134 results on '"Cremer, K."'
Search Results
2. Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism
- Author
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Bramswig, Nuria C., Lüdecke, H.-J., Pettersson, M., Albrecht, B., Bernier, R. A., Cremer, K., Eichler, E. E., Falkenstein, D., Gerdts, J., Jansen, S., Kuechler, A., Kvarnung, M., Lindstrand, A., Nilsson, D., Nordgren, A., Pfundt, R., Spruijt, L., Surowy, H. M., de Vries, B. B. A., Wieland, T., Engels, H., Strom, T. M., Kleefstra, T., and Wieczorek, D. more...
- Published
- 2017
- Full Text
- View/download PDF
Catalog
3. The effect of surgical strategy in difficult cholecystectomy cases on postoperative complications outcome:a value-based healthcare comparative study
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Cremer, K., Kloppenberg, F. W.H., Vanhommerig, J. W., Dijksman, L. M., Bode, N., Donkervoort, S. C., Cremer, K., Kloppenberg, F. W.H., Vanhommerig, J. W., Dijksman, L. M., Bode, N., and Donkervoort, S. C. more...
- Abstract
Background: In patients undergoing laparoscopic cholecystectomy (LC) for complicated biliary disease, complication rates increase up to 30%. The aim of this study is to assess the effect of differences in surgical strategy comparing outcome data of two large volume hospitals. Methods: A prospective database was created for all the patients who underwent a LC in two large volume hospitals between January 2017 and December 2018. In cases of difficult cholecystectomy in clinic A, regular LC or conversion were surgical strategies. In clinic B, laparoscopic subtotal cholecystectomy was performed as an alternative in difficult cases. The difficulty of the cholecystectomy (score 1–4) and surgical strategy (regular LC, subtotal cholecystectomy, conversion) were scored. Postoperative complications, reinterventions, and ICU admission were assessed. For predicting adverse postoperative complication outcomes, uni- and multivariable analyses were used. Results: A total of 2104 patients underwent a LC in the study period of which 974 were from clinic A and 1130 were from clinic B. In total, 368 procedures (17%) were scored as a difficult cholecystectomy. In clinic A, more conversions were performed (4.4%) compared to clinic B (1.0%; p < 0.001). In clinic B, more subtotal laparoscopic cholecystectomies were performed (1.8%) compared to clinic A (0%; p = < 0.001). Overall complication rate was 8.2% for clinic A and 10.2% for clinic B (p = 0.121). Postoperative complication rates per group for regular LC, conversion, and subtotal cholecystectomy in difficult cholecystectomies were 45 (15%), 12 (24%), and 7 (35%; p = 0.035), respectively. The strongest predictor for Clavien–Dindo grade 3–5 complication was subtotal cholecystectomy. Conclusion: Surgical strategy in case of a difficult cholecystectomy seems to have an important impact on postoperative complication outcome. The effect of a subtotal cholecystectomy on complications is of great concern. more...
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- 2022
4. Catch them if you are aware: PTEN postzygotic mosaicism in clinically suspicious patients with PTEN Hamartoma Tumour Syndrome and literature review
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Hendricks, L.A.J., Schuurs-Hoeijmakers, J.H.M., Spier, I., Haadsma, M.L., Eijkelenboom, A., Cremer, K., Mensenkamp, A.R., Aretz, S., Vos, J.R., Hoogerbrugge, N., Hendricks, L.A.J., Schuurs-Hoeijmakers, J.H.M., Spier, I., Haadsma, M.L., Eijkelenboom, A., Cremer, K., Mensenkamp, A.R., Aretz, S., Vos, J.R., and Hoogerbrugge, N. more...
- Abstract
Item does not contain fulltext, PTEN germline variants cause PTEN Hamartoma Tumour Syndrome (PHTS). Of individuals fulfilling diagnostic criteria, 41-88% test negative for PTEN germline variants, while mosaicism could be an explanation. Here we describe two individuals with PTEN mosaicism. First, a 21-year-old female presented with macrocephaly and a venous malformation. Next generation sequencing analysis on her venous malformation identified the mosaic pathogenic PTEN variant c.493-2A>G (23%). This variant was initially missed in blood due to low frequency (<1%), but detected in buccal swab (21%). Second, a 13-year-old male presented with macrocephaly, language developmental delay, behavioral problems, and an acral hyperkeratotic papule. Targeted PTEN analysis identified the mosaic pathogenic variant c.284C>T (11%) in blood, which was confirmed via buccal swab. These two cases suggest that PTEN mosaicism might be more common than currently reported. PTEN mosaicism awareness is important to enable diagnosis, which facilitates timely inclusion in cancer surveillance programs improving prognosis and life expectancy. more...
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- 2022
5. Daily Patterns of Shoot Elongation in Pinus radiata and Eucalyptus regnans
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Cremer, K. W.
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- 1976
6. De novo mutations of MYT1L in individuals with intellectual disability
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Cremer, K., Windheuser, I., Becker, J., Wieland, T., Zink, A., Help, H., Degenhardt, F., Mangold, E., Wieczorek, Dagmar, and Engels, H.
- Subjects
Medizin ,ComputingMethodologies_GENERAL - Abstract
Poster Abstract
- Published
- 2019
7. De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder
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Reijnders, MRF, Miller, KA, Alvi, M, Goos, JAC, Lees, MM, de Burca, A, Henderson, A, Kraus, A, Mikat, B, de Vries, BBA, Isidor, B, Kerr, B, Marcelis, C, Schluth-Bolard, C, Deshpande, C, Ruivenkamp, CAL, Wieczorek, D, Deciphering Developmental Disorders Study, Baralle, D, Blair, EM, Engels, H, Lüdecke, H-J, Eason, J, Santen, GWE, Clayton-Smith, J, Chandler, K, Tatton-Brown, K, Payne, K, Helbig, K, Radtke, K, Nugent, KM, Cremer, K, Strom, TM, Bird, LM, Sinnema, M, Bitner-Glindzicz, M, van Dooren, MF, Alders, M, Koopmans, M, Brick, L, Kozenko, M, Harline, ML, Klaassens, M, Steinraths, M, Cooper, NS, Edery, P, Yap, P, Terhal, PA, van der Spek, PJ, Lakeman, P, Taylor, RL, Littlejohn, RO, Pfundt, R, Mercimek-Andrews, S, Stegmann, APA, Kant, SG, McLean, S, Joss, S, Swagemakers, SMA, Douzgou, S, Wall, SA, Küry, S, Calpena, E, Koelling, N, McGowan, SJ, Twigg, SRF, Mathijssen, IMJ, Nellaker, C, Brunner, HG, and Wilkie, AOM more...
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Adult ,Male ,Adolescent ,kinase ,Messenger ,Inheritance Patterns ,Translocation ,Medical and Health Sciences ,Cell Line ,Young Adult ,Genetic ,Clinical Research ,Loss of Function Mutation ,Genetics ,2.1 Biological and endogenous factors ,Humans ,Aetiology ,Child ,Preschool ,Genetic Association Studies ,Genetics & Heredity ,Tousled-like ,Base Sequence ,Human Genome ,Neurosciences ,Facies ,Infant ,Deciphering Developmental Disorders Study ,Biological Sciences ,Brain Disorders ,haploinsufficiency ,Neurodevelopmental Disorders ,intellectual disability ,RNA ,Female ,Protein Kinases ,facial averaging ,Biotechnology - Abstract
Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2. more...
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- 2018
8. De Novo and Inherited Loss-of-Function Variants in TLK2 : Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder
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Reijnders, M.R.F., Miller, K.A., Alvi, M., Goos, J.A.C., Lees, M.M., Burca, A. de, Henderson, A., Kraus, A., Mikat, B., Vries, B.B.A. de, Isidor, B., Kerr, B., Marcelis, C.L.M., Schluth-Bolard, C., Deshpande, C., Ruivenkamp, C.A.L., Wieczorek, D., Baralle, D., Blair, E.M., Engels, H., Ludecke, H.J., Eason, J., Santen, G.W.E., Clayton-Smith, J., Chandler, K., Tatton-Brown, K., Payne, K., Helbig, K., Radtke, K., Nugent, K.M., Cremer, K., Strom, T.M., Bird, L.M., Sinnema, M., Bitner-Glindzicz, M., Dooren, M.F. van, Alders, M., Koopmans, M., Brick, L., Kozenko, M., Harline, M.L., Klaassens, M., Steinraths, M., Cooper, N.S., Edery, P., Yap, P., Terhal, P.A., Spek, P.J. van der, Lakeman, P., Taylor, R.L., Littlejohn, R.O., Pfundt, R.P., Mercimek-Andrews, S., Stegmann, A.P.A., Kant, S.G., McLean, S., Joss, S., Swagemakers, S.M.A., Douzgou, S., Wall, S.A., Kury, S., Calpena, E., Koelling, N., McGowan, S.J., Twigg, S.R.F., Mathijssen, I.M.J., Nellaker, C., Brunner, H.G., Wilkie, A.O.M., Plastic and Reconstructive Surgery and Hand Surgery, Clinical Genetics, and Pathology more...
