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1. Adeno-associated virus 2 infection in children with non-A–E hepatitis

Author

Ho, Antonia, Orton, Richard, Tayler, Rachel, Asamaphan, Patawee, Herder, Vanessa, Davis, Chris, Tong, Lily, Smollett, Katherine, Manali, Maria, Allan, Jay, Rawlik, Konrad, McDonald, Sarah E., Vink, Elen, Pollock, Louisa, Gannon, Louise, Evans, Clair, McMenamin, Jim, Roy, Kirsty, Marsh, Kimberly, Divala, Titus, Holden, Matthew T.G., Lockhart, Michael, Yirrell, David, Currie, Sandra, O’Leary, Maureen, Henderson, David, Shepherd, Samantha J., Jackson, Celia, Gunson, Rory, MacLean, Alasdair, McInnes, Neil, Bradley-Stewart, Amanda, Battle, Richard, Hollenbach, Jill A., Henderson, Paul, Nijman, Ruud, Peters, Mark, Emonts, Marieke, van der Zee, Carlijn C.W., Vermont, Clementien L., Moll, Henriëtte A., Borensztajn, Dorine M., Hagedoorn, Nienke N., Tan, Chantal, Zachariasse, Joany, Dik, W., van der Flier, Michiel, Stocker, Martin, Tempel, Dennie, Hoffmann, Florian, Pediatrics, Erasmus MC other, Rehabilitation Medicine, Immunology, Cardiology, and Business Economics

Subjects
SDG 3 - Good Health and Well-being
Abstract

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland 1 in April 2022 and has now been identified in 35 countries 2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case–control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10−12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a ‘helper virus’ to support AAV2 replication) and disease susceptibility related to HLA class II status.

Published
2023

2. Genomic investigations of unexplained acute hepatitis in children

Author

Morfopoulou, Sofia, Buddle, Sarah, Torres Montaguth, Oscar Enrique, Atkinson, Laura, Guerra-Assunção, José Afonso, Moradi Marjaneh, Mahdi, Zennezini Chiozzi, Riccardo, Storey, Nathaniel, Campos, Luis, Hutchinson, J. Ciaran, Counsell, John R., Pollara, Gabriele, Roy, Sunando, Venturini, Cristina, Antinao Diaz, Juan F., Siam, Ala’a, Tappouni, Luke J., Asgarian, Zeinab, Ng, Joanne, Hanlon, Killian S., Lennon, Alexander, McArdle, Andrew, Nijman, Ruud, Peters, Mark, Emonts, Marieke, van der Zee, Carlijn, Vermont, Clementien L., Moll, Henriëtte A., Borensztajn, Dorine M., Hagedoorn, Nienke N., Tan, Chantal, Zachariasse, Joany, Dik, W., van der Flier, Michiel, Stocker, Martin, Tempel, Dennie, Hoffmann, Florian, de Groot, Ronald, Willems, Esther, de Haan, L., Neeleman, C., Tramper-Stranders, G. A., Baas, Bryan, Kloosterhuis, Lieke, Oosthoek, Wilma, de Vries, Gabriella, van den Berg, J. M., Barendregt, A. M., Breuer, Judith, Pediatrics, Erasmus MC other, Rehabilitation Medicine, Immunology, Cardiology, Business Economics, Erasmus School of Economics, Radiotherapy, Economics, Obstetrics & Gynecology, Psychiatry, and BV's

Subjects
SDG 3 - Good Health and Well-being
Abstract

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.

