Pieter van Paassen

Maastricht University, Maestricht, Limburg, Netherlands

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Publications (53)380.86 Total impact

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    ABSTRACT: To investigate the prevalence and prognostic relevance of cardiac involvement in an ANCA-associated vasculitis (AAV) population of eosinophilic granulomatosis with polyangiitis (EGPA) and granulomatosis with polyangiitis (GPA) patients. Prospective cohort study of fifty EGPA and forty-one GPA patients in sustained remission without previous in-depth cardiac screening attending our clinical immunology outpatient department. Cardiac screening included clinical evaluation, ECG, 24-hour Holter registration, echocardiography and cardiac magnetic resonance imaging (CMR) with coronary angiography and endomyocardial biopsy upon indication. Fifty age-, sex- and cardiovascular risk factor-matched control subjects were randomly selected from a population study. Long-term outcome was assessed using all-cause and cardiovascular mortality. A total of 91 AAV-patients (age 60±11, range 63-87years) were compared to 50-matched control subjects (age 60±9years, range 46-78years). ECG and echocardiography demonstrated cardiac abnormalities in 62% EGPA and 46% GPA patients vs 20% controls (P<0.001 and P=0.014, respectively). A total of 69 AAV-patients underwent additional CMR, slightly increasing the prevalence of cardiac involvement to 66% in EGPA and 61% in GPA patients. After a mean follow-up of 53±18months, presence of cardiac involvement using ECG and echocardiography in AAV-patients showed increased all-cause and cardiovascular mortality (Log-rank P=0.015 and Log-rank P=0.021, respectively). Cardiac involvement in EGPA and GPA patients with sustained remission is high, even if symptoms are absent and ECG is normal. Moreover, cardiac involvement is a strong predictor of (cardiovascular) mortality. Therefore, risk stratification using cardiac imaging is recommended in all AAV-patients, irrespective of symptoms or ECG abnormalities. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    International journal of cardiology 07/2015; 199:170-179. DOI:10.1016/j.ijcard.2015.06.087 · 6.18 Impact Factor
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    ABSTRACT: In patients with GN or vasculitis, ANCAs are directed against proteinase 3 (PR3) or myeloperoxidase (MPO). The differences between PR3-ANCA-associated vasculitis (AAV) and MPO-AAV described in the past have been supplemented during the last decade. In this review, we discuss the differences between these two small-vessel vasculitides, focusing especially on possible etiologic and pathophysiologic differences. PR3-AAV is more common in northern parts of the world, whereas MPO-AAV is more common in southern regions of Europe, Asia, and the Pacific, with the exception of New Zealand and Australia. A genetic contribution has been extensively studied, and there is a high prevalence of the HLA-DPB1*04:01 allele in patients with PR3-AAV as opposed to patients with MPO-AAV and/or healthy controls. Histologically, MPO-AAV and PR3-AAV are similar but show qualitative differences when analyzed carefully. Clinically, both serotypes are difficult to distinguish, but quantitative differences are present. More organs are affected in PR3-AAV, whereas renal limited vasculitis occurs more often in patients with MPO-AAV. For future clinical trials, we advocate classifying patients by ANCA serotype as opposed to the traditional disease type classification. Copyright © 2015 by the American Society of Nephrology.
    Journal of the American Society of Nephrology 05/2015; DOI:10.1681/ASN.2014090903 · 9.47 Impact Factor
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    ABSTRACT: Background/AimANCA-associated (AAV) vasculitis is an autoimmune small-vessel-vasculitis and may be associated with accelerated atherosclerosis as suggested by current literature. Antibodies against oxidized-lipoproteins (OxLDL) and phosphorycholine (Pc) protect from atherosclerosis. This study characterizes these antibodies in AAV.Methods Pc- and anti-OxLDL antibodies were determined in sera of 39 AAV patients and 44 healthy controls (HC). Intima-media thickness (IMT, carotides) and pulse-wave-velocity (PWV, A. femoralis) were measured.ResultsPc-/OxLDL-IgM antibodies were significantly reduced in AAV. IMT and PWV were negatively associated with anti-Pc antibodies in HC only.Conclusion Atheroprotective anti-Pc/anti-OxLDL antibodies are significantly reduced in AAV possibly explaining accelerated atherosclerosis in vasculitis patients.This article is protected by copyright. All rights reserved.
