The 5-year data of the DESIR cohort

Funding Information: Acknowledgements the dESIr cohort was sponsored by the département de la recherche Clinique et du développement de l’Assistance publique–Hôpitaux de paris. this study is conducted under the umbrella of the French Society of rheumatology and InSErM (Institut national de la Santé et de la recherche Médicale). the database management is performed within the department of epidemiology and biostatistics (professor paul Landais, d.I.M., nîmes, France). An unrestricted grant from pfizer was allocated for the 10 years of the follow-up of the recruited patients. the authors would like to thank the different regional participating centres: pr Maxime dougados (paris – Cochin B), pr André Kahan (paris - Cochin A), pr olivier Meyer (paris - Bichat), pr pierre Bourgeois (paris - La pitié Salpetrière), pr Francis Berenbaum (paris - Saint Antoine), pr pascal Claudepierre (Créteil), pr Maxime Breban (Boulogne Billancourt), dr Bernadette Saint-Marcoux (Aulnay-sous-Bois), pr philippe Goupille (tours), pr Jean-Francis Maillefert (dijon), dr xavier puéchal, dr Emmanuel dernis (Le Mans), pr daniel Wendling (Besançon), pr Bernard Combe (Montpellier), pr Liana Euller-Ziegler (nice), pr philippe orcel, dr pascal richette (paris - Lariboisière), pr pierre Lafforgue (Marseille), dr patrick Boumier (Amiens), pr Jean-Michel ristori, pr Martin Soubrier (Clermont-Ferrand), dr nadia Mehsen (Bordeaux), pr damien Loeuille (nancy), pr rené-Marc Flipo (Lille), pr Alain Saraux (Brest), pr Corinne Miceli (Le Kremlin Bicêtre), pr Alain Cantagrel (toulouse), pr olivier Vittecoq (rouen). the authors would also like to thank UrC-CIC paris Centre for the coordination and monitoring of the study. Contributors All authors contributed and finally approved the current manuscript. Competing interests none declared. Patient consent obtained. ethics approval Comitte de protection des personnes Ile de France III. Provenance and peer review not commissioned; externally peer reviewed. Open Access this is an open Access article distributed in accordance with the Creative Commons Attribution non Commercial (CC BY-nC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/ licenses/by-nc/4.0/ © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. no commercial use is permitted unless otherwise expressly granted. Publisher Copyright: © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved.Objective To estimate sacroiliac joint radiographic (X-SIJ) progression in patients with axial spondyloarthritis (axSpA) and to evaluate the effects of inflammation on MRI (MRI-SIJ) on X-SIJ progression. Methods X-SIJ and MRI-SIJ at baseline and after 2 and 5 years in patients with recent onset axSpA from the DESIR cohort were scored by three central readers. Progression was defined as (1) the shift from non-radiographic (nr) to radiographic (r) sacroiliitis (by modified New York (mNY) criteria) or alternative criteria, (2) a change of at least one grade or (3) a change of at least one grade but ignoring a change from grade 0 to 1. The effects of baseline inflammation on MRI-SIJ on 5-year X-SIJ damage (mNY) were tested by generalised estimating equations. Results In 416 patients with pairs of baseline and 5-year X-SIJ present, net progression occurred in 5.1% (1), 13.0% (2) and 10.3% (3) respectively, regarding a shift from nr-axSpA to r-axSpA (1), a change of at least one grade (2) or a change of at least one grade but ignoring a change from grade 0 to 1 (3). Baseline MRI-SIJ predicted structural damage after 5 years in human leukocyte antigen-B27 (HLA-B27) positive (OR 5.39 (95% CI 3.25 to 8.94)) and in HLA-B27 negative (OR 2.16 (95% CI 1.04 to 4.51)) patients. Conclusions Five-year progression of X-SIJ damage in patients with recent onset axSpA is limited but present beyond measurement error. Baseline MRI-SIJ inflammation drives 5-year radiographic changes.publishersversionpublishe

Vital NETosis vs. suicidal NETosis during normal pregnancy and preeclampsia

Background: NETosis occurs in the context of infection or inflammation and results in the expulsion of decondensed DNA filaments called NETs (Neutrophil Extracellular Traps) into the extracellular environment. NETosis activates coagulation and contributes to the thrombotic risk of inflammatory diseases. To date, two mechanisms of NETosis have been identified: suicidal NETosis, in which neutrophils die after expelling the filaments; and vital NETosis, in which expulsion appears without altering the membrane. Human pregnancy is associated with a mild pro-inflammatory state, which is increased in the event of complications such as preeclampsia (PE). NETosis has been observed in these situations, but the mechanism of its production has not yet been studied. The aim of our study was to evaluate the balance of vital vs. suicidal NETosis in normal pregnancy and in PE.Patients/Methods: Neutrophils from healthy volunteers were stimulated with plasma from normal pregnancies (n = 13) and from women developing preeclampsia (n = 13). Immunofluorescent labelling was performed to determine the percentages and origin of NETs in both groups. Inhibition with suicidal or vital NETosis inhibitors was also performed to validate our results.Results: We found a significant increase in NETs in women with PE compared to women with normal pregnancies. We showed that vital and non-vital NETosis are present in normal and preeclamptic pregnancies. We demonstrated that the higher proportion of NETs observed in PE was due to non-vital NETosis whose main component is represented by suicidal NETosis.Discussion: These results suggest the important part of non-vital NETosis in the pathophysiology of PE

