Publications by authors named "Benedicte Y De Winter"

77 Publications

Intestinal barrier dysfunction in irritable bowel syndrome: a systematic review.

Therap Adv Gastroenterol 2021 24;14:1756284821993586. Epub 2021 Feb 24.

Department of Medicine and Physiology, Enteric NeuroScience Program, 200 First St SW, Rochester, MN 55905, USA.

Background And Aim: Irritable bowel syndrome (IBS) is a complex and heterogeneous disorder. Sensory, motor and barrier dysfunctions are the key physiological endophenotypes of IBS. Our aim is to review studies evaluating barrier dysfunction in adults and children with IBS, as well as to link those changes with IBS symptomatology and quality of life.

Methods: A comprehensive and systematic review of multiple databases was performed up to March 2020 to identify studies comparing intestinal permeability in IBS patients with healthy controls. Both and studies were considered.

Results: We identified 66 studies, of which 27 used intestinal probes to quantify barrier function. The prevalence of barrier dysfunction differed between PI-IBS (17-50%), IBS-D (37-62%) and IBS-C (4-25%). At a group level, permeability was increased compared with healthy controls in IBS-D (9/13 studies) and PI-IBS (4/4 studies), but only a minority of IBS-C (2/7 studies) and not in the only IBS-M study. All four studies in children with IBS demonstrated loss of barrier function. A heterogeneous set of tight junction genes were found to be altered in small and large intestines of adults with IBS, but these have not been evaluated in children. Positive associations were identified between barrier dysfunction and bowel disturbances (6/9 studies), abdominal pain (9/13 studies), overall symptom severity (1/6 studies), depression and anxiety (1/1 study) and quality of life (1/4 studies). Fecal slurry or supernatants of IBS patients were found to induce barrier disruption in animal models (5/6 studies).

Conclusions: Barrier dysfunction is present in a significant proportion of adult and all pediatric IBS studies, especially in the IBS-D and PI-IBS subtype. The majority of studies indicated a positive association between loss of barrier function and symptoms such as abdominal pain and changes in the bowel function.
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http://dx.doi.org/10.1177/1756284821993586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925957PMC
February 2021

Improving Self-Reflection Assessment Practices: Comparative Judgment as an Alternative to Rubrics.

Teach Learn Med 2021 Feb 11:1-11. Epub 2021 Feb 11.

Skills Lab at the Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.

Background: Medical practitioners' reflective skills are increasingly considered important and therefore included in the medical education curriculum. However, assessing students' reflective skills using rubrics does not appear to guarantee adequate inter-rater reliabilities. Recently, comparative judgment was introduced as a new method to evaluate performance assessments. This study investigates the merits and limitations of the comparative judgment method for assessing students' written self-reflections. More specifically, it examines the reliability in relation to the time spent assessing, the correlation between the scores obtained using the two methods (rubrics and comparative judgment), and, raters' perceptions of the comparative judgment method. : Twenty-two self-reflections, that had previously been scored using a rubric, were assessed by a group of eight raters using comparative judgment. Two hundred comparisons were completed and a rank order was calculated. Raters' impressions were investigated using a focus group.

Findings: Using comparative judgment, each self-reflection needed to be compared seven times with another self-reflection to reach a scale separation reliability of .55. The inter-rater reliability of rating (ICC, (1, k)) using rubrics was .56. The time investment required for these reliability levels in both methods was around 24 minutes. The Kendall's tau rank correlation indicated a strong correlation between the scores obtained via both methods. Raters reported that making comparisons made them evaluate the quality of self-reflections in a more nuanced way. Time investment was, however, considered heavy, especially for the first comparisons. Although raters appreciated that they did not have to assign a grade to each self-reflection, the fact that the method does not automatically lead to a grade or feedback was considered a downside.

Conclusions: First evidence was provided for the comparative judgment method as an alternative to using rubrics for assessing students' written self-reflections. Before comparative judgment can be implemented for summative assessment, more research is needed on the time investment required to ensure no contradictory feedback is given back to students. Moreover, as the comparative judgment method requires an additional standard setting exercise to obtain grades, more research is warranted on the merits and limitations of this method when a pass/fail approach is used.
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http://dx.doi.org/10.1080/10401334.2021.1877709DOI Listing
February 2021

Body composition monitoring in children and adolescents: reproducibility and reference values.

Eur J Pediatr 2021 Jun 22;180(6):1721-1732. Epub 2021 Jan 22.

Laboratory of Experimental Medicine and Pediatrics and member of the Infla-Med Centre of Excellence, University of Antwerp, Wilrijk, Belgium.

There is an increasing need for suitable tools to evaluate body composition in paediatrics. The Body Composition Monitor (BCM) shows promise as a method, but reference values in children are lacking. Twenty children were included and measured twice by 4 different raters to asses inter- and intra-rater reproducibility of the BCM. Reliability was assessed using the Bland-Altman method and by calculating intraclass correlation coefficients (ICCs). The intra-rater ICCs were high (≥ 0.97) for all parameters measured by BCM as were the inter-rater ICCs for all parameters (≥ 0.98) except for overhydration (0.76). Consequently, a study was set up in which BCM measurements were performed in 2058 healthy children aged 3-18.5 years. The age- and gender-specific percentile values and reference curves for body composition (BMI, waist circumference, fat mass and lean tissue mass) and fluid status (extracellular and intracellular water and total body water) relative to age were produced using the GAMLSS method for growth curves.Conclusion: A high reproducibility of BCM measurements was found for fat mass, lean tissue mass, extracellular water and total body water. Reference values for these BCM parameters were calculated in over 2000 children and adolescents aged 3 to 18 years. What is Known • The 4-compartment model is regarded as the 'gold standard' of body composition methods, but is inappropriate for regular follow-up or screening of large groups, because of associated limitations. • Body Composition Monitor® is an inexpensive field method that has the potential to be an adequate monitoring tool. What is New • Good reproducibility of BCM measurements in children provides evidence to use the device in longitudinal follow-up, multicentre and comparative studies. • Paediatric reference values relative to age and sex for the various compartments of the body are provided.
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http://dx.doi.org/10.1007/s00431-021-03936-0DOI Listing
June 2021

Review, Performance Comparison, and Validation of Models Predicting Type 2 Diabetes Remission After Bariatric Surgery in a Western European Population.

Obes Surg 2021 Apr 4;31(4):1549-1560. Epub 2021 Jan 4.