- Subjects
Tousled-like ,Facial Averaging ,Haploinsufficiency ,Intellectual Disability ,Kinase ,Adult ,Male ,Adolescent ,kinase ,viruses ,Inheritance Patterns ,Medizin ,Translocation, Genetic ,Cell Line ,Young Adult ,Loss of Function Mutation ,Report ,Humans ,RNA, Messenger ,Child ,Genetic Association Studies ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Base Sequence ,Facies ,Infant ,haploinsufficiency ,Neurodevelopmental Disorders ,intellectual disability ,Child, Preschool ,Female ,Protein Kinases ,facial averaging ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Human adenovirus (HAdV) E1B-55K is a multifunctional regulator of productive viral replication and oncogenic transformation in nonpermissive mammalian cells. These functions depend on E1B-55K's posttranslational modification with the SUMO protein and its binding to HAdV E4orf6. Both early viral proteins recruit specific host factors to form an E3 ubiquitin ligase complex that targets antiviral host substrates for proteasomal degradation. Recently, we reported that the PML-NB associated factor Daxx represses efficient HAdV productive infection and is proteasomally degraded via a SUMO-E1B-55K-dependent, E4orf6-independent pathway, the details of which remained to be established. RNF4, a cellular SUMO-targeted ubiquitin ligase (STUbL), induces ubiquitinylation of specific SUMOy lated proteins and plays an essential role during DNA repair. Here, we show that E1B-55K recruits RNF4 to the insoluble nuclear matrix fraction of the infected cell to support RNF4/Daxx association, promoting Daxx PTM and thus inhibiting this antiviral factor. Removing RNF4 from infected cells using RNA interference resulted in blocking the proper establishment of viral replication centers and significantly diminished viral gene expression. These results provide a model for how HAdV antagonize the antiviral host responses by exploiting the functional capacity of cellular STUbLs. Thus, RNF4 and its STUbL function represent a positive factor during lytic infection and a novel candidate for future therapeutic antiviral intervention strategies.IMPORTANCE Daxx is a PML-NB-associated transcription factor that was recently shown to repress efficient HAdV productive infection. To counteract this antiviral measurement during infection, Daxx is degraded via a novel pathway including viral E1B-55K and host proteasomes. This virus-mediated degradation is independent of the classical HAdV E3 ubiquitin ligase complex, which is essential during viral infection to target other host antiviral substrates. To maintain a productive viral life cycle, HAdV E1B-55K early viral protein inhibits the chromatin-remodeling factor Daxx in a SUMO-dependent manner. In addition, viral E1B-55K protein recruits the STUbL RNF4 and sequesters it into the insoluble fraction of the infected cell. E1B-55K promotes complex formation between RNF4-and E1B-55K-targeted Daxx protein, supporting Daxx posttranslational modification prior to functional inhibition. Hence, RNF4 represents a novel host factor that is beneficial for HAdV gene expression by supporting Daxx counteraction. In this regard, RNF4 and other STUbL proteins might represent novel targets for therapeutic intervention. more...
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- 2018
9. De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder
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Reijnders, M R F, Miller, KA, Alvi, M, Goos, Jacqueline, Lees, MM, de Burca, A, Henderson, A, Kraus, A, Mikat, B, de Vries, BBA, Isidor, B, Kerr, B, Marcelis, C, Schluth-Bolard, C, Deshpande, C, Ruivenkamp, CAL, Wieczorek, D, Baralle, D, Blair, EM, Engels, H, Ludecke, HJ, Eason, J, Santen, GWE, Clayton-Smith, J, Chandler, K, Tatton-Brown, K, Payne, K, Helbig, K, Radtke, K, Nugent, KM, Cremer, K, Strom, TM, Bird, LM, Sinnema, M, Bitner-Glindzicz, M, van Dooren, Marieke, Alders, M, Koopmans, M, Brick, L, Kozenko, M, Harline, ML, Klaassens, M, Steinraths, M, Cooper, NS, Edery, P, Yap, P, Terhal, PA, van der Spek, Peter, Lakeman, P, Taylor, RL, Littlejohn, RO, Pfundt, R, Mercimek-Andrews, S, Stegmann, APA, Kant, SG, McLean, S, Joss, S, Swagemakers, Sigrid, Douzgou, S, Wall, SA, Kury, S, Calpena, E, Koelling, N, McGowan, SJ, Twigg, SRF, Mathijssen, Irene, Nellaker, C, Brunner, HG, Wilkie, AOM, Reijnders, M R F, Miller, KA, Alvi, M, Goos, Jacqueline, Lees, MM, de Burca, A, Henderson, A, Kraus, A, Mikat, B, de Vries, BBA, Isidor, B, Kerr, B, Marcelis, C, Schluth-Bolard, C, Deshpande, C, Ruivenkamp, CAL, Wieczorek, D, Baralle, D, Blair, EM, Engels, H, Ludecke, HJ, Eason, J, Santen, GWE, Clayton-Smith, J, Chandler, K, Tatton-Brown, K, Payne, K, Helbig, K, Radtke, K, Nugent, KM, Cremer, K, Strom, TM, Bird, LM, Sinnema, M, Bitner-Glindzicz, M, van Dooren, Marieke, Alders, M, Koopmans, M, Brick, L, Kozenko, M, Harline, ML, Klaassens, M, Steinraths, M, Cooper, NS, Edery, P, Yap, P, Terhal, PA, van der Spek, Peter, Lakeman, P, Taylor, RL, Littlejohn, RO, Pfundt, R, Mercimek-Andrews, S, Stegmann, APA, Kant, SG, McLean, S, Joss, S, Swagemakers, Sigrid, Douzgou, S, Wall, SA, Kury, S, Calpena, E, Koelling, N, McGowan, SJ, Twigg, SRF, Mathijssen, Irene, Nellaker, C, Brunner, HG, and Wilkie, AOM more...
- Published
- 2018
10. Personal exposure to traffic-related air pollutants and health outcomes in urban green space workers
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Demoury, C, primary, Guilbert, A, additional, De Cremer, K, additional, Heene, B, additional, Aerts, R, additional, Declerck, P, additional, Brasseur, O, additional, and Van Nieuwenhuyse, A, additional more...
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- 2018
- Full Text
- View/download PDF
11. Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism
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Bramswig, N.C., Ludecke, H.J., Pettersson, M., Albrecht, B., Bernier, R.A., Cremer, K., Eichler, E.E., Falkenstein, D., Gerdts, J., Jansen, S, Kuechler, A., Kvarnung, M., Lindstrand, A., Nilsson, D., Nordgren, A., Pfundt, R.P., Spruijt, L., Surowy, H.M., Vries, B.B. de, Wieland, T., Engels, H., Strom, T.M., Kleefstra, T., Wieczorek, D., Bramswig, N.C., Ludecke, H.J., Pettersson, M., Albrecht, B., Bernier, R.A., Cremer, K., Eichler, E.E., Falkenstein, D., Gerdts, J., Jansen, S, Kuechler, A., Kvarnung, M., Lindstrand, A., Nilsson, D., Nordgren, A., Pfundt, R.P., Spruijt, L., Surowy, H.M., Vries, B.B. de, Wieland, T., Engels, H., Strom, T.M., Kleefstra, T., and Wieczorek, D. more...
- Abstract
Contains fulltext : 169702.pdf (publisher's version ) (Closed access), The ubiquitin pathway is an enzymatic cascade including activating E1, conjugating E2, and ligating E3 enzymes, which governs protein degradation and sorting. It is crucial for many physiological processes. Compromised function of members of the ubiquitin pathway leads to a wide range of human diseases, such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. Mutations in the thyroid hormone receptor interactor 12 (TRIP12) gene (OMIM 604506), which encodes an E3 ligase in the ubiquitin pathway, have been associated with autism spectrum disorder (ASD). In addition to autistic features, TRIP12 mutation carriers showed intellectual disability (ID). More recently, TRIP12 was postulated as a novel candidate gene for intellectual disability in a meta-analysis of published ID cohorts. However, detailed clinical information characterizing the phenotype of these individuals was not provided. In this study, we present seven novel individuals with private TRIP12 mutations including two splice site mutations, one nonsense mutation, three missense mutations, and one translocation case with a breakpoint in intron 1 of the TRIP12 gene and clinically review four previously published cases. The TRIP12 mutation-positive individuals presented with mild to moderate ID (10/11) or learning disability [intelligence quotient (IQ) 76 in one individual], ASD (8/11) and some of them with unspecific craniofacial dysmorphism and other anomalies. In this study, we provide detailed clinical information of 11 TRIP12 mutation-positive individuals and thereby expand the clinical spectrum of the TRIP12 gene in non-syndromic intellectual disability with or without ASD. more...
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- 2017
12. Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity
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Witteveen, J.S., Willemsen, M.H., Dombroski, T.C., Bakel, N.H. van, Nillesen, W.M., Hulten, J.A. van, Jansen, E.J., Verkaik, D., Veenstra-Knol, H.E., Ravenswaaij-Arts, C.M.A. van, Wassink-Ruiter, J.S., Vincent, M., David, A., Le Caignec, C., Schieving, J., Gilissen, C., Foulds, N., Rump, P., Strom, T., Cremer, K., Zink, A.M., Engels, H., Munnik, S.A. de, Visser, J.E., Brunner, H.G., Martens, G.J., Pfundt, R.P., Kleefstra, T., Kolk, S.M., Witteveen, J.S., Willemsen, M.H., Dombroski, T.C., Bakel, N.H. van, Nillesen, W.M., Hulten, J.A. van, Jansen, E.J., Verkaik, D., Veenstra-Knol, H.E., Ravenswaaij-Arts, C.M.A. van, Wassink-Ruiter, J.S., Vincent, M., David, A., Le Caignec, C., Schieving, J., Gilissen, C., Foulds, N., Rump, P., Strom, T., Cremer, K., Zink, A.M., Engels, H., Munnik, S.A. de, Visser, J.E., Brunner, H.G., Martens, G.J., Pfundt, R.P., Kleefstra, T., and Kolk, S.M. more...
- Abstract
Contains fulltext : 165654.pdf (publisher's version ) (Closed access), Numerous genes are associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder (ASD), but their dysfunction is often poorly characterized. Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2) in individuals who, in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature. This phenotype is highly related to that of individuals with atypical 15q24 microdeletions, linking SIN3A to this microdeletion syndrome. Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly. Intriguingly, in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain. Together, our data establish that haploinsufficiency of SIN3A is associated with mild syndromic intellectual disability and that SIN3A can be considered to be a key transcriptional regulator of cortical brain development. more...
- Published
- 2016
13. Short-Term Effect of Pollen and Spore Exposure on Allergy Morbidity in the Brussels-Capital Region
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Guilbert, A, Simons, K, Hoebeke, L, Packeu, A, Hendrickx, M, De Cremer, K, Buyl, R, Coomans, D, Van Nieuwenhuyse, A, Guilbert, A, Simons, K, Hoebeke, L, Packeu, A, Hendrickx, M, De Cremer, K, Buyl, R, Coomans, D, and Van Nieuwenhuyse, A more...