    European Journal of Clinical Investigation 05/2015; DOI:10.1111/eci.12457 · 2.83 Impact Factor
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    ABSTRACT: Outcome in patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (AGN) is difficult to predict. Scoring of renal biopsies has significant but limited predictive value. We investigated whether analysis of plasma and urine levels, and immunostaining of biopsies for the pro-fibrotic peptide connective tissue growth factor (CTGF), might improve prediction of renal outcome. ANCA-positive patients were included. Renal biopsies were classified according to the AGN classification. Biopsies were stained for CTGF protein. CTGF was measured by ELISA at the time of renal biopsy in plasma and urine, and during follow-up in plasma. Eighty-two patients were included. CTGF staining was positive in crescentic lesions. Plasma CTGF at the time of renal biopsy was 2.4 ± 1.7 pmol/mL when compared with 0.5 ± 0.0 pmol/mL in healthy controls (P < 0.01). Plasma CTGF was associated with cellular crescents, but not when corrected for renal function. Plasma CTGF at baseline was associated with fibrous crescents in the follow-up biopsy, also after correction for renal function. Plasma CTGF at baseline predicted renal survival more accurately than the AGN classification. In AGN patients, CTGF was overexpressed in crescentic glomeruli. Baseline plasma CTGF predicted the percentage of fibrous crescents in later biopsies, and renal survival, suggesting that CTGF is involved in the cicatrization, as opposed to resolution of cellular crescents in AGN. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
    Nephrology Dialysis Transplantation 04/2015; DOI:10.1093/ndt/gfv088 · 3.49 Impact Factor
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    ABSTRACT: Glomerular diseases with severe defects in glomerular permeability give rise to heavy proteinuria and can present as nephrotic syndrome. There are many different causes of the nephrotic syndrome and a renal biopsy is nearly always needed to elucidate the underlying disease. During the last decade, substantial advances have occurred in the understanding of the pathophysiological mechanisms involved in immune-mediated glomerular diseases. Here, we review the diagnostic and prognostic implications of recent progress on the understanding of membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, amyloidosis, IgA nephropathy and membranoproliferative glomerulonephritis.
    Expert Review of Clinical Immunology 03/2015; DOI:10.1586/1744666X.2015.1024659 · 3.34 Impact Factor
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    ABSTRACT: The RITUXVAS trial reported similar remission induction rates and safety between rituximab and cyclophosphamide based regimens for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 12 months; however, immunosuppression maintenance requirements and longer-term outcomes after rituximab in ANCA-associated renal vasculitis are unknown. Forty-four patients with newly diagnosed ANCA-associated vasculitis and renal involvement were randomised, 3:1, to glucocorticoids plus either rituximab (375 mg/m(2)/week×4) with two intravenous cyclophosphamide pulses (n=33, rituximab group), or intravenous cyclophosphamide for 3-6 months followed by azathioprine (n=11, control group). The primary end point at 24 months was a composite of death, end-stage renal disease and relapse, which occurred in 14/33 in the rituximab group (42%) and 4/11 in the control group (36%) (p=1.00). After remission induction treatment all patients in the rituximab group achieved complete B cell depletion and during subsequent follow-up, 23/33 (70%) had B cell return. Relapses occurred in seven in the rituximab group (21%) and two in the control group (18%) (p=1.00). All relapses in the rituximab group occurred after B cell return. At 24 months, rates of the composite outcome of death, end-stage renal disease and relapse did not differ between groups. In the rituximab group, B cell return was associated with relapse. ISRCTN28528813. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Annals of the Rheumatic Diseases 03/2015; 74(6). DOI:10.1136/annrheumdis-2014-206404 · 10.38 Impact Factor
