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7. Physiological hypoxia restrains the senescence-associated secretory phenotype via AMPK-mediated mTOR suppression

Author

van Vliet, T. Varela-Eirin, M. Wang, B. Borghesan, M. Brandenburg, S.M. Franzin, R. Evangelou, K. Seelen, M. Gorgoulis, V. Demaria, M.

Subjects
fungi
Abstract

Cellular senescence is a state of stable proliferative arrest triggered by damaging signals. Senescent cells persist during aging and promote age-related pathologies via the pro-inflammatory senescence-associated secretory phenotype (SASP), whose regulation depends on environmental factors. In vivo, a major environmental variable is oxygenation, which varies among and within tissues. Here, we demonstrate that senescent cells express lower levels of detrimental pro-inflammatory SASP factors in physiologically hypoxic environments, as measured in culture and in tissues. Mechanistically, exposure of senescent cells to low-oxygen conditions leads to AMPK activation and AMPK-mediated suppression of the mTOR-NF-κB signaling loop. Finally, we demonstrate that treatment with hypoxia-mimetic compounds reduces SASP in cells and tissues and improves strength in chemotherapy-treated and aged mice. Our findings highlight the importance of oxygen as a determinant for pro-inflammatory SASP expression and offer a potential new strategy to reduce detrimental paracrine effects of senescent cells. © 2021 Elsevier Inc.

Published
2021

17. Insights Into Enhanced Complement Activation by Structures of Properdin and Its Complex With the C-Terminal Domain of C3b

Author

Bos, R.M. van den, Pearce, N.M., Granneman, J., Brondijk, T.H.C., Gros, P., Berger, S., Born, J. van den, Heuvel, L. van den, Kar, N. van de, Kooten, C. van, Seelen, M., Vries, A. de, COMBAT Consortium, Groningen Institute for Organ Transplantation (GIOT), and Groningen Kidney Center (GKC)

Subjects
lcsh:Immunologic diseases. Allergy, Glycosylation, CONVERTASE, Immunology, alternative pathway, PROTEIN, chemical and pharmacologic phenomena, Complement factor I, Protomer, C3b, Complement factor B, POSITIVE REGULATOR, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Protein Domains, ALTERNATIVE-PATHWAY, MACROMOLECULAR STRUCTURES, factor B, BINDING, Humans, Immunologic Factors, Immunology and Allergy, Complement Activation, complement system, Original Research, FACTOR-B, 030304 developmental biology, 0303 health sciences, REFINEMENT, Chemistry, C-terminus, O-FUCOSYLATION, Recombinant Proteins, 3. Good health, Complement system, Antibody opsonization, properdin, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], HEK293 Cells, RESOLUTION, Complement C3b, Alternative complement pathway, Biophysics, Properdin, lcsh:RC581-607, 030215 immunology
Abstract

Properdin enhances complement-mediated opsonization of targeted cells and particles for immune clearance. Properdin occurs as dimers, trimers and tetramers in human plasma, which recognize C3b-deposited surfaces, promote formation, and prolong the lifetime of C3bBb-enzyme complexes that convert C3 into C3b, thereby enhancing the complement-amplification loop. Here, we report crystal structures of monomerized properdin, which was produced by co-expression of separate N- and C-terminal constructs that yielded monomer-sized properdin complexes that stabilized C3bBb. Consistent with previous low-resolution X-ray and EM data, the crystal structures revealed ring-shaped arrangements that are formed by interactions between thrombospondin type-I repeat (TSR) domains 4 and 6 of one protomer interacting with the N-terminal domain (which adopts a short transforming-growth factor B binding protein-like fold) and domain TSR1 of a second protomer, respectively. Next, a structure of monomerized properdin in complex with the C-terminal domain of C3b showed that properdin-domain TSR5 binds along the C-terminal a-helix of C3b, while two loops, one from domain TSR5 and one from TSR6, extend and fold around the C3b C-terminus like stirrups. This suggests a mechanistic model in which these TSR5 and TSR6 "stirrups" bridge interactions between C3b and factor B or its fragment Bb, and thereby enhance formation of C3bB pro-convertases and stabilize C3bBb convertases. In addition, properdin TSR6 would sterically block binding of the protease factor I to C3b, thus limiting C3b proteolytic degradation. The presence of a valine instead of a third tryptophan in the canonical Trp-ladder of TSR domains in TSR4 allows a remarkable ca. 60 degrees-domain bending motion of TSR4. Together with variable positioning of TSR2 and, putatively, TSR3, this explains the conformational flexibility required for properdin to form dimers, trimers, and tetramers. In conclusion, the results indicate that binding avidity of oligomeric properdin is needed to distinguish surface-deposited C3b molecules from soluble C3b or C3 and suggest that properdin-mediated interactions bridging C3b-B and C3b-Bb enhance affinity, thus promoting convertase formation and stabilization. These mechanisms explain the enhancement of complement-mediated opsonization of targeted cells and particle for immune clearance.

