Karim Zouaoui Boudjeltia

Université Libre de Bruxelles, Bruxelles, Brussels Capital Region, Belgium

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Publications (112)338.25 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Seeds and aerial parts of Peganum harmala L. (P. harmala) are widely used in Algeria as anti-inflammatory remedies. Evaluation of P. harmala total alkaloids extracts and pure β-carboline compounds as an anti-inflammatory treatment by the inhibition of an enzyme key of inflammatory, myeloperoxidase (MPO) and HPLC quantification of the alkaloids from the different parts of plant. MPO inhibition was tested using taurine chloramine test. The inhibition of LDL oxidation induced by MPO was carried out. The molecular docking analysis of P. harmala alkaloids on MPO was performed using the Glide XP docking protocol and scoring function and the redox potential of alkaloids was determined using an Epsilon potentiostat. The concentration of harmala alkaloids was determined using HPLC analysis. The HPLC profiling of theactive total alkaloids indicates that β-carboline e.g. harmine, harmaline, harmane, harmol and harmalol are major components. As β-carbolines resemble tryptamine, of which derivatives are efficient inhibitors of MPO, the harmala alkaloids were tested for their activity on this enzyme. Total alkaloids of the seeds and of the aerial parts strongly inhibited MPO at 20µg/ml (97±5 and 43±4%, respectively) whereas, at the same concentration, those of the roots showed very low inhibition (15±6%). Harmine, harmaline and harmane demonstrated a significant inhibition of MPO at IC50 of 0.26, 0.08 and 0.72µM respectively. These alkaloids exerted a similar inhibition effects on MPO-induced LDL oxidation. Molecular docking analysis of P. harmala alkaloids on MPO showed that all active P. harmala alkaloids have a high affinity on the active site of MPO (predicted free energies of binding up to -3.1kcal/mol). Measurement of redox potentials versus the normal hydrogen electrode clearly differentiated (i) the high MPO inhibitory activity of harmine, harmaline and harmane (+1014, 1014 and 1003mV, respectively); and (ii) the low activity of harmalol and harmol (+ 629/778 and 532/644mV, respectively).A reverse phase HPLC method has been developed to determine simultaneously five alkaloids of P. harmala. Seeds contained all five β-carboline derivatives with the main active alkaloids, harmaline and harmine, being up to 3.8 and 2.9%, respectively. Up to 3.2% of harmine was determined in the roots. The four β-carboline derivatives, harmine, harmaline, harmane and harmalol were identified in the aerial parts. The highest inhibitory effect observed in seeds and the moderate effect of aerial parts could be explained by their harmine and harmaline content. In contrast, the very weak inhibition of the root extract, despite the presence of harmine, may tentatively be explained by the high concentration of harmol which can reduce Compound II of MPO to the native form. The inhibition of MPO by P. harmala β-carboline alkaloids, herein reported for the first time, may explain the anti-inflammatory effect traditionally attributed to its herbal medicine.
    Journal of ethnopharmacology 04/2014; · 2.32 Impact Factor
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    ABSTRACT: Oxidation of low-density lipoprotein (LDL) by myeloperoxidase (MPO)-H2O2-chloride system is a key event in the development of atherosclerosis. The present study aimed at investigating the interaction of MPO with native and modified LDL and at revealing post-translational modifications on apolipoprotein-B-100 (the unique apolipoprotein of LDL) in vitro and in vivo. Using amperometry we demonstrate that MPO activity increases up to 90% when it is adsorbed at the surface of LDL. This phenomenon is apparently reflected by local structural changes in MPO observed by circular dichroism. Using mass spectrometry we further analyzed in vitro modifications of apolipoprotein-B-100 by HOCl generated by the MPO-H2O2-chloride system or added as a reagent. A total of 97 peptides containing modified residues could be identified. Furthermore, differences were observed between LDL oxidized by reagent HOCl or HOCl generated by the MPO-H2O2-chloride system. Finally, LDL was isolated from patients with high cardiovascular risk to confirm that our in vitro findings are also relevant in vivo. We show that several of HOCl-mediated modifications of apolipoprotein-B-100 identified in vitro were also present on LDL isolated from patients who have increased levels of plasma MPO and MPO-modified LDL. In conclusion, these data emphasize the specificity of MPO to oxidize LDL.
