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ABCB5 encodes a full transporter (ABCB5FL) and a half transporter (ABCB5β), which is unique in the ATP binding cassette (ABC) transporter superfamily. We discuss the roles of both isoforms in undifferentiated slow-cycling cells, multidrug resistance, and tumorigenesis, and their regulation pathways.

Intra-articular (IA) injection of a chondroprotective candidate may delay the osteoarthritis (OA) course, but its rapid absorption into systemic circulation may limit efficacy and produce untoward effects. We compared the pharmacokinetics (PK) of IA rapamycin injected as sustained release in nanoparticles (NPs) versus a free rapamycin suspension in the rat knee compared to an intravenous (IV) free rapamycin shot taken as a reference. Rats received either a single IV injection of free rapamycin (10 µM) or an IA of free or NPs-loaded rapamycin. After sequential exsanguination (15, 30, 60, 180, 360 min, D1, and D7), knee synovial tissue (ST) and cartilage histology were performed. Blood and ST concentrations (LC-MS/MS), PK parameters (area under the curve: AUC; mean residence time: MRT; elimination half-life: T

Background Asthmatics and COPD patients have more severe outcomes with viral infections than people without obstructive disease. Objective To evaluate if obstructive diseases are risk factors for ICU stay and death due to COVID19. Methods We collected data from the electronic medical record from 596 adult patients hospitalized in University hospital of Liege between 18th of March and 17th of April 2020 for SARS-CoV2 infection. We classified patients in three groups according to the underlying respiratory disease, present prior to COVID19 pandemics. Results Among patients requiring hospitalization for COVID19, asthma and COPD accounted for 9.6% and 7.7% respectively. The proportions of asthmatics, COPD and patients without obstructive airway disease hospitalized in ICU were 17.5%, 19.6% and 14% respectively. One third of COPD patients died during hospitalization while only 7.0% of asthmatics and 13.6% of patients without airway obstruction died due to SARS-CoV2. The multivariate analysis showed that asthma, COPD, ICS treatment and OCS treatment were not independent risk factors for ICU admission or death. Male gender (OR:1.9; 95%CI: 1.1 to 3.2) and obesity (OR:8.5; 95%CI: 5.1 to 14.1) were predictors of ICU admission while male gender (OR1.9; 95%CI: 1.1-3.2), older age (OR:1.9; 95%CI: 1.6-2.3), cardiopathy (OR: 1.8; 95%CI: 1.1-3.1) and immunosuppressive diseases (OR: 3.6; 95%CI: 1.5-8.4) were independent predictors of death. Conclusion Asthma and COPD are not risk factors for ICU admission and death related to SARS-CoV2 infection., Highlights What is already known about this topic? Asthmatics and COPD patients are at risk of more severe outcomes with common cold virus infections. Prior studies have suggested that allergic diseases, asthma and COPD may not be risk factors for SARS-CoV-2 infection. What does this article add to our knowledge? The strength of this study is the characterization of obstructive disease according to lung function testing. In our study, asthma, COPD, treatment with ICS or OCS were not risk factors for admission to the ICU or mortality. How does this study impact current management guidelines? Our results confirm the recommendations that patients with obstructive airway disease should not decrease the dose of ICS during SARS-CoV2 infection. Asthma and COPD treatments should be pursued and adapted to ensure optimal control of the lung disease throughout the pandemic, potentially reducing the risk of severe COVID19 disease.

Summary Introduction Intravenous iron infusion may be complicated by extravasation and lead to cutaneous pigmentation. Methods We queried the French pharmacovigilance database to assess the spontaneously reported cases over the 2000–2016 period. Results Fifty-one cases of cutaneous pigmentation related to intravenous iron extravasation were retrieved, none was associated to necrosis. Most of patients were women aged 20 to 49 years old. The pigmentation was mostly a brown coloration, persisting over one month in 19 cases (37.2%) and over 6 months in 9 cases (17.6%). The management of extravasation and pigmentation was heterogeneous and was rarely followed by a decrease of the coloration. Conclusion Cutaneous pigmentation after intravenous iron extravasation can persist over time and create an aesthetic prejudice, particularly in young women. Standardized extravasation and iron-induced pigmentation management procedures appear necessary.