Published
2019
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18. Role of properdin in complement-mediated kidney diseases

Author

Essen, M.F. van, Ruben, J.M., Vries, A.P.J. de, Kooten, C. van, Berger, S., Born, J. van den, Gros, P., Heuvel, L. van den, Kar, N. van de, Seelen, M., Vries, A. de, and COMBAT Consortium

Subjects
kidney, DECAY-ACCELERATING FACTOR, 030232 urology & nephrology, chemical and pharmacologic phenomena, 030204 cardiovascular system & hematology, urologic and male genital diseases, ALTERNATIVE PATHWAY, ACTIVATION, LECTIN PATHWAY, 03 medical and health sciences, 0302 clinical medicine, Immune system, BINDING, Membranoproliferative glomerulonephritis, medicine, Humans, C3 glomerulopathy, complement, GLOMERULAR DEPOSITION, Complement Activation, Decay-accelerating factor, Autoantibodies, Transplantation, Innate immune system, business.industry, medicine.disease, Immunity, Innate, Complement system, properdin, MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS, Nephrology, Lectin pathway, NEPHRITIC FACTORS, CELLS, Immunology, Alternative complement pathway, Properdin, Kidney Diseases, business, glomerulonephritis
Abstract

As part of the innate immune system, the complement system is an important mechanism in our first line of defence, but it can also contribute to the onset of various diseases. In renal diseases, the dysregulation of the complement system is often caused by mutations in-and autoantibodies directed against-members of the complement system, and contributes to disease onset and severity. As the only known positive regulator of the complement system, the role of properdin in complement-mediated diseases is largely unknown. In this review, we provide an overview of the detection of properdin in kidney biopsies and urine, serum or plasma samples from patients with complement-mediated renal diseases, such as immune complex-mediated glomerulonephritis and C3 glomerulopathy. Advances towards a better understanding of the role of properdin in ( local) complement activation will provide insight into its potential role and offer opportunities to improve diagnosis and therapeutic interventions.

Published
2019
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25. Decreased Graft Survival of Retransplants can Largely be Explained By Increased Hla-immunization

Author

Kamburova, Elena G., Wisse, B. W., Joosten, I., Allebes, W. A., van der Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, Eric, Hack, C. E., van Reekum, F., van Zuilen, A. D., Verhaar, M. C., Bots, M. L., Plaisier, L., Seelen, M. A. J., Sanders, J. S. F., Hepkema, B. G., Lambeck, A. J., Bungener, L. B., Roozendaal, C., Tilanus, M. G. J., Voorter, C. E., Wieten, L., van Duijnhoven, E., Gelens, M., Christiaans, M., van Ittersum, F., Nurmohamed, A., Lardy, N. M., Swelsen, W. T., van der Pant, K. A. M. I., van der Weerd, N. C., ten Berge, I. J. M., Bemelman, F. J., Hoitsma, A. J., van der Boog, P. J. M., de Fijter, J. W., Betjes, M. G. H., Heidt, Sebastiaan, Roelen, D. L., Claas, F. H. J., Otten, H. G., Groningen Institute for Organ Transplantation (GIOT), and Groningen Kidney Center (GKC)

Published
2018

26. Complement activation during ischemia/reperfusion injury induces pericyte-to-myofibroblast transdifferentiation regulating peritubular capillary Lumen Reduction Through pERK Signaling

Author

Castellano, G., Franzin, R., Stasi, A., Divella, C., Sallustio, F., Pontrelli, P., Lucarelli, G., Battaglia, M., Staffieri, F., Crovace, A., Stallone, G., Seelen, M., Daha, M. R., Grandaliano, Giuseppe, Gesualdo, L., Grandaliano G. (ORCID:0000-0003-1213-2177), Castellano, G., Franzin, R., Stasi, A., Divella, C., Sallustio, F., Pontrelli, P., Lucarelli, G., Battaglia, M., Staffieri, F., Crovace, A., Stallone, G., Seelen, M., Daha, M. R., Grandaliano, Giuseppe, Gesualdo, L., and Grandaliano G. (ORCID:0000-0003-1213-2177)

Published
2018

27. Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant

Author

Kamburova, E. G., Wisse, B. W., Joosten, I., Allebes, W. A., van der Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, E., Hack, C. E., van Reekum, F. E., van Zuilen, A. D., Verhaar, M. C., Bots, M. L., Drop, A. C.A.D., Plaisier, L., Seelen, M. A.J., Sanders, J. S.F., Hepkema, B. G., Lambeck, A. J.A., Bungener, L. B., Roozendaal, C., Tilanus, M. G.J., Voorter, C. E., Wieten, L., van Duijnhoven, E. M., Gelens, M., Christiaans, M. H.L., van Ittersum, F. J., Nurmohamed, S. A., Lardy, N. M., Swelsen, W., van der Pant, K. A., van der Weerd, N. C., ten Berge, I. J.M., Bemelman, F. J., Hoitsma, A., van der Boog, P. J.M., de Fijter, J. W., Betjes, M. G.H., Heidt, S., Roelen, D. L., Claas, F. H., Otten, H. G., Kamburova, E. G., Wisse, B. W., Joosten, I., Allebes, W. A., van der Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, E., Hack, C. E., van Reekum, F. E., van Zuilen, A. D., Verhaar, M. C., Bots, M. L., Drop, A. C.A.D., Plaisier, L., Seelen, M. A.J., Sanders, J. S.F., Hepkema, B. G., Lambeck, A. J.A., Bungener, L. B., Roozendaal, C., Tilanus, M. G.J., Voorter, C. E., Wieten, L., van Duijnhoven, E. M., Gelens, M., Christiaans, M. H.L., van Ittersum, F. J., Nurmohamed, S. A., Lardy, N. M., Swelsen, W., van der Pant, K. A., van der Weerd, N. C., ten Berge, I. J.M., Bemelman, F. J., Hoitsma, A., van der Boog, P. J.M., de Fijter, J. W., Betjes, M. G.H., Heidt, S., Roelen, D. L., Claas, F. H., and Otten, H. G.