Department of Abdominal Surgery, Antwerp University Hospital, Edegem (Antwerp), Belgium.

Purpose: The majority of patients with type 2 diabetes (T2DM) achieve remission after bariatric surgery. Several models are available to preoperatively predict T2DM remission. This study compares the performance of these models in a Western population one year after surgery and explores their predictive value in comparison to a model specifically designed for our study population.

Materials And Methods: Prediction models were retrieved using a literature search. Patients were retrospectively selected from a database of the Antwerp University Hospital. Performance of the models was assessed by determining the area under the receiver operating characteristic curve (AUROC), the accuracy, and the goodness of fit, and by comparing them to a custom-made logistic model.

Results: The probability of T2DM remission was calculated using 11 predictive scoring models and 8 regression models in a cohort of 250 patients. Complete T2DM remission occurred in 64.0% of patients. The IMS score (AUROC = 0.912; accuracy = 83.6%), DiaBetter score (0.907; 82.0%), and Ad-DiaRem score (0.903; 82.8%) best predicted T2DM remission and closely approached the performance of the custom-constructed model (0.917; 84.0%). The model by Ioffe et al. (0.630; 69.2%), Umemura et al. (0.692; 71.4%), and the ABCD score (0.757; 72.8%) were the least accurate.

Conclusion: Most T2DM remission models reliably predicted one-year T2DM remission, with limited inter-model differences. The accuracy of most models approached that of the custom-constructed model, indicating a high predictive capability and performance in our patient cohort. To date, most models are only validated to estimate T2DM remission one year after surgery and they do not predict long-term remission.
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http://dx.doi.org/10.1007/s11695-020-05157-0DOI Listing
April 2021

Functional respiratory imaging provides novel insights into the long-term respiratory sequelae of bronchopulmonary dysplasia.

Eur Respir J 2020 Dec 10. Epub 2020 Dec 10.

Laboratory for Experimental Medicine and Paediatrics, University of Antwerp, Antwerp, Belgium.

Rationale: Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Lung function and imaging are classically used to assess BPD. Functional Respiratory Imaging (FRI) combines a structural and functional assessment of the airways and their vasculature. We aimed to assess BPD with FRI and to correlate these findings with the clinical presentation.

Methods: We included 37 adolescents with a history of preterm birth (22 BPD cases and 15 preterm controls). The study protocol included a detailed history, lung function testing and CT (at TLC and FRC) with FRI. CT images were also assessed using the Aukland scoring system.

Results: BPD patients had lower FEV/FVC (p=0.02) and impaired diffusion capacity (p=0.02).Aukland CT scores were not different between the two groups. FRI analysis showed higher lobar volumes in BPD patients at FRC (p<0.01) but not at TLC. Airway resistance was significantly higher in the BPD group, especially in the distal airways. Additionally, FRI showed more air trapping in BPD patients, in contrast to findings on conventional CT images.

Conclusion: This study is the first to use FRI in research for BPD. FRI analysis showed higher lobar volumes in BPD patients, indicating air trapping and reduced inspiratory capacity. In contrast to Aukland CT scores, FRI showed more air trapping in the BPD group, suggesting that FRI might be a more sensitive detection method. Importantly, we also showed increased distal airway resistance in BPD patients. By combining structural and functional assessment, FRI may help to better understand the long-term sequelae of BPD.
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http://dx.doi.org/10.1183/13993003.02110-2020DOI Listing
December 2020

Donor-derived cell-free DNA as a biomarker for rejection after kidney transplantation: a systematic review and meta-analysis.

Transpl Int 2020 12 14;33(12):1626-1642. Epub 2020 Oct 14.

Laboratory of Experimental Medicine and Pediatrics and Member of the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.

A systematic review and meta-analysis were performed to investigate the value of donor-derived cell-free DNA (dd-cfDNA) as a noninvasive biomarker in diagnosing kidney allograft rejection. We searched PubMed, Web of Science and the Cochrane Library for original research papers published between January 1994 and May 2020 on dd-cfDNA fractions in blood of kidney allograft recipients. A single-group meta-analysis was performed by computing pooled estimates for dd-cfDNA fractions using the weighted median of medians or quantile estimation (QE) approach. Weighted median differences in medians (WMDMs) and median differences based on the QE method were used for pairwise comparisons. Despite heterogeneity among the selected studies, the meta-analysis revealed significantly higher median dd-cfDNA fractions in patients with antibody-mediated rejection (ABMR) than patients without rejection or patients with stable graft function. When comparing patients with T cell-mediated rejection (TCMR) and patients with ABMR, our two statistical approaches revealed conflicting results. Patients with TCMR did not have different median dd-cfDNA fractions than patients without rejection or patients with stable graft function. dd-cfDNA may be a useful marker for ABMR, but probably not for TCMR.
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http://dx.doi.org/10.1111/tri.13753DOI Listing
December 2020

Adoptive Cell Transfer of Regulatory T Cells Exacerbates Hepatic Steatosis in High-Fat High-Fructose Diet-Fed Mice.

Front Immunol 2020 31;11:1711. Epub 2020 Jul 31.

Translational Research in Immunology and Inflammation, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.

Non-alcoholic steatohepatitis (NASH) is a multisystem condition, involving the liver, adipose tissue, and immune system. Regulatory T (Treg) cells are a subset of T cells that exert an immune-controlling effect. Previously, a reduction of Treg cells in the visceral adipose tissue (VAT) was shown to be associated with a more severe degree of liver disease. We aimed to correct this immune disruption through adoptive cell transfer (ACT) of Treg cells. Male 8-week-old C57BL/6J mice were fed a high-fat high-fructose diet (HFHFD) for 20 weeks. Treg cells were isolated from the spleens of healthy 8 to 10-week-old C57BL/6J mice and were adoptively transferred to HFHFD-fed mice. PBS-injected mice served as controls. Plasma ALT and lipid levels were determined. Liver and adipose tissue were assessed histologically. Cytotoxic T (Tc), Treg, T helper (Th) 1 and Th17 cells were characterized in VAT, liver, subcutaneous adipose tissue (SAT), blood, and spleen via flow cytometry. Gene expression analysis was performed in SAT and VAT of mice fed either the HFHFD or a control diet for 10-32 weeks. ACT increased Treg cells in SAT, but not in any of the other tissues. Moreover, the ACT induced a decrease in Th1 cells in SAT, liver, blood, and spleen. Higher plasma ALT levels and a higher degree of steatosis were observed in ACT mice, whereas the other HFHFD-induced metabolic and histologic disruptions were unaffected. Expression analysis of genes related to Treg-cell proliferation revealed a HFHFD-induced decrease in all investigated genes in the SAT, while in the VAT the expression of these genes was largely unaffected, except for a decrease in . ACT of Treg cells in HFHFD-fed mice exacerbated hepatic steatosis, which was possibly related to the increase of Treg cells in the SAT and/or the general decrease in Th1 cells. Moreover, the HFHFD-induced decrease in expression appeared critical in the decrease of Treg cells at the level of the VAT and the inability to replenish the amount of Treg cells by the ACT, while the mechanism of Treg cell accumulation at the level of the SAT remained unclear.
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http://dx.doi.org/10.3389/fimmu.2020.01711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412973PMC
April 2021

