P Roux-Lombard

University of Geneva, Genève, Geneva, Switzerland

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Publications (76)357.55 Total impact

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    ABSTRACT: Background: Interferon γ (IFNγ) is considered a seminal cytokine in the pathogenesis of giant cell arteritis (GCA), but its functional role has not been investigated. We explored changes in infiltrating cells and biomarkers elicited by blocking IFNγ with a neutralising monoclonal antibody, A6, in temporal arteries from patients with GCA. Methods: Temporal arteries from 34 patients with GCA (positive histology) and 21 controls were cultured on 3D matrix (Matrigel) and exposed to A6 or recombinant IFNγ. Changes in gene/protein expression were measured by qRT-PCR/western blot or immunoassay. Changes in infiltrating cells were assessed by immunohistochemistry/immunofluorescence. Chemotaxis/adhesion assays were performed with temporal artery-derived vascular smooth muscle cells (VSMCs) and peripheral blood mononuclear cells (PBMCs). Results: Blocking endogenous IFNγ with A6 abrogated STAT-1 phosphorylation in cultured GCA arteries. Furthermore, selective reduction in CXCL9, CXCL10 and CXCL11 chemokine expression was observed along with reduction in infiltrating CD68 macrophages. Adding IFNγ elicited consistent opposite effects. IFNγ induced CXCL9, CXCL10, CXCL11, CCL2 and intracellular adhesion molecule-1 expression by cultured VSMC, resulting in increased PBMC chemotaxis/adhesion. Spontaneous expression of chemokines was higher in VSMC isolated from GCA-involved arteries than in those obtained from controls. Incubation of IFNγ-treated control arteries with PBMC resulted in adhesion/infiltration by CD68 macrophages, which did not occur in untreated arteries. Conclusions: Our ex vivo system suggests that IFNγ may play an important role in the recruitment of macrophages in GCA by inducing production of specific chemokines and adhesion molecules. Vascular wall components (ie, VSMC) are mediators of these functions and may facilitate progression of inflammatory infiltrates through the vessel wall.
    No preview · Article · Dec 2015 · Annals of the rheumatic diseases
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    ABSTRACT: Background The etiopathogenesis of rheumatoid arthritis (RA) is viewed as a multi-step process whereby environmental factors induce pathologic activation of the immune system that eventually leads to clinical onset of RA in genetically susceptible individuals. Systemic autoimmunity associated with RA is one of the phases preceding the development of the disease. The role of female hormonal factors is controversial and their relation in the transition to systemic autoimmunity has not been studied. Recently, observational studies have suggested differences in the role of female reproductive factors between anti-citrullinated protein antibodies (ACPA) negative and positive RA. Objectives To analyze the association between female reproductive factors and the development of systemic autoimmunity associated with RA. Methods This is a prospective cohort study of first degree relatives (FDRs) of patients with established RA. Only individuals without clinical evidence of RA are enrolled and followed-up yearly. We included in this analysis only female participants with available ACPA status (anti-CCP 2.0 or 3.1) and full information on reproductive factors. The outcome of interest was the presence of ACPA. The predictor of interest was the cumulative lifetime estrogen (CLE) exposure as previously described (1). This composite score integrates a history of menarche ≤10 years, 3 or more pregnancies, hysterectomy, hormonal contraceptive or replacement therapy and age at menopause ≥53 years. Based on the CLE score, women were categorized as being low, moderate or high estrogen exposed. We used logistic regression to analyze univariate and multivariate associations between ACPA positive status, CLE exposure and other specific reproductive factors. Results A total of 583 women FDRs were analyzed, of which 93 (16%) were ACPA-positive. Characteristics were balanced between ACPA positive and negative FDRs with a mean age of 48.3 and 44.9 years and heavy tobacco smoking (>10 pack-years) in 45 and 46% respectively. Positive shared epitope (SE) in 8 and 10% and positive rheumatoid factor in 17% of subjects in both groups. In a multivariate adjusted analysis, low CLE exposure was associated with ACPA positivity (OR 1.88, p=0.03). High CLE exposure was also numerically associated with an increased risk of ACPA (OR 1.57, p=0.36), even though not significantly. We found no significant association between ACPA positivity and SE, ever smoking, obesity, breastfeeding or postmenopausal status. Conclusions In women at increased risk of RA, the development of ACPAs was found to be associated with low lifetime exposure to estrogens, however high lifetime estrogen exposure also tended to increase the risk of ACPAs positivity, suggesting a non-linear association between estrogenic exposure and the development of ACPAs. We plan to replicate these findings in a separate cohort. If this non-linear association was