- Abstract
Belgium is among the European countries that are the most affected by allergic rhinitis. Pollen grains and fungal spores represent important triggers of symptoms. However, few studies have investigated their real link with disease morbidity over several years. Based on aeroallergen counts and health insurance datasets, the relationship between daily changes in pollen, fungal spore concentrations and daily changes in reimbursable systemic antihistamine sales has been investigated between 2005 and 2011 in the Brussels-Capital Region. A Generalized Linear Model was used and adjusted for air pollution, meteorological conditions, flu, seasonal component and day of the week. We observed an augmentation in drug sales despite no significant increase in allergen levels in the long term. The relative risk of buying allergy medications associated with an interquartile augmentation in pollen distributions increased significantly for Poaceae, Betula, Carpinus, Fraxinus and Quercus. Poaceae affected the widest age group and led to the highest increase of risk which reached 1.13 (95% CI [1.11-1.14]) among the 19- to 39-year-old men. Betula showed the second most consistent relationship across age groups. Clear identification of the provoking agents may improve disease management by customizing prevention programmes. This work also opens several research perspectives related to impact of climate modification or subpopulation sensitivity. more...
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- 2016
14. Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism
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Bramswig, Nuria C., primary, Lüdecke, H.-J., additional, Pettersson, M., additional, Albrecht, B., additional, Bernier, R. A., additional, Cremer, K., additional, Eichler, E. E., additional, Falkenstein, D., additional, Gerdts, J., additional, Jansen, S., additional, Kuechler, A., additional, Kvarnung, M., additional, Lindstrand, A., additional, Nilsson, D., additional, Nordgren, A., additional, Pfundt, R., additional, Spruijt, L., additional, Surowy, H. M., additional, de Vries, B. B. A., additional, Wieland, T., additional, Engels, H., additional, Strom, T. M., additional, Kleefstra, T., additional, and Wieczorek, D., additional more...
- Published
- 2016
- Full Text
- View/download PDF
15. Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement
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Haack, T.B., Jackson, C.B., Murayama, K., Kremer, L.S., Schaller, A., Kotzaeridou, U., Vries, M.C. de, Schottmann, G., Santra, S., Büchner, B., Wieland, T., Graf, E., Freisinger, P., Eggimann, S., Ohtake, A., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Sauer, S., Memari, Y., Kolb-Kokocinski, A., Durbin, R., Hasselmann, O., Cremer, K., Albrecht, B., Wieczorek, D., Engels, H., Hahn, D., Zink, A.M., Alston, C.L., Taylor, R.W., Rodenburg, R.J., Trollmann, R., Sperl, W., Strom, T.M., Hoffmann, G.F., Mayr, J.A., Meitinger, T., Bolognini, R., Schuelke, M., Nuoffer, J.M., Kölker, S., Prokisch, H., Klopstock, T., Haack, T.B., Jackson, C.B., Murayama, K., Kremer, L.S., Schaller, A., Kotzaeridou, U., Vries, M.C. de, Schottmann, G., Santra, S., Büchner, B., Wieland, T., Graf, E., Freisinger, P., Eggimann, S., Ohtake, A., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Sauer, S., Memari, Y., Kolb-Kokocinski, A., Durbin, R., Hasselmann, O., Cremer, K., Albrecht, B., Wieczorek, D., Engels, H., Hahn, D., Zink, A.M., Alston, C.L., Taylor, R.W., Rodenburg, R.J., Trollmann, R., Sperl, W., Strom, T.M., Hoffmann, G.F., Mayr, J.A., Meitinger, T., Bolognini, R., Schuelke, M., Nuoffer, J.M., Kölker, S., Prokisch, H., and Klopstock, T. more...
- Abstract
Contains fulltext : 154949.pdf (publisher's version ) (Open Access)
- Published
- 2015
16. De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment
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Hempel, M., Cremer, K., Ockeloen, C.W., Lichtenbelt, K.D., Herkert, J.C., Denecke, J., Haack, T.B., Zink, A.M., Becker, J., Wohlleber, E., Johannsen, J., Alhaddad, B., Pfundt, R., Fuchs, S., Wieczorek, D., Strom, T.M., Gassen, K.L. van, Kleefstra, T., Kubisch, C., Engels, H., Lessel, D., Hempel, M., Cremer, K., Ockeloen, C.W., Lichtenbelt, K.D., Herkert, J.C., Denecke, J., Haack, T.B., Zink, A.M., Becker, J., Wohlleber, E., Johannsen, J., Alhaddad, B., Pfundt, R., Fuchs, S., Wieczorek, D., Strom, T.M., Gassen, K.L. van, Kleefstra, T., Kubisch, C., Engels, H., and Lessel, D. more...
- Abstract
Item does not contain fulltext, CHAMP1 encodes a protein with a function in kinetochore-microtubule attachment and in the regulation of chromosome segregation, both of which are known to be important for neurodevelopment. By trio whole-exome sequencing, we have identified de novo deleterious mutations in CHAMP1 in five unrelated individuals affected by intellectual disability with severe speech impairment, motor developmental delay, muscular hypotonia, and similar dysmorphic features including short philtrum and a tented upper and everted lover lip. In addition to two frameshift and one nonsense mutations, we found an identical nonsense mutation, c.1192C>T (p.Arg398( *)), in two affected individuals. All mutations, if resulting in a stable protein, are predicted to lead to the loss of the functionally important zinc-finger domains in the C terminus of the protein, which regulate CHAMP1 localization to chromosomes and the mitotic spindle, thereby providing a mechanistic understanding for their pathogenicity. We thus establish deleterious de novo mutations in CHAMP1 as a cause of intellectual disability. more...
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- 2015
17. De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum
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Kuechler, A., Willemsen, M.H., Albrecht, B., Bacino, C.A., Bartholomew, D.W., Bokhoven, H. van, Boogaard, M.J. van den, Bramswig, N., Buttner, C., Cremer, K., Czeschik, J.C., Engels, H., Gassen, K. van, Graf, E., Haelst, M. van, He, W., Hogue, J.S., Kempers, M., Koolen, D., Monroe, G., Munnik, S. de, Pastore, M., Reis, A., Reuter, M.S., Tegay, D.H., Veltman, J., Visser, G., Hasselt, P. van, Smeets, E., Vissers, L., Wieland, T., Wissink, W.M., Yntema, H., Zink, A.M., Strom, T.M., Ludecke, H.J., Kleefstra, T., Wieczorek, D., Kuechler, A., Willemsen, M.H., Albrecht, B., Bacino, C.A., Bartholomew, D.W., Bokhoven, H. van, Boogaard, M.J. van den, Bramswig, N., Buttner, C., Cremer, K., Czeschik, J.C., Engels, H., Gassen, K. van, Graf, E., Haelst, M. van, He, W., Hogue, J.S., Kempers, M., Koolen, D., Monroe, G., Munnik, S. de, Pastore, M., Reis, A., Reuter, M.S., Tegay, D.H., Veltman, J., Visser, G., Hasselt, P. van, Smeets, E., Vissers, L., Wieland, T., Wissink, W.M., Yntema, H., Zink, A.M., Strom, T.M., Ludecke, H.J., Kleefstra, T., and Wieczorek, D. more...
- Abstract
Contains fulltext : 154935.pdf (publisher's version ) (Closed access), Recently, de novo heterozygous loss-of-function mutations in beta-catenin (CTNNB1) were described for the first time in four individuals with intellectual disability (ID), microcephaly, limited speech and (progressive) spasticity, and functional consequences of CTNNB1 deficiency were characterized in a mouse model. Beta-catenin is a key downstream component of the canonical Wnt signaling pathway. Somatic gain-of-function mutations have already been found in various tumor types, whereas germline loss-of-function mutations in animal models have been shown to influence neuronal development and maturation. We report on 16 additional individuals from 15 families in whom we newly identified de novo loss-of-function CTNNB1 mutations (six nonsense, five frameshift, one missense, two splice mutation, and one whole gene deletion). All patients have ID, motor delay and speech impairment (both mostly severe) and abnormal muscle tone (truncal hypotonia and distal hypertonia/spasticity). The craniofacial phenotype comprised microcephaly (typically -2 to -4 SD) in 12 of 16 and some overlapping facial features in all individuals (broad nasal tip, small alae nasi, long and/or flat philtrum, thin upper lip vermillion). With this detailed phenotypic characterization of 16 additional individuals, we expand and further establish the clinical and mutational spectrum of inactivating CTNNB1 mutations and thereby clinically delineate this new CTNNB1 haploinsufficiency syndrome. more...
- Published
- 2015
18. Short-term health effects following a major train accident with acrylonitrile in Belgium
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Van Nieuwenhuyse, A, primary, Simons, K, additional, De Smedt, T, additional, Stove, C, additional, De Paepe, P, additional, Nemery, B, additional, Bader, M, additional, Vleminckx, C, additional, Van Overmeire, I, additional, Fierens, S, additional, Mertens, B, additional, De Cremer, K, additional, Goën, T, additional, Schettgen, T, additional, Van Oyen, H, additional, and Van Loco, J, additional more...
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- 2015
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19. Nicotine dependence and urinary nicotine, cotinine and hydroxycotinine levels in daily smokers
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Van Overmeire, I, primary, De Smedt, T, additional, Dendale, P, additional, Nackaerts, K, additional, Vanacker, H, additional, Vanoeteren, J, additional, Roosebrouck, P, additional, Achten, F, additional, Van Nieuwenhuyse, A, additional, Van Loco, J, additional, and De Cremer, K, additional more...
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- 2015
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20. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study
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Rauch, A., Wieczorek, D., Graf, E., Wieland, T., Endele, S., Schwarzmayr, T., Albrecht, B., Bartholdi, D., Beygo, J., Di Donato, N., Dufke, A., Cremer, K., Hempel, M., Horn, D., Hoyer, J., Joset, P., Ropke, A., Moog, U., Riess, A., Thiel, C.T., Tzschach, A., Wiesener, A., Wohlleber, E., Zweier, C., Ekici, A.B., Zink, A.M., Rump, A., Meisinger, C., Grallert, H., Sticht, H., Schenck, A., Engels, H., Rappold, G., Schrock, E., Wieacker, P., Riess, O., Meitinger, T., Reis, A., Strom, T.M., Rauch, A., Wieczorek, D., Graf, E., Wieland, T., Endele, S., Schwarzmayr, T., Albrecht, B., Bartholdi, D., Beygo, J., Di Donato, N., Dufke, A., Cremer, K., Hempel, M., Horn, D., Hoyer, J., Joset, P., Ropke, A., Moog, U., Riess, A., Thiel, C.T., Tzschach, A., Wiesener, A., Wohlleber, E., Zweier, C., Ekici, A.B., Zink, A.M., Rump, A., Meisinger, C., Grallert, H., Sticht, H., Schenck, A., Engels, H., Rappold, G., Schrock, E., Wieacker, P., Riess, O., Meitinger, T., Reis, A., and Strom, T.M. more...