Published
2018

28. Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant

Author

CTI Otten, Infection & Immunity, CDL Celdiagnostiek, CTI, MS Nefrologie, Circulatory Health, Nefro Vasculaire Geneeskunde, Regenerative Medicine and Stem Cells, Cardiovasculaire Epi Team 5, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, MS Mondziekten/Kaakchirurgie, Kamburova, E. G., Wisse, B. W., Joosten, I., Allebes, W. A., van der Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, E., Hack, C. E., van Reekum, F. E., van Zuilen, A. D., Verhaar, M. C., Bots, M. L., Drop, A. C.A.D., Plaisier, L., Seelen, M. A.J., Sanders, J. S.F., Hepkema, B. G., Lambeck, A. J.A., Bungener, L. B., Roozendaal, C., Tilanus, M. G.J., Voorter, C. E., Wieten, L., van Duijnhoven, E. M., Gelens, M., Christiaans, M. H.L., van Ittersum, F. J., Nurmohamed, S. A., Lardy, N. M., Swelsen, W., van der Pant, K. A., van der Weerd, N. C., ten Berge, I. J.M., Bemelman, F. J., Hoitsma, A., van der Boog, P. J.M., de Fijter, J. W., Betjes, M. G.H., Heidt, S., Roelen, D. L., Claas, F. H., Otten, H. G., CTI Otten, Infection & Immunity, CDL Celdiagnostiek, CTI, MS Nefrologie, Circulatory Health, Nefro Vasculaire Geneeskunde, Regenerative Medicine and Stem Cells, Cardiovasculaire Epi Team 5, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, MS Mondziekten/Kaakchirurgie, Kamburova, E. G., Wisse, B. W., Joosten, I., Allebes, W. A., van der Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, E., Hack, C. E., van Reekum, F. E., van Zuilen, A. D., Verhaar, M. C., Bots, M. L., Drop, A. C.A.D., Plaisier, L., Seelen, M. A.J., Sanders, J. S.F., Hepkema, B. G., Lambeck, A. J.A., Bungener, L. B., Roozendaal, C., Tilanus, M. G.J., Voorter, C. E., Wieten, L., van Duijnhoven, E. M., Gelens, M., Christiaans, M. H.L., van Ittersum, F. J., Nurmohamed, S. A., Lardy, N. M., Swelsen, W., van der Pant, K. A., van der Weerd, N. C., ten Berge, I. J.M., Bemelman, F. J., Hoitsma, A., van der Boog, P. J.M., de Fijter, J. W., Betjes, M. G.H., Heidt, S., Roelen, D. L., Claas, F. H., and Otten, H. G.

Published
2018

30. Risk factors for amyotrophic lateral sclerosis : Lifestyle, environment and genetics

Author

Seelen, M., Berg, L.H. van den, Veldink, J.H., Es, M.A. van, Vermeulen, R.C.H., and University Utrecht

Subjects
Metabolism, Risk factors, Epidemiology, Genetics, Air pollution, ALS, Environment, Amyotrophic lateral sclerosis, Lifestyle, Head trauma
Abstract

In this thesis the results of studies aiming to identify risk factors for amyotrophic lateral sclerosis (ALS) are described. A population-based case-control design was used to perform (1) epidemiological risk factor studies, examining lifestyle factors and environmental exposures, and (2) genetic studies determining genetic risk variants in ALS. Within these studies novel exposures have been established, which had not been implicated in ALS before, including exposure to traffic related air pollution and diesel motor exhaust. We were able to identify these exposures in two independent populations, in The Netherlands and Ireland, as well as through different study approaches (residential and occupational exposure assessment), presenting convincing evidence for the positive association with ALS risk. These and other ALS associated risk factors described in this thesis (e.g. physical activity, head trauma, high dietary fat intake, low BMI and cholesterol levels, and low alcohol consumption) have provided us with new clues for pathophysiological mechanisms, such as mitochondrial dysfunction, oxidative stress, neuroinflammation and glutamate excitotoxicity. Moreover, we have shown that ALS has a complex etiology in which multiple genetic (and most probably also lifestyle and environmental) factors co-occur to cause ALS. Specifically co-occurring repeat expansions in C9orf72 and NIPA1 were identified. Taking all studies together, we have generated new hypotheses for futurefunctional biologicalstudies to elucidatepathophysiological mechanisms leading to this complex and devastating disease.

Published
2015

31. Exploring the fitness hypothesis in ALS: a population-based case-control study of parental cause of death and lifespan

Author

Visser, A.E., Seelen, M., Hulsbergen, A., Graaf, Joris de, Kooi, A.J. van der, Raaphorst, J., Veldink, J.H., Berg, L.H. van den, Visser, A.E., Seelen, M., Hulsbergen, A., Graaf, Joris de, Kooi, A.J. van der, Raaphorst, J., Veldink, J.H., and Berg, L.H. van den

Abstract

Item does not contain fulltext, OBJECTIVE: To investigate the theory of premorbid fitness in amyotrophic lateral sclerosis (ALS), we studied whether a common genetic profile for physical or cardiovascular fitness was manifest in progenitors leading to less cardiovascular death and a longer lifespan in parents of patients with ALS compared with parents of controls. METHODS: Patient and disease characteristics, levels of physical activity, parental cause and age of death were obtained using a structured questionnaire from a population-based, case-control study of ALS in the Netherlands. Logistic regression was used for the analyses of parental cause of death and levels of physical activity. Cox proportional hazard models were applied to study the association between parental survival and ALS, or specific patient subgroups. All models were adjusted for age at inclusion, level of education, body mass index, diabetes, hypercholesterolaemia and hypertension. RESULTS: 487 patients and 1092 controls were included. Parents of patients died less frequently from a cardiovascular disease compared with parents of controls (OR=0.78, p=0.009). Their survival, however, was neither significantly longer nor shorter. Neither rates of cardiovascular causes of death, nor survival of parents was related to the extent to which patients were physically active in leisure time (all p>0.05). CONCLUSIONS: Exploring the fitness hypothesis in the pathogenesis of ALS, our findings provide evidence for a shared mechanism underlying a favourable cardiovascular fitness profile and ALS susceptibility.