confirmed it could explain some discordant findings in the literature. References Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Anorexia nervosa (AN) is a serious, potentially life-threatening disorder characterized by severe weight loss, dysregulated eating, and often excessive exercise. While psychiatric illnesses such as depression are associated with increased levels of pro-inflammatory mediators, evidence for such disturbances in patients with AN has been less clear. In an exploratory study of possible disturbances in immune responses in AN, we assayed a panel of cytokines and chemokines in the blood of patients undergoing inpatient treatment, testing the hypothesis that metabolic disturbances in this disease would lead to a pattern of immune disturbances distinct from that of other psychiatric diseases. For this purpose, we evaluated patients by the Beck Depression Inventory-II (BDI-II) and the Eating Disorders Examination-Questionnaire and assessed cytokines and chemokines by enzyme-linked immunosorbent assays. Patients reported a moderate level of depression (mean BDI-II = 22.6) but exhibited few immunologic abnormalities of the kind associated with major depressive disorder [e.g., increased interleukin (IL)-6]; RANTES showed the most frequent elevations and was increased in 4 of the patients studied. Together, these findings suggest that features of AN such as loss of adipose tissue and excessive exercise may attenuate cytokine production and thus modulate the experience of illness that impacts on core features of disease.
    Full-text · Article · Sep 2014 · Cytokine
  • I. von Muhlenen · A. Finckh · P. Roux-Lombard · C. Gabay
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    ABSTRACT: Background The diagnosis of Spondylarthritis remains a challenge (1). We present a case series of patients with overlaping clinical manifestations of Spondylarthritis and autoinflammatory Syndromes making the diagnosis difficult. Objectives We hypothesized that SpA and other autoinflammatory syndromes may coexist. Methods We provide a brief clinical description of several patients initially diagnosed only as SpA. We performed a genetic analysis of these patients and of their family members, focusing on well-characterized hereditary autoinflammatory syndromes. Results Patient (P1) presented with undifferentiated arthritis and exhibited some clinical and radiological characteristics of Spondyloarthritis (SpA), including inflammatory back pain, inflammatory arthralgias, sacro-iliitis on MRI, high acute-phase response (CRP and ESR), but negative HLA B-27. The disease activity and acute-phase response remained high despite anti-TNF and c-DMARD therapy. Because the patient also complained of abdominal pain, myalgia and urticaria, we searched for an immunodeficiency and found high levels of IgD. Two other patients (P2 and P3) were consequently identified with similar clinical and laboratory features, including inflammatory back pain and arthralgias, high acute-phase response, negative HLA B-27, high serum IgD levels and only limited responsiveness to c-DMARDs and TNF-inhibitors. P1 was found to have a heterozygous mutation in the MEFV- Gene (K695R) suggestive of FMF. P2 carries a heterozygous mutation in the TNFRSF1A gene (R92Q) and a heterozygous mutation in the MEFV-gene (E148Q), suggestive of FMF and TRAPS. No mutations were found for P3. In family of P1 (SpA & FMF), the same mutation was found in the mother, the sister and 3 nieces. Of note, the sister also has SpA and one of the nieces, also displays high IgD, arthralgias, abdominal pains and severe aphthosis. In family of P2 (SpA-FMF-TRAPS), both mutations were found in his/her mother and two sisters. His/her father displayed typical features of SpA, the mother had episodes of pleuritis and abdominal pain and the two sisters had similar, though less severe, clinical manifestations as the index patient. Conclusions Our findings support the presence of overlapping clinical manifestations between SpA and periodic fever syndromes in some patients. These patient's low penetration genetic mutations may have influenced the clinical manifestations of SpA. SpA in general does have some autoimmune but also some autoinflammatory features (2). High serum levels of IgD are commonly reported in some autoinflammatory diseases and may represent a useful biomarker for these overlap presentations between SpA and autoinflammatory diseases. References Disclosure of Interest I. von Mühlenen Grant/research support: Novartis, A. Finckh Grant/research support: Novartis, P. Roux-Lombard Grant/research support: Novartis, C. Gabay Grant/research support: Novartis DOI 10.1136/annrheumdis-2014-eular.3669