- Abstract
Item does not contain fulltext, BACKGROUND: The genetic cause of intellectual disability in most patients is unclear because of the absence of morphological clues, information about the position of such genes, and suitable screening methods. Our aim was to identify de-novo variants in individuals with sporadic non-syndromic intellectual disability. METHODS: In this study, we enrolled children with intellectual disability and their parents from ten centres in Germany and Switzerland. We compared exome sequences between patients and their parents to identify de-novo variants. 20 children and their parents from the KORA Augsburg Diabetes Family Study were investigated as controls. FINDINGS: We enrolled 51 participants from the German Mental Retardation Network. 45 (88%) participants in the case group and 14 (70%) in the control group had de-novo variants. We identified 87 de-novo variants in the case group, with an exomic mutation rate of 1.71 per individual per generation. In the control group we identified 24 de-novo variants, which is 1.2 events per individual per generation. More participants in the case group had loss-of-function variants than in the control group (20/51 vs 2/20; p=0.022), suggesting their contribution to disease development. 16 patients carried de-novo variants in known intellectual disability genes with three recurrently mutated genes (STXBP1, SYNGAP1, and SCN2A). We deemed at least six loss-of-function mutations in six novel genes to be disease causing. We also identified several missense alterations with potential pathogenicity. INTERPRETATION: After exclusion of copy-number variants, de-novo point mutations and small indels are associated with severe, sporadic non-syndromic intellectual disability, accounting for 45-55% of patients with high locus heterogeneity. Autosomal recessive inheritance seems to contribute little in the outbred population investigated. The large number of de-novo variants in known intellectual disability genes is only partially attributable to known more...
- Published
- 2012
21. Update on Kleefstra Syndrome
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Willemsen, M.H., Vulto-van Silfhout, A.T., Nillesen, W.M., Wissink, W.M., Bokhoven, J.H.L.M. van, Philip, N., Berry-Kravis, E.M., Kini, U., van Ravenswaaij-Arts, C.M., Delle Chiaie, B., Innes, A.M., Houge, G., Kosonen, T., Cremer, K., Fannemel, M., Stray-Pedersen, A., Reardon, W., Ignatius, J., Lachlan, K., Mircher, C., Helderman van den Enden, P.T., Mastebroek, M., Cohn-Hokke, P.E., Yntema, H.G., Drunat, S., Kleefstra, T., Willemsen, M.H., Vulto-van Silfhout, A.T., Nillesen, W.M., Wissink, W.M., Bokhoven, J.H.L.M. van, Philip, N., Berry-Kravis, E.M., Kini, U., van Ravenswaaij-Arts, C.M., Delle Chiaie, B., Innes, A.M., Houge, G., Kosonen, T., Cremer, K., Fannemel, M., Stray-Pedersen, A., Reardon, W., Ignatius, J., Lachlan, K., Mircher, C., Helderman van den Enden, P.T., Mastebroek, M., Cohn-Hokke, P.E., Yntema, H.G., Drunat, S., and Kleefstra, T. more...
- Abstract
Item does not contain fulltext, Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual disability, (childhood) hypotonia and distinct facial features. The syndrome can be either caused by a microdeletion in chromosomal region 9q34.3 or by a mutation in the euchromatin histone methyltransferase 1 (EHMT1) gene. Since the early 1990s, 85 patients have been described, of which the majority had a 9q34.3 microdeletion (>85%). So far, no clear genotype-phenotype correlation could be observed by studying the clinical and molecular features of both 9q34.3 microdeletion patients and patients with an intragenic EHMT1 mutation. Thus, to further expand the genotypic and phenotypic knowledge about the syndrome, we here report 29 newly diagnosed patients, including 16 patients with a 9q34.3 microdeletion and 13 patients with an EHMT1 mutation, and review previous literature. The present findings are comparable to previous reports. In addition to our former findings and recommendations, we suggest cardiac screening during follow-up, because of the possible occurrence of cardiac arrhythmias. In addition, clinicians and caretakers should be aware of the regressive behavioral phenotype that might develop at adolescent/adult age and seems to have no clear neurological substrate, but is rather a so far unexplained neuropsychiatric feature. more...
- Published
- 2012
22. MACS syndrome: A combined collagen and elastin disorder due to abnormal Golgi trafficking.
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Albrecht, B., Brouwer, A.P.M. de, Lefeber, D.J., Cremer, K., Hausser, I., Rossen, N., Wortmann, S.B., Wevers, R.A., Kornak, U., Morava, E., Albrecht, B., Brouwer, A.P.M. de, Lefeber, D.J., Cremer, K., Hausser, I., Rossen, N., Wortmann, S.B., Wevers, R.A., Kornak, U., and Morava, E. more...
- Abstract
1 november 2010, Item does not contain fulltext
- Published
- 2010
23. Update on Kleefstra Syndrome
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Willemsen, M.H., primary, Vulto-van Silfhout, A.T., additional, Nillesen, W.M., additional, Wissink-Lindhout, W.M., additional, van Bokhoven, H., additional, Philip, N., additional, Berry-Kravis, E.M., additional, Kini, U., additional, van Ravenswaaij-Arts, C.M.A., additional, Delle Chiaie, B., additional, Innes, A.M.M., additional, Houge, G., additional, Kosonen, T., additional, Cremer, K., additional, Fannemel, M., additional, Stray-Pedersen, A., additional, Reardon, W., additional, Ignatius, J., additional, Lachlan, K., additional, Mircher, C., additional, Helderman van den Enden, P.T.J.M., additional, Mastebroek, M., additional, Cohn-Hokke, P.E., additional, Yntema, H.G., additional, Drunat, S., additional, and Kleefstra, T., additional more...
- Published
- 2011
- Full Text
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24. Article Commentary: Animal Models of Retrovirus-Associated Malignancies
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Cremer, K. J., primary and Gruber, J., additional
- Published
- 1992
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25. In vitro suppression of UAG and UGA mutants in the thymidine kinase gene of herpes simplex virus.
- Author
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Cremer, K J, Bodemer, M, Summers, W P, Summers, W C, and Gesteland, R F
- Abstract
We have studied the in vitro translation, in nuclease-treated reticulocyte lysates, of mRNA from cells infected with several thymidine kinase-deficient mutants of herpes simplex virus type I. The addition of suppressor tRNAs from yeast resulted in suppression of the mutant property in the case of two mutants. Synthesis of enzymatically active viral thymidine kinase was restored by serine-inserting amber suppressor tRNA in the case of HSV TK4- and synthesis of the intact, but inactive, thymidine kinase protein was restored by serine- and leucine-inserting UGA suppressor tRNAs in the case of HSV TK43-. Read-through of the normal termination at the end of the thymidine kinase gene was promoted by UGA suppressor tRNAs. We conclude that HSV-TK4- is an amber (UAG) mutant and that HSV-TK43- is an opal (UGA) mutant. more...
- Published
- 1979
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26. Immunization with a vaccinia virus recombinant expressing herpes simplex virus type 1 glycoprotein D: long-term protection and effect of revaccination
- Author
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Rooney, J F, Wohlenberg, C, Cremer, K J, Moss, B, and Notkins, A L
- Abstract
Previously we showed that mice immunized with a vaccinia virus vector expressing the herpes simplex virus type 1 (HSV-1) glycoprotein D (gD) gene (vaccinia/gD) were protected against both lethal and latent infections with HSV-1 for at least 6 weeks after immunization (K. J. Cremer, M. Mackett, C. Wohlenberg, A. L. Notkins, and B. Moss, Science 228:737-740, 1985). In the experiments described here, we examined long-term immunity to HSV following vaccinia/gD vaccination, the effect of revaccination with vaccinia/gD, and the impact of previous immunity to vaccinia virus on immunization with the gD recombinant. Mice immunized with vaccinia/gD showed 100, 100, and 80% protection against lethal infection with HSV-1 at 18, 44, and 60 weeks postimmunization, respectively. Protection against latent trigeminal ganglionic infection was 70, 50, and 31% at 6, 41, and 60 weeks postvaccination, respectively. To study the effect of reimmunization on antibody levels, mice vaccinated with vaccinia/gD were given a second immunization (booster dose) 3 months after the first. These mice developed a 10-fold increase in neutralizing-antibody titer (221 to 2,934) and demonstrated a significant increase in protection against lethal HSV-1 challenge compared with animals that received only one dose of vaccinia/gD. To determine whether preexisting immunity to vaccinia virus inhibited the response to vaccination with vaccinia/gD virus, mice were immunized with a recombinant vaccinia virus vector expressing antigens from either influenza A or hepatitis B virus and were then immunized (2 to 3 months later) with vaccinia/gD. These mice showed reduced titers of neutralizing antibody to HSV-1 and decreased protection against both lethal and latent infections with HSV-1 compared with animals vaccinated only with vaccinia/gD. We conclude that vaccination with vaccinia/gD produces immunity against HSV-1 that lasts over 1 year and that this immunity can be increased by a booster but that prior immunization with a vaccinia recombinant virus expressing a non-HSV gene reduces the levels of neutralizing antibody and protective immunity against HSV-1 challenge. more...
- Published
- 1988
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27. Cell-free synthesis of herpes simplex virus proteins
- Author
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Cremer, K J, Summers, W C, and Gesteland, R F
- Abstract
Polyribosomes isolated from herpes simplex virus type I (HSV-1)-infected cells have been used to program a eucaryotic cell-free translation system. At least 10 HSV-specific polypeptides, with apparent molecular weights of 25,000 to 160,000, are synthesized by wild-type HSV-infected polyribosomes. Polyribosomes prepared from thymidine kinase-negative mutants of HSV direct the synthesis of three putative nonsense termination polypeptides. HSV-specific polypeptides synthesized in vitro are precipitated with antiserum to HSV-infected cell proteins. more...
