0.647; p = 0.017).

Conclusion: We found an alarming increase in the number of children who presented to our emergency department with FBI and associated complications. A standardized diagnostic and therapeutic approach may reduce and prevent serious complications. Further preventive measures within the home environment are needed to stop this trend.
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http://dx.doi.org/10.1186/s12887-020-02444-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747382PMC
December 2020

Acute Infectious Gastroenteritis in Infancy and Childhood.

Dtsch Arztebl Int 2020 Sep;117(37):615-624

Department of Pediatric and Adolescent Medicine, University Medical Center Ulm; Department of Pediatrics, GFO-Kliniken Bonn, St. Marienhospital Bonn; Department of Pediatric and Adolescent Medicine, Klinikum Links der Weser and Klinikum Bremen-Mitte, Bremen; Practice for Pediatric and Adolescent Medicine, Arnsberg; DKD Helios Klinik Wiesbaden, Betriebsstätte Helios Dr. Horst Schmidt Klinik; Department of Pediatric and Adolescent Medicine, Dr. von Hauner Children's Hospital, LMU Klinikum der Universität München; Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland.

Background: Despite the introduction of vaccination against rotavirus, and even though it can often be treated on an outpatient basis, acute infectious gastroenteritis is nevertheless the second most common non-traumatic cause of emergency hospitaliza - tion in children aged 1 to 5 years, accounting for approximately 9% of cases (39 410 cases in 2017). The most common path - ogens are viruses (47% rotavirus, 29% norovirus, and 14% adenovirus).

Methods: This review is based on publications retrieved by a selective search in PubMed employing the terms "acute gastro - enteritis children" AND "dehydration" OR "rehydration" OR "prevention," and by manual searching (based, for example, on reference lists and expert knowledge), with subsequent evaluation including consideration of the relevant guidelines.

Results: The degree of dehydration can be judged from weight loss and other clinical findings. In 17 randomized controlled trials conducted on a total of 1811 children with mild or moderate dehydration, oral rehydration with oral rehydration solution was just as effective as intravenous rehydration with respect to weight gain, duration of diarrhea, and fluid administration, and was associated with shorter hospital stays (weighted mean difference, -1.2 days; 95% confidence interval [-2.38; -0.02]). Oral rehydration therapy failed in 4% of patients [1; 7]. In children who are vomiting or who refuse oral rehydration solution, continuous nasogastric application is just as effective as intravenous rehydration and is the treatment of first choice.

Conclusion: In Germany, children with mild or moderate dehydration are often hospitalized for intravenous rehydration therapy, despite the good evidence supporting ambulatory oral rehydration. Obstacles to intersectoral care, the nursing shortage, and inadequate reimbursement must all be overcome in order to reduce unnecessary hospitalizations and thereby lessen the risk of nosocomial infection.
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http://dx.doi.org/10.3238/arztebl.2020.0615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805585PMC
September 2020

Varicella-zoster-virus vaccination of immunosuppressed children with inflammatory bowel disease or autoimmune hepatitis: A prospective observational study.

Vaccine 2020 11 5;38(50):8024-8031. Epub 2020 Nov 5.

University Medical Center Ulm, Department of Pediatrics and Adolescent Medicine, Ulm, Germany. Electronic address:

Background And Aims: Children with inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH) receiving immunosuppressive treatment are at risk for severe varicella zoster virus (VZV)-induced disease. This study evaluated vaccination of susceptible patients with stable disease and documented immunoreactivity without interruption of their current immunosuppression (IS).

Methods: This prospective multicentre observational study used a prevaccination checklist to select patients with low-intensity and high-intensity IS for VZV vaccination. Tolerability and safety after immunization were assessed by questionnaire. The immune response was measured by the VZV-IgG concentration, relative avidity index (RAI), and specific lymphocyte proliferative response.