    No preview · Article · Jun 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Anti-nuclear antibodies (ANA) are fundamental for the diagnosis of autoimmune diseases, and have been determined by indirect immunofluorescence assay (IIFA) for decades. As the demand for ANA testing increased, alternative techniques were developed challenging the classic IIFA. These alternative platforms differ in their antigen profiles, sensitivity and specificity, raising uncertainties regarding standardisation and interpretation of incongruent results. Therefore, an international group of experts has created recommendations for ANA testing by different methods. Two groups of experts participated in this initiative. The European autoimmunity standardization initiative representing 15 European countries and the International Union of Immunologic Societies/World Health Organization/Arthritis Foundation/Centers for Disease Control and Prevention autoantibody standardising committee. A three-step process followed by a Delphi exercise with closed voting was applied. Twenty-five recommendations for determining ANA (1–13), anti-double stranded DNA antibodies (14–18), specific antibodies (19–23) and validation of methods (24–25) were created. Significant differences between experts were observed regarding recommendations 24–25 (p<0.03). Here, we formulated recommendations for the assessment and interpretation of ANA and associated antibodies. Notably, the roles of IIFA as a reference method, and the importance of defining nuclear and cytoplasmic staining, were emphasised, while the need to incorporate alternative automated methods was acknowledged. Various approaches to overcome discrepancies between methods were suggested of which an improved bench-to-bedside communication is of the utmost importance. These recommendations are based on current knowledge and can enable harmonisation of local algorithms for testing and evaluation of ANA and related autoantibodies. Last but not least, new more appropriate terminologies have been suggested.
    Full-text · Article · Jan 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background: Rheumatoid arthritis (RA) is a risk factor for the development of Felty's syndrome and large granular lymphocyte (LGL) leukemia. Anti-cyclic citrullinated peptide (CCP) antibodies are considered highly specific for RA and are directed against various citrullinated antigens, including citrullinated fibrinogen. Anti-CCP antibodies may interfere with the detection of citrullinated proteins and their function. In this article, we describe the possible inhibition of fibrinogen by anti-CCP antibodies with clinical consequences which have never been reported in the literature to our best knowledge. Case report: We present the case of a 79-year-old Caucasian woman with a longstanding history of untreated seropositive RA and who had been investigated for severe neutropenia since several months. The association of splenomegaly led to suspicion of Felty's syndrome. Flux cytometry was compatible with T-cell LGL leukemia. In addition, severe hypofibrinogenemia was detected. The later finding has not been consistently associated with the former clinical entities. Further investigations demonstrated that the anti-CCP antibodies of the patient also recognized the P41 peptide of citrullinated fibrinogen. The patient deceased of intracranial hemorrhage. Conclusion: It is likely, yet not definite, that high anti-citrullinated fibrinogen titers may contribute to low fibrinogen levels and could have contributed to the fatal hemorrhagic event.
    Full-text · Article · Oct 2013 · Modern Rheumatology
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    Nicolas Vuilleumier · J M Dayer · Arnold von Eckardstein · Pascale Roux-Lombard
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    ABSTRACT: Apolipoprotein A-1 (apoA-1) is the principal protein fraction of high-density lipoprotein (HDL), conferring to the latter many of its pleiotropic atheroprotective functions. After its effect on cholesterol efflux, the second most studied feature of apoA-1 is its anti-inflammatory property. In addition, it interferes with lipid peroxidation and innate immune receptors. These anti-inflammatory effects are due to various properties, in particular the ability to inhibit the transendothelial migration of immune cells by reducing integrin expression, to inhibit monocyte activation and cytokine production induced by T-cell contact, to inhibit lipid peroxidation and to interfere with innate immune receptors. Recent studies have demonstrated that during chronic systemic inflammation HDL could lose some of its atheroprotective functions and become dysfunctional or even proinflammatory. Recent evidence suggests that specific post-translational modifications of apoA-1 transform this genuine anti-inflammatory molecule into a proinflammatory one. The structural changes include chlorination, nitration and carbamylation of amino acids by myeloperoxidase, oxidation by reactive carbonyls, as well as glycation. Humoral autoimmunity to apoA-1 and HDL has been reported in populations at high cardiovascular risk and constitutes another emerging mechanism contributing to the loss of functions of apoA-1 and HDL. The fact that in recent trials cholesteryl ester transfer protein inhibitors (torcerapib and dalcetrapib) have unfortunately failed to prevent cardiovascular disease despite increasing cholesterol efflux in vitro and HDL levels in vivo, further highlights the clinical importance of understanding the mechanisms driving apoA-1 and HDL towards pro- or anti-inflammatory molecules. These findings should not affect current dyslipidaemia management guidelines.