    The Journal of Lipid Research 02/2014; · 4.39 Impact Factor
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    ABSTRACT: ABSTRACT Objective Plasma and synovial myeloperoxidase (MPO) and its products were strongly associated with osteoarthritis (OA) and rheumatoid arthritis (RA). In addition, it is well known that there is a link between oxidative stress and cytokines. The present study aims at investigating the link between synovial MPO (and its products), IL-18, which is involved in the degradation of articular cartilage in RA, and IL-8, which is involved in recruitment and activation of neutrophils during inflammation. Effects of the treatment of RA on the biological parameters were also investigated. Methods Patients (n=105) were studied including 39 patients with OA, 33 with RA and 33 with RA receiving a specific treatment. DAS-28 was calculated whereas MPO antigen/activity, neutrophils, chloro-tyrosine, homocitrulline, IL-8 and IL-18 were measured in synovial fluid (SF) and CRP was measured in serum. Results DAS-28 and CRP level were not significantly different between groups. MPO activity, and MPO, chloro-tyrosine and homocitrulline levels were significantly higher in SF of RA patients than OA patients. MPO specific activity (MPO activity/antigen ratio) was significantly lower in treated than in untreated RA patients as was IL-8. MPO activity and concentration were correlated with IL-8 and IL-18 in untreated but not in treated RA patients. Conclusions MPO level is related to IL-8 and IL-18 levels in untreated RA patients. A link has been shown between treatment and decrease of IL-8, MPO specific activity and homocitrulline in SF. The causal role of MPO in SF inflammation and how treatment can affect MPO specific activity need further investigations.
    Free Radical Research 01/2014; · 3.28 Impact Factor
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    ABSTRACT: Because propolis contains many types of antioxidant compounds such as polyphenols and flavonoids, it can be useful in preventing oxidative damages. Ethyl acetate extracts of propolis from several Algerian regions show high activity by scavenging free radicals, preventing lipid peroxidation and inhibiting myeloperoxidase (MPO). By fractioning and assaying ethyl acetate extracts, it was observed that both polyphenols and flavonoids contribute to these activities. A correlation was observed between the polyphenol content and the MPO inhibition. However, it seems that kaempferol, a flavonoid, contributes mainly to the MPO inhibition. This molecule is in a high amount in the ethyl acetate extract and demonstrates the best efficiency towards the enzyme with an inhibiting concentration at 50% of 4 ± 2 µM.
    International Journal of Molecular Sciences 01/2014; 15(2):2327-45. · 2.46 Impact Factor
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    ABSTRACT: Due to its production of potent antimicrobial oxidants including hypochlorous acid, human myeloperoxidase (MPO) plays a critical role in innate immunity and inflammatory diseases. Thus MPO is an attractive target in drug design. Aminoalkyl-fluoroindole derivatives were detected to be very potent MPO inhibitors; however, they also promote inhibition of the serotonin reuptake transporter (SERT) at the same concentration range. Using structure-based drug design, a new series of MPO inhibitors derived from 3-alkylindole were synthesized and their effects were assessed on the MPO-mediated taurine chlorination and LDL oxidation as well as on inhibition of SERT. The fluoroindole compound with 3 carbons in the side chain and one amide group exhibited a selectivity index of 35 (Ki/IC50) with a high inhibition of MPO activity (IC50= 18 nM) whereas its effect on SERT was in the micromolar range. Structure-function relationships, mechanism of action and safety of the molecule were discussed in the manuscript.