Nuclear Importation of Mariner Transposases among Eukaryotes: Motif Requirements and Homo-Protein Interactions

Mariner-like elements (MLEs) are widespread transposable elements in animal genomes. They have been divided into at least five sub-families with differing host ranges. We investigated whether the ability of transposases encoded by Mos1, Himar1 and Mcmar1 to be actively imported into nuclei varies between host belonging to different eukaryotic taxa. Our findings demonstrate that nuclear importation could restrict the host range of some MLEs in certain eukaryotic lineages, depending on their expression level. We then focused on the nuclear localization signal (NLS) in these proteins, and showed that the first 175 N-terminal residues in the three transposases were required for nuclear importation. We found that two components are involved in the nuclear importation of the Mos1 transposase: an SV40 NLS-like motif (position: aa 168 to 174), and a dimerization sub-domain located within the first 80 residues. Sequence analyses revealed that the dimerization moiety is conserved among MLE transposases, but the Himar1 and Mcmar1 transposases do not contain any conserved NLS motif. This suggests that other NLS-like motifs must intervene in these proteins. Finally, we showed that the over-expression of the Mos1 transposase prevents its nuclear importation in HeLa cells, due to the assembly of transposase aggregates in the cytoplasm

Détection d'agrégats temporels et spatiaux

The aim of this work is to propose new solutions in the field of health event cluster detection. This type of analysis is traditionally used in the survey of diseases of which the aetiology is unknown in order to locate and detect aggregates which have an abnormally high density in time and/or in space. The determination of these clusters generally represents a preliminary stage in search of risk factors.We propose a review of existing methods as well as our contribution in various directions. Two approaches are proposed in the temporal frame. The first allows to avoid the use of simulations. The second makes it possible to take into account data of which the temporal information is incomplete. We have also developped a method for the detection of arbitrarily shaped spatial clusters in order to be able to analyse data of which the exact geographic location is known. This approach has been applied on particular data, those obtained by functional Magnetic Resonance Imaging. The perspectives of spatio-temporal analysis are finally evoked.L'objectif de ce travail est de proposer des solutions nouvelles dans le domaine de la détection de clusters d'évènements de santé. Ce type d'analyse est traditionnellement utilisé dans la surveillance de maladies dont l'étiologie est incertaine afin de localiser et mettre en évidence des agrégats ayant une densité anormalement élevée dans le temps et/ou dans l'espace. La détermination de ces clusters constitue généralement une étape préliminaire à la recherche de facteurs de risque.Nous proposons une revue des méthodes existantes ainsi que notre contribution dans différentes directions. Deux approches sont proposées dans le cadre temporel permettant pour l'une d'éviter l'utilisation de simulations et pour l'autre de prendre en compte les données dont l'information temporelle est incomplète. Nous avons également mis au point une méthode de détection de clusters spatiaux de forme arbitraire permettant d'analyser des données dont on connaît la localisation géographique exacte. Cette approche a été appliquée sur des données particulières, celles obtenues par Imagerie par Résonance Magnétique fonctionnelle. Les perspectives d'analyse spatio-temporelle sont finalement évoquées

Le Cam theorem on interval division by randomly chosen points: Pedagogical explanations and application to temporal cluster detection

The aim of this paper is to propose a pedagogical explanation of the Le Cam theorem and to illustrate its use, through a practical application, for temporal cluster detection. This theorem focusses on the interval division by randomly chosen points. The aim of the theorem is to characterize the asymptotic behavior of a certain category of sums of functions applied to the length of successive intervals between points. It is not very intuitive and its understanding needs some deepening. After enouncing the theorem, its different aspects are explained and detailed in a way as pedagogical as possible. Theoretical applications are proposed through the proof of two propositions. Then a very concrete application of this theorem for temporal cluster detection is presented, tested by a power study, and compared with other global cluster detection tests. Finally, this approach is applied to the well-known Knox temporal data set.Le Cam theorem, uniform spacings, cluster detection, temporal cluster, Knox data set,

Spatial cluster detection for socio-economic data

International audienceThis article focuses on spatial cluster detection methods, mainly the scan methods. Weintroduce the scan scatistics and the mathematical concepts they rely on and we discuss aboutthe choice of the underlying model. Finally these methods are applied to two socio-economicdata sets

Characterizing Deep White Matter Hyperintensities in Patients with Symptomatic Isolated Cortical Superficial Siderosis