Osteoarthritis (OA) is the most common degenerative joint disease. Rapamycin is a potential candidate for OA treatment by increasing the autophagy process implicated in its physiopathology. To optimize Rapamycin profit and avoid systemic side effects, intra-articular (i.a.) administration appeared helpful. However, Rapamycin's highly hydrophobic nature and low bioavailability made it challenging to develop purpose-made drug delivery systems to overcome these limitations. We developed Rapamycin-loaded nanoparticles (NPs) using poly (lactic-co-glycolic acid) by emulsion/evaporation method. We evaluated these NPs' cytocompatibility towards cartilage (chondrocytes) and synovial membrane cells (synoviocytes) for a potential i.a. administration. The in vitro characterization of Rapamycin-loaded NPs had shown a suitable profile for an i.a. administration. In vitro biocompatibility of NPs was highlighted to 10 µM of Rapamycin for both synoviocytes and chondrocytes, but significant toxicity was observed with higher concentrations. Besides, synoviocytes are more sensitive to Rapamycin-loaded NPs than chondrocytes. Finally, we observed in vitro that an adapted formulated Rapamycin-loaded NPs could be safe at suitable i.a. injection concentrations. The toxic effect of Rapamycin encapsulated in these NPs on both articular cells was dose-dependent. After Rapamycin-loaded NPs i.a. administration, local retention, in situ safety, and systemic release should be evaluated with experimental in vivo models.

Contexte Les effets indesirables a long terme de l’hormonotherapie (HT) d’affirmation de genre sont mal elucides, en raison du manque des etudes de cohorte prospectives. Les declarations aupres des centres de pharmacovigilance representent donc un outil precieux pour detecter les effets indesirables potentiels. Objectif Decrire le profil d’effets indesirables imputables a l’HT chez les personnes transgenres Methode Etude descriptive, retrospective des cas enregistres dans la base de donnees nationale de pharmacovigilance depuis sa creation jusqu’au 27 mai 2020 pour identifier les effets indesirables lies a l’HT d’affirmation de genre. Les cas deja publies ont ete exlus. Resultats Vingt huit cas d’effets indesirables ont ete identifies. Six concernaient les hommes transgenres (21–40 ans) et 22 femmes transgenres (22–68 ans). Chez les hommes transgenres sous traitement par l’enanthate de testosterone, tous les effets indesirables etaient les evenements cardiovasculaires avec une embolie pulmonaire dans 50 % des cas. Chez les femmes transgenres, les anti-androgenes, principalement l’acetate de cyproterone, etaient impliques dans 68 % des cas. Les œstrogenes etaient impliques dans 77 % des cas, principalement en association avec la progestine ou l’acetate de cyproterone. Le meningiome etait le principal effet indesirable, suivi des evenements cardiovasculaires. Conclusion Nos resultats montrent une proportion non negligeable des cas d’evenements cardiovasculaires chez les jeunes hommes transgenres sous l’enanthate de testosterone. Chez les femmes transgenres, les evenements cardiovasculaires representent le deuxieme effet indesirable signale. Les etudes ulterieures sont necessaires pour identifier des facteurs de risque pouvant contribuer a l’individualisation de la strategie therapeutique en particulier chez les sujets jeunes.