    Journal of Medicinal Chemistry 04/2013; · 5.61 Impact Factor
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    ABSTRACT: Due to its production of potent antimicrobial oxidants including hypochlorous acid, human myeloperoxidase (MPO) plays a critical role in innate immunity and inflammatory diseases. Thus MPO is an attractive target in drug design. Aminoalkyl-fluoroindole derivatives were detected to be very potent MPO inhibitors; however, they also promote inhibition of the serotonin reuptake transporter (SERT) at the same concentration range. Using structure-based drug design, a new series of MPO inhibitors derived from 3-alkylindole were synthesized and their effects were assessed on the MPO-mediated taurine chlorination and LDL oxidation as well as on inhibition of SERT. The fluoroindole compound with 3 carbons in the side chain and one amide group exhibited a selectivity index of 35 (Ki/IC50) with a high inhibition of MPO activity (IC50= 18 nM) whereas its effect on SERT was in the micromolar range. Structure-function relationships, mechanism of action and safety of the molecule were discussed in the manuscrip
    Journal of Medicinal Chemistry 04/2013; · 5.61 Impact Factor
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    ABSTRACT: Intermittent hypoxia (hypoxia-reoxygenation) is often associated with cardiovascular morbidity and mortality. We describe a new device which can be used to submit cohorts of mice to controlled and standardised hypoxia-normoxia cycles at an individual level. Mice were placed in individual compartments to which similar gas flow parameters were provided using an open loop strategy. Evaluations made using computational fluid dynamics were confirmed by studying changes in haemoglobin oxygen saturation in vivo. We also modified the parameters of the system and demonstrated its ability to generate different severities of cyclic hypoxemia very precisely, even with very high frequency cycles of hypoxia-reoxygenation. The importance of the parameters on reoxygenation was shown. This device will allow investigators to assess the effects of hypoxia–reoxygenation on different pathological conditions, such as obstructive sleep apnoea or chronic obstructive pulmonary disease.
    PLoS ONE 04/2013; 8(4):e59973. · 3.73 Impact Factor
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    ABSTRACT: Over 90% of head and neck cancers are squamous cell carcinomas (HNSCC) and the overall 5-year survival rate is up to 50%. The redox status of these cancers is an important factor in carcinogenesis and plays a role in radioresistance and therefore locoregional recurrences. However, knowledge of the redox status is rather limited. Glutathione is the major reactive oxygen species scavenger in normal cells. We compared the levels of tissue redox potential in HNSCC tumor tissue and compared them with those of the adjacent, histologically cancer-free, mucosa. A total of 36 patients with HNSCC were included in the study. The redox status of tumor and normal adjacent tissue was measured by the oxidized/reduced glutathione (GSSG/GSH) ratio in capillary electrophoresis. The GSSG/GSH ratio in the tumor tissue was lower compared with adjacent normal tissue in 38% of the patients. Pretherapy HNSCC tumor tissue has variable GSH levels compared with adjacent cancer-free mucosa. This difference was not related to clinical and pathological parameters. Further studies are required to determine whether the GSSG/GSH ratio plays a role in carcinogenesis and could predict radioresistance.
    European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP) 03/2013; · 2.21 Impact Factor
  • D. Dequanter, M. Shahla, K. Zouaoui Boudjeltia, P. Paulus, P. Lothaire
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    ABSTRACT: Introduction Nous avons cherché à déterminer la nécessité du curage médiastinal supérieur (MS) et son importance pronostique en cas de carcinome épidermoïde (CE) avancé des voies aéro-digestives supérieures. Méthodes Une analyse rétrospective a été faite des dossiers de 31 patients ayant subi une (pharyngo-)laryngectomie pour un CE avancé. L’analyse statistique a recherché une corrélation entre la présence de métastases ganglionnaires MS et les facteurs cliniques ; le seuil de signification statistique retenu est p < 0,05. Résultats Des ganglions positifs ont été retrouvés chez 20 des patients, dont six avec des ganglions positifs uniquement au niveau du MS. Les ganglions positifs au niveau du MS n’ont été trouvés dans aucun des cas de CE laryngé, mais dans six des 13 cas d’atteinte hypopharyngée, et toujours associés aux tumeurs de plus de 35 mm. On observe une forte association entre la présence de métastases ganglionnaires et la localisation de la tumeur primitive (laryngée ou hypopharyngée), bien que celle-ci ne soit pas statistiquement significative (p = 0,08). Conclusions Dans cette série, les CE laryngés avancés n’ont jamais été associés à des ganglions positifs du MS, alors que les CE hypopharyngés avancés ont montré une tendance à impliquer les ganglions du MS.