Published
2023

3. Febrile illness in high-risk children: a prospective, international observational study

Author

van der Velden, Fabian J. S., de Vries, Gabriella, Martin, Alexander, Lim, Emma, von Both, Ulrich, Kolberg, Laura, Carrol, Enitan D., Khanijau, Aakash, Herberg, Jethro A., De, Tisham, Galassini, Rachel, Kuijpers, Taco W., Martinón-Torres, Federico, Rivero-Calle, Irene, Vermont, Clementien L., Hagedoorn, Nienke N., Pokorn, Marko, Pollard, Andrew J., Schlapbach, Luregn J., Tsolia, Maria, Elefhteriou, Irini, Yeung, Shunmay, Zavadska, Dace, Fink, Colin, Voice, Marie, Zenz, Werner, Kohlmaier, Benno, Agyeman, Philipp K. A., Usuf, Effua, Secka, Fatou, de Groot, Ronald, Levin, Michael, van der Flier, Michiel, Emonts, Marieke, Cunnington, Aubrey, Herberg, Jethro, Kaforou, Myrsini, Wright, Victoria, Baumard, Lucas, Bellos, Evangelos, D’Souza, Giselle, Habgood-Coote, Dominic, Hamilton, Shea, Hoggart, Clive, Hourmat, Sara, Jackson, Heather, Maconochie, Ian, Menikou, Stephanie, Lin, Naomi, Nichols, Samuel, Nijman, Ruud, Powell, Oliver, Pena Paz, Ivonne, Shah, Priyen, Shen, Ching-Fen, Vito, Ortensia, Wilson, Clare, Abdulla, Amina, Ali, Ladan, Darnell, Sarah, Jorgensen, Rikke, Mustafa, Sobia, Persand, Salina, Stevens, Molly M., Kim, Nayoung, Kim, Eunjung, Fidler, Katy, Dudley, Julia, Richmond, Vivien, Tavliavini, Emma, Liu, Ching-Chuan, Wang, Shih-Min, Salas, Antonio, Álvez González, Fernando, Balo Farto, Cristina, Barral-Arca, Ruth, Barreiro Castro, María, Bello, Xabier, García, Mirian Ben, Carnota, Sandra, Cebey-López, Miriam, Curras-Tuala, María José, Durán Suárez, Carlos, García Vicente, Luisa, Gómez-Carballa, Alberto, Gómez Rial, Jose, Leboráns Iglesias, Pilar, Martinón-Torres, Nazareth, Martinón Sánchez, José María, Mosquera Pérez, Belén, Pardo-Seco, Jacobo, Rodríguez, Lidia Piñeiro, Pischedda, Sara, Vázquez, Sara Rey, Rivero Calle, Irene, Rodríguez-Tenreiro, Carmen, Redondo-Collazo, Lorenzo, Sadiki Ora, Miguel, Serén Fernández, Sonia, Serén Trasorras, Cristina, Vilas Iglesias, Marisol, Balode, Anda, Bārzdiņa, Arta, Deksne, Dārta, Gardovska, Dace, Grāvele, Dagne, Grope, Ilze, Meiere, Anija, Nokalna, Ieva, Pavāre, Jana, Pučuka, Zanda, Selecka, Katrīna, Rudzāte, Aleksandra, Svile, Dace, Urbāne, Urzula Nora, Bojang, Kalifa, Zaman, Syed M. A., Anderson, Suzanne, RocaIsatou Sarr, Anna, Saidykhan, Momodou, Darboe, Saffiatou, Ceesay, Samba, D’alessandro, Umberto, Moll, Henriëtte A., Vermont, Clementien L, Borensztajn, Dorine M., Tan, Chantal, Zachariasse, Joany, Dik, W, Agyeman, Philipp KA, Berger, Christoph, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M, Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian R., Natalucci, Giancarlo, Relly, Christa, Riedel, Thomas, Aebi, Christoph, Schlapbach, Luregn J, Carrol, Enitan D, Cocklin, Elizabeth, Jennings, Rebecca, Johnston, Joanne, Leigh, Simon, Lewis-Burke, Nadia, Newall, Karen, Romaine, Sam, Eleftheriou, Irini, Tambouratzi, Maria, Marmarinos, Antonis, Xagorari, Marietta, Syggelou, Kelly, Calvo-Bado, Leo, Schweintzger, Nina A., Sagmeister, Manfred G., Kohlfürst, Daniela S., Zurl, Christoph, Binder, Alexander, Hösele, Susanne, Leitner, Manuel, Pölz, Lena, Rajic, Glorija, Bauchinger, Sebastian, Baumgart, Hinrich, Benesch, Martin, Ceolotto, Astrid, Eber, Ernst, Gallistl, Siegfried, Gores, Gunther, Haidl, Harald, Hauer, Almuthe, Hude, Christa, Keldorfer, Markus, Krenn, Larissa, Pilch, Heidemarie, Pfleger, Andreas, Pfurtscheller, Klaus, Nordberg, Gudrun, Niedrist, Tobias, Rödl, Siegfried, Skrabl-Baumgartner, Andrea, Sperl, Matthias, Stampfer, Laura, Strenger, Volker, Till, Holger, Trobisch, Andreas, Löffler, Sabine, Dewez, Juan Emmanuel, Hibberd, Martin, Bath, David, Miners, Alec, Fitchett, Elizabeth, de Jonge, Marien I., van Aerde, Koen, Alkema, Wynand, van den Broek, Bryan, Gloerich, Jolein, van Gool, Alain J., Henriet, Stefanie, Huijnen, Martijn, Philipsen, Ria, Willems, Esther, Gerrits, G.P.J.M., van Leur, M., Heidema, J., de Haan, L., Miedema, C.J., Neeleman, C., Obihara, C.C., Tramper-Stranders, G.A., Kandasamy, Rama, Paulus, Stéphane, Carter, Michael J., O’Connor, Daniel, Bibi, Sagida, Kelly, Dominic F., Gurung, Meeru, Thorson, Stephen, Ansari, Imran, Murdoch, David R., Shrestha, Shrijana, Oliver, Zoe, Valentine, Lucille, Allen, Karen, Bell, Kathryn, Chan, Adora, Crulley, Stephen, Devine, Kirsty, Fabian, Daniel, King, Sharon, McAlinden, Paul, McDonald, Sam, McDonnell, Anne, Pickering, Ailsa, Thomson, Evelyn, Wood, Amanda, Wallia, Diane, Woodsford, Phil, Baxter, Frances, Bell, Ashley, Rhodes, Mathew, Agbeko, Rachel, Mackerness, Christine, Baas, Bryan, Kloosterhuis, Lieke, Oosthoek, Wilma, Arif, Tasnim, Bennet, Joshua, Collings, Kalvin, van der Giessen, Ilona, Martin, Alex, Rashid, Aqeela, Rowlands, Emily, van der Velden, Fabian, Soon, Joshua, Martin, Mike, Mistry, Ravi, Zwerenz, Manuela, Buschbeck, Judith, Bidlingmaier, Christoph, Binder, Vera, Danhauser, Katharina, Haas, Nikolaus, Griese, Matthias, Feuchtinger, Tobias, Keil, Julia, Kappler, Matthias, Lurz, Eberhard, Muench, Georg, Reiter, Karl, Schoen, Carola, Mallet, François, Brengel-Pesce, Karen, Pachot, Alexandre, Mommert, Marine, Kolnik, Mojca, Vincek, Katarina, Srovin, Tina Plankar, Bahovec, Natalija, Prunk, Petra, Osterman, Veronika, Avramoska, Tanja, Kuijpers, Taco, Jongerius, Ilse, van den Berg, J. M., Schonenberg, D., Barendregt, A. M., Pajkrt, D., van der Kuip, M., van Furth, A. M., Sprenkeler, Evelien, Zandstra, Judith, van Mierlo, G., Geissler, J., consortium, PERFORM, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Infectious diseases, ARD - Amsterdam Reproduction and Development, and Pediatrics