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    ABSTRACT: PURPOSE: The objective of the study was to systematically assess aortic inflammation in patients with granulomatosis with polyangiitis (GPA) using 18F-2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET)/CT. METHODS: Aortic inflammation was studied in PET/CT scans obtained from 21 patients with GPA; 14 patients with sarcoidosis were included as disease controls, 7 patients with stage I or II head and neck carcinoma ascertained during routine clinical practice were used as healthy controls (HC) and 5 patients with large vessel vasculitis (LVV) were used as positive controls. Aortic 18F-FDG uptake was expressed as the blood-normalized maximum standardized uptake value (SUVmax), known as the target to background ratio (mean TBRmax). RESULTS: The mean TBRmax (interquartile range) of the aorta in patients with GPA, sarcoidosis, HC and LVV were 1.75 (1.32-2.05), 1.62 (1.54-1.74), 1.29 (1.22-1.52) and 2.03 (1.67-2.45), respectively. The mean TBRmax was significantly higher in patients suffering from GPA or LVV compared to HC (p < 0.05 and p < 0.005, respectively) and tended to be higher in patients suffering from sarcoidosis, but this did not reach statistical significance (p = 0.098). The mean TBRmax of the most diseased segment was significantly higher compared to HC [1.57 (1.39-1.81)] in LVV patients [2.55 (2.22-2.82), p < 0.005], GPA patients [2.17 (1.89-2.83), p < 0.005] and patients suffering from sarcoidosis [2.04 (1.88-2.20), p < 0.05]. In GPA patients, the mean TBRmax of the aorta was significantly higher in patients with previous renal involvement [2.01 (1.69-2.53)] compared to patients without renal involvement in the past [1.60 (1.51-1.80), p < 0.05]. Interrater reproducibility with a second reader was high (all intraclass correlation coefficients >0.9). CONCLUSION: Patients suffering from GPA show marked aortic FDG uptake.
    European journal of nuclear medicine and molecular imaging 01/2015; DOI:10.1007/s00259-015-3081-y · 5.22 Impact Factor
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    ABSTRACT: Tools for evaluation of disease activity in patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) include scoring clinical manifestations, determination of biochemical parameters of inflammation, and obtaining tissue biopsies. These tools, however, are sometimes inconclusive. 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) positron emission tomography (PET) scans are commonly used to detect inflammatory or malignant lesions. Our objective is to explore the ability of PET scanning to assess the extent of disease activity in patients with AAV. Consecutive PET scans made between December 2006 and March 2014 in Maastricht (MUMC) and between July 2008 and June 2013 in Brussels (EUH) to assess disease activity in patients with AAV were retrospectively included. Scans were re-examined and quantitatively scored using maximum standard uptake values (SUVmax). PET findings were compared with C-reactive protein (CRP) and ANCA positivity at the time of scanning. Forty-four scans were performed in 33 patients during a period of suspected active disease. All but 2 scans showed PET-positive sites, most commonly the nasopharynx (n = 22) and the lung (n = 22). Forty-one clinically occult lesions were found, including the thyroid gland (n = 4 patients), aorta (n = 8), and bone marrow (n = 7). The amount of hotspots, but not the highest observed SUVmax value, was higher if CRP levels were elevated. Seventeen follow-up scans were made in 13 patients and showed decreased SUVmax values. FDG PET scans in AAV patients with active disease show positive findings in multiple sites of the body even when biochemical parameters are inconclusive, including sites clinically unsuspected and difficult to assess otherwise.