Published
2017

32. Combined C4d and CD3 immunostaining predicts IgA nephropathy progression

Author

Faria, Bernardo, Henriques, Carla, Matos, Ana, Daha, M., Pestana, M., and Seelen, M.

Subjects
autoimmunity, T cells, complement, urologic and male genital diseases
Abstract

A number of molecules have been shown recently to be involved in the pathogenesis and progression of immunoglobulin (Ig)A nephropathy(IgAN). Among these, we have selected C4d (complement lectin pathway involvement), CD3 (T cell marker, traducing interstitial inflammation),transglutaminase 2 (TGase-2, involved in tissue fibrosis development) and p-extracelluar-regulated kinase (ERK)1/2 (protein kinase intracellular signaling molecule) to perform a panel of immunohistological biomarkers and assess its predictive value for disease progression. Immunohistochemical staining of these biomarkers was performed in paraffin sections from 74 renal biopsy cases with the clinical diagnosis of IgAN. Association between score analysis of these parameters and disease course was assessed through univariate and multivariate analysis, including baseline clinical and histological data. Univariate analysis showed that glomerular C4d,tubulointerstitial TGase2 and CD3 scores were associated with baseline proteinuria and disease progression. Multivariate analysis showed that only baseline estimated glomerular filtration rate (eGFR), C4d and CD3 were associated independently with progressive kidney disease (decline of at least 50% in the eGFR or progression to end-stage renal disease (ESRD) during the follow-up period). Establishing an accurate prediction model for IgAN progression is still a matter of research in clinical nephrology. The complement system, particularly lectin pathway activation, and T cell activation, have been shown previously to be potential modifiers of the disease course. Here we show that the combination of two histological biomarkers (C4d and CD3) can be a powerful predictor of IgAN progression and a potential useful tool for the clinical approach of this disease.

Published
2015

33. Parkinson's Disease Case Ascertainment in the EPIC Cohort: The NeuroEPIC4PD Study

Author

Gallo, V. Brayne, C. Forsgren, L. Barker, R.A. Petersson, J. Hansson, O. Lindqvist, D. Ruffmann, C. Ishihara, L. Luben, R. Arriola, L. Bergareche, A. Gavrila, D. Erro, M.E. Vanacore, N. Sacerdote, C. Bueno-De-Mesquita, B. Vermeulen, R. Seelen, M. Sieri, S. Masala, G. Ramat, S. Kyrozis, A. Thricopolou, A. Panico, S. Mattiello, A. Kaaks, R. Teucher, B. Katzke, V. Kloss, M. Curry, L. Calboli, F. Ribolil, E. Vineisl, P. Middleton, L.

Abstract

Background/Aims: Large epidemiological prospective studies represent an important opportunity for investigating risk factors for rare diseases such as Parkinson's disease (PD). Here we describe the procedures we used for ascertaining PD cases in the EPIC (European Prospective Investigation into Cancer and Nutrition) study. Methods: The following three-phase procedure was used: (1) elaboration of a NeuroEPIC4PD template for clinical data collection, (2) identification of all potential PD cases via record linkage and (3) validation of the diagnosis through clinical record revision, in a population of 220,494 subjects recruited in 7 European countries. All cases were labelled with the NeuroEPIC4PD diagnoses of 'definite','very likely', 'probable', or 'possible' PD. Results: A total of 881 PD cases were identified, with over 2,741,780 person-years of follow-up (199 definite, 275 very likely, 146 probable, and 261 possible). Of these, 734 were incident cases. The mean age at diagnosis was 67.9 years (SD 9.2) and 458 patients (52.0%) were men. Bradykinesia was the most frequent presenting motor sign (76.5%). Tremor-dominant and akinetic rigid forms of PD were the most common types of PD. A total of 289 patients (32.8%) were dead at the time of the last followup. Conclusions: This exercise proved that it is feasible to ascertain PD in large population-based cohort studies and offers a potential framework to be replicated in similar studies.cidence of the disease - the NeuroEPIC4PD study. The methods used in this study are expected to be generalisable to other cohorts. © 2015 S. Karger AG, Basel.

Published
2015

34. Tumor Necrosis Factor-α Gene Polymorphism is Associated with Short- and Long-Term Kidney Allograft Outcomes

Author

Poppelaars F, Gaya da Costa M, Faria B, Eskandari SK, Seelen MA, and Damman J

Subjects
cytokines, kidney transplantation, nephrology, genetics, Pathology, RB1-214, Therapeutics. Pharmacology, RM1-950
Abstract