A Literature Review of the Potential Diagnostic Biomarkers of Head and Neck Neoplasms.

Front Oncol 2020 26;10:1020. Epub 2020 Jun 26.

Laboratorium of Experimental Medicine and Pediatrics and Member of the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.

Head and neck neoplasms have a poor prognosis because of their late diagnosis. Finding a biomarker to detect these tumors in an early phase could improve the prognosis and survival rate. This literature review provides an overview of biomarkers, covering the different -omics fields to diagnose head and neck neoplasms in the early phase. To date, not a single biomarker, nor a panel of biomarkers for the detection of head and neck tumors has been detected with clinical applicability. Limitations for the clinical implementation of the investigated biomarkers are mainly the heterogeneity of the study groups (e.g., small population in which the biomarker was tested, and/or only including high-risk populations) and a low sensitivity and/or specificity of the biomarkers under study. Further research on biomarkers to diagnose head and neck neoplasms in an early stage, is therefore needed.
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http://dx.doi.org/10.3389/fonc.2020.01020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332560PMC
June 2020

The scent of COVID-19: viral (semi-)volatiles as fast diagnostic biomarkers?

J Breath Res 2020 07 21;14(4):042001. Epub 2020 Jul 21.

Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium and Antwerp University Hospital, Edegem, Belgium. Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium. Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium. Pulmonology and Thoracic Oncology, Antwerp University Hospital, Edegem, Belgium. Author to whom any correspondence should be addressed.

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http://dx.doi.org/10.1088/1752-7163/aba105DOI Listing
July 2020

Diet Reversal and Immune Modulation Show Key Role for Liver and Adipose Tissue T Cells in Murine Nonalcoholic Steatohepatitis.

Cell Mol Gastroenterol Hepatol 2020 29;10(3):467-490. Epub 2020 Apr 29.

Translational Research in Immunology and Inflammation, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium; Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium; Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.

Background & Aims: Nonalcoholic steatohepatitis (NASH) is a multisystem condition, implicating liver and adipose tissue. Although the general involvement of the innate and adaptive immune system has been established, we aimed to define the exact role of the functionally diverse T-cell subsets in NASH pathogenesis through diet reversal and immunologic modulation.

Methods: Multiple experimental set-ups were used in 8-week-old C57BL/6J mice, including prolonged high-fat high-fructose diet (HFHFD) feeding, diet reversal from HFHFD to control diet, and administration of anti-CD8a and anti-interleukin 17A antibodies. Plasma alanine aminotransferase, glucose, and lipid levels were determined. Liver and adipose tissue were assessed histologically. Cytotoxic T (Tc), regulatory T, T helper (Th) 1, and Th17 cells were characterized in liver and visceral adipose tissue (VAT) via flow cytometry and RNA analysis.

Results: HFHFD feeding induced the metabolic syndrome and NASH, which coincided with an increase in hepatic Th17, VAT Tc, and VAT Th17 cells, and a decrease in VAT regulatory T cells. Although diet reversal induced a phenotypical metabolic and hepatic normalization, the observed T-cell disruptions persisted. Treatment with anti-CD8a antibodies decreased Tc cell numbers in all investigated tissues and induced a biochemical and histologic attenuation of the HFHFD-induced NASH. Conversely, anti-interleukin 17A antibodies decreased hepatic inflammation without affecting other features of NASH or the metabolic syndrome.

Conclusions: HFHFD feeding induces important immune disruptions in multiple hepatic and VAT T-cell subsets, refractory to diet reversal. In particular, VAT Tc cells are critically involved in NASH pathogenesis, linking adipose tissue inflammation to liver disease.
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http://dx.doi.org/10.1016/j.jcmgh.2020.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365964PMC
April 2020

Volatomics in inflammatory bowel disease and irritable bowel syndrome.

EBioMedicine 2020 Apr 21;54:102725. Epub 2020 Apr 21.

Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Infla-Med Research Consortium of Excellence, University of Antwerp, Antwerp, Belgium; Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium. Electronic address:

Volatile organic compounds (VOCs) are produced by the human metabolism, inflammation and gut microbiota and form the basis of innovative volatomics research. VOCs detected through breath and faecal analysis hence serve as attractive, non-invasive biomarkers for diagnosing and monitoring irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). This review describes the clinical applicability of volatomics in discriminating between IBS, IBD and healthy volunteers with acceptable accuracy in breath (70%-100%) and faecal (58%-85%) samples. Promising compounds are propan-1-ol for diagnosing and monitoring of IBD patients, and 1-methyl-4-propan-2-ylcyclohexa-1,4-diene as biomarker for IBS diagnosis. However, these VOCs often seem to be related to inflammation and probably will need to be used in conjunction with other clinical evidence. Furthermore, three interventional studies underlined the potential of VOCs in predicting treatment outcome and patient follow-up. This shows great promise for future use of VOCs as non-invasive breath and faecal biomarkers in personalised medicine. However, properly designed studies that correlate VOCs to IBD/IBS pathogenesis, while taking microbial influences into account, are still key before clinical implementation can be expected.
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http://dx.doi.org/10.1016/j.ebiom.2020.102725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177032PMC
April 2020

In-Depth Study of Transmembrane Mucins in Association with Intestinal Barrier Dysfunction During the Course of T Cell Transfer and DSS-Induced Colitis.

J Crohns Colitis 2020 Jul;14(7):974-994

Laboratory of Experimental Medicine and Pediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.