- Published
- 1977
- Full Text
- View/download PDF
28. Characterization of the mRNA for herpes simplex virus thymidine kinase by cell-free synthesis of active enzyme.
- Author
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Cremer, K, Bodemer, M, and Summers, W C
- Abstract
The cytoplasmic mRNA which codes for the herpes simplex virus specific thymidine kinase (TK) is polyadenylated and is 14.5s in size. This corresponds to an RNA of 1400 nucleotides. The TK polypeptide is about 42,000 daltons, which requires 1100 nucleotide. We conclude that the cytoplasmic mRNA is monocistronic. The reticulocyte lysate cell-free translation system synthesizes enzymatically active HSV-TK which can be assayed with high specificity and sensitivity by use of 125I-iododeoxycytidine as a substrate. more...
- Published
- 1978
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- View/download PDF
29. Decreased virulence of recombinant vaccinia virus expression vectors is associated with a thymidine kinase-negative phenotype.
- Author
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Buller, R. M. L., Smith, G. L., Cremer, K., Notkins, A. L., and Moss, Bernard
- Published
- 1985
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30. Immunized Mice Challenged with Herpes Simplex Virus by the Intranasal Route Show Protection Against Latent Infection
- Author
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Rooney, J. F., primary, Wohlenberg, C., additional, Cremer, K. J., additional, and Norkins, A. L., additional
- Published
- 1989
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31. A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3.
- Author
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Paul MS, Michener SL, Pan H, Chan H, Pfliger JM, Rosenfeld JA, Lerma VC, Tran A, Longley MA, Lewis RA, Weisz-Hubshman M, Bekheirnia MR, Bekheirnia N, Massingham L, Zech M, Wagner M, Engels H, Cremer K, Mangold E, Peters S, Trautmann J, Perne C, Mester JL, Guillen Sacoto MJ, Person R, McDonnell PP, Cohen SR, Lusk L, Cohen ASA, Le Pichon JB, Pastinen T, Zhou D, Engleman K, Racine C, Faivre L, Moutton S, Denommé-Pichon AS, Koh HY, Poduri A, Bolton J, Knopp C, Julia Suh DS, Maier A, Toosi MB, Karimiani EG, Maroofian R, Schaefer GB, Ramakumaran V, Vasudevan P, Banos-Pinero B, Pagnamenta AT, Prasad C, Osmond M, Schuhmann S, Vasileiou G, Russ-Hall S, Scheffer IE, Carvill GL, Mefford H, Bacino CA, Lee BH, and Chao 趙孝端 HT more...
- Published
- 2024
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32. Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features.
- Author
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Liu Z, Xin B, Smith IN, Sency V, Szekely J, Alkelai A, Shuldiner A, Efthymiou S, Rajabi F, Coury S, Brownstein CA, Rudnik-Schöneborn S, Bruel AL, Thevenon J, Zeidler S, Jayakar P, Schmidt A, Cremer K, Engels H, Peters SO, Zaki MS, Duan R, Zhu C, Xu Y, Gao C, Sepulveda-Morales T, Maroofian R, Alkhawaja IA, Khawaja M, Alhalasah H, Houlden H, Madden JA, Turchetti V, Marafi D, Agrawal PB, Schatz U, Rotenberg A, Rotenberg J, Mancini GMS, Bakhtiari S, Kruer M, Thiffault I, Hirsch S, Hempel M, Stühn LG, Haack TB, Posey JE, Lupski JR, Lee H, Sarn NB, Eng C, Gonzaga-Jauregui C, Zhang B, and Wang H more...
- Subjects
- Male, Humans, Protein Phosphatase 1 genetics, Glucose, Glycogen, Intellectual Disability genetics, Intellectual Disability complications, Autism Spectrum Disorder genetics, Autistic Disorder genetics, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders complications
- Abstract
Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that PPP1R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that PPP1R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.) more...
- Published
- 2023
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33. BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients.
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Engel C, Valence S, Delplancq G, Maroofian R, Accogli A, Agolini E, Alkuraya FS, Baglioni V, Bagnasco I, Becmeur-Lefebvre M, Bertini E, Borggraefe I, Brischoux-Boucher E, Bruel AL, Brusco A, Bubshait DK, Cabrol C, Cilio MR, Cornet MC, Coubes C, Danhaive O, Delague V, Denommé-Pichon AS, Di Giacomo MC, Doco-Fenzy M, Engels H, Cremer K, Gérard M, Gleeson JG, Heron D, Goffeney J, Guimier A, Harms FL, Houlden H, Iacomino M, Kaiyrzhanov R, Kamien B, Karimiani EG, Kraus D, Kuentz P, Kutsche K, Lederer D, Massingham L, Mignot C, Morris-Rosendahl D, Nagarajan L, Odent S, Ormières C, Partlow JN, Pasquier L, Penney L, Philippe C, Piccolo G, Poulton C, Putoux A, Rio M, Rougeot C, Salpietro V, Scheffer I, Schneider A, Srivastava S, Straussberg R, Striano P, Valente EM, Venot P, Villard L, Vitobello A, Wagner J, Wagner M, Zaki MS, Zara F, Lesca G, Yassaee VR, Miryounesi M, Hashemi-Gorji F, Beiraghi M, Ashrafzadeh F, Galehdari H, Walsh C, Novelli A, Tacke M, Sadykova D, Maidyrov Y, Koneev K, Shashkin C, Capra V, Zamani M, Van Maldergem L, Burglen L, and Piard J more...
- Subjects
- Humans, Nuclear Proteins genetics, Phenotype, Genotype, Genetic Association Studies, Atrophy, Epilepsy genetics, Neurodegenerative Diseases genetics
- Abstract
BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17)., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.) more...
- Published
- 2023
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34. Noninvasive integrative approach applied to children in the context of recent air pollution exposure demonstrates association between fractional exhaled nitric oxide (FeNO) and urinary CC16.
- Author
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Nauwelaerts SJD, Van Goethem N, De Cremer K, Sierra NB, Vercauteren J, Stroobants C, Bernard A, Nawrot T, Roosens NHC, and De Keersmaecker SCJ
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- Child, Humans, Fractional Exhaled Nitric Oxide Testing, Particulate Matter analysis, Air Pollutants adverse effects, Air Pollution adverse effects, Environmental Exposure analysis, Nitric Oxide analysis
- Abstract
Exposure to the air pollutant particulate matter (PM) is associated with increased risks of respiratory diseases and enhancement of airway inflammation in children. In the context of large scale air pollution studies, it can be challenging to measure fractional exhaled nitric oxide (FeNO) as indicator of lung inflammation. Urinary CC16 (U-CC16) is a potential biomarker of increased lung permeability and toxicity, increasing following short-term PM
2.5 exposure. The single nucleotide polymorphism (SNP) CC16 G38A (rs3741240) affects CC16 levels and respiratory health. Our study aimed at assessing the use of U-CC16 (incl. CC16 G38A from saliva) as potential alternative for FeNO by investigating their mutual correlation in children exposed to PM. Samples from a small-scale study conducted in 42 children from urban (n = 19) and rural (n = 23) schools examined at two time points, were analysed. When considering recent (lag1) low level exposure to PM2.5 as air pollution measurement, we found that U-CC16 was positively associated with FeNO (β = 0.23; 95% CI [-0.01; 0.47]; p = 0.06) in an adjusted analysis using a linear mixed effects model. Further, we observed a positive association between PM2.5 and FeNO (β = 0.56; 95% CI [0.02; 1.09]; p = 0.04) and higher FeNO in urban school children as compared to rural school children (β = 0.72; 95% CI [0.12; 1.31]; p = 0.02). Although more investigations are needed, our results suggest that inflammatory responses evidenced by increased FeNO are accompanied by potential increased lung epithelium permeability and injury, evidenced by increased U-CC16. In future large scale studies, where FeNO measurement is less feasible, the integrated analysis of U-CC16 and CC16 G38A, using noninvasive samples, might be a suitable alternative to assess the impact of air pollution exposure on the respiratory health of children, which is critical for policy development at population level., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:All authors reports financial support was provided by Belgian Federal Science Policy Office., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.) more...- Published
- 2023
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35. SARS-CoV-2 Transmission in Belgian French-Speaking Primary Schools: An Epidemiological Pilot Study.
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Frère J, Chatzis O, Cremer K, Merckx J, De Keukeleire M, Renard F, Ribesse N, Minner F, Ruelle J, Kabamba B, Rodriguez-Villalobos H, Bearzatto B, Delforge ML, Henin C, Bureau F, Gillet L, Robert A, and Van der Linden D more...
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- Child, Humans, Pilot Projects, Belgium epidemiology, Prospective Studies, Schools, SARS-CoV-2 genetics, COVID-19 epidemiology
- Abstract
Schools have been a point of attention during the pandemic, and their closure one of the mitigating measures taken. A better understanding of the dynamics of the transmission of SARS-CoV-2 in elementary education is essential to advise decisionmakers. We conducted an uncontrolled non-interventional prospective study in Belgian French-speaking schools to describe the role of attending asymptomatic children and school staff in the spread of COVID-19 and to estimate the transmission to others. Each participant from selected schools was tested for SARS-CoV-2 using a polymerase chain reaction (PCR) analysis on saliva sample, on a weekly basis, during six consecutive visits. In accordance with recommendations in force at the time, symptomatic individuals were excluded from school, but per the study protocol, being that participants were blinded to PCR results, asymptomatic participants were maintained at school. Among 11 selected schools, 932 pupils and 242 school staff were included between January and May 2021. Overall, 6449 saliva samples were collected, of which 44 came back positive. Most positive samples came from isolated cases. We observed that asymptomatic positive children remaining at school did not lead to increasing numbers of cases or clusters. However, we conducted our study during a period of low prevalence in Belgium. It would be interesting to conduct the same analysis during a high prevalence period. more...