Results: A total of 29 VZV vaccinations were performed in 17 seronegative patients aged 3-16 years (IBD n = 15, AIH n = 2). Eight patients received high-intensity immunosuppression, another six low-intensity immunosuppression, and three patients interrupted IS before VZV vaccination. All 29 vaccinations were well tolerated; only minor side effects such as fever and abdominal pain, were reported in two patients. One patient experienced a flare of Crohn's disease the day after vaccination. The VZV-IgG-concentration increased significantly (p = 0.018) after vaccination, and a specific lymphocyte response towards VZV in vitro was detected in all tested patients which correlated with the RAI (r = 0.489; p = 0.078).

Conclusions: VZV vaccination was well tolerated, safe and immunogenic in children receiving ongoing IS due to IBD and AIH. Ensuring immunoreactivity by clinical and laboratory parameters, rather than the type and dosage of IS, is a reasonable approach to decide on live-attenuated virus vaccinations in immunosuppressed children (German clinical trials DRKS00016357).
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http://dx.doi.org/10.1016/j.vaccine.2020.10.028DOI Listing
November 2020

[Crohn's Disease Exclusion Diet - an alternative to exlusive enteral nutritional therapy in children and adolescents with Crohn's disease? Statement of the GPGE working groups CEDATA and Nutrition/Nutrition Medicine].

Z Gastroenterol 2020 Sep 18;58(9):890-894. Epub 2020 Sep 18.

Klinik für Kinder- und Jugendmedizin der Ruhr-Universität Bochum im St. Josef-Hospital, Katholisches Klinikum Bochum, Germany.

Epidemiological an clinical observations as well as results from animal studies indicate that nutrition can play a role in the development of inflammatory bowel disease (IBD). Exclusive enteral nutrition therapy represents an example for modulating inflammatory responses solely through diet modification. Therefore, caretakers, patients, families, doctors and nutritionists seek for more dietary options to control IBD. These options include partial enteral nutrition therapy as for example the socalled Crohn's disease exclusion diet. The following statement summarizes existing data and provides recommendations for the current management of enteral nutrition therapy in pediatric Crohn's disease.
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http://dx.doi.org/10.1055/a-1199-6751DOI Listing
September 2020

[The gut: center of immunity : Rare inflammatory bowel diseases caused by immunodeficiencies].

Pathologe 2020 May;41(3):211-223

Institut für Pathologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 8, 89081, Ulm, Deutschland.

The gut is the largest immune organ of the human body with an enormous mucosal interface. By acting as a physical barrier and by hosting many of the body's immune cells and tissues, the gut is the first line of defense against potentially harmful substances. Therefore, diseases leading to impaired immune response or disruption of the epithelial barrier result in autoimmune, infectious, or inflammatory bowel disease, frequently associated with diarrhea, malabsorption, melena, and growth failure. The differential diagnosis represents an interdisciplinary challenge in this group of rare diseases. The diseases are characterized by clinical, immunological, and histopathological features caused by mutations in single genes. In the following, we will focus on histological findings within the various entities of immunodeficiencies.
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http://dx.doi.org/10.1007/s00292-020-00775-yDOI Listing
May 2020

Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease.

Nat Commun 2020 02 21;11(1):995. Epub 2020 Feb 21.

NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.
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http://dx.doi.org/10.1038/s41467-019-14275-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035382PMC
February 2020

Lack of Correlation of Mean Corpuscular Volume to White Blood Cell Ratio to Thiopurine Levels.

J Pediatr Gastroenterol Nutr 2020 05;70(5):e107-e110

GPGE-Educational Center for Pediatric Gastroenterology, Department of Pediatrics, Medical University of Graz, Graz, Austria.

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http://dx.doi.org/10.1097/MPG.0000000000002662DOI Listing
May 2020

Roles of Lactose and Fructose Malabsorption and Dietary Outcomes in Children Presenting with Chronic Abdominal Pain.

Nutrients 2019 Dec 16;11(12). Epub 2019 Dec 16.

University of Potsdam, Department Psychology, Counseling Psychology, Karl-Liebknecht-Str. 24-25, 14476 Potsdam, Germany.