Background And Aims: There is evidence for a disturbed intestinal barrier function in inflammatory bowel diseases [IBD] but the underlying mechanisms are unclear. Because mucins represent the major components of the mucus barrier and disturbed mucin expression is reported in the colon of IBD patients, we studied the association between mucin expression, inflammation and intestinal permeability in experimental colitis.

Methods: We quantified 4-kDa FITC-dextran intestinal permeability and the expression of cytokines, mucins, junctional and polarity proteins at dedicated time points in the adoptive T cell transfer and dextran sodium sulfate [DSS]-induced colitis models. Mucin expression was also validated in biopsies from IBD patients.

Results: In both animal models, the course of colitis was associated with increased interleukin-1β [IL-1β] and tumour necrosis factor-α [TNF-α] expression and increased Muc1 and Muc13 expression. In the T cell transfer model, a gradually increasing Muc1 expression coincided with gradually increasing 4-kDa FITC-dextran intestinal permeability and correlated with enhanced IL-1β expression. In the DSS model, Muc13 expression coincided with rapidly increased 4-kDa FITC-dextran intestinal permeability and correlated with TNF-α and Muc1 overexpression. Moreover, a significant association was observed between Muc1, Cldn1, Ocln, Par3 and aPKCζ expression in the T cell transfer model and between Muc13, Cldn1, Jam2, Tjp2, aPkcζ, Crb3 and Scrib expression in the DSS model. Additionally, MUC1 and MUC13 expression was upregulated in inflamed mucosa of IBD patients.

Conclusions: Aberrantly expressed MUC1 and MUC13 might be involved in intestinal barrier dysfunction upon inflammation by affecting junctional and cell polarity proteins, indicating their potential as therapeutic targets in IBD.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa015DOI Listing
July 2020

Effects of intestinal alkaline phosphatase on intestinal barrier function in a cecal ligation and puncture (CLP)-induced mouse model for sepsis.

Neurogastroenterol Motil 2020 03 21;32(3):e13754. Epub 2019 Nov 21.

Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, Antwerp, Belgium.

Background: Sepsis is a severe pathological condition associated with systemic inflammation, intestinal inflammation, and gastrointestinal barrier dysfunction. Intestinal alkaline phosphatase (IAP) has been demonstrated to detoxify lipopolysaccharide, an important mediator in the pathophysiology of sepsis. We investigated the effect of treatment with IAP on intestinal permeability, intestinal inflammation, and bacterial translocation.

Methods: OF-1 mice were divided into 4 groups (n = 12/group), undergoing either a sham or cecal ligation and puncture (CLP) procedure to induce sepsis. Mice received IAP or a vehicle intraperitoneally 5 minutes prior to the onset of the CLP or sham procedure, which was repeated every 12 hours for two consecutive days. After two days, in vivo intestinal permeability, intestinal inflammation, and bacterial translocation were determined.

Key Results: CLP-induced sepsis resulted in significantly more weight loss, worse clinical disease scores, bacterial translocation, and elevated inflammatory cytokines. Intestinal permeability was increased up to 5-fold (P < .001). IAP activity was significantly increased in septic animals. Treatment with IAP had no effect on clinical outcomes but reduced the increased permeability of the small intestine by 50% (P = .005). This reduction in permeability was accompanied by a modified gene expression of claudin-1 (P = .025), claudin-14 (P = .035), and interleukin 12 (P = .015). A discriminant analysis showed that treatment with IAP is linked to modified mRNA levels of several tight junction proteins and cytokines.

Conclusions And Inferences: Treatment with IAP diminished CLP-induced intestinal barrier disruption, associated with modified expression of several cytokines and claudins. Nevertheless, this effect did not translate into better clinical outcomes in our experimental setup.
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http://dx.doi.org/10.1111/nmo.13754DOI Listing
March 2020

Clinical- and surgery-specific risk factors for post-operative sepsis: a systematic review and meta-analysis of over 30 million patients.

Surg Today 2020 May 6;50(5):427-439. Epub 2019 Jun 6.

Department of Abdominal Surgery, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium.

Post-operative sepsis is a severe complication of surgery, which often worsens the clinical outcomes. While several risk factors have been identified, the importance of others remains uncertain. This systematic review and meta-analysis aimed to determine patient and surgery-related risk factors for post-operative sepsis. We reviewed Medline, the Web of Science, and the Cochrane library, systematically, for articles describing risk factors for sepsis. The role of eligible risk factors was investigated using a random-effects model, while analyzing univariate and multivariate data separately. Among 193 pro- and retrospective articles, comprising over 30 million patients, 38 eligible risk factors were selected for this meta-analysis. The patient-related risk factors associated with post-operative sepsis included male gender (odds ratio, OR 1.41), pre-existing heart failure (OR 2.53), diabetes (OR 1.41), and chronic kidney disease (OR 1.26). The surgery-related risk factors identified included emergency surgery (OR 3.38), peri-operative blood transfusion (OR 1.90), inpatient hospital stay (OR 2.31), and open surgery (OR 1.80). The adjusted overall incidence of surgical sepsis was 1.84%. In conclusion, multiple-patient and surgery-related risk factors are associated with the development of post-operative sepsis. Recognizing these risk factors could assist in the pre-operative identification of patients at risk of post-operative sepsis.
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http://dx.doi.org/10.1007/s00595-019-01827-4DOI Listing
May 2020

Mas-related G protein-coupled receptor C11 (Mrgprc11) induces visceral hypersensitivity in the mouse colon: A novel target in gut nociception?

Neurogastroenterol Motil 2019 08 22;31(8):e13623. Epub 2019 May 22.

Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium.

Background: Visceral hypersensitivity, an important cause of abdominal pain in disorders such as IBD and IBS, presents with a poorly understood pathophysiology and limited treatment options. Several members of the Mas-related G protein-coupled receptor family (Mrgprs) have become promising targets in pain research. The potential link between the murine Mrgpr C11 (Mrgprc11) and gut nociception is currently uninvestigated. Therefore, we explored the expression and functional role of Mrgprc11 in the gut nociceptive innervation.

Methods: Mrgprc11 expression was evaluated in DRG neurons innervating the mouse colon using in situ hybridization and immunohistochemistry. Visceromotor responses to colorectal distension (CRD) assessed the effect of the Mrgprc11 agonist, BAM(8-22), on colonic pain sensitivity in healthy mice. Moreover, we determined pERK1/2-immunoreactivity in the thoracolumbar spinal cord after noxious CRD. Finally, from a translational point of view, we looked for expression of the human counterpart of Mrgprc11, MRGPRX1, in human thoracolumbar DRGs.