- Published
- 2022
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36. Urinary CC16, a potential indicator of lung integrity and inflammation, increases in children after short-term exposure to PM 2.5 /PM 10 and is driven by the CC16 38GG genotype.
- Author
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Nauwelaerts SJD, Van Goethem N, Ureña BT, De Cremer K, Bernard A, Saenen ND, Nawrot TS, Roosens NHC, and De Keersmaecker SCJ
- Subjects
- Biomarkers, Child, Environmental Exposure adverse effects, Genotype, Humans, Inflammation, Retinol-Binding Proteins, Plasma, Air Pollutants toxicity, Lung pathology, Particulate Matter toxicity, Uteroglobin genetics, Uteroglobin urine
- Abstract
Particular matter (PM) exposure is a big hazard for public health, especially for children. Serum CC16 is a well-known biomarker of respiratory health. Urinary CC16 (U-CC16) can be a noninvasive alternative, albeit requiring adequate adjustment for renal handling. Moreover, the SNP CC16 G38A influences CC16 levels. This study aimed to monitor the effect of short-term PM exposure on CC16 levels, measured noninvasively in schoolchildren, using an integrative approach. We used a selection of urine and buccal DNA samples from 86 children stored in an existing biobank. Using a multiple reaction monitoring method, we measured U-CC16, as well as RBP4 (retinol binding protein 4) and β2M (beta-2-microglobulin), required for adjustment. Buccal DNA samples were used for CC16 G38A genotyping. Linear mixed-effects models were used to find relevant associations between U-CC16 and previously obtained data from recent daily PM ≤ 2.5 or 10 μm exposure (PM
2.5 , PM10 ) modeled at the child's residence. Our study showed that exposure to low PM at the child's residence (median levels 18.9 μg/m³ (PM2.5 ) and 23.6 μg/m³ (PM10 )) one day before sampling had an effect on the covariates-adjusted U-CC16 levels. This effect was dependent on the CC16 G38A genotype, due to its strong interaction with the association between PM levels and covariates-adjusted U-CC16 (P = 0.024 (PM2.5 ); P = 0.061 (PM10 )). Only children carrying the 38GG genotype showed an increase of covariates-adjusted U-CC16, measured 24h after exposure, with increasing PM2.5 and PM10 (β = 0.332; 95% CI: 0.110 to 0.554 and β = 0.372; 95% CI: 0.101 to 0.643, respectively). To the best of our knowledge, this is the first study using an integrative approach to investigate short-term PM exposure of children, using urine to detect early signs of pulmonary damage, and taking into account important determinants such as the genetic background and adequate adjustment of the measured biomarker in urine., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.) more...- Published
- 2022
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37. Assessment of the Feasibility of a Future Integrated Larger-Scale Epidemiological Study to Evaluate Health Risks of Air Pollution Episodes in Children.
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Nauwelaerts SJD, De Cremer K, Bustos Sierra N, Gand M, Van Geel D, Delvoye M, Vandermassen E, Vercauteren J, Stroobants C, Bernard A, Saenen ND, Nawrot TS, Roosens NHC, and De Keersmaecker SCJ
- Subjects
- Biomarkers analysis, Child, Environmental Exposure analysis, Epidemiologic Studies, Feasibility Studies, Humans, Particulate Matter analysis, Air Pollutants analysis, Air Pollution adverse effects, Air Pollution analysis
- Abstract
Air pollution exposure can lead to exacerbation of respiratory disorders in children. Using sensitive biomarkers helps to assess the impact of air pollution on children's respiratory health and combining protein, genetic and epigenetic biomarkers gives insights on their interrelatedness. Most studies do not contain such an integrated approach and investigate these biomarkers individually in blood, although its collection in children is challenging. Our study aimed at assessing the feasibility of conducting future integrated larger-scale studies evaluating respiratory health risks of air pollution episodes in children, based on a qualitative analysis of the technical and logistic aspects of a small-scale field study involving 42 children. This included the preparation, collection and storage of non-invasive samples (urine, saliva), the measurement of general and respiratory health parameters and the measurement of specific biomarkers (genetic, protein, epigenetic) of respiratory health and air pollution exposure. Bottlenecks were identified and modifications were proposed to expand this integrated study to a higher number of children, time points and locations. This would allow for non-invasive assessment of the impact of air pollution exposure on the respiratory health of children in future larger-scale studies, which is critical for the development of policies or measures at the population level. more...
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- 2022
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38. Catch them if you are aware: PTEN postzygotic mosaicism in clinically suspicious patients with PTEN Hamartoma Tumour Syndrome and literature review.
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Hendricks LAJ, Schuurs-Hoeijmakers J, Spier I, Haadsma ML, Eijkelenboom A, Cremer K, Mensenkamp AR, Aretz S, Vos JR, and Hoogerbrugge N
- Subjects
- Adolescent, Adult, Child, Developmental Disabilities, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Mosaicism, PTEN Phosphohydrolase genetics, Young Adult, Hamartoma Syndrome, Multiple diagnosis, Hamartoma Syndrome, Multiple genetics, Hamartoma Syndrome, Multiple pathology, Megalencephaly
- Abstract
PTEN germline variants cause PTEN Hamartoma Tumour Syndrome (PHTS). Of individuals fulfilling diagnostic criteria, 41-88% test negative for PTEN germline variants, while mosaicism could be an explanation. Here we describe two individuals with PTEN mosaicism. First, a 21-year-old female presented with macrocephaly and a venous malformation. Next generation sequencing analysis on her venous malformation identified the mosaic pathogenic PTEN variant c.493-2A>G (23%). This variant was initially missed in blood due to low frequency (<1%), but detected in buccal swab (21%). Second, a 13-year-old male presented with macrocephaly, language developmental delay, behavioral problems, and an acral hyperkeratotic papule. Targeted PTEN analysis identified the mosaic pathogenic variant c.284C>T (11%) in blood, which was confirmed via buccal swab. These two cases suggest that PTEN mosaicism might be more common than currently reported. PTEN mosaicism awareness is important to enable diagnosis, which facilitates timely inclusion in cancer surveillance programs improving prognosis and life expectancy., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.) more...
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- 2022
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39. Implant functionalization with mesoporous silica: A promising antibacterial strategy, but does such an implant osseointegrate?
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Vandamme K, Thevissen K, Mesquita MF, Coropciuc RG, Agbaje J, Thevissen P, da Silva WJ, Vleugels J, De Cremer K, Gerits E, Martens JA, Michiels J, Cammue BPA, and Braem A
- Subjects
- Animals, Anti-Bacterial Agents, Dental Implants, Peri-Implantitis prevention & control, Silicon Dioxide, Surface Properties, Swine, Swine, Miniature, Titanium, Prostheses and Implants
- Abstract
Objectives: New strategies for implant surface functionalization in the prevention of peri-implantitis while not compromising osseointegration are currently explored. The aim of this in vivo study was to assess the osseointegration of a titanium-silica composite implant, previously shown to enable controlled release of therapeutic concentrations of chlorhexidine, in the Göttingen mini-pig oral model., Material and Methods: Three implant groups were designed: macroporous titanium implants (Ti-Porous); macroporous titanium implants infiltrated with mesoporous silica (Ti-Porous + SiO
2 ); and conventional titanium implants (Ti-control). Mandibular last premolar and first molar teeth were extracted bilaterally and implants were installed. After 1 month healing, the bone in contact with the implant and the bone regeneration in the peri-implant gap was evaluated histomorphometrically., Results: Bone-to-implant contact and peri-implant bone volume for Ti-Porous versus Ti-Porous + SiO2 implants did not differ significantly, but were significantly higher in the Ti-Control group compared with Ti-Porous + SiO2 implants. Functionalization of titanium implants via infiltration of a SiO2 phase into the titanium macropores does not seem to inhibit implant osseointegration. Yet, the importance of the implant macro-design, in particular the screw thread design in a marginal gap implant surgery set-up, was emphasized by the outstanding results of the Ti-Control implant., Conclusions: Next-generation implants made of macroporous Ti infiltrated with mesoporous SiO2 do not seem to compromise the osseointegration process. Such implant functionalization may be promising for the prevention and treatment of peri-implantitis given the evidenced potential of mesoporous SiO2 for controlled drug release., (© 2020 The Authors. Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.) more...- Published
- 2021
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40. Development of a multiplex mass spectrometry method for simultaneous quantification of urinary proteins related to respiratory health.
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Nauwelaerts SJD, Roosens NHC, Bernard A, De Keersmaecker SCJ, and De Cremer K
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- Biomarkers urine, Child, Child, Preschool, Female, Humans, Male, Osteopontin urine, Prospective Studies, Respiratory Tract Diseases diagnosis, Retinol-Binding Proteins, Plasma urine, beta 2-Microglobulin urine, Chromatography, High Pressure Liquid methods, Respiratory Tract Diseases urine, Tandem Mass Spectrometry methods, Urine chemistry
- Abstract
Respiratory health of children is a health priority. Club cell protein (CC16) is an interesting biomarker of lung diseases and adverse effects towards the airway epithelium integrity. Osteopontin (OPN) and nuclear factor-kappa B (NF-κB) also play a role in respiratory health. The use of urine as biomarker source is useful in studies involving children but necessitates proper adjustment for physiological confounders influencing the urinary excretion, potentially characterized with beta-2-microglobulin (β2M), retinol binding protein 4 (RBP4) or myoglobin (MYO), as well as adjustment for possible renal dysfunction, characterized by human serum albumin (HSA). The simultaneous quantification of all these proteins in urine could facilitate children's health monitoring. A multiple reaction monitoring method (MRM) was developed and validated for the relative quantification of the seven mentioned urinary proteins. A total of nine proteotypic peptides were selected and used for the relative quantification of the seven proteins. The MRM method was completely validated for all proteins and partially for OPN. LOQ's ranged from 0.3 to 42.8 ng/ml, a good reproducibility and a good linearity were obtained across the analytical measurement range (r
2 > 0.98). The method yielded varying correlations (r2 of 0.78, 0.71, 0.34 and 0.15 for CC16, β2M, RBP4 and HSA respectively) with available immunoassay data. It also allowed the identification and successful quantification of β2M and RBP4 as a protein candidate for adjustment of renal handling and dysfunction. All proteins were detected in the urine samples except for MYO and NF-κB. Our validated MRM-method is able to simultaneously quantify in urine biomarkers of airway epithelium integrity and biomarkers of variation in renal function and urinary dilution. This will allow to investigate further in future studies if urine can be used as a good surrogate source for biomarkers of airway epithelium integrity, and to understand the complex relationship between cause and effect in children's respiratory health monitoring. more...- Published
- 2021
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41. New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics.