    Medicine 01/2015; 94(20):e747. DOI:10.1097/MD.0000000000000747 · 4.87 Impact Factor
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    ABSTRACT: The value of measuring ANCA during follow-up to predict a relapse is controversial. On the basis of recently obtained pathophysiologic insights, we postulated that measuring ANCA is useful in patients with renal involvement but is less valuable in patients with nonrenal disease. One hundred sixty-six consecutive patients with ANCA-associated vasculitis, positive for either proteinase 3 (PR3)-ANCA or myeloperoxidase (MPO)-ANCA, were included in our study, followed at regular intervals, and tested for PR3-ANCA and MPO-ANCA. In this cohort, 104 patients had renal involvement (72 with PR3-ANCA, 32 with MPO-ANCA) and 62 patients had nonrenal disease (36 with PR3-ANCA, 26 with MPO-ANCA). During an average (±SD) follow-up of 49±33 months and 18±14 ANCA measurements, 89 ANCA rises and 74 relapses were recorded. ANCA rises correlated with relapses in patients who presented with renal involvement (hazard ratio [HR], 11.09; 95% confidence interval [95% CI], 5.01 to 24.55), but in comparison, associated only weakly with relapses in patients who presented with nonrenal disease (HR, 2.79; 95% CI, 1.30 to 5.98). In conclusion, longitudinal ANCA measurements may be useful in patients with renal involvement but is less valuable in patients with nonrenal disease.
    Journal of the American Society of Nephrology 10/2014; 26(3). DOI:10.1681/ASN.2013111233 · 9.47 Impact Factor
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    ABSTRACT: Objectives: Autoantibodies against the M-type phospholipase A2 receptor 1 (anti-PLA2R1) have been demonstrated to be very specific for idiopathic membranous nephropathy (MN). We studied a novel enzyme-linked immunosorbent assay (ELISA) and compared results with results obtained using an indirect immunofluorescence (IF) and a Western blotting test (WB). Methods: One-hundred nine patients with idiopathic MN were recruited between November 1979 and March 2011. The control cohort comprised serum samples from patients with secondary MN (n = 16) and nephrotic controls (n = 17). The presence of anti-PLA2R1 in serum samples obtained at the time of renal biopsy was determined using ELISA, IIF, and WB. Results: With similar specificity (>= 97%), sensitivity varied from 68% (IIF) to 72% (ELISA, WB). Remarkably, patients who were seronegative for anti-PLA2R1 more often entered spontaneous remission (P = .038), whereas seropositive patients were more frequently treated with immunosuppressive agents (P < .001). Conclusions: ELISA performs excellently in differentiating idiopathic from secondary MN. Furthermore, ELISA shared high agreement with WB and IIF.
    American Journal of Clinical Pathology 07/2014; 142(1):29-34. DOI:10.1309/AJCP8QMOY5GLRSFP · 3.01 Impact Factor
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    International journal of cardiology 11/2013; 170(3). DOI:10.1016/j.ijcard.2013.11.028 · 6.18 Impact Factor
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    ABSTRACT: Abstract The objective of this study was to research the functionality of anti-endothelial cell antibodies (AECA) in pulmonary arterial hypertension (PAH) by assessing the effects of IgG from AECA-positive PAH patients on the induction of adhesion molecules on human umbilical vein endothelial cells (HUVECs) and on the production of pro-inflammatory cytokines and chemokines by HUVECs. To achieve this purified IgG from 28 PAH patients were included. IgG from systemic sclerosis (SSc) (n = 58) and systemic lupus erythematosus (SLE) (n = 16) patients without PAH were included as disease controls. Intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin expression on HUVECs, incubated with patient IgG, were quantified by flow cytometry. Production of interleukin (IL)-1β, -6, -8, and CC chemokine ligand 2 (CCL2) by HUVECs, incubated with patient IgG, were quantified by multiplex flow cytometry. Our results showed that IgG from AECA-positive PAH, SSc and SLE patients induced significantly higher expression of ICAM-1, VCAM-1, and E-selectin and production of IL-6, -8, and CCL2 compared to IgG from AECA-negative patients and IgG from healthy controls. Like in SLE and SSc, IgG from AECA-positive PAH patients can activate endothelial cells to a pro-adhesive and pro-inflammatory state. Therefore, IgG AECA could play a pathogenic role by inducing inflammatory injury of vascular endothelium which is considered a key player in the initiation and progression of PAH.