Key Results: In situ hybridization and immunohistochemistry revealed Mrgprc11 expression in colonic DRG neurons. Intracolonic administration of BAM(8-22) significantly increased colonic pain sensitivity in an Mrgprc11-dependent manner, and led to a significantly increased degree of neuronal activation in the splanchnic spinal cord upon noxious stimulation. Furthermore, MRGPRX1 expression was also detected in human thoracolumbar DRG neurons. CONCLUSIONS & INFERENCES: Our findings established a novel function for Mrgprc11 in the gut nociceptive innervation and propose the receptor as a new player in visceral hypersensitivity. Given the presence of MRGPRX1 in human DRG neurons, our study warrants future research on its therapeutic potential in abdominal pain disorders.
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http://dx.doi.org/10.1111/nmo.13623DOI Listing
August 2019

The use of plasma donor-derived, cell-free DNA to monitor acute rejection after kidney transplantation.

Nephrol Dial Transplant 2020 04;35(4):714-721

Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium.

Background: After transplantation, cell-free deoxyribonucleic acid (DNA) derived from the donor organ (ddcfDNA) can be detected in the recipient's circulation. We aimed to investigate the role of plasma ddcfDNA as biomarker for acute kidney rejection.

Methods: From 107 kidney transplant recipients, plasma samples were collected longitudinally after transplantation (Day 1 to 3 months) within a multicentre set-up. Cell-free DNA from the donor was quantified in plasma as a fraction of the total cell-free DNA by next generation sequencing using a targeted, multiplex polymerase chain reaction-based method for the analysis of single nucleotide polymorphisms.

Results: Increases of the ddcfDNA% above a threshold value of 0.88% were significantly associated with the occurrence of episodes of acute rejection (P = 0.017), acute tubular necrosis (P = 0.011) and acute pyelonephritis (P = 0.032). A receiver operating characteristic curve analysis revealed an equal area under the curve of the ddcfDNA% and serum creatinine of 0.64 for the diagnosis of acute rejection.

Conclusions: Although increases in plasma ddcfDNA% are associated with graft injury, plasma ddcfDNA does not outperform the diagnostic capacity of the serum creatinine in the diagnosis of acute rejection.
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http://dx.doi.org/10.1093/ndt/gfz091DOI Listing
April 2020

The Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity.

Front Immunol 2019 6;10:82. Epub 2019 Feb 6.

Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology and Hepatology, University of Antwerp, Antwerp, Belgium.

Non-alcoholic fatty liver disease (NAFLD) constitutes a spectrum of disease states characterized by hepatic steatosis and is closely associated to obesity and the metabolic syndrome. In non-alcoholic steatohepatitis (NASH), additionally, inflammatory changes and hepatocellular damage are present, representing a more severe condition, for which the treatment is an unmet medical need. Pathophysiologically, the immune system is one of the main drivers of NAFLD progression and other obesity-related comorbidities, and both the innate and adaptive immune system are involved. T cells form the cellular component of the adaptive immune system and consist of multiple differentially active subsets, i.e., T helper (Th) cells, regulatory T (Treg) cells, and cytotoxic T (Tc) cells, as well as several innate T-cell subsets. This review focuses on the role of these T-cell subsets in the pathogenesis of NAFLD, as well as the association with obesity and type 2 diabetes mellitus, reviewing the available evidence from both animal and human studies. Briefly, Th1, Th2, Th17, and Th22 cells seem to have an attenuating effect on adiposity. Th2, Th22, and Treg cells seem to decrease insulin resistance, whereas Th1, Th17, and Tc cells have an aggravating effect. Concerning NAFLD, both Th22 and Treg cells appear to have an overall tempering effect, whereas Th17 and Tc cells seem to induce more liver damage and fibrosis progression. The evidence regarding the role of the innate T-cell subsets is more controversial and warrants further exploration.
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http://dx.doi.org/10.3389/fimmu.2019.00082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372559PMC
December 2019

Epidermal growth factor and its influencing variables in healthy children and adults.

PLoS One 2019 24;14(1):e0211212. Epub 2019 Jan 24.

Laboratory of experimental medicine and pediatrics, University of Antwerp, Antwerp, Belgium.

Background & Objective: Epidermal growth factor (EGF) stimulates cell proliferation and differentiation after binding to its receptor. Next to its role in magnesium homeostasis, EGF disturbances have been described in oncology, diabetes and autism spectrum disorders. The aim of this study was to determine EGF serum and urine values for both healthy children and adults. Next, we investigated the relation between several variables and urinary and serum EGF concentrations.

Methods: Both healthy adults (n = 50) and children (n = 78) were included. Serum and urinary EGF concentrations were measured with ELISA technology.

Results: Serum EGF was inversely correlated with age (r = -0.873; p<0.001) and positively correlated with serum magnesium (r = 0.597; p<0.001). The urinary EGF was also inversely correlated with age (r = -0.855; p<0.001). In adults and children older than 13 years of age, the urinary EGF significantly differed between sexes (p = 0.001). Urinary EGF was positively correlated with serum magnesium (r = 0.583; p<0.001) and creatinine clearance (r = 0.524; p<0.001) and negatively correlated with the fractional excretion of magnesium (r = 0.248; p = 0.014). In a multivariate model, age and serum magnesium remained independently related to serum EGF while age, serum EGF and serum magnesium remained independently related to urinary EGF.

Conclusions: This study provides valuable insights in urinary and serum EGF patterns in healthy subjects. By systematically correcting EGF for body surface, significant correlations with age, gender and magnesium were observed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211212PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345470PMC
November 2019

Plasma donor-derived cell-free DNA kinetics after kidney transplantation using a single tube multiplex PCR assay.

PLoS One 2018 6;13(12):e0208207. Epub 2018 Dec 6.

Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium.

Background: After transplantation, cell-free DNA derived from the donor organ (ddcfDNA) can be detected in the recipient's circulation. We aimed to quantify ddcfDNA levels in plasma of kidney transplant recipients thereby investigating the kinetics of this biomarker after transplantation and determining biological variables that influence ddcfDNA kinetics in stable and non-stable patients.