Intolerance to lactose or fructose is frequently diagnosed in children with chronic abdominal pain (CAP). However, the causal relationship remains a matter of discussion. A cohort of 253 patients, aged 7-12 years, presenting with unexplained CAP received standardized diagnostics. Additional diagnostic tests were performed based on their medical history and physical and laboratory investigations. Fructose and lactose hydrogen breath tests (HBT) as well as empiric diagnostic elimination diets were performed in 135 patients reporting abdominal pain related to the consumption of lactose or fructose to evaluate carbohydrate intolerance as a potential cause of CAP. Carbohydrate malabsorption by H2BT was found in 55 (41%) out of 135 patients. An abnormal increase in H2BT was revealed in 30% (35/118) of patients after fructose consumption and in 18% (20/114) of patients after lactose administration. Forty-six percent (25/54) reported pain relief during a diagnostic elimination diet. In total, 17 patients had lactose malabsorption, 29 fructose malabsorption, and nine combined carbohydrate malabsorption. Carbohydrate intolerance as a cause of CAP was diagnosed at follow-up in only 18% (10/55) of patients with malabsorption after the elimination of the respective carbohydrate. Thus, carbohydrate malabsorption appears to be an incidental finding in children with functional abdominal pain disorders, rather than its cause. Therefore, testing of carbohydrate intolerance should only be considered in children with a strong clinical suspicion and with the goal to prevent long-term unnecessary dietary restrictions in children suffering from CAP.
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http://dx.doi.org/10.3390/nu11123063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950325PMC
December 2019

Vaccination rate and immunity of children and adolescents with inflammatory bowel disease or autoimmune hepatitis in Germany.

Vaccine 2020 02 24;38(7):1810-1817. Epub 2019 Dec 24.

University Medical Center Ulm, Department of Pediatrics and Adolescent Medicine, Ulm, Germany. Electronic address:

Background And Aims: Immunosuppressed patients are at risk of severe infections with vaccination preventable diseases. We evaluated vaccination rate and immunity of children and adolescents with inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH).

Methods: Immunization rate of 329 children with IBD (n = 300) and AIH (n = 29) was assessed in seven German centres using vaccination certificates, history of chicken pox and by determining anti-varicella zoster virus (VZV) and anti-measles IgG antibodies.

Results: Of the total cohort 86% received long-term immunosuppression. Four doses of a hexavalent vaccine were documented in 89%, at least one dose of measles, mumps, and rubella (MMR) vaccination was documented in 325 (99%), with 300 (92%) receiving two doses. Anti-measles IgG concentrations were insufficient in 11% of the immunized patients. VZV vaccination was officially recommended in Germany since 2004, and implemented in 88% born from 2005 onwards. In patients born earlier VZV catch up vaccination only reached 25% (n = 67). Of 118 patients with documented VZV vaccination 25 (21%) did not display sufficient anti-VZV IgG. Of 198 patients with a history of chicken pox, six had undetectable anti-VZV IgG. Of 29 patients having neither had chicken pox nor VZV vaccination, 20 were found to have sufficient anti-VZV IgG.

Conclusions: In our cohort vaccination coverage for hexavalent and MMR vaccinations was good, but insufficient for VZV vaccination in patients born before 2005. Neither the vaccination certificate nor the history of chicken pox is reliable to predict VZV immunity indicating a need for serologic investigations and if needed vaccination before initiating immunosuppressive therapy.
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http://dx.doi.org/10.1016/j.vaccine.2019.12.024DOI Listing
February 2020

Dataset of clinical, immunohistopathological and laboratory features of patients with MHC II deficiency suffering from enteropathy.

Data Brief 2019 Oct 28;26:104446. Epub 2019 Aug 28.

Department of Pathology, University of Ulm, 89075, Ulm, Germany.