Introduction L’hyperhidrose (HH) peut etre d’origine medicamenteuse et devenir invalidante. Apres l’observation au CHRU de Nancy de 2 cas d’HH invalidante chez des patients traites par adalimumab (ADA) sans autre etiologie identifiee, nous avons analyse retrospectivement les cas d’HH enregistres dans la base nationale de pharmacovigilance (BNPV) impliquant les biotherapies (BT) utilisees en dermatologie. Materiel et methodes Une requete a ete effectuee dans la BNPV le 31 mars 2020 en croisant les termes MedDRA « hyperhidrose », « sueurs nocturnes », « sueurs froides », « hypersudation compensatoire », « trouble des glandes sudoripares » et les BT suivantes : anti-TNFα, anti-IL17 (secukinumab, ixekizumab, brodalumab), anti-IL23 (guselkumab, risankizumab), anti-IL1 (anakinra, canakinumab), ustekinumab, dupilumab, rituximab, omalizumab, belimumab, inhibiteurs de check-point (ipilimumab, pembrolizumab, nivolumab, avelumab), cetuximab et interferon-alpha. Nous avons exclu les cas ayant une autre etiologie identifiee et ceux sans bilan etiologique ni evolution renseignes. Les HH au cours de reactions liees a la perfusion (RAP) ont ete analysees a part. Resultats Parmi les 240 notifications d’HH, 82 ont ete exclues et 131 etaient des RAP. L’âge moyen des 27 cas analyses etait de 50 ans, le sexe-ratio F/H a 1,7. Les BT les plus frequemment imputables etaient les anti-TNFα (ADA : n = 13, etanercept : n = 4, infliximab : n = 1) et l’ustekinumab (n = 5) en traitement de rhumatismes inflammatoires chroniques (60 %), psoriasis (22 %) et maladies inflammatoires chroniques de l’intestin (17 %). Le delai de survenue, renseigne dans 16/27 cas (60 %), etait inferieur a 1 mois (n = 2, 7 %), de 1 mois a 1 an (n = 7, 26 %) et de plus d’1 an (n = 7, 26 %). La BT etait arretee dans 15 cas (55 %), avec evolution favorable dans 11 cas. Elle etait poursuivie dans 9 cas (33 %), avec persistance de l’HH dans 7 cas, dont un cas d’HH axillaire traitee par toxine botulique. Un bilan etiologique permettait d’exclure les principales causes d’HH dans 13 cas (48 %). Discussion Hors contexte de RAP, l’HH est rarement induite par une BT utilisee en dermatologie et une autre cause doit etre recherchee en priorite (infectieuse, neoplasique, metabolique ou immunologique). De rares cas sont declares en pharmacovigilance, impliquant notamment les anti-TNFα, BT les plus prescrites. Une sous-notification de cet effet indesirable est tres probable. Dans la litterature, un seul cas d’HH est rapporte avec l’ADA et une possible composante familiale. Le mecanisme physiopathologique n’est pas clairement etabli. En cas d’HH invalidante lors d’une BT anti-TNFα, sans cause identifiee au prealable, un changement de classe therapeutique biologique pourrait etre envisage. Conclusion Devant une HH, il faut evoquer une cause medicamenteuse, dont les BT. Apres evaluation de la balance benefice-risque, l’arret du traitement permet souvent une evolution favorable.

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Introduction Au cours du premier semestre 2019, plusieurs signalements, concernant majoritairement des adolescents et des jeunes adultes domicilies dans la Marne ayant presente des symptomes apres vapotage ont ete declares au CEIP-A de Nancy. Cette etude visait a etudier ce signal. Methode Deux sources d’information ont ete utilisees : – les notifications spontanees recensees entre le 01/01/2018 et le 22/08/2019 ; – une etude observationnelle retrospective menee au CHU de Reims de janvier 2018 a aout 2019 (mots-cles : cannabis, CBD, cannabidiol, cigarette electronique). Resultats Un total de 101 observations ont ete analysees. Un seul profil de consommation : des adolescents et jeunes adultes d’âge moyen de 18 ± 7 ans (valeurs extremes : 12 a 56 ans), plutot de sexe masculin. La majorite des patients (90 %) ont ete pris en charge apres avoir utilise une e-cigarette supposee contenir du CBD qui leur avait ete offerte gratuitement (60 %), par le biais de dons ou de consommations partagees. Un total de 414 signes cliniques a ete identifie apres vapotage, en particulier : effets neurologiques et psychiatriques (72 %) mais aussi digestifs (13 %) et cardiovasculaires (10 %). Les prelevements biologiques de 48 patients ont ete analyses : 27 patients ont presente un depistage negatif, 12 ont ete testes positifs pour le cannabis, 9 pour le paracetamol et 4 pour l’alcool. Un patient a ete teste positif pour XRL11 et l’acadesine. Quatre cannabinoides synthetiques differents ont ete identifies dans cinq e-liquides : 5F-MDMB-PINACA (n = 1), 5F-CUMYL-PINACA (n = 1), XLR-11 (n = 2), 5F-MDMB-PICA (n = 1). Un autre echantillon d’e-liquide contenait du CBD (1 %) + THC. Conclusion Cette etude a mis en evidence une flambee d’effets nocifs supposes lies au vapotage dans une region specifique du nord-est de la France. Cependant, on ne sait toujours pas exactement ce qui causait ces symptomes. En effet, bien que des produits a base de cannabinoides aient ete identifies dans les six e-liquides testes, les depistages toxicologiques restent rares. En raison de ce signal inexplique, depuis septembre 2019, une enquete prospective (enquete Vapotox) est en cours dans le Nord-Est de la France, afin d’identifier, avec confirmation du laboratoire, la cause exacte de ce probleme de sante.