Materials And Methods: From 107 kidney transplant recipients, plasma samples were collected longitudinally after transplantation (day 1-3 months) within a multicenter set-up. Cell-free DNA from the donor was quantified in plasma as a fraction of the total cell-free DNA by next generation sequencing using a targeted, multiplex PCR-based method for the analysis of single nucleotide polymorphisms. A subgroup of stable renal transplant recipients was identified to determine a ddcfDNA threshold value.

Results: In stable transplant recipients, plasma ddcfDNA% decreased to a mean (SD) ddcfDNA% of 0.46% (± 0.21%) which was reached 9.85 (± 5.6) days after transplantation. A ddcfDNA threshold value of 0.88% (mean + 2SD) was determined in kidney transplant recipients. Recipients that did not reach this threshold ddcfDNA value within 10 days after transplantation showed a higher ddcfDNA% on the first day after transplantation and demonstrated a higher individual baseline ddcfDNA%.

Conclusion: In conclusion, plasma ddcfDNA fractions decreased exponentially within 10 days after transplantation to a ddcfDNA threshold value of 0.88% or less. To investigate the role of ddcfDNA for rejection monitoring of the graft, future research is needed to determine causes of ddcfDNA% increases above this threshold value.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208207PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283554PMC
May 2019

Newly developed serine protease inhibitors decrease visceral hypersensitivity in a post-inflammatory rat model for irritable bowel syndrome.

Br J Pharmacol 2018 09 23;175(17):3516-3533. Epub 2018 Jul 23.

Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium.

Background And Purpose: Serine proteases have been re suggested as important mediators of visceral pain. We investigated their effect by using newly developed serine protease inhibitors with a well-characterized inhibitory profile in a rat model of post-inflammatory irritable bowel syndrome (IBS).

Experimental Approach: Colitis was induced in rats receiving intrarectal trinitrobenzenesulphonic acid; controls received 0.9% NaCl. Colonoscopies were performed on day 3, to confirm colitis, and later until mucosal healing. Visceral hypersensitivity was quantified by visceromotor responses (VMRs) to colorectal distension, 30 min after i.p. injection of the serine protease inhibitors nafamostat, UAMC-00050 or UAMC-01162. Serine proteases, protease-activated receptors (PARs) and TRP channels were quantified by qPCR and immunohistochemistry. Proteolytic activity was characterized using fluorogenic substrates.

Key Results: VMR was significantly elevated in post-colitis rats. Nafamostat normalized VMRs at the lowest dose tested. UAMC-00050 and UAMC-01162 significantly decreased VMR dose-dependently. Expression of mRNA for tryptase-αβ-1and PAR4, and tryptase immunoreactivity was significantly increased in the colon of post-colitis animals. Trypsin-like activity was also significantly increased in the colon but not in the faeces. PAR2 and TRPA1 immunoreactivity co-localized with CGRP-positive nerve fibres in control and post-colitis animals.

Conclusions And Implications: Increased expression of serine proteases and activity together with increased expression of downstream molecules at the colonic and DRG level and in CGRP-positive sensory nerve fibres imply a role for serine proteases in post-inflammatory visceral hypersensitivity. Our results support further investigation of serine protease inhibitors as an interesting treatment strategy for IBS-related visceral pain.
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http://dx.doi.org/10.1111/bph.14396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086981PMC
September 2018

Longitudinal Study of the Role of Epidermal Growth Factor on the Fractional Excretion of Magnesium in Children: Effect of Calcineurin Inhibitors.

Nutrients 2018 May 27;10(6). Epub 2018 May 27.

Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Universiteitsplein 1, T3.34, 2610 Antwerp, Belgium.

Background: It was shown in animal models and adults that the epidermal growth factor (EGF) is involved in the pathophysiology of calcineurin inhibitor (CNI) induced renal magnesium loss. In children, however, the exact mechanism remains unclear, which was set as the purpose of the present study.

Methods: Children with nephrotic syndrome and renal transplant children treated with CNI ( = 50) and non-CNI treated children ( = 46) were included in this study. Urine and serum samples were collected at three time points to determine magnesium, creatinine, and EGF. The magnesium intake was calculated from a food frequency questionnaire.

Results: Serum Mg and urinary EGF/creatinine were significantly lower in the CNI treated children, with significantly more CNI-treated children developing hypomagnesaemia. In the latter patients, the fractional excretion of magnesium (FE Mg) was significantly higher. Urinary EGF, age, renal function, and serum magnesium were independent predictors of the FE Mg. Only 29% of the children reached the recommended daily intake of magnesium. The magnesium intake did not differ between hypomagnesemic and normomagnesemic patients and was not a predictor of the FE Mg.

Conclusions: In CNI-treated children who developed hypomagnesemia, the FE Mg was increased. The urinary EGF concentration, age, and renal function are independent predictors of the FE Mg.
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http://dx.doi.org/10.3390/nu10060677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024309PMC
May 2018

Severe steatosis induces portal hypertension by systemic arterial hyporeactivity and hepatic vasoconstrictor hyperreactivity in rats.

Lab Invest 2018 10 11;98(10):1263-1275. Epub 2018 Jan 11.

Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium.

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease. The presence of portal hypertension has been demonstrated in NAFLD prior to development of inflammation or fibrosis, and is a result of extrahepatic and intrahepatic factors, principally driven by vascular dysfunction. An increased intrahepatic vascular resistance potentially contributes to progression of NAFLD via intralobular hypoxia. However, the exact mechanisms underlying vascular dysfunction in NAFLD remain unknown. This study investigates systemic hemodynamics and both aortic and intrahepatic vascular reactivity in a rat model of severe steatosis. Wistar rats were fed a methionine-choline-deficient diet, inducing steatosis, or control diet for 4 weeks. In vivo hemodynamic measurements, aortic contractility studies, and in situ liver perfusion experiments were performed. The mean arterial blood pressure was lower and portal blood pressure was higher in steatosis compared to controls. The maximal contraction force in aortic rings from steatotic rats was markedly reduced compared to controls. While blockade of nitric oxide (NO) production did not reveal any differences, cyclooxygenase (COX) blockade reduced aortic reactivity in both controls and steatosis, whereas effects were more pronounced in controls. Effects could be attributed to COX-2 iso-enzyme activity. In in situ liver perfusion experiments, exogenous NO donation or endogenous NO stimulation reduced the transhepatic pressure gradient (THPG), whereas NO synthase blockade increased the THPG only in steatosis, but not in controls. Alpha-1-adrenergic stimulation and endothelin-1 induced a significantly more pronounced increase in THPG in steatosis compared to controls. Our results demonstrate that severe steatosis, without inflammation or fibrosis, induces portal hypertension and signs of a hyperdynamic circulation, accompanied by extrahepatic arterial hyporeactivity and intrahepatic vascular hyperreactivity. The arterial hyporeactivity seems to be NO-independent, but appears to be mediated by specific COX-2-related mechanisms. Besides, the increased intrahepatic vascular resistance in steatosis appears not to be NO-related but rather to vasoconstrictor hyperreactivity.
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http://dx.doi.org/10.1038/s41374-017-0018-zDOI Listing
October 2018