Major histocompatibility complex class II (MHC II) is essential for adaptive immune response. We recently reported on disturbed adaptive mucosal immunity due to MHC II deficiency and prolonged enteropathy. Here, we share medical history, flow cytometric analysis of blood lymphocytes, immunohistopathology, and fecal analysis of seven genetically confirmed patients with MHC II deficiency suffering from enteropathy. Data on flow cytometric analysis of HLA-DR expression on monocytes and B cells before hematopoietic stem cell transplantation (HSCT) and after stimulation is shown. The course of immune reconstitution after HSCT of MHC II deficient patients in comparison to severe combined immunodeficiency (SCID) patients is described. In addition, immunohistopathology illustrating CD4 and CD8 T cell infiltration, absence of B lymphocytes and plasma cells, and disturbed immunoglobulin expression in the gut as well as absent HLA-DR expression in the liver is shown. Furthermore, data from fecal analysis such as stool fat, nitrogen, and water fraction as well as faecal markers such as alpha-1-antitrypsin, pancreas specific elastase 1, eosinophilic protein X (EPX), and beta defensin 2 are presented. Altogether this data demonstrates the complex phenotype of MHC II deficiency. The data can be valuable for researchers interested in mucosal immunity. For further interpretation of the data presented in this article, please see the research article "Persisting enteropathy and disturbed adaptive mucosal immunity due to MHC class II deficiency" (Posovszky et al., 2019).
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http://dx.doi.org/10.1016/j.dib.2019.104446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736774PMC
October 2019

Buried Foreign Body in the Esophagus - Unusual Cause of Dysphagia in a 2-Year-Old Child.

Klin Padiatr 2019 07 17;231(4):214-216. Epub 2019 Jun 17.

Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.

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http://dx.doi.org/10.1055/a-0942-1838DOI Listing
July 2019

Persisting enteropathy and disturbed adaptive mucosal immunity due to MHC class II deficiency.

Clin Immunol 2019 06 24;203:125-133. Epub 2019 Apr 24.

Department of Pathology, University of Ulm, 89075 Ulm, Germany.

Intestinal epithelial cells (IECs) form a fundamental mucosal barrier and actively participate in tolerance and immunity against intestinal contents. Major histocompatibility complex class II (MHC II) and invariant chain (Ii) molecules are essential for adaptive immune response. MHC II deficiency often presents with gastrointestinal disorders. Intestinal biopsy samples revealed an absence of HLA-DR, Ii, and local immunoglobulins in both hematopoietic immune cells and IECs accompanied by a lack of faecal sIgA. After successful hematopoietic stem cell transplantation (HSCT) absent HLA-DR and Ii expression persisted in IECs and faecal stool analysis indicated inflammation and high microbial activity. We describe multifaceted disturbance of adaptive mucosal immunity in MHC II deficient patients suffering from enteropathy. HLA-DR and Ii expression on enterocytes is not restored by HSCT. This may account for increased susceptibility to enteric infections and intestinal inflammation leading to prolonged enteropathy reported in MHC II deficient patients.
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http://dx.doi.org/10.1016/j.clim.2019.04.012DOI Listing
June 2019

Carbon dioxide versus room air for colonoscopy in deeply sedated pediatric patients: a randomized controlled trial.

Endosc Int Open 2019 Feb 30;7(2):E290-E297. Epub 2019 Jan 30.

Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.

 Use of carbon dioxide (CO ) instead of room air (RA) during colonoscopy in adults revealed significantly less flatulence and abdominal pain in several studies. The objectives of this study were to investigate the effects of CO usage on post-interventional pain, abdominal discomfort, abdominal girth, pCO levels, and narcotic requirement in deeply sedated pediatric patients. A total of 97 children and adolescents aged 4 years to 17 years undergoing colonoscopy were randomized to RA or CO in a prospective, randomized, controlled trial. Age-appropriate pain scales assessed abdominal pain as primary outcome. In addition, abdominal girth, abdominal bloating, transcutaneous pCO , narcotic requirement to achieve deeply sedation, and post-procedural analgesic demand was analyzed in 73 patients. Overall, significantly fewer patients reported bloating in the CO group (  = 0.0012). However, we observed only a trend to lower post-interventional pain (  = 0.15) and a lower pain score. There was no significant difference in transcutaneous pCO level and no adverse events occurred. Although there was no difference in the dosage of propofol and midazolam, we observed a significant increased necessity for use of synthetic opioids in the RA group to achieve optimal examination conditions (  = 0.023). The benefits using CO in colonoscopy of deeply sedated children predominate. In particular, CO insufflation may allow a less painful post-interventional time and it significantly reduces abdominal bloating. Moreover, with CO , significantly less additional opioids were used. Thus, CO insufflation can be considered as safe in deeply sedated patients as there was no relevant pulmonary CO retention observed. (DRKS00013914).
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http://dx.doi.org/10.1055/a-0806-7060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353645PMC
February 2019