Felix Poppelaars,1 Mariana Gaya da Costa,1,2 Bernardo Faria,1,3 Siawosh K Eskandari,1 Marc A Seelen,1 Jeffrey Damman4 1Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 2Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; 3Nephrology and Infectious Disease R&D Group, INEB, Institute of Investigation and Innovation in Health (i3S), University of Porto, Porto, Portugal; 4Department of Pathology, Erasmus Medical Center, University Medical Center, Rotterdam, The NetherlandsCorrespondence: Felix Poppelaars, Tel +31 50 3610544, Fax +31 50 3619320, Email f.poppelaars@umcg.nlIntroduction: Kidney transplantation has excellent short-term results with current immunosuppression regimes, but long-term outcomes have barely improved over the past two decades. Hence, there is a need for new therapeutic options to increase long-term survival of kidney grafts. Drug development for kidney transplantation has slowly plateaued, limiting progress while making drug repurposing an attractive alternative. We, therefore, investigated the impact of tumor necrosis factor-alpha (TNF-α) gene (TNF) polymorphisms on kidney graft survival after transplantation.Methods: We performed a prospective cohort study to assess the association of TNF polymorphisms (rs1800629 G>A and rs3093662 A>G) with primary non-function and death-censored kidney allograft survival in 1271 kidney transplant pairs from the University Medical Center Groningen in The Netherlands.Results: The G-allele of the TNF rs3093662 polymorphism in donor kidneys was associated with a higher risk of immediate graft loss (odds ratio: 2.05; 95%-CI: 1.06– 3.97; P = 0.032). Furthermore, the G-allele of this TNF rs3093662 polymorphism in the donor was also associated with worse 5-year, 10-year, and 15-year death-censored kidney graft survival (P < 0.05). The cumulative incidence of graft loss was 15.9% in the reference AA-genotype group and 25.2% in the AG/GG-genotype group, respectively. In multivariable analysis, the association between the TNF rs3093662 polymorphism in the donor and 15-year death-censored kidney graft survival remained significant (hazard ratio: 1.51; 95%-CI: 1.05– 2.19, P = 0.028).Discussion: In conclusion, kidney allografts possessing a high-producing TNF polymorphism have a greater risk of immediate and late graft loss. Our study adds to a growing body of literature indicating the potential of TNF-α blockade in improving kidney transplantation outcomes.Keywords: cytokines, kidney transplantation, nephrology, genetics

Published
2022

35. Large-scale screening in sporadic amyotrophic lateral sclerosis identifies genetic modifiers in C9orf72 repeat carriers

Author

Dekker, A.M., Seelen, M., Doormaal, P.T. van, Rheenen, W. van, Bothof, R.J., Riessen, T. van, Brands, W.J., Kooi, A.J. van der, Visser, M de, Voermans, N.C., Pasterkamp, R.J., Veldink, J.H., Berg, L.H. van den, Es, M.A. van, Dekker, A.M., Seelen, M., Doormaal, P.T. van, Rheenen, W. van, Bothof, R.J., Riessen, T. van, Brands, W.J., Kooi, A.J. van der, Visser, M de, Voermans, N.C., Pasterkamp, R.J., Veldink, J.H., Berg, L.H. van den, and Es, M.A. van

Abstract

Item does not contain fulltext, Sporadic amyotrophic lateral sclerosis (ALS) is considered to be a complex disease with multiple genetic risk factors contributing to the pathogenesis. Identification of genetic risk factors that co-occur frequently could provide relevant insight into underlying mechanisms of motor neuron degeneration. To dissect the genetic architecture of sporadic ALS, we undertook a large sequencing study in 755 apparently sporadic ALS cases and 959 controls, analyzing 10 ALS genes: SOD1, C9orf72, TARDBP, FUS, ANG, CHMP2B, ATXN2, NIPA1, SMN1, and UNC13A. We observed sporadic cases with multiple genetic risk variants in 4.1% compared with 1.3% in controls. The overall difference was not in excess of what is to be expected by chance (binomial test, p = 0.59). We did, however, observe a higher frequency than expected of C9orf72 repeat carriers with co-occurring susceptibility variants (ATXN2, NIPA1, and SMN1; p = 0.001), which is mainly because of the co-occurrence of NIPA1 repeats in 15% of C9orf72 repeat carriers (p = 0.006).

Published
2016

36. How can we reduce costs of solid-phase multiplex-bead assays used to determine anti-HLA antibodies?

Author

Kamburova, E. G., Wisse, B. W., Joosten, I., Allebes, W. A., van der Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, E., Hack, C. E., van Reekum, F. E., van Zuilen, A. D., Verhaar, M., Bots, M. L., Drop, A. C A D, Plaisier, L., Seelen, M. A J, Sanders, J. S F, Hepkema, B. G., Lambeck, A. J., Bungener, L. B., Roozendaal, C., Tilanus, M. G J, Vanderlocht, J., Voorter, C. E., Wieten, L., van Duijnhoven, E. M., Gelens, M., Christiaans, M. H L, van Ittersum, F. J., Nurmohamed, A., Lardy, N. M., Swelsen, W., van der Pant, K. A., van der Weerd, N. C., ten Berge, I. J M, Bemelman, F. J., Hoitsma, A., van der Boog, P. J M, de Fijter, J. W., Betjes, M. G H, Heidt, S., Roelen, D. L., Claas, F. H., Otten, H. G., Kamburova, E. G., Wisse, B. W., Joosten, I., Allebes, W. A., van der Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, E., Hack, C. E., van Reekum, F. E., van Zuilen, A. D., Verhaar, M., Bots, M. L., Drop, A. C A D, Plaisier, L., Seelen, M. A J, Sanders, J. S F, Hepkema, B. G., Lambeck, A. J., Bungener, L. B., Roozendaal, C., Tilanus, M. G J, Vanderlocht, J., Voorter, C. E., Wieten, L., van Duijnhoven, E. M., Gelens, M., Christiaans, M. H L, van Ittersum, F. J., Nurmohamed, A., Lardy, N. M., Swelsen, W., van der Pant, K. A., van der Weerd, N. C., ten Berge, I. J M, Bemelman, F. J., Hoitsma, A., van der Boog, P. J M, de Fijter, J. W., Betjes, M. G H, Heidt, S., Roelen, D. L., Claas, F. H., and Otten, H. G.