    Annales françaises d'Oto-rhino-laryngologie et de Pathologie Cervico-faciale. 02/2013; 130(1):4–7.
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    ABSTRACT: Oxidation of low-density lipoprotein (LDL) has a key role in atherogenesis. Among the different models of oxidation that have been studied, the one using myeloperoxidase (MPO) is thought to be more physiopathologically relevant. Apolipoprotein B-100 is the unique protein of LDL and is the major target of MPO. Furthermore, MPO rapidly adsorbs at the surface of LDL, promoting oxidation of amino acid residues and formation of oxidized lipoproteins that are commonly named Mox-LDL. The latter is not recognized by the LDL receptor and is accumulated by macrophages. In the context of atherogenesis, Mox-LDL accumulates in macrophages leading to foam cell formation. Furthermore, Mox-LDL seems to have specific effects and triggers inflammation. Indeed, those oxidized lipoproteins activate endothelial cells and monocytes/macrophages and induce proinflammatory molecules such as TNF α and IL-8. Mox-LDL may also inhibit fibrinolysis mediated via endothelial cells and consecutively increase the risk of thrombus formation. Finally, Mox-LDL has been involved in the physiopathology of several diseases linked to atherosclerosis such as kidney failure and consequent hemodialysis therapy, erectile dysfunction, and sleep restriction. All these issues show that the investigations of MPO-dependent LDL oxidation are of importance to better understand the inflammatory context of atherosclerosis.
    Mediators of Inflammation 01/2013; 2013:971579. · 3.88 Impact Factor
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    ABSTRACT: Infection is often difficult to recognize in critically ill patients because of the marked coexisting inflammatory process. Lack of early recognition prevents timely resuscitation and effective antimicrobial therapy, resulting in increased morbidity and mortality. Measurement of a biomarker, such as C-reactive protein (CRP) concentration, in addition to history and physical signs, could facilitate diagnosis. Although frequently measured in clinical practice, few studies have reported on the pathophysiological role of this biomarker and its predictive value in critically ill patients. In this review, we discuss the pathophysiological role of CRP and its potential interpretation in the inflammatory processes observed in critically ill patients.
    BioMed research international. 01/2013; 2013:124021.
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    ABSTRACT: Low-grade systemic inflammation was suggested to participate to the decline of physiological functions and increased vulnerability encountered in older patients. Geriatric syndromes encompass various features such as functional dependence, polymorbidity, depression and malnutrition. There is a strong prevalence of cardiovascular diseases and related risk factors and chronic cytomegalovirus infections in the geriatric population. As these underlying conditions were proposed to influence the inflammatory state, the aim of this study was to assess their potential contribution to the association of geriatric syndromes with inflammatory parameters. We recruited 100 subjects in the general population or hospitalized for chronic medical conditions (age, 23-96 years). We collected information on clinical status (medical history, ongoing comorbidities, treatments and geriatric scales), biological parameters (hematological tests, cytomegalovirus serology) and cytokines production (basal and alum-induced interleukin (IL)-1β and IL-6 levels). Using stepwise backward multivariate analyses, we defined which set of clinical and biological variables could be predictive for increased inflammatory markers. We confirmed the age-associated increase of circulating IL-6 levels. In contrast to geriatric scales, we found history of cardiovascular diseases to be strongly associated for this parameter as for high IL-6 production upon ex vivo stimulation with alum. Association between low-grade inflammation and geriatric conditions could be linked to underlying cardiovascular diseases.