Subjects
All institutes and research themes of the Radboud University Medical Center, Fever, SDG 3 - Good Health and Well-being, Antibiotics, Paediatric, Pediatrics, Perinatology and Child Health, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 610 Medicine & health, Infection, 610 Medizin und Gesundheit, Immunocompromised
Abstract

To assess and describe the aetiology and management of febrile illness in children with primary or acquired immunodeficiency at high risk of serious bacterial infection, as seen in emergency departments in tertiary hospitals. Prospective data on demographics, presenting features, investigations, microbiology, management, and outcome of patients within the ‘Biomarker Validation in HR patients’ database in PERFORM, were analysed. Immunocompromised children (N = 492); 94.3% proven/presumed bacterial (N = 164), 66.1% proven/presumed viral (N = 84), and 93.2% unknown bacterial or viral infections (N = 177). Mortality was 1.9% (N = 11) and 87.1% made full recovery (N = 522). Conclusion: The aetiology of febrile illness in immunocompromised children is diverse. In one-third of cases, no cause for the fever will be identified. Justification for standard intravenous antibiotic treatment for every febrile immunocompromised child is debatable, yet effective. Better clinical decision-making tools and new biomarkers are needed for this population. What is Known:• Immunosuppressed children are at high risk for morbidity and mortality of serious bacterial and viral infection, but often present with fever as only clinical symptom.• Current diagnostic measures in this group are not specific to rule out bacterial infection, and positivity rates of microbiological cultures are low. What is New:• Febrile illness and infectious complications remain a significant cause of mortality and morbidity in HR children, yet management is effective.• The aetiology of febrile illness in immunocompromised children is diverse, and development of pathways for early discharge or cessation of intravenous antibiotics is debatable, and requires better clinical decision-making tools and biomarkers.