    Full-text · Article · May 2013 · Schweizerische medizinische Wochenschrift
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    ABSTRACT: Background: Search for therapeutic targets in giant-cell arteritis (GCA) is hampered by the scarcity of functional systems. We developed a new model consisting of temporal artery culture in tri-dimensional matrix and assessed changes in biomarkers induced by glucocorticoid treatment. Methods: Temporal artery sections from 28 patients with GCA and 22 controls were cultured in Matrigel for 5 days in the presence or the absence of dexamethasone. Tissue mRNA concentrations of pro-inflammatory mediators and vascular remodelling molecules was assessed by real-time RT-PCR. Soluble molecules were measured in the supernatant fluid by immunoassay. Results: Histopathological features were exquisitely preserved in cultured arteries. mRNA concentrations of pro-inflammatory cytokines (particularly IL-1β and IFNγ), chemokines (CCL3/MIP-1α, CCL4/MIP-1β, CCL5/RANTES) and MMP-9 as well as IL-1β and MMP-9 protein concentrations in the supernatants were significantly higher in cultured arteries from patients compared with control arteries. The culture system itself upregulated expression of cytokines and vascular remodelling factors in control arteries. This minimised differences between patients and controls but underlines the relevance of changes observed. Dexamethasone downregulated pro-inflammatory mediator (IL-1β, IL-6, TNFα, IFNγ, MMP-9, TIMP-1, CCL3 and CXCL8) mRNAs but did not modify expression of vascular remodelling factors (platelet derived growth factor, MMP-2 and collagens I and III). Conclusions: Differences in gene expression in temporal arteries from patients and controls are preserved during temporal artery culture in tri-dimensional matrix. Changes in biomarkers elicited by glucocorticoid treatment satisfactorily parallel results obtained in vivo. This may be a suitable model to explore pathogenetic pathways and to perform preclinical studies with new therapeutic agents.
    No preview · Article · Apr 2013 · Annals of the Rheumatic Diseases
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    ABSTRACT: Obstructive sleep apnea (OSA) is inducing oxidative stress and consequently promotes systemic inflammation and cardiovascular morbidity. The respective impact of obesity, sleep apnea and acute cardiovascular events on the profile of inflammatory cytokines has not been extensively evaluated. We examined the profile of circulating cytokines in a case-control study comparing nonobese or obese patients with or without sleep apnea and with or without an acute cardiovascular event. Patients were assessed by sleep studies and inflammatory (hs-CRP, Leptin, RANTES, MCP1, IL6, IL8, TNF-α) and anti-inflammatory (adiponectin, IL1-Ra) cytokines profile. A cardiovascular phenotyping was performed including carotid intima-media thickness, pulse wave velocity and 24h blood pressure monitoring. In comparison with patients without sleep apnea or without comorbidities, patients with the combination of an acute cardiovascular event and pre-existing sleep apnea showed a higher burden of systemic inflammation with significant increase in serum levels of hs-CRP, IL1-Ra, IL-8, IL-6, TNF-α, Rantes and sICAM. Rantes and sICAM serum levels were independently associated with AHI after an acute cardiovascular event. Serum levels of different inflammatory markers were significantly increased in patients with the combination of sleep apnea and an acute cardiovascular event. Since these biomarkers could be associated with worsened cardiovascular outcome, diagnosing and treating associated sleep apnea is potentially important in patients after an acute cardiovascular event.