International audienceBACKGROUND:In patient with cerebral amyloid angiopathy (CAA) presenting with lobar hemorrhage (LH), magnetic resonance imaging (MRI) white matter hyperintensities (WMH) tend to be predominant in posterior regions with the "multiple subcortical spots" WMH pattern as the most frequent topographical WMH pattern. Our aim was to analyze WMH severity and topographical distribution in patients with cortical superficial siderosis (CSS).METHODS:We retrospectively analyzed MRIs from consecutive symptomatic isolated (i.e., without LH) CSS and LH-CAA (with or without associated CSS) patients. We analyzed baseline clinical characteristics including age, history of hypertension, diabetes, hypercholesterolemia, and pre-existing cognitive deficit. The presence of lobar microbleeds (MB) was scored on T2*. FLAIR (fluid-attenuated inversion recovery) WMH severity (using the Fazekas scale) and topographical distribution (using [slightly modified] earlier described WMH patterns) were analyzed and compared between both groups.RESULTS:Twenty CSS and 63 LH-CAA patients were analyzed. Baseline clinical characteristics were similar between both groups, except for hypercholesterolemia less frequently present in the CSS group (P = .026). Lobar MB were significantly less frequently present in the CSS group (P < .01), and CSS was more frequently focal in the CSS group compared with LH-CAA patients with associated CSS (P = .03). Mean Fazekas scale was significantly lower in CSS patients (P = .011). WMH patterns did not differ between both groups, with the multiple subcortical spots pattern as the most frequently observed pattern.CONCLUSIONS:Relative severe WMH scores and similar topographical distribution in CSS patients argue for WMH as a CAA-related feature in these patients with isolated CSS, adding level of evidence that isolated CSS could correspond to early manifestations of CAA

Cerebrospinal Fluid Alzheimer’s Disease Biomarkers in Isolated Supratentorial Cortical Superficial Siderosis

International audienceWe evaluated cerebrospinal fluid amyloid-β 1-40 (Aβ40), amyloid-β 1-42 (Aβ42), total and phosphorylated-tau (t-tau and p-tau) in patients with symptomatic isolated cortical supratentorial superficial siderosis (SS), by prospectively recruiting ten patients with SS in the absence of pre-existing cognitive dysfunction, and comparing biomarkers with lobar hematoma cerebral amyloid angiopathy patients (LH-CAA, n = 13), Alzheimer's disease patients (AD, n = 42), and controls (n = 16). Compared to controls, SS patients showed statistically significant higher t-tau (p = 0.019) and lower Aβ42 (p = 0.0084). Compared to other groups, SS showed statistically significant lower t-tau, p-tau, and Aβ40 compared to AD (p = 0.0063, p = 0.0004, and p = 0022, respectively), and higher p-tau compared to LH-CAA (p = 0.012)

Small obliquely oriented cortical cerebellar infarctions are associated with cardioembolic stroke

International audienceBACKGROUND:A revised classification of cerebellar infarctions (CI) may uncover unrecognized associations with etiologic stroke subtypes. We hypothesized that obliquely oriented small cortical cerebellar infarction (SCCI) representing end zone infarctions on MRI would be associated with cardiac embolism.METHODS:We retrospectively analyzed consecutive stroke patients recruited between January-December 2016 in our center. Analyzed baseline characteristics: sex, age, cardiovascular risk factors, history of stroke or atrial fibrillation (AF). TOAST classification was used for determining stroke subtype. Acute infarction location (anterior/posterior/mixed anterior-posterior circulation), acute uni- or multiterritorial infarction, and acute or chronic CI/SCCI/non-SCCI were assessed by MRI, and vertebrobasilar stenosis/occlusion by vessel imaging. Pre-specified analysis was also performed in patients without known high cardioembolic risk (known AF history or acute multiterritorial infarction).RESULTS:We included 452 patients (CI in 154, isolated SCCI in 55, isolated non-SCCI in 50, and mixed SCCI/non-SCCI in 49). Both SCCI and non-SCCI were associated with AF history (SCCI, p = 0.021; non-SCCI, p = 0.004), additional acute posterior circulation infarction (p < 0.001 both CI-subtypes), multiterritorial infarctions (SCCI, p = 0.003; non-SCCI, p < 0.001) and cardioembolic more frequent than large-artery atherosclerosis origin (p < 0.001 for both CI-subtypes). SCCI was associated with older age (p < 0.001), whereas non-SCCI was associated with stroke history (p = 0.036) and vertebrobasilar stenosis/occlusion (p = 0.002). SCCI were older (p = 0.046) than non-SCCI patients, had less frequently prior stroke (p < 0.001), and more frequent cardioembolic infarction (p = 0.025). In patients without known high cardioembolic risk (n = 348), SCCI was strongly associated with subsequent cardioembolism diagnosis (OR 3.00 [CI 1.58-5.73, p < 0.001]). No such association was present in non-SCCI.CONCLUSIONS:Acute or chronic SCCI are strongly associated with a cardioembolic origin