Published
2016

37. How can we reduce costs of solid-phase multiplex-bead assays used to determine anti-HLA antibodies?

Author

CTI Otten, Infection & Immunity, CDL Celdiagnostiek, CTI, Lab exp immunologie / biomarkers ontst., MS Nefrologie, Circulatory Health, Nefro Vasculaire Geneeskunde, Regenerative Medicine and Stem Cells, Cardiovasculaire Epi Team 5, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Kamburova, E. G., Wisse, B. W., Joosten, I., Allebes, W. A., van der Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, E., Hack, C. E., van Reekum, F. E., van Zuilen, A. D., Verhaar, M., Bots, M. L., Drop, A. C A D, Plaisier, L., Seelen, M. A J, Sanders, J. S F, Hepkema, B. G., Lambeck, A. J., Bungener, L. B., Roozendaal, C., Tilanus, M. G J, Vanderlocht, J., Voorter, C. E., Wieten, L., van Duijnhoven, E. M., Gelens, M., Christiaans, M. H L, van Ittersum, F. J., Nurmohamed, A., Lardy, N. M., Swelsen, W., van der Pant, K. A., van der Weerd, N. C., ten Berge, I. J M, Bemelman, F. J., Hoitsma, A., van der Boog, P. J M, de Fijter, J. W., Betjes, M. G H, Heidt, S., Roelen, D. L., Claas, F. H., Otten, H. G., CTI Otten, Infection & Immunity, CDL Celdiagnostiek, CTI, Lab exp immunologie / biomarkers ontst., MS Nefrologie, Circulatory Health, Nefro Vasculaire Geneeskunde, Regenerative Medicine and Stem Cells, Cardiovasculaire Epi Team 5, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Kamburova, E. G., Wisse, B. W., Joosten, I., Allebes, W. A., van der Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, E., Hack, C. E., van Reekum, F. E., van Zuilen, A. D., Verhaar, M., Bots, M. L., Drop, A. C A D, Plaisier, L., Seelen, M. A J, Sanders, J. S F, Hepkema, B. G., Lambeck, A. J., Bungener, L. B., Roozendaal, C., Tilanus, M. G J, Vanderlocht, J., Voorter, C. E., Wieten, L., van Duijnhoven, E. M., Gelens, M., Christiaans, M. H L, van Ittersum, F. J., Nurmohamed, A., Lardy, N. M., Swelsen, W., van der Pant, K. A., van der Weerd, N. C., ten Berge, I. J M, Bemelman, F. J., Hoitsma, A., van der Boog, P. J M, de Fijter, J. W., Betjes, M. G H, Heidt, S., Roelen, D. L., Claas, F. H., and Otten, H. G.

Published
2016

39. How can we reduce costs of solid-phase multiplex-bead assays used to determine anti-HLA antibodies?

Author

Kamburova, E. G., primary, Wisse, B. W., additional, Joosten, I., additional, Allebes, W. A., additional, van der Meer, A., additional, Hilbrands, L. B., additional, Baas, M. C., additional, Spierings, E., additional, Hack, C. E., additional, van Reekum, F. E., additional, van Zuilen, A. D., additional, Verhaar, M., additional, Bots, M. L., additional, Drop, A. C. A. D., additional, Plaisier, L., additional, Seelen, M. A. J., additional, Sanders, J. S. F., additional, Hepkema, B. G., additional, Lambeck, A. J., additional, Bungener, L. B., additional, Roozendaal, C., additional, Tilanus, M. G. J., additional, Vanderlocht, J., additional, Voorter, C. E., additional, Wieten, L., additional, van Duijnhoven, E. M., additional, Gelens, M., additional, Christiaans, M. H. L., additional, van Ittersum, F. J., additional, Nurmohamed, A., additional, Lardy, N. M., additional, Swelsen, W., additional, van der Pant, K. A., additional, van der Weerd, N. C., additional, ten Berge, I. J. M., additional, Bemelman, F. J., additional, Hoitsma, A., additional, van der Boog, P. J. M., additional, de Fijter, J. W., additional, Betjes, M. G. H., additional, Heidt, S., additional, Roelen, D. L., additional, Claas, F. H., additional, and Otten, H. G., additional

Published
2016
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43. The verbal fluency index: Dutch normative data for cognitive testing in ALS

Author

Beeldman, E., Jaeger, B., Raaphorst, J., Seelen, M., Veldink, J., Berg, L. van den, Visser, M de, Schmand, B.A., Beeldman, E., Jaeger, B., Raaphorst, J., Seelen, M., Veldink, J., Berg, L. van den, Visser, M de, and Schmand, B.A.

Abstract

Item does not contain fulltext, Objective: Executive dysfunction occurs in 30-50% of amyotrophic lateral sclerosis (ALS) patients and is most frequently assessed with the verbal fluency test. The verbal fluency index (VFI) has been developed to correct for slowness of speech in ALS, and reflects the average thinking time per word. However, its use as a marker of cognitive impairment is hindered by the absence of valid norm scores. Therefore, we provide normative data for the VFI. METHODS: Dutch volunteers were demographically matched to the Dutch ALS population and completed the verbal fluency index (one-minute and three-minute spoken letter fluency). Multiple stepwise linear regression was performed to assess the influence of demographic variables, past medical history and medication use. RESULTS: 273 volunteers participated in this study. Educational level was negatively correlated to one-minute and three-minute VFI performance (r = -0.3 and r = -0.4, p < 0.001, respectively). No correlations for age, gender, medication and past medical history were found. A formula for standardized z-scores, corrected for educational level, for the one-minute and three-minute VFI was calculated. CONCLUSIONS: We provide Dutch normative data for the spoken verbal fluency index, which can be used internationally, but validation in other languages is recommended. The findings illustrate the importance of valid disease-specific norm scores for time-dependent cognitive tests in ALS.