    No preview · Article · Mar 2013 · Cytokine
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    ABSTRACT: We aimed at challenging the prognostic accuracies of myeloperoxidase (MPO) and antibodies anti-apolipoprotein A-1 (anti-apoA-1 IgG), alone or in combination, for major adverse cardiovascular events (MACE) prediction, one year after carotid endarterectomy (CEA). In this prospective single centre study, 178 patients undergoing elective CEA were included. Serum anti-apoA-1 IgG and MPO were assessed by enzyme-linked immunosorbent assay prior to the surgery. Post-hoc determination of the MPO cut-off was performed by receiver operating characteristics (ROC) analyses. MACE was defined by the occurrence of fatal or non-fatal acute coronary syndromes or stroke during one year follow-up. Prognostic accuracy of anti-apoA-1 IgG was assessed by ROC curve analyses, survival analyses and reclassification statistics. During follow-up, 5% (9/178) of patients presented a MACE, and 29% (52/178) were positive for anti-apoA-1 IgG. Patients with MACE had higher median MPO and anti-apoA-1 IgG levels at admission (p=0.01), but no difference for the 10-year global Framingham risk score (FRS) was observed (p=0.22). ROC analyses indicated that both MPO and anti-apoA-1 IgG were significant predictors of subsequent MACE (area under the curve [AUC]: 0.75, 95% confidence interval [95%CI]: 0.61-0.89, p=0.01; and 0.74, 95%CI: 0.59-90; p=0.01), but combining anti-apoA-1 IgG positivity and MPO>857 ng/ml displayed the best predictive accuracy (AUC: 0.78, 95%CI: 0.65-0.91; p=0.007). It was associated with a poorer MACE-free survival (98.2% vs. 57.1%; p<0.001, LogRank), with a positive likelihood ratio of 13.67, and provided incremental predictive ability over FRS. In conclusion, combining the assessment of anti-apoA-1 IgG and MPO appears as a promising risk stratification tool in patients with severe carotid stenosis.
    No preview · Article · Jan 2013 · Thrombosis and Haemostasis
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    P A Wick · A Mombelli · S Pagano · X Moren · C Giannopoulou · F Mach · P Roux-Lombard · N Vuilleumier
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    ABSTRACT: Background and objective: Anti-apolipoprotein A-1 (anti-apoA-1) IgG is a potential marker of atherosclerotic plaque vulnerability and cardiovascular complications. In patients with periodontitis the presence of anti-apoA-1 IgGs in serum and their association with atherosclerosis is unknown. Material and methods: One-hundred and thirty subjects with periodontal disease and 46 healthy subjects, matched for age and gender, participated in this study. Anti-apoA-1 IgG, high-sensitivity C-reactive protein (hsCRP) and matrix metalloproteinase (MMP) -2, -3, -8 and -9 were measured in serum samples. An ankle-brachial index (ABI) value below 1.11 served as a surrogate marker of atherosclerosis. Predictive accuracies of biomarkers for abnormal ABI were determined using receiver-operating characteristics curves and logistic regression analyses. Results: Compared with healthy controls, periodontitis patients showed lower median ABI values (1.10 vs. 1.15; p < 0.0001), a higher prevalence of anti-apoA-1 IgG positivity (23.8% vs. 6.5%; p = 0.009) and higher concentrations of hsCRP (1.62 mg/L vs. 0.85 mg/L; p = 0.02) and MMP-9 (435 μg/mL vs. 283 μg/mL; p < 0.0001). In patients younger than 50 years of age (n = 66), anti-apoA-1 IgG was found to be the best predictor for an abnormal ABI (area under the curve = 0.63; p = 0.03). Anti-apoA-1 IgG positivity increased the risk of having an abnormal ABI (odds ratio = 4.20; p = 0.04), independently of diabetes, smoking and body mass index. Conclusions: Anti-apoA-1 IgG positivity and atherosclerosis, as reflected by abnormal ABI, were more prevalent in periodontitis patients than in age- and gender-matched controls. In younger periodontitis patients, anti-apoA-1 IgG was found to be the best predictor of atherosclerosis burden.