Failed Downregulation of Circulating MicroRNA-155 in the Early Phase after ST Elevation Myocardial Infarction Is Associated with Adverse Left Ventricular Remodeling.

Cardiology 2017;138(2):91-96. Epub 2017 Jun 16.

Cardiovascular Diseases, University of Antwerp, Antwerp, Belgium.

Background: MicroRNA are noncoding RNA that have a significant role in both inflammatory and cardiovascular diseases.

Aims: We aimed to assess whether the inflammation-related microRNA-155 is associated with the development of adverse left ventricular (LV) remodeling following ST elevation myocardial infarction (STEMI).

Methods: Peripheral blood samples were collected in the inflammatory (day 2), proliferative (day 5), and maturation phases (6 months) after STEMI (n = 20). Granulocytes, monocytes, and lymphocytes were enumerated with flow cytometry. The changes in LV volumes were assessed with 3-D echocardiography on day 1 and after 6 months. Adverse remodeling was defined as a >20% increase in end-diastolic volume. Healthy subjects were recruited as controls.

Results: MicroRNA-155 measured on day 5 correlated positively with the relative change in end-diastolic volume (ρ = 0.490, p = 0.028). MicroRNA-155 (day 5) was significantly higher in patients with compared to patients without adverse LV remodeling. The expression level was similar in healthy subjects (n = 8) and in patients with LV remodeling. There was a positive correlation between microRNA-155 and the amount of monocytes (day 5, ρ = 0.463, p = 0.046).

Conclusion: Impaired downregulation of microRNA-155 during the second phase of the post- STEMI inflammatory response is a determinant of the development of adverse LV remodeling.
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http://dx.doi.org/10.1159/000477235DOI Listing
August 2018

Regulation of intestinal permeability: The role of proteases.

World J Gastroenterol 2017 Mar;23(12):2106-2123

Hanne Van Spaendonk, Hannah Ceuleers, Leonie Witters, Eveline Patteet, Joris G De Man, Benedicte Y De Winter, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, 2610 Antwerp, Belgium.

The gastrointestinal barrier is - with approximately 400 m - the human body's largest surface separating the external environment from the internal milieu. This barrier serves a dual function: permitting the absorption of nutrients, water and electrolytes on the one hand, while limiting host contact with noxious luminal antigens on the other hand. To maintain this selective barrier, junction protein complexes seal the intercellular space between adjacent epithelial cells and regulate the paracellular transport. Increased intestinal permeability is associated with and suggested as a player in the pathophysiology of various gastrointestinal and extra-intestinal diseases such as inflammatory bowel disease, celiac disease and type 1 diabetes. The gastrointestinal tract is exposed to high levels of endogenous and exogenous proteases, both in the lumen and in the mucosa. There is increasing evidence to suggest that a dysregulation of the protease/antiprotease balance in the gut contributes to epithelial damage and increased permeability. Excessive proteolysis leads to direct cleavage of intercellular junction proteins, or to opening of the junction proteins activation of protease activated receptors. In addition, proteases regulate the activity and availability of cytokines and growth factors, which are also known modulators of intestinal permeability. This review aims at outlining the mechanisms by which proteases alter the intestinal permeability. More knowledge on the role of proteases in mucosal homeostasis and gastrointestinal barrier function will definitely contribute to the identification of new therapeutic targets for permeability-related diseases.
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http://dx.doi.org/10.3748/wjg.v23.i12.2106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374123PMC
March 2017

Sleep-disordered breathing, systemic adipokine secretion, and metabolic dysregulation in overweight and obese children and adolescents.

Sleep Med 2017 02 8;30:52-56. Epub 2015 Dec 8.

Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium; Department of Pediatrics, Antwerp University Hospital, Edegem, Belgium.

Objective: Obstructive sleep apnea (OSA) is common among overweight and obese children, and it is an independent risk factor for developing metabolic syndrome. However, the mechanisms linking OSA and metabolic syndrome are still unclear, but a role for adipose tissue dysfunction caused by intermittent hypoxia has been suggested. Therefore, the goal of this study was to investigate the relationship between OSA and systemic adipokine concentrations in overweight and obese children.

Methods: We included 164 overweight and obese children in a tertiary center and distributed them in groups based on their obstructive apnea-hypopnea index (111 controls, 28 mild OSA, 25 moderate-to-severe OSA). All subjects underwent polysomnography and a blood sample was taken to determine leptin, adiponectin, tumor necrosis factor alpha, and interleukin-6 levels.

Results: No significant differences were found in adipokine levels between subjects with or without OSA. Leptin correlated with oxygen desaturation index (r = -0.17, p = 0.03), adiponectin correlated with mean oxygen saturation (r = 0.24, p = 0.002) and with the percentage of sleep time with an oxygen saturation >95% (r = 0.25, p = 0.001). However, these associations did not persist after correction for adiposity. No correlations between interleukin-6 and tumor necrosis factor alpha, and OSA severity were found.

Conclusion: These results suggest that serum adipokine levels are mostly dependent on central obesity, while they are not influenced by OSA in an obese pediatric population.
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http://dx.doi.org/10.1016/j.sleep.2015.11.014DOI Listing
February 2017

Long-Term Depletion of Conventional Dendritic Cells Cannot Be Maintained in an Atherosclerotic Zbtb46-DTR Mouse Model.

PLoS One 2017 6;12(1):e0169608. Epub 2017 Jan 6.

Laboratory of Physiopharmacology, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium.