    PLoS ONE 01/2013; 8(11):e81911. · 3.73 Impact Factor
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    ABSTRACT: The present paradigm of atherogenesis proposes that low density lipoproteins (LDLs) are trapped in subendothelial space of the vascular wall where they are oxidized. Previously, we showed that oxidation is not restricted to the subendothelial location. Myeloperoxidase (MPO), an enzyme secreted by neutrophils and macrophages, can modify LDL (Mox-LDL) at the surface of endothelial cells. In addition we observed that the activation of the endothelial cells by angiotensin II amplifies this process. We suggested that induction of the NADPH oxidase complex was a major step in the oxidative process. Based on these data, we asked whether there was an independent association, in 121 patients, between NADPH oxidase modulators, such as angiotensin II, adiponectin, and levels of circulating Mox-LDL. Our observations suggest that the combination of blood angiotensin II, MPO activity, and adiponectin explains, at least partially, serum Mox-LDL levels.
    Mediators of Inflammation 01/2013; 2013:750742. · 3.88 Impact Factor
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    ABSTRACT: Aging is associated with progressive alterations of immune functions, leading to higher susceptibility to bacterial and viral infections and reduced vaccine responses. Data concerning cytokine production in response to Toll-like receptor (TLR) ligands are highly variable in old people, reflecting the heterogeneity of the geriatric population. The aim of our study was to define the relative contribution of age and clinical status on TLR-induced interleukin (IL)-12p70 and IL-23 production as these cytokines play an important role in the protection against intracellular and extracellular pathogens, respectively. For this purpose, we recruited 100 subjects (aged 23-96 years) in the general population or hospitalized for chronic diseases. We collected information on clinical status (medical history, ongoing comorbidities, treatments and geriatric scales), biological parameters (biochemical and hematological tests, telomere length determination, cytomegalovirus serology). Whole blood samples were stimulated with a combination of TLR4 and TLR7/8 ligands. We performed univariate and stepwise backward multivariate analyses regression to define which set of clinical variables could be predictive for IL-12p70 and IL-23 production in these conditions. Our results indicated that age was not correlated with TLR-mediated IL-12p70 and IL-23 production. In contrast, poor nutritional status and frailty in subjects >75 years were associated with decreased IL-12p70 and IL-23 production. By intracytoplasmic staining, we confirmed that production of IL-12/23p40 by conventional dendritic cells (DCs) upon TLR ligation was decreased in frail patients. However, proportion of DCs and monocytes subsets, phenotypic maturation and proximal signaling events were found to be comparable in frail and healthy old subjects. These results suggest the importance of age-associated clinical parameters and not age by itself in the alteration of innate immune responses in old individuals and emphasis the importance of innate immune responses in the susceptibility of frail geriatric patients to infections.
    PLoS ONE 01/2013; 8(6):e65325. · 3.73 Impact Factor
  • D Dequanter, M Shahla, K Zouaoui Boudjeltia, P Paulus, P Lothaire
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    ABSTRACT: INTRODUCTION: The present study sought to determine the necessity and prognostic impact of superior mediastinum (SM) dissection in advanced upper aerodigestive tract squamous cell carcinoma (SCC). METHODS: A retrospective review was made of the records of 31 patients who had undergone (pharyngo-) laryngectomy for advanced SCC. Statistical analysis examined correlations between the presence of SM lymph node metastasis and clinical factors, with a significance threshold of P<0.05. RESULTS: Positive cervical and/or SM lymph nodes were found in 20 cases, including six with isolated positive SM nodes. Positive SM nodes were found in none of the patients with laryngeal SCC, versus six of the 13 patients with hypopharyngeal SCC, where they were associated with tumors greater than 35mm. Presence of paratracheal lymph node metastasis showed a strong but not statistically significant association with the primary site (larynx vs. hypopharynx: P=0.08). CONCLUSIONS: In the present series, advanced laryngeal carcinoma was never associated with positive SM nodes, whereas advanced hypopharyngeal carcinoma showed a trend in favor of paratracheal lymph node involvement.