Published
2022

8. De vitaliteit van vrijzinnigheid

Author

Alma, H. A., Boxtel, van R., Dik, W., Graaf, de Th., Rinnooy Kan, A., Wijers, H., Meaning of life, and Geestelijke begeleiding (GB)

Published
2009

9. A loading device for radon seed elastoplast moulds

Author

Dik W

Subjects
Reduction (complexity), Dual purpose, chemistry, Radon, Environmental science, chemistry.chemical_element, Humans, Radiology, Nuclear Medicine and imaging, Soil science, General Medicine, Radium
Abstract

The loading former which is illustrated was introduced at this Institute for the dual purpose of obtaining uniform accuracy of distribution and of facilitating the loading of elastoplast moulds, with consequent reduction of exposure time to members of staff. It has been in general use now for 18 months and has proved effective from both standpoints.

Published
1955

10. Monocyte mitochondrial dysfunction, inflammaging, and inflammatory pyroptosis in major depression

Author

Sara Poletti, Marion Leboyer, Bartholomeus C M Haarman, Gara Arteaga-Henríquez, Maria S Simon, Annemarie J. M. Wijkhuijs, Carmen Schiweck, Olya Mikova, Richard Musil, Volker Arolt, Elske Vrieze, Stephan Claes, Francesco Benedetti, Raf Berghmans, W A Dik, Silke Joergens, Roberto Furlan, Bernhard T. Baune, Hemmo A. Drexhage, Markus J. Schwarz, Harm de Wit, Norbert Müller, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Immunology, Simon, M. S., Schiweck, C., Arteaga-Henriquez, G., Poletti, S., Haarman, B. C. M., Dik, W. A., Schwarz, M., Vrieze, E., Mikova, O., Joergens, S., Musil, R., Claes, S., Baune, B. T., Leboyer, M., Benedetti, F., Furlan, R., Berghmans, R., de Wit, H., Wijkhuijs, A., Arolt, V., Muller, N., and Drexhage, H. A.

Subjects
Male, DISORDER, STRESS, Gene Expression, Apoptosis, Monocytes, PATHWAY, 0302 clinical medicine, Adverse Childhood Experiences, Gene cluster, HISTORY, Medicine, Pharmacology & Pharmacy, GENE-EXPRESSION, Psychiatry, Microglia, CHOLESTEROL, Pyroptosis, Mitochondria, medicine.anatomical_structure, PCR, Female, medicine.symptom, Life Sciences & Biomedicine, Adult, Premature aging, Clinical Neurology, Inflammation, Major depressive disorder, DIAGNOSIS, 03 medical and health sciences, Downregulation and upregulation, Cholesterol pathway, Humans, Biological Psychiatry, METAANALYSIS, Pharmacology, Depressive Disorder, Major, Science & Technology, business.industry, Macrophages, Monocyte, Neurosciences, 030227 psychiatry, Cross-Sectional Studies, Immunology, Childhood adversity, Neurosciences & Neurology, business, CD163
Abstract

BACKGROUND: The macrophage theory of depression states that macrophages play an important role in Major Depressive Disorder (MDD). METHODS: MDD patients (N = 140) and healthy controls (N = 120) participated in a cross-sectional study investigating the expression of apoptosis/growth and lipid/cholesterol pathway genes (BAX, BCL10, EGR1, EGR2, HB-EGF, NR1H3, ABCA1, ABCG1, MVK, CD163, HMOX1) in monocytes (macrophage/microglia precursors). Gene expressions were correlated to a set of previously determined and reported inflammation-regulating genes and analyzed with respect to various clinical parameters. RESULTS: MDD monocytes showed an overexpression of the apoptosis/growth/cholesterol and the TNF genes forming an inter-correlating gene cluster (cluster 3) separate from the previously described inflammation-related gene clusters (containing IL1 and IL6). While upregulation of monocyte gene cluster 3 was a hallmark of monocytes of all MDD patients, upregulation of the inflammation-related clusters was confirmed to be found only in the monocytes of patients with childhood adversity. The latter group also showed a downregulation of the cholesterol metabolism gene MVK, which is known to play an important role in trained immunity and proneness to inflammation. CONCLUSIONS: The upregulation of cluster 3 genes in monocytes of all MDD patients suggests a premature aging of the cells, i.e. mitochondrial apoptotic dysfunction and TNF "inflammaging", as a general feature of MDD. The overexpression of the IL-1/IL-6 containing inflammation clusters and the downregulation of MVK in monocytes of patients with childhood adversity indicates a shift in this condition to a more severe inflammation form (pyroptosis) of the cells, additional to the signs of premature aging and inflammaging. ispartof: PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY vol:111 ispartof: location:England status: published

Published
2021

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