Background And Aims: Increased evidence suggests a pro-atherogenic role for conventional dendritic cells (cDC). However, due to the lack of an exclusive marker for cDC, their exact contribution to atherosclerosis remains elusive. Recently, a unique transcription factor was described for cDC, namely Zbtb46, enabling us to selectively target this cell type in mice.

Methods: Low-density lipoprotein receptor-deficient (Ldlr-/-) mice were transplanted with bone marrow from Zbtb46-diphtheria toxin receptor (DTR) transgenic mice following total body irradiation. Zbtb46-DTR→Ldlr-/- chimeras were fed a Western-type diet for 18 weeks while cDC were depleted by administering diphtheria toxin (DT).

Results: Although we confirmed efficient direct induction of cDC death in vitro and in vivo upon DT treatment of Zbtb46-DTR mice, advanced atherosclerotic plaque size and composition was not altered. Surprisingly, however, analysis of Zbtb46-DTR→Ldlr-/- chimeras showed that depletion of cDC was not sustained following 18 weeks of DT treatment. In contrast, high levels of anti-DT antibodies were detected.

Conclusions: Because of the observed generation of anti-DT antibodies and consequently the partial depletion of cDC, no clear decision can be taken on the role of cDC in atherosclerosis. Our results underline the unsuitability of Zbtb46-DTR→Ldlr-/- mice for studying the involvement of cDC in maintaining the disease process of atherosclerosis, as well as of other chronic inflammatory diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169608PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5218565PMC
August 2017

Visceral hypersensitivity in inflammatory bowel diseases and irritable bowel syndrome: The role of proteases.

World J Gastroenterol 2016 Dec;22(47):10275-10286

Hannah Ceuleers, Hanne Van Spaendonk, Nikita Hanning, Jelena Heirbaut, Joris G De Man, Benedicte Y De Winter, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, 2610 Antwerp, Belgium.

Proteases, enzymes catalyzing the hydrolysis of peptide bonds, are present at high concentrations in the gastrointestinal tract. Besides their well-known role in the digestive process, they also function as signaling molecules through the activation of protease-activated receptors (PARs). Based on their chemical mechanism for catalysis, proteases can be classified into several classes: serine, cysteine, aspartic, metallo- and threonine proteases represent the mammalian protease families. In particular, the class of serine proteases will play a significant role in this review. In the last decades, proteases have been suggested to play a key role in the pathogenesis of visceral hypersensitivity, which is a major factor contributing to abdominal pain in patients with inflammatory bowel diseases and/or irritable bowel syndrome. So far, only a few preclinical animal studies have investigated the effect of protease inhibitors specifically on visceral sensitivity while their effect on inflammation is described in more detail. In our accompanying review we describe their effect on gastrointestinal permeability. On account of their promising results in the field of visceral hypersensitivity, further research is warranted. The aim of this review is to give an overview on the concept of visceral hypersensitivity as well as on the physiological and pathophysiological functions of proteases herein.
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http://dx.doi.org/10.3748/wjg.v22.i47.10275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5175241PMC
December 2016

Sleep disordered breathing and autonomic function in overweight and obese children and adolescents.

ERJ Open Res 2016 Oct 12;2(4). Epub 2016 Dec 12.

Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium; Dept of Paediatrics, Antwerp University Hospital, Edegem, Belgium.

Obstructive sleep apnoea (OSA), common in children with obesity, is associated with cardiovascular morbidity. Autonomic dysfunction has been suggested to be a key player in the development of these complications. We investigated the relationship between obesity, OSA and sympathetic activity in children. 191 children with obesity were included and distributed into two groups: 131 controls and 60 with OSA. Beat-to-beat RR interval data were extracted from polysomnography for heart rate variability analysis. Urinary free cortisol levels were determined. Urinary free cortisol did not differ between groups and was not associated with OSA, independent of the level of obesity. Differences in heart rate variability measures were found: mean RR interval decreased with OSA, while low/high-frequency band ratio and mean heart rate increased with OSA. Heart rate variability measures correlated with OSA, independent of obesity parameters and age: oxygen desaturation index correlated with mean heart rate (r=0.19, p=0.009) and mean RR interval (r= -0.18, p=0.02), while high-frequency bands and low/high-frequency band ratio correlated with arterial oxygen saturation measured by pulse oximetry ( ) (r= -0.20, p=0.008 and r= -0.16, p=0.04) and nadir (r=0.23, p=0.003 and r= -0.19, p=0.02). These results suggest that sympathetic heart activity is increased in children with obesity and OSA. Measures of hypoxia were related to increased sympathetic tone, suggesting that intermittent hypoxia is involved in autonomic dysfunction.
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http://dx.doi.org/10.1183/23120541.00038-2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5168620PMC
October 2016

In Vitro Recording of Mesenteric Afferent Nerve Activity in Mouse Jejunal and Colonic Segments.

J Vis Exp 2016 10 25(116). Epub 2016 Oct 25.

Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp;

Afferent nerves not only convey information concerning normal physiology, but also signal disturbed homeostasis and pathophysiological processes of the different organ systems from the periphery towards the central nervous system. As such, the increased activity or 'sensitization' of mesenteric afferent nerves has been allocated an important role in the pathophysiology of visceral hypersensitivity and abdominal pain syndromes. Mesenteric afferent nerve activity can be measured in vitro in an isolated intestinal segment that is mounted in a purpose-built organ bath and from which the splanchnic nerve is isolated, allowing researchers to directly assess nerve activity adjacent to the gastrointestinal segment. Activity can be recorded at baseline in standardized conditions, during distension of the segment or following the addition of pharmacological compounds delivered intraluminally or serosally. This technique allows the researcher to easily study the effect of drugs targeting the peripheral nervous system in control specimens; besides, it provides crucial information on how neuronal activity is altered during disease. It should be noted however that measuring afferent neuronal firing activity only constitutes one relay station in the complex neuronal signaling cascade, and researchers should bear in mind not to overlook neuronal activity at other levels (e.g., dorsal root ganglia, spinal cord or central nervous system) in order to fully elucidate the complex neuronal physiology in health and disease. Commonly used applications include the study of neuronal activity in response to the administration of lipopolysaccharide, and the study of afferent nerve activity in animal models of irritable bowel syndrome. In a more translational approach, the isolated mouse intestinal segment can be exposed to colonic supernatants from IBS patients. Furthermore, a modification of this technique has been recently shown to be applicable in human colonic specimens.
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http://dx.doi.org/10.3791/54576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5092238PMC
October 2016