    Full-text · Article · Oct 2012 · Journal of Periodontal Research
  • Wick PA · Mombelli A · Pagano S · Moren X · Giannopoulou C · Mach F · Roux-Lombard P · Vuilleumier N

    No preview · Article · Sep 2012 · Journal of Periodontal Research
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    ABSTRACT: Liver kidney microsomal type 1 (LKM-1) antibodies have been shown to decrease the CYP2D6 activity in vitro and are present in a minority of patients with chronic hepatitis C infection. We investigated whether LKM-1 antibodies might reduce the CYP2D6 activity in vivo. All patients enrolled in the Swiss Hepatitis C Cohort Study and tested for LKM-1 antibodies were assessed (n = 1723): 10 eligible patients were matched with patients without LKM-1 antibodies. Patients were genotyped for CYP2D6 variants to exclude individuals with a poor metabolizer genotype. CYP2D6 activity was measured by a specific substrate using the dextromethorphan/dextrorphan metabolic ratio to classify patients into four activity phenotypes. All patients had a CYP2D6 extensive metabolizer genotype. The observed phenotype was concordant with the CYP2D6 genotype in most LKM-negative patients, whereas only three LKM-1 positive patients had a concordant phenotype (six presented an intermediate and one a poor metabolizer phenotype). The median DEM/DOR ratio was sixfold higher in LKM-1 positive than in LKM-1 negative patients (0.096 vs. 0.016, P = 0.004), indicating that CYP2D6 metabolic function was significantly reduced in the presence of LKM-1 antibodies. In chronic hepatitis C patients with LKM-1 antibodies, the CYP2D6 metabolic activity was on average reduced by 80%. The impact of LKM-1 antibodies on CYP2D6-mediated drug metabolism pathways warrants further translational studies.
    Full-text · Article · Aug 2012 · Journal of Viral Hepatitis
  • P.A. WICK · N. VUILLEUMIER · P. ROUX-LOMBARD · C. GIANNOPOULOU · A. MOMBELLI
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    ABSTRACT: Objective: To explore the prevalence of serum anti-apolipoprotein A-1 (anti-Apo A-1) IgG autoantibody and its relationship to atherosclerosis and disease severity in periodontally healthy and diseased subjects. Method: 130 subjects with, and 46 subjects without periodontal disease, matched for age and gender, participated in this cross-sectional study. Anti-ApoA-1 IgG, as well as C-reactive protein (CRP), and matrix metalloproteinase (MMP) 3 and 9 were measured in serum samples. The ankle-brachial index (ABI) served as surrogate marker of atherosclerosis. The number of periodontal pockets >4 mm bleeding on probing (G4BOP) per subject served as surrogate marker of periodontal disease severity. Biomarker respective predictive accuracies were tested using ROC curves and logistic regression analyses. Result: Periodontitis patients showed a higher prevalence of anti-Apo A-1 IgG positivity as compared to controls (24.6% vs. 6.5%, p=0.005), lower median ABI values (1.10 vs 1.15; p<0.0001), and higher concentrations of CRP (16.2mg/l vs. 8.5 mg/l, p=0.02) and MMP-9 (434µg/ml vs. 283µg/l, p=0.0001). In patients younger than 50 years (n=66), anti-apoA-1 IgG was found to be the best predictor for abnormal ABI (ABI<1.11; AUC=0.63; p=0.03) and severe periodontitis (G4BOP>26; AUC=0.72; p=0.0004). Periodontitis patients positive for anti-apoA-1 IgG had an increased risk of having an abnormal ABI (OR=4.20, p=0.04) but were protected from severe periodontitis (OR=0.24; p=0.04), independently of diabetes, smoking and body mass index. Conclusion: Anti-Apo A-1 IgG positivity and atherosclerosis, as reflected by abnormal ABI, are more prevalent in periodontitis patients than in age and gender-matched controls. In younger periodontitis patients, anti-apo A-1 IgG was found to be the best predictor of atherosclerosis and disease severity.