    Autoimmunity 11/2013; 46(7):463-470. DOI:10.3109/08916934.2013.812080 · 2.75 Impact Factor
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    ABSTRACT: Traditionally, for DNA analyses, DNA is recovered from buffy coats. Since DNA in urine has been reported to deteriorate quickly, this option is often not considered. To complete our DNA database in patients with ANCA-associated vasculitis, we aimed to extract DNA from stored urine. Urine was stored at the time of kidney biopsy from patients included in our regional kidney biopsy database, who had given informed consent for further study. Urine was subsequently filtered, dialyzed, concentrated and freeze dried and finallyresolubilized and centrifuged. DNA was extracted using the high pure PCR template preparation kit (Roche Diagnostics). Next, concentration and purity were determined by Nanodrop analysis and by Quant-iT analysis. One hundred and eighty-one patients with ANCA-associated vasculitis were included. Of 114 patients (63%), DNA was available. From 53 of the remaining 67 patients, stored urine was available. Of the 53 samples that were processed, 46 (86.8%) yielded DNA with a mean concentration of 258.7 ng/muL (range 33.2-529) with a mean purity ratio of 1.81 (lamda 260/280). DNA extraction from fresh urine has been described before, yielding DNA usable for PCR analysis in healthy subjects. Storage of fresh urine at 4[degree sign]C or lower temperatures results in significant degradation of the DNA, making recovery of DNA more difficult with longer periods of storage. In the current study, we demonstrated that DNA could be retrieved from subsequently filtered, dialyzed, concentrated and freeze dried urine that was stored at room temperature. In addition, we demonstrated tthat this DNA could be used for PCR analysis. This method is useful when no other material from these patients is available.
    BMC Nephrology 10/2013; 14(1):238. DOI:10.1186/1471-2369-14-238 · 1.52 Impact Factor
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    ABSTRACT: Despite advances in preventive therapy, prognosis in chronic kidney disease (CKD) is still grim. Clinical cohorts of CKD patients provide a strategic resource to identify factors that drive progression in the context of clinical care and to provide a basis for improvement of outcome. The combination with biobanking, moreover, provides a resource for fundamental and translational studies. In 2007, the Dutch government initiated and funded the String of Pearls Initiative (PSI), a strategic effort to establish infrastructure for disease-based
    Nephrology Dialysis Transplantation 10/2013; DOI:10.1093/ndt/gft307 · 3.49 Impact Factor
  • American Journal of Kidney Diseases 09/2013; DOI:10.1053/j.ajkd.2013.07.019 · 5.76 Impact Factor
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    ABSTRACT: Endothelial cell (EC) apoptosis seems to play an important role in the pathophysiology of pulmonary arterial hypertension (PAH). We aimed to test the hypothesis that circulating anti-endothelial cell antibodies (AECA) of PAH patients induce EC apoptosis. IgG was purified from sera of PAH patients (n=26), patients with SLE nephritis without PAH (n=16), patient with systemic sclerosis (SSc) without PAH (n=58), and healthy controls (n=14). Human umbilical vein endothelial cells (HUVECs) were incubated with patient or healthy control IgG for 24 hrs. Thereafter, apoptosis was quantified by annexin A5 binding and hypoploid cell enumeration by flow cytometry. Furthermore, real-time cell electronic sensing (RT-CES™) technology was used to monitor the effects of purified IgG from patient and healthy control IgG on HUVECs. As demonstrated previously, IgG of AECA-positive SLE nephritis patients (n=7) induced a higher percentage of apoptosis of HUVECs as compared to IgG of AECA-negative SLE nephritis patients and healthy controls. Furthermore, IgG of AECA-positive SLE nephritis patients induced a marked decrease in cell index as assessed by RT-CES™ technology. IgG of AECA-positive PAH patients (n=12) and SSc patients (n=13) did not alter the percentage of HUVEC apoptosis or cell index as compared to IgG of AECA-negative PAH and SSc patients and healthy controls. AECA-positive PAH patients, in contrast to SLE nephritis patients, do not have circulating IgG AECA that enhances apoptosis of HUVECs in vitro. Further studies should focus on other mechanisms by which AECA may enhance EC apoptosis in PAH, such as antibody-dependent cell-mediated cytotoxicity.