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Begemann A, Sticht H, Begtrup A, Vitobello A, Faivre L, Banka S, Alhaddad B, Asadollahi R, Becker J, Bierhals T, Brown KE, Bruel AL, Brunet T, Carneiro M, Cremer K, Day R, Denommé-Pichon AS, Dyment DA, Engels H, Fisher R, Goh ES, Hajianpour MJ, Haertel LRM, Hauer N, Hempel M, Herget T, Johannsen J, Kraus C, Le Guyader G, Lesca G, Mau-Them FT, McDermott JH, McWalter K, Meyer P, Õunap K, Popp B, Reimand T, Riedhammer KM, Russo M, Sadleir LG, Saenz M, Schiff M, Schuler E, Syrbe S, Van der Ven AT, Verloes A, Willems M, Zweier C, Steindl K, Zweier M, and Rauch A more...
- Subjects
- Actins genetics, Adaptor Proteins, Signal Transducing metabolism, Humans, Seizures, Intellectual Disability genetics, Neurodevelopmental Disorders genetics
- Abstract
Purpose: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority., Methods: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC., Results: Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype-phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts., Conclusion: Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism. more...
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- 2021
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42. Repurposing the Antidepressant Sertraline as SHMT Inhibitor to Suppress Serine/Glycine Synthesis-Addicted Breast Tumor Growth.
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Geeraerts SL, Kampen KR, Rinaldi G, Gupta P, Planque M, Louros N, Heylen E, De Cremer K, De Brucker K, Vereecke S, Verbelen B, Vermeersch P, Schymkowitz J, Rousseau F, Cassiman D, Fendt SM, Voet A, Cammue BPA, Thevissen K, and De Keersmaecker K more...
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Cell Line, Tumor, Cell Proliferation drug effects, Female, Glycine Hydroxymethyltransferase metabolism, Humans, Mice, Inbred NOD, Mice, SCID, Molecular Docking Simulation, Phosphoglycerate Dehydrogenase metabolism, Thimerosal pharmacology, Mice, Antidepressive Agents pharmacology, Breast Neoplasms pathology, Drug Repositioning, Glycine biosynthesis, Glycine Hydroxymethyltransferase antagonists & inhibitors, Serine blood, Sertraline pharmacology
- Abstract
Metabolic rewiring is a hallmark of cancer that supports tumor growth, survival, and chemotherapy resistance. Although normal cells often rely on extracellular serine and glycine supply, a significant subset of cancers becomes addicted to intracellular serine/glycine synthesis, offering an attractive drug target. Previously developed inhibitors of serine/glycine synthesis enzymes did not reach clinical trials due to unfavorable pharmacokinetic profiles, implying that further efforts to identify clinically applicable drugs targeting this pathway are required. In this study, we aimed to develop therapies that can rapidly enter the clinical practice by focusing on drug repurposing, as their safety and cost-effectiveness have been optimized before. Using a yeast model system, we repurposed two compounds, sertraline and thimerosal, for their selective toxicity against serine/glycine synthesis-addicted breast cancer and T-cell acute lymphoblastic leukemia cell lines. Isotope tracer metabolomics, computational docking, enzymatic assays, and drug-target interaction studies revealed that sertraline and thimerosal inhibit serine/glycine synthesis enzymes serine hydroxymethyltransferase and phosphoglycerate dehydrogenase, respectively. In addition, we demonstrated that sertraline's antiproliferative activity was further aggravated by mitochondrial inhibitors, such as the antimalarial artemether, by causing G
1 -S cell-cycle arrest. Most notably, this combination also resulted in serine-selective antitumor activity in breast cancer mouse xenografts. Collectively, this study provides molecular insights into the repurposed mode-of-action of the antidepressant sertraline and allows to delineate a hitherto unidentified group of cancers being particularly sensitive to treatment with sertraline. Furthermore, we highlight the simultaneous inhibition of serine/glycine synthesis and mitochondrial metabolism as a novel treatment strategy for serine/glycine synthesis-addicted cancers., (©2020 American Association for Cancer Research.) more...- Published
- 2021
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43. Regulation of PD-L1 expression in K-ras-driven cancers through ROS-mediated FGFR1 signaling.
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Glorieux C, Xia X, He YQ, Hu Y, Cremer K, Robert A, Liu J, Wang F, Ling J, Chiao PJ, and Huang P
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- Humans, Immunotherapy, Reactive Oxygen Species, Receptor, Fibroblast Growth Factor, Type 1 genetics, Signal Transduction, B7-H1 Antigen genetics, Neoplasms genetics, Proto-Oncogene Proteins p21(ras)
- Abstract
K-ras mutations are major genetic events that drive cancer development associated with aggressive malignant phenotypes, while expression of the immune checkpoint molecule PD-L1 plays a key role in cancer evasion of the immune surveillance that also profoundly affects the patient outcome. However, the relationship between K-ras oncogenic signal and PD-L1 expressions as an important area that requires further investigation. Using both in vitro and in vivo experimental models of K-ras-driven cancer, we found that oncogenic K-ras significantly enhanced PD-L1 expression through a redox-mediated mechanism. Activation of K-ras
G12V promoted ROS generation and induced FGFR1 expression, leading to a significant upregulation of PD-L1. We further showed that exogenous ROS such as hydrogen peroxide alone was sufficient to activate FGFR1 and induce PD-L1, while antioxidants could largely abrogate PD-L1 expression in K-ras mutant cells, indicating a critical role of redox regulation. Importantly, genetic knockout of FGFR1 led to a decrease in PD-L1 expression, and impaired tumor growth in vivo due to a significant increase of T cell infiltration in the tumor tissues and thus enhanced T-cell-mediated tumor suppression. Our study has identified a novel mechanism by which K-ras promotes PD-L1 expression, and suggests that modulation of ROS or inhibition of the FGFR1 pathway could be a novel strategy to abrogate PD-L1-mediated immunosuppression and thus potentially improve the efficacy of immunotherapy in K-ras-driven cancers., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.) more...- Published
- 2021
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44. Gender-dependent association between exhaled nitric oxide and the CC16 38AA genotype in young school children.
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Nauwelaerts SJD, Roosens NHC, De Cremer K, Bernard A, and De Keersmaecker SCJ
- Subjects
- Child, Exhalation, Female, Genotype, Humans, Male, Schools, Nitric Oxide metabolism, Uteroglobin genetics
- Abstract
Background: Studies that investigated the association between the CC16 A38G polymorphism and the risk of asthma yielded conflicting results. The aim of this study among schoolchildren was to assess the relationships of CC16 A38G polymorphism with aeroallergen sensitization and fractional exhaled nitric oxide (FeNO), two outcomes predicting asthma later in life., Methods: The study included 139 children (72 boys), median age of 7.7. Information on each child's health, lifestyle, and environment was collected through a questionnaire completed by their parents. CC16 genotypes were determined using urinary DNA. We measured FeNO, the CC16 protein in urine and nasal lavage fluid and aeroallergen-specific immunoglobulin E in nasal mucosa fluid., Results: Children with the homozygous mutant CC16 38AA genotype had higher odds of increased FeNO (>30 ppb) compared with their peers with the wild-type genotype 38GG (OR, 9.85; 95% CI, 2.09-46.4; P = .004). This association was female gender specific (P = .002) not being observed in boys (P = .40). It was also independent of allergic sensitization, which yet emerged as the strongest predictor of FeNO along with the use of bleach for house cleaning. Children with the CC16 38AA genotype had lower covariates-adjusted urinary CC16 levels than those with 38GG (median, μg/L, 1.17 vs 2.08, P = .02)., Conclusion: Our study suggests that the CC16 38AA allele promotes airway inflammation as measured by FeNO through a gender-dependent association. Deficient levels of CC16 in the deep lung, measured noninvasively in urine, as a possible proxy for serum CC16, might underlie this promoting effect., (© 2020 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.) more...
- Published
- 2020
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45. Combination of Miconazole and Domiphen Bromide Is Fungicidal against Biofilms of Resistant Candida spp.
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Tits J, Cools F, De Cremer K, De Brucker K, Berman J, Verbruggen K, Gevaert B, Cos P, Cammue BPA, and Thevissen K
- Subjects
- Animals, Antifungal Agents pharmacology, Antifungal Agents therapeutic use, Biofilms, Candida albicans, Female, Humans, Microbial Sensitivity Tests, Quaternary Ammonium Compounds, Rats, Candida, Miconazole pharmacology
- Abstract
The occurrence and recurrence of mucosal biofilm-related Candida infections, such as oral and vulvovaginal candidiasis, are serious clinical issues. Vaginal infections caused by Candida spp., for example, affect 70 to 75% of women at least once during their lives. Miconazole (MCZ) is the preferred topical treatment against these fungal infections, yet it has only moderate antibiofilm activity. Through screening of a drug-repurposing library, we identified the quaternary ammonium compound domiphen bromide (DB) as an MCZ potentiator against Candida biofilms. DB displayed synergistic anti- Candida albicans biofilm activity with MCZ, reducing the number of viable biofilm cells 1,000-fold. In addition, the MCZ-DB combination also resulted in significant killing of biofilm cells of azole-resistant C. albicans , C. glabrata , and C. auris isolates. In vivo , the MCZ-DB combination had significantly improved activity in a vulvovaginal candidiasis rat model compared to that of single-compound treatments. Data from an artificial evolution experiment indicated that the development of resistance against the combination did not occur, highlighting the potential of MCZ-DB combination therapy to treat Candida biofilm-related infections., (Copyright © 2020 American Society for Microbiology.) more...
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- 2020
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46. The antifungal plant defensin HsAFP1 induces autophagy, vacuolar dysfunction and cell cycle impairment in yeast.