Published
2014

44. Prior medical conditions and the risk of amyotrophic lateral sclerosis

Author

Seelen, M., Doormaal, P.T. van, Visser, A.E., Huisman, M.H., Roozekrans, M.H., Jong, S.W. de, Kooi, A.J. van der, Visser, M de, Voermans, N.C., Veldink, J.H., Berg, L.H. van den, Seelen, M., Doormaal, P.T. van, Visser, A.E., Huisman, M.H., Roozekrans, M.H., Jong, S.W. de, Kooi, A.J. van der, Visser, M de, Voermans, N.C., Veldink, J.H., and Berg, L.H. van den

Abstract

Item does not contain fulltext, Sporadic amyotrophic lateral sclerosis (ALS) is believed to be a complex disease in which multiple exogenous and genetic factors interact to cause motor neuron degeneration. Elucidating the association between medical conditions prior to the first symptoms of ALS could lend support to the theory that specific subpopulations are at risk of developing ALS and provide new insight into shared pathogenic mechanisms. We performed a population-based case-control study in the Netherlands, including 722 sporadic ALS patients and 2,268 age and gender matched controls. Data on medical conditions and use of medication were obtained through a structured questionnaire. Multivariate analyses showed that hypercholesterolemia (OR 0.76, 95% CI 0.63-0.92, P = 0.006), the use of statins (OR 0.45, 95% CI 0.35-0.59, P = 1.86 x 10(-9)) or immunosuppressive drugs (OR 0.26, 95% CI 0.08-0.86, P = 0.03) were associated with a decreased risk of ALS. Head trauma was associated with an increased ALS susceptibility (OR 1.95, 95% CI 1.11-3.43, P = 0.02). No association was found with autoimmune diseases, cancer, psychiatric disorders or cardiovascular diseases, or survival. The lower frequency of hypercholesterolemia and less use of statins in ALS patients indicate a favorable lipid profile prior to symptom onset in at least a subpopulation of ALS. Prior head trauma is a risk factor for ALS and the significantly lower use of immunosuppressive drugs in ALS patients could suggest a protective effect. The identification of specific subpopulations at risk for ALS may provide clues towards possible pathogenic mechanisms.

Published
2014

45. No mutations in hnRNPA1 and hnRNPA2B1 in Dutch patients with amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy

Author

Seelen, M., Visser, A.E., Overste, D.J., Kim, H.J., Palud, A., Wong, T.H., Swieten, J.C. van, Scheltens, P., Voermans, N.C., Baas, F., Jong, J.M. de, Kooi, A.J. van der, Visser, M de, Veldink, J.H., Taylor, J.P., Es, M.A. van, Berg, L.H. van den, Seelen, M., Visser, A.E., Overste, D.J., Kim, H.J., Palud, A., Wong, T.H., Swieten, J.C. van, Scheltens, P., Voermans, N.C., Baas, F., Jong, J.M. de, Kooi, A.J. van der, Visser, M de, Veldink, J.H., Taylor, J.P., Es, M.A. van, and Berg, L.H. van den

Abstract

Item does not contain fulltext, Inclusion body myopathy (IBM) associated with Paget disease of the bone, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), sometimes called IBMPFD/ALS or multi system proteinopathy, is a rare, autosomal dominant disorder characterized by progressive degeneration of muscle, brain, motor neurons, and bone with prominent TDP-43 pathology. Recently, 2 novel genes for multi system proteinopathy were discovered; heterogenous nuclear ribonucleoprotein (hnRNP) A1 and A2B1. Subsequently, a mutation in hnRNPA1 was also identified in a pedigree with autosomal dominant familial ALS. The genetic evidence for ALS and other neurodegenerative diseases is still insufficient. We therefore sequenced the prion-like domain of these genes in 135 familial ALS, 1084 sporadic ALS, 68 familial FTD, 74 sporadic FTD, and 31 sporadic IBM patients in a Dutch population. We did not identify any mutations in these genes in our cohorts. Mutations in hnRNPA1 and hnRNPA2B1 prove to be a rare cause of ALS, FTD, and IBM in the Netherlands.

Published
2014

46. Functional EPO gene polymorphism rs1617640 affects graft survival after deceased donor kidney transplantation

Author

van Rijt, W.G., primary, Damman, J., additional, Snieder, H., additional, Seelen, M., additional, van Goor, H., additional, Navis, G., additional, van den Born, J., additional, de Borst, M.H., additional, Hepkema, B.G., additional, Hillebrands, J.L., additional, Ploeg, R.J., additional, Bakker, S.J.L., additional, and Leuvenink, H.G.D., additional

Published
2014
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48. Differential effects of donor‐specific HLAantibodies in living versus deceased donor transplant

Author

Kamburova, E. G., Wisse, B. W., Joosten, I., Allebes, W. A., Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, E., Hack, C. E., Reekum, F. E., Zuilen, A. D., Verhaar, M. C., Bots, M. L., Drop, A. C. A. D., Plaisier, L., Seelen, M. A. J., Sanders, J. S .F., Hepkema, B. G., Lambeck, A. J. A., Bungener, L. B., Roozendaal, C., Tilanus, M. G. J., Voorter, C. E., Wieten, L., Duijnhoven, E. M., Gelens, M., Christiaans, M. H. L., Ittersum, F. J., Nurmohamed, S. A., Lardy, N. M., Swelsen, W., Pant, K. A., Weerd, N. C., Berge, I. J. M., Bemelman, F. J., Hoitsma, A., Boog, P. J. M., Fijter, J. W., Betjes, M. G. H., Heidt, S., Roelen, D. L., Claas, F. H., and Otten, H. G.