Introduction Depuis 2003 sont commercialisees des specialites de fentanyl d’action rapide (FAR) par voie transmuqueuse buccale (Abstral®, Actiq®, Breakyl®, Effentora® et Recivit®) ou nasale (Instanyl® et Pecfent®). Elles sont indiquees uniquement dans le traitement des acces douloureux paroxystiques chez les patients adultes recevant deja un traitement de fond opioide pour des douleurs chroniques d’origine cancereuse. Leur pharmacocinetique -forte absorption, action rapide- majore les risques d’abus/dependance et de surdoses [1] . Face au possible mesusage des FAR, l’ANSM a mis en place un suivi national realise par les 2 reseaux nationaux de pharmacovigilance et d’addictovigilance, dont nous presentons ici les donnees actualisees. Methodes Analyse des cas cliniques rapportes aux reseaux de pharmacosurveillance et des donnees des enquetes pharmaco-epidemiologiques d’addictovigilance. La periode d’etude s’etend du 01.01.2016 au 30.06.2019 pour Abstral®, Actiq®, Effentora®, Instanyl® et Pecfent® (suivies depuis 2009) et d’avril 2013 et juin 2014 au 30.06.2019 pour les specialites plus recemment commercialisees (Breakyl® et Recivit®). Resultats Au total, 328 cas signales aupres des reseaux de pharmacovigilance et d’addictovigilance ont ete retenus et analyses. L’analyse montre un non-respect des recommandations, persistant depuis le debut du suivi : indications hors AMM (56 %), absence ou insuffisance de traitement de fond (31 %), frequence de prises superieure a 4 par jour (au-dela de laquelle le risque de surdosage opioide est majeur) [41 %]. Le nombre de surdoses a plus que double entre 2015 et 2019 (13 % entre 2016 et 2019 vs 5 % entre 2013 et 2015) ( Fig. 1 ). Parmi les 328 cas signales entre 2016 et 2019, 47 % des patients presentent un abus et/ou une dependance de FAR (vs 32 % entre 2013 et 2015). 70 % de ces cas concernent des patients avec des douleurs hors cancer, principalement rhumatologiques ou neuropathiques. Pour pres de 30 % des cas d’abus/dependance, le traitement de fond est inexistant ou insuffisant. Les femmes comme les hommes sont concernes et meme si le comprime avec applicateur buccal et les sprays nasaux sont plus frequemment rapportes, toutes les specialites de FAR font l’objet de mesusages et d’abus. Discussion Un mesusage tres important en termes de non-respect de l’AMM persiste [2] . L’addictovigilance pointe, de plus, sur une problematique d’abus/dependance en augmentation chez des patients souffrant majoritairement de douleurs chroniques non cancereuses pour lesquelles, de surcroit, le FTM est inefficace. A la lumiere de ces informations, il apparait necessaire que les prescripteurs soient informes des consequences d’une prescription de FTM non adaptee, et sensibilises a l’importance d’une prescription aux seuls patients relevant de l’AMM, en association avec un traitement de fond opioide stabilise.