    Clinical & Experimental Immunology 07/2013; 174(3). DOI:10.1111/cei.12166 · 3.28 Impact Factor
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    ABSTRACT: A histopathological classification system for ANCA-associated vasculitis was recently published, but whether this system predicts renal outcome requires validation. Here, we analyzed data from 164 consecutive patients with biopsy-proven renal involvement of ANCA-associated vasculitis. The ANCA-associated GN (AGN) classification categorizes patients as having focal, mixed, crescentic, or sclerotic GN. Five-year renal survival rates by categories of the AGN classification scheme were 91% for focal, 69% for mixed, and 64% for crescentic (log-rank P<0.0001). Only one patient was classified as sclerotic. Furthermore, the percentage of normal glomeruli found on biopsy estimated renal survival with the same precision as did the AGN classification scheme. Patients classified as crescentic or mixed, however, had worse survival when the percentage of normal glomeruli was <25%. In conclusion, the AGN classification for renal biopsy specimens is a practical and informative scheme with which to categorize patients
    Journal of the American Society of Nephrology 06/2013; DOI:10.1681/ASN.2012090912 · 9.47 Impact Factor
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    ABSTRACT: OBJECTIVES: B cells have immunoregulatory function acting as antigen-presenting cells. A separate subset of interleukin (IL)-10 producing B cells (Breg) regulating T cell mediated immunity has been identified. In the present study, we investigated the role of Breg in antineutrophil cytoplasmic antibodies-associated vasculitis (AAV). METHODS: 17 healthy controls (HCs) and 41 patients with AAV were enrolled. 30 patients with AAV were in remission. Furthermore, 11 patients with AAV with active disease were studied. Breg were defined as IL-10(+)CD19(+) B cells upon culture with cytosine-phosphate-guanosine oligodeoxynucleotide (CpG ODN) 2006. Next to Breg, CD4(+)CD127(low)CD25(hi)CD39(neg)/CD39(+) regulatory T-cells (Treg), interferon (IFN)γ(+), IL-4(+) and Il-17A(+)T helper cell subsets were determined via flow cytometry. RESULTS: Patients with active or quiescent disease showed a diminished fraction of Breg as compared with HCs. The frequency of IFNγ(+) T helper cells was negatively associated with Breg in untreated AAV in remission but not in active vasculitis or in HCs. Interestingly, the total Treg population and the CD39(+) Treg subpopulation correlated positively with Breg in inactive patients with AAV. CONCLUSIONS: IL-10 producing B cells are diminished in AAV. Furthermore, Breg might regulate Th1 cells and are associated with Treg in quiescent AAV. Suppression of Th1 cells by Breg may be insufficient in active AAV.
    Annals of the rheumatic diseases 05/2013; 72(8). DOI:10.1136/annrheumdis-2012-202986 · 10.38 Impact Factor
  • La Presse Médicale 04/2013; 42(4):758-759. DOI:10.1016/j.lpm.2013.02.252 · 1.17 Impact Factor
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    La Presse Médicale 04/2013; 42(4):747-748. DOI:10.1016/j.lpm.2013.02.226 · 1.17 Impact Factor

Publication Stats

989 Citations
380.86 Total Impact Points

Institutions

  • 2003–2015
    • Maastricht University
      • • Department of Cardiology
      • • Interne Geneeskunde
      Maestricht, Limburg, Netherlands
  • 2013
    • Linköping University
      Linköping, Östergötland, Sweden
  • 2004–2013
    • Maastricht Universitair Medisch Centrum
      • Central Diagnostic Laboratory
      Maestricht, Limburg, Netherlands