Abstract

The presence of donor‐specific anti‐HLAantibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAsagainst HLAclass I, class II,or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long‐term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement‐dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAsagainst class I or IIantigens after transplant. Class I and II DSAscombined resulted in decreased 10‐year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAshad a 10‐year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs(76%). The combination of class I and II DSAsresulted in a 10‐year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAsare a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAsseem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence. Via a retrospective multicenter study, the authors investigate the impact of pretransplant donor‐specific HLA antibodies on long‐term graft survival in deceased and living donor kidney transplantations.

Published
2018
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49. Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases.

Author

Rheenen, W. van, Blitterswijk, M. van, Huisman, M.H., Vlam, L., Doormaal, P.T. van, Seelen, M., Medic, J., Dooijes, D., Visser, M. de, Kooi, A.J. van der, Raaphorst, J., Schelhaas, H.J., Pol, W.L. van der, Veldink, J.H., Berg, L.H. van den, Rheenen, W. van, Blitterswijk, M. van, Huisman, M.H., Vlam, L., Doormaal, P.T. van, Seelen, M., Medic, J., Dooijes, D., Visser, M. de, Kooi, A.J. van der, Raaphorst, J., Schelhaas, H.J., Pol, W.L. van der, Veldink, J.H., and Berg, L.H. van den

Abstract

Item does not contain fulltext, OBJECTIVE: To assess the frequency and phenotype of hexanucleotide repeat expansions in C9ORF72 in a large cohort of patients of Dutch descent with familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS). METHODS: Included were 78 patients with fALS, 1,422 with sALS, 246 with PMA, and 110 with PLS, and 768 control subjects. Repeat expansions were determined by a repeat primed PCR. Familial aggregation of dementia and Parkinson disease (PD) was examined among patients with ALS who carried the repeat expansion. RESULTS: The expanded repeat was found in 33 (37%) of all patients with fALS, in 87 (6.1%) patients with sALS, in 4 (1.6%) patients with PMA, and in 1 (0.9%) patient with PLS. None of the controls carried the mutation. Patients with ALS with the repeat expansion had an earlier age at onset (median 59.3 vs 61.9 years, hazard ratio 1.55, p = 5 x 10(-5)) and shorter survival (median 2.5 vs 2.7 years, hazard ratio 1.46, p = 8 x 10(-4)). Dementia, but not PD, occurred nearly twice as often in relatives of patients with the expansion compared to all patients with ALS or controls (p = 9 x 10(-4)). CONCLUSIONS: The hexanucleotide repeat expansion in C9ORF72 is a major cause of fALS and apparently sporadic ALS in the Netherlands. Patients who carry the repeat expansion have an earlier onset, shorter survival, and familial aggregation of dementia. These results challenge the classic definition of fALS and may justify genetic testing in patients with sALS.

Published
2012

50. CUBN as a novel locus for end-stage renal disease: insights from renal transplantation.

Author

Reznichenko, A., Snieder, H., Born, J. van den, Borst, M.H. de, Damman, J., Dijk, M.C.R.F. van, Goor, H. van, Hepkema, B.G., Hillebrands, J.L., Leuvenink, H.G., Niesing, J., Bakker, S.J., Seelen, M., Navis, G., Reznichenko, A., Snieder, H., Born, J. van den, Borst, M.H. de, Damman, J., Dijk, M.C.R.F. van, Goor, H. van, Hepkema, B.G., Hillebrands, J.L., Leuvenink, H.G., Niesing, J., Bakker, S.J., Seelen, M., and Navis, G.

Abstract

Contains fulltext : 110462.pdf (publisher's version ) (Open Access), Chronic kidney disease (CKD) is a complex disorder. As genome-wide association studies identified cubilin gene CUBN as a locus for albuminuria, and urinary protein loss is a risk factor for progressive CKD, we tested the hypothesis that common genetic variants in CUBN are associated with end-stage renal disease (ESRD) and proteinuria. First, a total of 1142 patients with ESRD, admitted for renal transplantation, and 1186 donors were genotyped for SNPs rs7918972 and rs1801239 (case-control study). The rs7918972 minor allele frequency (MAF) was higher in ESRD patients comparing to kidney donors, implicating an increased risk for ESRD (OR 1.39, p = 0.0004) in native kidneys. Second, after transplantation recipients were followed for 5.8 [3.8-9.2] years (longitudinal study) documenting ESRD in transplanted kidneys--graft failure (GF). During post-transplant follow-up 92 (9.6%) cases of death-censored GF occurred. Donor rs7918972 MAF, representing genotype of the transplanted kidney, was 16.3% in GF vs 10.7% in cases with functioning graft. Consistently, a multivariate Cox regression analysis showed that donor rs7918972 is a predictor of GF, although statistical significance was not reached (HR 1.53, p = 0.055). There was no association of recipient rs7918972 with GF. Rs1801239 was not associated with ESRD or GF. In line with an association with the outcome, donor rs7918972 was associated with elevated proteinuria levels cross-sectionally at 1 year after transplantation. Thus, we identified CUBN rs7918972 as a novel risk variant for renal function loss in two independent settings: ESRD in native kidneys and GF in transplanted kidneys.

Published
2012

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