Preserved in vitro immunoreactivity in children receiving long-term immunosuppressive therapy due to inflammatory bowel disease or autoimmune hepatitis.

Mol Cell Pediatr 2018 Jan 19;5(1). Epub 2018 Jan 19.

Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.

Background: Children with inflammatory bowel disease (IBD) or autoimmune hepatitis (AIH) are at risk for severe infections. This is partially a result of their chronic disease condition but, moreover, a side effect of their immunosuppressive therapy. Currently, vaccinations with live vaccines are regarded as contraindicated under immunosuppressive therapy, mainly because of concerns about side effects and a lack of data showing an adequate immune reaction. As there is no systematic study on the individual immunoreactivity under immunosuppressive therapy in this patient group, we analyzed the lymphocyte subgroups and immunoreactivity of lymphocytes in children with IBD or AIH with and without immunosuppressive therapy in vitro.

Methods: We collected whole blood samples from 17 children with IBD or AIH on high-level immunosuppression (IS) (group 1) and 8 on low-level IS (group 2) in comparison with 6 patients without systemic IS (group 3). After Ficoll separation of peripheral mononuclear cells, the samples were analyzed by flow cytometry to determine the lymphocyte subgroups. Furthermore, we stimulated the isolated lymphocytes with phytohemagglutinin (PHA), tetanus antigen, and adenovirus antigen and measured their proliferation by incorporation of H-thymidine detected in a beta counter. The statistical evaluation was performed by Kruskal-Wallis test and Mann-Whitney U test using a bilateral level of significance of α = 5%.

Results: Patients with low- or high-level IS showed no significant difference in the number of lymphocytes or T cells. Interestingly, IS did not influence the lymphocyte proliferation assay significantly regarding median reaction to PHA, tetanus antigen, or adenovirus antigen between the three groups. However, comparing all immunosuppressed patients to the patients without IS, there was a significant difference towards stimulation with tetanus antigen.

Conclusions: Contrary to expectations of a strong influence of IS therapy on the immunoreactivity, this study showed only minor differences between the groups with high-level, low-level, and no IS. Particularly, the in vitro reactivity to adenovirus antigen was nearly the same in all three groups. We assume that-provided a normal distribution and count of lymphocyte subgroups-patients with moderate immunosuppression might be capable of raising an effective immune response to inactivated and live vaccines.
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http://dx.doi.org/10.1186/s40348-018-0079-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775189PMC
January 2018

MYO5B, STX3, and STXBP2 mutations reveal a common disease mechanism that unifies a subset of congenital diarrheal disorders: A mutation update.

Hum Mutat 2018 03 17;39(3):333-344. Epub 2018 Jan 17.

Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Microvillus inclusion disease (MVID) is a rare but fatal autosomal recessive congenital diarrheal disorder caused by MYO5B mutations. In 2013, we launched an open-access registry for MVID patients and their MYO5B mutations (www.mvid-central.org). Since then, additional unique MYO5B mutations have been identified in MVID patients, but also in non-MVID patients. Animal models have been generated that formally prove the causality between MYO5B and MVID. Importantly, mutations in two other genes, STXBP2 and STX3, have since been associated with variants of MVID, shedding new light on the pathogenesis of this congenital diarrheal disorder. Here, we review these additional genes and their mutations. Furthermore, we discuss recent data from cell studies that indicate that the three genes are functionally linked and, therefore, may constitute a common disease mechanism that unifies a subset of phenotypically linked congenital diarrheal disorders. We present new data based on patient material to support this. To congregate existing and future information on MVID geno-/phenotypes, we have updated and expanded the MVID registry to include all currently known MVID-associated gene mutations, their demonstrated or predicted functional consequences, and associated clinical information.
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http://dx.doi.org/10.1002/humu.23386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838515PMC
March 2018

Development and Anatomy of the Enteroendocrine System in Humans.

Endocr Dev 2017 15;32:20-37. Epub 2017 Aug 15.

The gastrointestinal (GI) tract exhibits an enormous surface area that consists mostly of absorptive enterocytes. Enteroendocrine cells (EECs) are found scattered along the GI tract between absorptive enterocytes and other secretory cells, and comprise around 1% of the epithelial cell population. Interestingly, they develop from the same crypt stem cell as the other absorptive or secretory cells of the gut. EECs differentiate along the crypt villus axis and are renewed every 4-6 days, and hence possess a high plasticity. They constitute the largest endocrine system in the human body by secreting multiple peptide hormones to control, for example, postprandial digestion, insulin homeostasis, food intake, and gut motility. For this purpose, most EECs exhibit luminal sensors that detect the GI tract content. Thereafter, they may act either in a classical endocrine fashion, or by paracrine effects on nearby neural and immune cells. This creates a pivotal role for EECs to influence the GI immune system and the enteric nervous system. In this chapter, the anatomical characteristics, development, differentiation and maturation of EECs are described, and their important biological potential illustrated as part of the gut interacting sensory system.
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http://dx.doi.org/10.1159/000475729DOI Listing
February 2018

Disrupted apical exocytosis of cargo vesicles causes enteropathy in FHL5 patients with Munc18-2 mutations.

JCI Insight 2017 Jul 20;2(14). Epub 2017 Jul 20.

Division of Cell Biology, Medical University of Innsbruck, Innsbruck, Austria.

Familial hemophagocytic lymphohistiocytosis 5 (FHL5) is an autosomal recessive disease caused by mutations in STXBP2, coding for Munc18-2, which is required for SNARE-mediated membrane fusion. FHL5 causes hematologic and gastrointestinal symptoms characterized by chronic enteropathy that is reminiscent of microvillus inclusion disease (MVID). However, the molecular pathophysiology of FHL5-associated diarrhea is poorly understood. Five FHL5 patients, including four previously unreported patients, were studied. Morphology of duodenal sections was analyzed by electron and fluorescence microscopy. Small intestinal enterocytes and organoid-derived monolayers displayed the subcellular characteristics of MVID. For the analyses of Munc18-2-dependent SNARE-protein interactions, a Munc18-2 CaCo2-KO model cell line was generated by applying CRISPR/Cas9 technology. Munc18-2 is required for Slp4a/Stx3 interaction in fusion of cargo vesicles with the apical plasma membrane. Cargo trafficking was investigated in patient biopsies, patient-derived organoids, and the genome-edited model cell line. Loss of Munc18-2 selectively disrupts trafficking of certain apical brush-border proteins (NHE3 and GLUT5), while transport of DPPIV remained unaffected. Here, we describe the molecular mechanism how the loss of function of Munc18-2 leads to cargo-selective mislocalization of brush-border components and a subapical accumulation of cargo vesicles, as it is known from the loss of polarity phenotype in MVID.
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http://dx.doi.org/10.1172/jci.insight.94564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518552PMC
July 2017

Vedolizumab in Paediatric Inflammatory Bowel Disease: A Retrospective Multi-Centre Experience From the Paediatric IBD Porto Group of ESPGHAN.

J Crohns Colitis 2017 10;11(10):1230-1237

Shaare Zedek Medical Center, Jerusalem, Israel.