    No preview · Conference Paper · Jun 2012
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    ABSTRACT: Adipose tissue may release mediators that induce a chronic inflammatory state and alterations in coagulation, which contribute to insulin resistance, atherosclerosis, and thrombosis. We investigated whether inflammatory and/or prothrombotic states exist in obese children and assessed their interrelationship. Sixty-one subjects were recruited, aged between 6 and 16 years, to participate in a cross-sectional study at Children's University Hospital of Geneva. Selected pro/anti-inflammatory cytokines/chemokines and hemostasis parameters were measured in obese children and lean controls. Cardiovascular risk factors in the family were indexed. Fasting glucose level, insulin, prothrombin time (PT), fibrinogen, activated partial thromboplastin time (aPTT), D-dimer, endogenous thrombin potential (ETP), C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-10 (IL-10), interferon-γ-inducible-protein (IP-10), monocyte chemoattractant protein 1 (MCP-1), and interleukin-1 receptor antagonist (IL-1Ra) were measured. We estimated insulin resistance by homeostatic model assessment (HOMA). Anti- (IL-1Ra) and proinflammatory cytokines (MCP-1, IL-6) were significantly increased in obese children in comparison to the control group, even before puberty. Hemostasis was also altered in obese children with a significantly increased fibrinogen level, increased D-dimer, a shortened PT, as well as an increased ETP. No correlation was found between cytokine levels and hemostasis parameters, except for IL-6 and fibrinogen. Obese children present with inflammatory and prothrombotic states as early as 6 years of age and these states are similar in prepubertal and pubertal obese children. The cytokines IL-1Ra and MCP-1 were most significantly increased in obese children. Further investigation is necessary to determine if these cytokines, together with ETP, can reliably predict the development of diabetes and atherosclerosis.
    Full-text · Article · Apr 2012 · Obesity
  • Pruijm M · Schmidtko J · Aho A · Pagano S · Roux-Lombard P · Teta D · Burnier M · Vuilleumier N

    No preview · Article · Jan 2012 · Therapeutic Apheresis and Dialysis
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    ABSTRACT: The "blood vulnerability", resulting from the complex balance between serum molecules and inflammatory cell atherosclerotic activities, is a major determinant in the evaluation of the "global patient cardiovascular vulnerability". In the present study, we focused on the role of the soluble receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL, a potential marker of coronary calcification and vulnerability) in the release of neutrophilic proteases. Then, the association between these mediators and the degree of coronary calcification (assessed by coronary calcium score [CCS]) was investigated in 20 subjects (aged ≥65 years) asymptomatic for cardiovascular disease. Results showed that RANKL dose-dependently induced matrix metalloprotease (MMP)-8 and MMP-9 release from human primary neutrophils cultured in Teflon dishes (suspension condition, mimicking cells circulating in the blood stream). Conversely, when adherent to polystyrene, neutrophils became unresponsive to RANKL. RANKL did not influence the release of other neutrophilic products in suspension and adherence cultures as well as neutrophil migration. RANKL-induced release of MMPs was dependent on the activation of defined intracellular signalling pathways (PI3K/Akt and ERK1/2). In asymptomatic subjects, serum levels of RANKL, MMP-8 and MMP-9 positively correlated with CCS, reflecting a potential relationship between circulating RANKL and coronary calcification. In conclusion, RANKL increased the release of neutrophilic products potentially related to the "blood" vulnerability via defined intracellular pathways. Serum levels of RANKL might represent a potential biomarker of coronary calcification and related cardiovascular risk.
    Full-text · Article · Nov 2011 · Thrombosis and Haemostasis
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    ABSTRACT: Open studies suggest that treatment of obesity hypoventilation syndrome (OHS) by noninvasive ventilation (NIV) restores sleep quality and daytime vigilance and reduces cardiovascular morbidity. However, to our knowledge no randomized controlled trial (RCT) comparing NIV to conservative measures is available in the field. The goal of this study was to assess in patients with OHS, during an RCT, effects of 1-month NIV compared with lifestyle counseling on blood gas measurements, sleep quality, vigilance, and cardiovascular, metabolic, and inflammatory parameters. Thirty-five patients in whom OHS was newly diagnosed were randomized either to the NIV group or the control group represented by lifestyle counseling. Assessments included blood gas levels, subjective daytime sleepiness, metabolic parameters, inflammatory (hsCRP, leptin, regulated upon activation normal T-cell express and secreted [RANTES], monocyte chemoattractant protein-1, IL-6, IL-8, tumor necrosis factor-α, resistin) and antiinflammatory (adiponectin, IL-1-RA) cytokines, sleep studies, endothelial function (reactive hyperemia measured by peripheral arterial tonometry [RH-PAT]), and arterial stiffness. Despite randomization, NIV group patients (n = 18) were older (58 ± 11 years vs 54 ± 6 years) with a higher baseline Paco(2) (47.9 ± 4.2 mm Hg vs 45.2 ± 3 mm Hg). In intention-to-treat analysis, compared with control group, NIV treatment significantly reduced daytime Paco(2) (difference between treatments: -3.5 mm Hg; 95% CI, -6.2 to -0.8) and apnea-hypopnea index (-40.3/h; 95% CI, -62.4 to -18.2). Sleep architecture was restored, although nonrespiratory microarousals increased (+9.4/h of sleep; 95% CI, 1.9-16.9), and daytime sleepiness was not completely normalized. Despite a dramatic improvement in sleep hypoxemia, glucidic and lipidic metabolism parameters as well as cytokine profiles did not vary significantly. Accordingly, neither RH-PAT (+0.02; 95% CI, -0.24 to 0.29) nor arterial stiffness (+0.22 m/s; 95% CI, -1.47 to 1.92) improved. One month of NIV treatment, although improving sleep and blood gas measurements dramatically, did not change inflammatory, metabolic, and cardiovascular markers. Trial registry: ClinicalTrials.gov; No.: NCT00603096; URL: www.clinicaltrials.gov.