Acetaminophen (paracetamol), the highest over-the-counter (OTC) selling drug in France, is also the first cause of acute hepatic failure. We aimed to assess the good use and the knowledge of acetaminophen in a setting of urban self-medicated patients. We conducted a prospective observational study in randomly selected community pharmacies of Metz (France) agglomeration. Patients coming to buy OTC acetaminophen for themselves or their family had to answer to an anonymous autoquestionnaire. Responses were individually and concomitantly analyzed through 3 scores: good use, knowledge and overdosage. Twenty-four community pharmacies participated and 302 patients were interviewed by mean of a dedicated questionnaire. Most of patients (84.4%) could be considered as "good users" and independent factors of good use were (i) a good knowledge of acetaminophen (OR=5.3; P

Resume L’incidence des reactions anaphylactiques a un curare est croissante. Sa frequence varie selon les pays. En France, l’incidence de ces reactions est evaluee a 184,0 [139,3–229,7]/million d’anesthesies, avec une mortalite evaluee a 4,4 %. Les substances les plus frequemment en cause sont la succinylcholine et le rocuronium. Des facteurs environnementaux semblent responsables de l’apparition d’une sensibilisation en l’absence d’une exposition prealable. La pholcodine presente dans certains sirops antitussifs pourrait etre impliquee dans cette sensibilisation. Une etude cas-temoins (ALPHO) debute en France en 2014. Elle a pour objectif de rechercher un lien entre exposition a la pholcodine et survenue d’un choc anaphylactique a un curare. Tous les anesthesistes sont invites a y participer en declarant leurs cas a l’aide d’un numero vert (0 800 871 943).

Introduction Actuellement, differentes options sont disponibles pour le traitement des lesions focales du cartilage mais restent dans la majorite des cas insatisfaisantes a long terme. C’est pourquoi la recherche s’oriente vers une nouvelle strategie basee sur l’impression 3D qui s’avere une veritable revolution en medecine regenerative pour faconner des tissus et des organes bio-imprimes a partir de cellules du patient. Notre objectif a ete de developper une nouvelle strategie de traitement des lesions focales cartilagineuses par ingenierie tissulaire a l’aide d’un procede d’impression 3D par bio-extrusion. Materiels et methodes Les substituts cartilagineux ont ete produits couche par couche a l’aide d’un procede d’impression 3D par bio-extrusion a partir d’une bio-encre a base d’alginate et de cellules souches mesenchymateuses (CSMs) issues de moelle osseuse humaine. Deux densites cellulaires ont ete testees : 1 et 2 millions de cellules/mL de bio-encre. Les substituts ont ete cultives durant 28 jours dans un milieu contenant de l’ITS (condition n’induisant pas la chondrogenese) supplemente ou non avec du TGF-s1 (10 ng/mL) pour induire la chondrogenese. L’expression des genes a ete analysee afin de caracteriser la differenciation chondrogenique (collagene de type 2 [COL2A1], agrecane [ACAN], SOX9, COMP) ; la differenciation fibrotique (versican [VCAN]) ; et la derive hypertrophique ou osteogenique (collagene de type 10 [COL10A1], RUNX2, phosphatase alcaline [ALP], osteocalcine [BGLAP]). La qualite de la matrice extracellulaire synthetisee a ete evaluee par histologie et immunohistochimie. Resultats Notre procede d’impression 3D par bio-extrusion nous a permis d’obtenir des substituts fonctionnels. Le facteur de croissance TGF-s1 a induit une importante surexpression des genes COL2A1, COL10A1, ACAN, SOX9 tandis que les marqueurs fibrotiques (VCAN) et osteogeniques (BGLAP, RUNX2) etaient faiblement surexprimes. La meilleure induction des genes chondrogeniques, COL2A1, ACAN, and SOX9, a ete observee avec la densite cellulaire de 1 million par mL. En histologie, contrairement a la condition ITS, une synthese matricielle riche en collagene de type II et de proteoglycannes a ete visualisee et d’autant plus avec la densite cellulaire d’un million/ml au sein des substituts produits par impression 3D traites par le TGF-s1. Les bases de production de substituts cartilagineux par un procede d’impression 3D par bio-extrusion ont pu ainsi etre etablies. Conclusion Cette technique additive s’avere une strategie tres prometteuse pour la medecine regeneratrice personnalisee des tissus stratifies tel que le cartilage. Ces travaux sont finances par la Direction Generale des Armees (No ANR-16-ASTR-0021), la fondation de l’avenir (No AP-RM-16-042), l’Universite de Lorraine et la Region Grand-Est.