Background: Vedolizumab, an anti-integrin antibody, has proven to be effective in adults with inflammatory bowel disease [IBD], but the data in paediatrics are limited. We describe the short-term effectiveness and safety of vedolizumab in a European multi-centre paediatric IBD cohort.

Method: Retrospective review of children [aged 2-18 years] treated with vedolizumab from 19 centres affiliated with the Paediatric IBD Porto group of ESPGHAN. Primary outcome was Week 14 corticosteroid-free remission [CFR].

Results: In all, 64 children were included (32 [50%] male, mean age 14.5 ± 2.8 years, with a median follow-up 24 weeks [interquartile range 14-38; range 6-116]); 41 [64%] cases of ulcerative colitis/inflammatory bowel disease unclassified [UC/IBD-U] and 23 [36%] Crohn's disease [CD]. All were previously treated with anti-tumour necrosis factor [TNF] [28% primary failure, 53% secondary failure]. Week 14 CFR was 37% in UC, and 14% in CD [P = 0.06]. CFR by last follow-up was 39% in UC and 24% in CD [p = 0.24]. Ten [17%] children required surgery, six of whom had colectomy for UC. Concomitant immunomodulatory drugs did not affect remission rate [42% vs 35%; p = 0.35 at Week 22]. There were three minor drug-related adverse events. Only 3 of 16 children who underwent endoscopic evaluation had mucosal healing after treatment (19%).

Conclusions: Vedolizumab was safe and effective in this cohort of paediatric refractory IBD. These data support previous findings of slow induction rate of vedolizumab in CD and a trend to be less effective compared with patients with UC.
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http://dx.doi.org/10.1093/ecco-jcc/jjx082DOI Listing
October 2017

Bowel preparation in pediatric colonoscopy: results of an open observational study.

Endosc Int Open 2016 Jul 2;4(7):E820-7. Epub 2016 Jun 2.

Department of Newborn, Child and Adolescent Medicine, Klinikum Nürnberg, Nürnberg, Germany.

Background And Study Aims: The goal of this study was to analyze the bowel cleansing methods currently used for pediatric colonoscopy in terms of effectiveness, tolerance and safety.

Patients And Methods: Data from 768 colonoscopies reported by 28 centers were registered in an online database for further analysis. Binary logistic regression was used to determine how preparation methods affected the cleaning effect (Aronchick score) and the rate of adverse events (Aes) and complications.

Results: The most frequently reported cleansing agents were sodium picosulphate (54.2 %) and polyethylene-glycol (41.3 %) in various combinations. The cleaning effect was good to excellent in 72.6 % of patients. AEs during the preparation period occurred in 21.5 % of patients. Complications during endoscopy were reported in 12.1 % and were mostly mild. The different agents had no influence on the cleaning effect. In contrast the risk of AEs during preparation was significantly increased when polyethylene-glycol was used (odds ratio (OR) 2.112, P = 0.002) but reduced with the use of sodium picosulphate (OR 0.380, P < 0.001). In particular, the risk of needing a nasogastric tube to complete clean-out was about 10-fold higher when polyethylene-glycol was used.

Conclusions: A large variety of regimens are used for bowel preparation in children. We found a good overall cleaning result independent of the agents used. Cleansing agents, on the other hand, had a significant influence on tolerance and safety.
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http://dx.doi.org/10.1055/s-0042-107789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993869PMC
July 2016

The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders.