- Author
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Struyfs C, Cools TL, De Cremer K, Sampaio-Marques B, Ludovico P, Wasko BM, Kaeberlein M, Cammue BPA, and Thevissen K
- Subjects
- Antifungal Agents chemistry, Antifungal Agents pharmacology, Apoptosis drug effects, Candida albicans drug effects, Cell Cycle drug effects, Defensins genetics, Defensins pharmacology, G2 Phase Cell Cycle Checkpoints drug effects, Saccharomyces cerevisiae genetics, Autophagy drug effects, Defensins chemistry, Heuchera chemistry, Saccharomyces cerevisiae drug effects
- Abstract
The plant defensin HsAFP1 is characterized by broad-spectrum antifungal activity and induces apoptosis in Candida albicans. In this study, we performed a transcriptome analysis on C. albicans cultures treated with HsAFP1 to gain further insight in the antifungal mode of action of HsAFP1. Various genes coding for cell surface proteins, like glycosylphosphatidylinositol (GPI)-anchored proteins, and proteins involved in cation homeostasis, autophagy and in cell cycle were differentially expressed upon HsAFP1 treatment. The biological validation of these findings was performed in the model yeast Saccharomyces cerevisiae. To discriminate between events linked to HsAFP1's antifungal activity and those that are not, we additionally used an inactive HsAFP1 mutant. We demonstrated that (i) HsAFP1-resistent S. cerevisiae mutants that are characterized by a defect in processing GPI-anchors are unable to internalize HsAFP1, and (ii) moderate doses (FC50, fungicidal concentration resulting in 50% killing) of HsAFP1 induce autophagy in S. cerevisiae, while high HsAFP1 doses result in vacuolar dysfunction. Vacuolar function is an important determinant of replicative lifespan (RLS) under dietary restriction (DR). In line, HsAFP1 specifically reduces RLS under DR. Lastly, (iii) HsAFP1 affects S. cerevisiae cell cycle in the G2/M phase. However, the latter HsAFP1-induced event is not linked to its antifungal activity, as the inactive HsAFP1 mutant also impairs the G2/M phase. In conclusion, we demonstrated that GPI-anchored proteins are involved in HsAFP1's internalization, and that HsAFP1 induces autophagy, vacuolar dysfunction and impairment of the cell cycle. Collectively, all these data provide novel insights in the mode of action of HsAFP1 as well as in S. cerevisiae tolerance mechanisms against this peptide., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.) more...
- Published
- 2020
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47. Weight and head circumference at birth in function of placental paraben load in Belgium: an ENVIRONAGE birth cohort study.
- Author
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Vrijens K, Van Overmeire I, De Cremer K, Neven KY, Carollo RM, Vleminckx C, Van Loco J, and Nawrot TS
- Subjects
- Belgium, Cohort Studies, Environmental Monitoring, Female, Humans, Infant, Newborn, Pregnancy, Birth Weight, Environmental Pollutants metabolism, Head anatomy & histology, Maternal Exposure, Parabens metabolism, Placenta chemistry
- Abstract
Background: Parabens are a group of esters of para-hydroxybenzoic acid utilized as antimicrobial preservatives in many personal care products. Epidemiological studies regarding the adverse effects of parabens on fetuses are limited. The aim of this study was to determine the association between placental paraben exposure and birth outcomes. We assessed paraben concentrations in placental tissue, which potentially gives a better understanding of fetal exposure than the maternal urinary concentrations which are the current golden standard., Methods: Placental tissue was collected immediately after birth from 142 mother-child pairs from the ENVIRONAGE birth cohort. The placental concentrations of four parabens (methyl (MeP), ethyl (EtP), propyl (PrP), and butyl (BuP)) were determined by ultra-performance liquid chromatography coupled with tandem mass-spectrometry. Generalized linear regression models were used to determine the association between paraben exposure levels and birth outcomes., Results: The geometric means of placental MeP, EtP, PrP, and BuP were 1.84, 2.16, 1.68 and 0.05 ng/g tissue, respectively. The sum of parabens (∑ parabens, including MeP, EtP and PrP) was negatively associated with birth weight in newborn girls (- 166 g, 95% CI: - 322, - 8.6, p = 0.04) after adjustment for a priori selected covariates. The sum of parabens was negatively associated with head circumference (- 0.6 cm, 95% CI: - 1.1, - 0.2, p = 0.008) and borderline associated with birth length (- 0.6 cm, 95% CI:-1.3, 0.1, p = 0.08). In newborn girls the placental concentration of EtP was negatively associated with head circumference (- 0.6 cm, 95% CI:-1.1, - 0.1, p = 0.01) and borderline significantly associated with birth weight and birth length. Lastly, placental EtP and ∑parabens were negatively associated with placental weight in newborn girls but not in newborn boys (- 45.3 g, 95% CI:-86.2, - 4.4, p = 0.03)., Conclusion: The negative association between maternal paraben exposure and birth outcomes warrants further research and follow-up over time to determine long term effects of gestational exposure to parabens. more...
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- 2020
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48. Selection of a Noninvasive Source of Human DNA Envisaging Genotyping Assays in Epidemiological Studies: Urine or Saliva?
- Author
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Nauwelaerts SJD, Van Geel D, Delvoye M, De Cremer K, Bernard A, Roosens NHC, and De Keersmaecker SCJ
- Subjects
- Biomarkers analysis, Biomarkers urine, Body Fluids, Child, DNA analysis, DNA genetics, DNA isolation & purification, Female, Genotype, Humans, Male, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Secretoglobins genetics, Uteroglobin genetics, DNA urine, Genotyping Techniques methods, Molecular Epidemiology methods, Saliva metabolism, Specimen Handling methods
- Abstract
Genetic epidemiology requires an appropriate approach to measure genetic variation within the population. The aim of this study was to evaluate the characteristics and genotyping results of DNA extracted from 2 human DNA sources, selected for their rapid and noninvasive sampling, and the use of simple and standardized protocols that are essential for large-scale epidemiologic studies. Saliva and urine samples were collected at the same day from 20 subjects aged 9-10 yr. Genomic DNA was extracted using commercial kits. Quantitative and qualitative evaluation was done by assessing the yield, the purity, and integrity of the extracted DNA. As a proof-of-concept, genotyping was performed targeting CC16 A38G and uteroglobin-related protein 1 ( UGRP1 )-112G/A. Saliva was found to provide the highest yield and concentration of total DNA extracted. Salivary DNA showed higher purity and a significantly less degraded state compared to urinary DNA. Consequently, the salivary DNA gave better genotyping results than urinary DNA. Therefore, if the choice exists, saliva is the preferred noninvasive matrix for genotyping purposes in large-scale genetic epidemiologic studies. Only in particular cases using urine could nevertheless be considered useful, although specific limitations need to be taken into account., (© Association of Biomolecular Resource Facilities.) more...
- Published
- 2020
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49. PEDIA: prioritization of exome data by image analysis.
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Hsieh TC, Mensah MA, Pantel JT, Aguilar D, Bar O, Bayat A, Becerra-Solano L, Bentzen HB, Biskup S, Borisov O, Braaten O, Ciaccio C, Coutelier M, Cremer K, Danyel M, Daschkey S, Eden HD, Devriendt K, Wilson S, Douzgou S, Đukić D, Ehmke N, Fauth C, Fischer-Zirnsak B, Fleischer N, Gabriel H, Graul-Neumann L, Gripp KW, Gurovich Y, Gusina A, Haddad N, Hajjir N, Hanani Y, Hertzberg J, Hoertnagel K, Howell J, Ivanovski I, Kaindl A, Kamphans T, Kamphausen S, Karimov C, Kathom H, Keryan A, Knaus A, Köhler S, Kornak U, Lavrov A, Leitheiser M, Lyon GJ, Mangold E, Reina PM, Carrascal AM, Mitter D, Herrador LM, Nadav G, Nöthen M, Orrico A, Ott CE, Park K, Peterlin B, Pölsler L, Raas-Rothschild A, Randolph L, Revencu N, Fagerberg CR, Robinson PN, Rosnev S, Rudnik S, Rudolf G, Schatz U, Schossig A, Schubach M, Shanoon O, Sheridan E, Smirin-Yosef P, Spielmann M, Suk EK, Sznajer Y, Thiel CT, Thiel G, Verloes A, Vrecar I, Wahl D, Weber I, Winter K, Wiśniewska M, Wollnik B, Yeung MW, Zhao M, Zhu N, Zschocke J, Mundlos S, Horn D, and Krawitz PM more...
- Subjects
- Algorithms, Databases, Genetic, Deep Learning, Exome genetics, Female, Genomics, Humans, Male, Phenotype, Software, Computational Biology methods, Image Processing, Computer-Assisted methods, Sequence Analysis, DNA methods
- Abstract
Purpose: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists., Methods: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds., Results: The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene., Conclusion: Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis. more...
- Published
- 2019
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50. KCNC1-related disorders: new de novo variants expand the phenotypic spectrum.
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Park J, Koko M, Hedrich UBS, Hermann A, Cremer K, Haberlandt E, Grimmel M, Alhaddad B, Beck-Woedl S, Harrer M, Karall D, Kingelhoefer L, Tzschach A, Matthies LC, Strom TM, Ringelstein EB, Sturm M, Engels H, Wolff M, Lerche H, and Haack TB more...
- Subjects
- Animals, Ataxia genetics, Child, Codon, Nonsense, Humans, Intellectual Disability genetics, Male, Myoclonic Epilepsies, Progressive, Seizures genetics, Shaw Potassium Channels physiology, Xenopus laevis, Genetic Association Studies, Mutation, Missense, Shaw Potassium Channels genetics
- Abstract
A recurrent de novo missense variant in KCNC1, encoding a voltage-gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.Thr399Met), or epilepsy with myoclonic, absence and generalized tonic-clonic seizures, ataxia, and developmental delay (p.Ala421Val, three patients). Functional analyses demonstrated no measurable currents for all identified variants and dominant-negative effects for p.Thr399Met and p.Ala421Val predicting neuronal disinhibition as the underlying disease mechanism., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.) more...
- Published
- 2019
- Full Text
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