Knee osteoarthritis deals with the loss of cartilaginous substances. Biomaterial implant using mesenchymal stromal cells was usually used to perform cartilage regeneration. The bio-integration and biofunctionality assessments of the used biomaterial implant on the injury sites require the longitudinal monitoring of the cartilage over times. The aim of this present study was to develop a characterization framework of the cartilage in knee osteoarthritis especially its morphological properties and contact areas derived from high-resolution magnetic resonance imaging (MRI) technique. Manual segmentation procedure was applied for extracting cartilage from surrounding biological tissues. Geometrical computing techniques were applied to calculate characterization properties of the rat cartilage. As clinical case study, curvature, thickness, volume and relative contact area properties of the rat cartilage in knee osteoarthritis were quantified on each knee full model and/or its region of interest (ROI) models. We found that the cartilage thickness and volume of three cartilage compartments decrease at the beginning (from 7 to 28 days). Tibial cartilage thickness increases at the end of the osteoarthritis process (from 28 to 56 days). This is due to the fact that the cartilage swelling occurred during osteoarthritis process. These findings were confirmed when observing cartilage curvature; we noted that there is an increasing curvature due to the incurvation effect of the cartilage during osteoarthritis process. The relative contact areas of three cartilage compartments increase slightly. However, the difference between control knees and osteoarthritis knees is significant. ROIs analyses of the thickness and curvature properties were also reported on the femoral and tibial cartilages.

Resume Objectifs Recenser et caracteriser les observations de sarcoidose associees a la prise d’anti-TNF colligees dans la base nationale de Pharmacovigilance et dans la litterature Resultats Sept observations ont ete notifiees dans la base nationale de Pharmacovigilance et 39 cas (37 supplementaires) ont ete rapportes a l’echelon international. Anticorps monoclonaux (infliximab et adalimumab) et proteine de fusion (etanercept) sont egalement impliques. Les sarcoidoses ont toutes ete confirmees histologiquement et se sont declarees majoritairement au cours des polyarthrites rhumatoides (22) et des spondylarthropathies (16). Conclusion L’absence de biais protopathique suggere que ces sarcoidoses paradoxales lors des traitements par anti-TNF sont un effet de classe, a l’instar des psoriasis, uveites, et les maladies chroniques inflammatoires de l’intestin (MICI) declarees dans des conditions similaires. Leur pathogenie reste a elucider.

Objectives The objective is to evaluate the use of the Appropriateness Evaluation Protocol (AEP) as a screening tool for determining the causes of the non-justified days to help hospitals to decrease the length of stay while preserving the quality of care. Methods Three successive cross-sectional surveys were conducted from 2003 till 2005, in 23 Belgian hospitals. During this period, 10 921 days were audited by means of the AEP. This study is focused on adult acute non-intensive care units. The appropriateness of each day of the sample was assessed, and for those considered as inappropriate, the reasons explaining the prolongation of the stay were investigated. Results The proportion of inappropriate days was 24.61%. There is a high variability across specialties and hospitals. Regarding inappropriate days, the analysis of causes of prolongation, globally, by bed index or by hospital, indicated clearly internal and external factors that lengthen stays. The most frequent reasons are waits for an examination (22%) and the lack of extra-hospital structures (31%). Conclusions The use of AEP as a tool of internal audit to measure the proportion of non-justified days and their causes turns out to be possible and the obtained results has provided some accurate and useful information for the participating, and allowed them to take concrete decisions which lead to shrinking of the length of hospital stay.