Dis Model Mech 2016 Jan;9(1):1-12

Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands

Congenital diarrheal disorders are rare, often fatal, diseases that are difficult to diagnose (often requiring biopsies) and that manifest in the first few weeks of life as chronic diarrhea and the malabsorption of nutrients. The etiology of congenital diarrheal disorders is diverse, but several are associated with defects in the predominant intestinal epithelial cell type, enterocytes. These particular congenital diarrheal disorders (CDD(ENT)) include microvillus inclusion disease and congenital tufting enteropathy, and can feature in other diseases, such as hemophagocytic lymphohistiocytosis type 5 and trichohepatoenteric syndrome. Treatment options for most of these disorders are limited and an improved understanding of their molecular bases could help to drive the development of better therapies. Recently, mutations in genes that are involved in normal intestinal epithelial physiology have been associated with different CDD(ENT). Here, we review recent progress in understanding the cellular mechanisms of CDD(ENT). We highlight the potential of animal models and patient-specific stem-cell-based organoid cultures, as well as patient registries, to integrate basic and clinical research, with the aim of clarifying the pathogenesis of CDD(ENT) and expediting the discovery of novel therapeutic strategies.
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http://dx.doi.org/10.1242/dmm.022269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728335PMC
January 2016

Regulation of appetite, satiation, and body weight by enteroendocrine cells. Part 2: therapeutic potential of enteroendocrine cells in the treatment of obesity.

Horm Res Paediatr 2015 14;83(1):11-8. Epub 2015 Jan 14.

University Outpatient Clinic for Pediatric Gastroenterology and Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.

Obesity is an epidemic and medical issue. Investigating the pathways regulating appetite, food intake, and body weight is crucial to find strategies for the prevention and treatment of obesity. In the context of therapeutic strategies, we focus here on the potential of enteroendocrine cells (EECs) and their secreted hormones in the regulation of body weight. We review the role of the enteroendocrine system during weight loss after lifestyle intervention or after bariatric surgery. We discuss the therapeutic potential of EECs and their hormones as targets for new treatment strategies. In fact, targeting nutrient receptors of EECs with a nutritional approach, pharmaceutical agents or prebiotics delivered to the lumen may provide a promising new approach.
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http://dx.doi.org/10.1159/000369555DOI Listing
December 2015

Regulation of appetite, satiation, and body weight by enteroendocrine cells. Part 1: characteristics of enteroendocrine cells and their capability of weight regulation.

Horm Res Paediatr 2015 28;83(1):1-10. Epub 2014 Nov 28.

University Outpatient Clinic for Pediatric Gastroenterology, and Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.

The gastrointestinal tract is the gateway for food in our body. Food ingestion and the ensuing digestive processes depend on the composition and amount of ingested nutrients. This complex process of nutrient digestion and absorption is effectively regulated by the enteroendocrine system. Enteroendocrine cells (EECs) reside scattered throughout the intestinal epithelium. They express nutrient receptors that face the lumen and secrete peptide hormones in response to food. Besides regulating digestion, gastrointestinal endocrine cells are involved in the regulation of appetite and satiety. The first part of this review describes the anatomical and biological characteristics of EECs and discusses the capability of their hormones to influence appetite, satiety, and body weight. In the second part, we then discuss the therapeutic potential of EECs in the treatment of obesity.
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http://dx.doi.org/10.1159/000368898DOI Listing
December 2015

Head Injury in Children: Has a Change in Circumstances Caused an Increase in Treatment Numbers?

J Child Neurol 2015 Aug 4;30(9):1153-8. Epub 2014 Nov 4.

Department of Neurosurgery, University of Ulm, Ulm, Germany

The number of hospitalizations for head injuries in children is rising. The exact causes remain unclear. We analyzed data of children aged between 0 and 18 years who sustained a head injury between 2010 and 2011. The analysis focused on data related to demographics, trauma mechanism, clinical course, results of imaging scans, concomitant injuries, and outcome. A total of 794 inpatient cases of head injury were treated. The leading mechanism of injury was a fall (at home) primarily at the age of 1 to 4 years (46.5%), with the majority of the children sustaining a mild brain injury (764, 96.2%). Neurosurgery was performed in 21 (2.64%) cases; average hospital stay was 2.9 days (range: 0-68 days). This study is not able to confirm that children are increasingly being brought to the hospital by their parents because of new trauma mechanisms or parents' uncertainty, nor can we confirm that the number of nonaccidental injuries is rising.
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http://dx.doi.org/10.1177/0883073814554655DOI Listing
August 2015