    No preview · Article · Sep 2011 · Chest
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    ABSTRACT: The aims of this study were to investigate the usefulness of serum C-reactive protein, procalcitonin, tumor necrosis factor alpha, interleukin-6, and interleukin-8 as postmortem markers of sepsis and to compare C-reactive protein and procalcitonin values in serum, vitreous humor, and cerebrospinal fluid in a series of sepsis cases and control subjects, in order to determine whether these measurements may be employed for the postmortem diagnosis of sepsis. Two study groups were formed, a sepsis group (eight subjects coming from the intensive care unit of two university hospitals, with a clinical diagnosis of sepsis in vivo) and control group (ten autopsy cases admitted to two university medicolegal centers, deceased from natural and unnatural causes, without elements to presume an underlying sepsis as the cause of death). Serum C-reactive protein and procalcitonin concentrations were significantly different between sepsis cases and control cases, whereas serum tumor necrosis factor alpha, interleukin-6, and interleukin-8 values were not significantly different between the two groups, suggesting that measurement of interleukin-6, interleukin-8, and tumor necrosis factor alpha is non-optimal for postmortem discrimination of cases with sepsis. In the sepsis group, vitreous procalcitonin was detectable in seven out of eight cases. In the control group, vitreous procalcitonin was clearly detectable only in one case, which also showed an increase of all markers in serum and for which the cause of death was myocardial infarction associated with multi-organic failure. According to the results of this study, the determination of vitreous procalcitonin may be an alternative to the serum procalcitonin for the postmortem diagnosis of sepsis.
    Full-text · Article · Jul 2011 · Deutsche Zeitschrift für die Gesamte Gerichtliche Medizin
  • P Roux-Lombard · S Pagano · F Montecucco · N Satta · N Vuilleumier
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    ABSTRACT: During the last 15 years, a growing body of evidence supported the fact that auto-antibodies represent not only emergent markers but also active mediators of cardiovascular disease (CVD), clinically represented mostly by acute coronary syndrome (ACS) and stroke. There is a contrasted relationship between auto-antibodies and CVD, some being protective, while others acting as potential risk factors. Therefore, we performed a review of the literature on the respective cardiovascular prognostic value of the most relevant auto-antibodies in ACS and stroke, and their putative pathophysiological properties in atherogenesis. This review highlights auto-antibodies as active modulators of the innate immune system in atherogenesis (either toward a pro- or anti-inflammatory response), or by affecting basal heart rate regulation (anti-apoA-1 IgG). Given their apparent prognostic independency towards traditional cardiovascular risk factors, the data available in the literature indicates that some of those auto-antibodies could be of valuable help for cardiovascular risk stratification in the future, especially because their deleterious effects have been shown to be potentially abrogated in vivo and in vitro by existing therapeutic modalities. Although evidence in humans is currently lacking, these studies may open innovative therapeutic perspectives for CVD in the future.
    No preview · Article · Dec 2010 · Clinical Reviews in Allergy & Immunology

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3k Citations
357.55 Total Impact Points

Institutions

  • 1986-2014
    • University of Geneva
      • • Division of Immunology and Allergology
      • • Department of Internal Medicine
      Genève, Geneva, Switzerland
  • 2009
    • Hôpitaux Universitaires de Genève
      • Service d'immunologie et d'allergologie
      Genève, Geneva, Switzerland
  • 1993
    • Unité Inserm U1077
      Caen, Lower Normandy, France