    European Annals of Otorhinolaryngology, Head and Neck Diseases 11/2012;
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    ABSTRACT: A high degree of uremia is common in patients with end-stage renal disease and has been linked to the development of chronic inflammation and cardiovascular diseases. In conditions where transplantation is not possible, uremia can be reduced by hemodialysis although the repeated interventions have been implicated in loss of renal function, partially as a result of chronic inflammation and/or oxidative stress processes. In this context, it has been suggested that myeloperoxidase (MPO) can contribute to the oxidative stress during hemodialysis and to the cardiovascular risk. Protein damages due to MPO activity have never been assessed during hemodialysis although two of its reaction products, 3-chlorotyrosine and homocitrulline, are of interest. Indeed, the first one is a specific product of MPO activity and the formation of the second one could be catalyzed by MPO. In order to analyze these products in plasma proteins, a total hydrolysis method followed by liquid chromatography mass spectrometry analysis was developed. Different conditions of hydrolysis were tested and the optimized procedure was assessed for complete hydrolysis and artifactual chlorination. Finally, the method was used for analyzing 3-chlorotyrosine and homocitrulline in plasma proteins during a hemodialysis session in fifteen patients and data were related to measurements of MPO concentration and activity. Both increases in MPO activity and protein-bound 3-chlorotyrosine were observed, highlighting the involvement of MPO in oxidative stress during hemodialysis and further demonstrating the link between hemodialysis and cardiovascular diseases.
    Talanta 09/2012; 99:603-9. · 3.50 Impact Factor
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    ABSTRACT: The invention relates to aromatic N-heterocycle derivatives for use as medicine. In particular, the invention refers to aromatic N-heterocycle derivatives for use in the treatment or the prophylaxis of inflammatory diseases or disorders.
    Year: 08/2012
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    ABSTRACT: Myeloperoxidase (MPO) is a major player of the innate immune defense system of human neutrophils and catalyzes the production of strong oxidizing and halogenating antimicrobial products. Because of its role in pathogenesis of many (inflammatory) diseases, there is great interest in the development of efficient and specific inhibitors. Here, using the X-ray structure of MPO, high-throughput molecular docking of 1350000 compounds was performed. From this virtual screening process, 81 were tested for inhibition of the chlorination activity of MPO, finally ending up with eight inhibiting candidates of different chemical structures. These were tested for inhibiting MPO-mediated low-density lipoprotein oxidation and for interacting with the relevant redox intermediates of MPO. The best inhibitors were bis-2,2'-[(dihydro-1,3(2H,4H)-pyrimidinediyl)bis(methylene)]phenol and 8-[(2-aminoethyl)amino]-3,7-dihydro-3-methyl-7-(3-phenoxypropyl)-1H-purine-2,6-dione. Both did not irreversibly inactivate the enzyme but efficiently trapped it in its compound II state. We discuss the mechanism of inactivation as well as pros and cons of the performed selection process.
    Journal of Medicinal Chemistry 07/2012; 55(16):7208-18. · 5.61 Impact Factor
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    Critical Care 04/2012; 4:1-1. · 4.93 Impact Factor
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    Myriam Kerkhofs, Karim Zouaoui Boudjeltia
    Sleep 01/2012; 35(7):895-6. · 5.10 Impact Factor

Publication Stats

765 Citations
338.25 Total Impact Points

Institutions

  • 2002–2014
    • Université Libre de Bruxelles
      • • Laboratory of Experimental Medicine (LME)
      • • Laboratory of Experimental Medicine (LABOMEDEX)
      Bruxelles, Brussels Capital Region, Belgium
  • 2006–2012
    • Centre Hospitalier Universitaire de Charleroi
      Charleroi, Walloon Region, Belgium
  • 2009–2011
    • University of Namur
      • • Research Unit in Plant Cellular and Molecular Biology (URBV)
      • • Laboratory of Cellular Biochemistry and Biology
      Namen, Walloon Region, Belgium
    • Centre Hospitalier Universitaire Tivoli
      Louvierre, Walloon Region, Belgium
  • 2003–2009
    • Free University of Brussels
      • Department of Intensive Care Medicine
      Bruxelles, Brussels Capital Region, Belgium
    • University Hospital Brussels
      Bruxelles, Brussels Capital Region, Belgium