Introduction Au CHRU de Nancy, la coordination entre les reseaux d’addictovigilance, toxicovigilance et pharmacovigilance permet a chacune de ces vigilances « produits » de porter rapidement un cas a la connaissance de la vigilance concernee. Methode Le CAPTV-Est extrait quotidiennement de la base nationale des cas d’intoxication, les dossiers des territoires d’intervention, regions Grand-Est et Bourgogne-Franche-Comte, concernant l’utilisation de drogue, un contexte de dependance, de soumission chimique et les dossiers fleches addictovigilance au cours de la consultation. Apres un premier suivi, il les transmet au CEIP-A. Par ailleurs, l’ensemble des cas regionaux concernant le medicament humain est communique au CRPV par le CAPTV ; il existe un flux depuis le CRPV vers le CEIP-A. Les cas ainsi recueillis in fine par le CEIP-A sur l’annee 2017 ont ete analyses selon les criteres suivants : âge et genre du sujet expose, circonstances de l’exposition, substances impliquees, presence de symptomes et gravite du cas. Resultats En 2017, 168 cas ont ete analyses par le CEIP-A. Les personnes exposees sont majoritairement des hommes (73 %). Les classes d’âge les plus representees sont les adultes jeunes (61 %) et les adolescents (21 %). Les deux principales circonstances d’exposition sont « toxicomanie et addiction » (50 %) et « mesusage » (26 %). Les substances psychoactives (SPA) impliquees sont des medicaments dans 49 % des cas, des SPA illicites dans 42 % et une association des deux dans 9 % des cas. Les medicaments les plus consommes sont les benzodiazepines (23 %), les antalgiques palier 2 (18 %) et les traitements de substitution aux opiaces (13 %). Les deux SPA illicites les plus retrouvees sont le cannabis (42 %) et la cocaine (26 %) ; 82 % des personnes exposees ont presente des symptomes et 17 % des cas ont ete codes « graves » par le CEIP-A. Discussion La collaboration entre les acteurs des vigilances « produits » permet au CEIP-A de recueillir, de maniere reguliere et continue, des informations utiles au reseau d’addictovigilance, qui ne seraient probablement pas spontanement remontees au centre d’addictovigilance par les structures ou usagers. Ces echanges reguliers entre les vigilances « produits » constituent un apport significatif important au dispositif d’addictovigilance, complementaire aux notifications spontanees.

Introduction L’immunotherapie avec l’utilisation des inhibiteurs du point de controle immunitaire (ICI) dans le traitement du cancer est recente. Elle est utilisee dans les cancers de sombre pronostic comme le melanome ou le cancer bronchique non a petites cellules mais s’accompagne d’effets indesirables de nature immunologique, dont de frequents effets endocriniens. Cette etude retrospective a pour but de decrire les thyroidites secondaires a l’utilisation des ICI commercialises actuellement en France et declarees au reseau francais des centres regionaux de pharmacovigilance. Materiel et methodes Les thyroidites survenues au decours de l’utilisation du nivolumab, du pembrolizumab et/ou de l’ipilimumab, enregistrees dans la Base nationale de pharmacovigilance avant le 30 avril 2017 ont ete revues par un endocrinologue et un pharmacologue. Resultats Nous avons retenu 110 cas de thyroidite concernant 52 femmes et 58 hommes. La plupart des patients (44,2 %) etaient asymptomatiques. Le mode de revelation etait equilibre, 55 patients etant en hypothyroidie et 55 en etat de thyrotoxicose, aucun n’ayant d’orbitopathie. Les recherches d’anticorps etaient peu informatives avec seulement 16 % de positivite. L’echographie etait positive dans 19 % des cas. Une supplementation par levothyroxine etait instauree chez 57 % des patients, avec arret possible chez 19 % d’entre eux. Le traitement par immunotherapie a pu etre poursuivi dans la grande majorite des cas. Conclusion Les thyroidites sont le plus souvent asymptomatiques et s’accompagnent d’un deficit hormonal necessitant une supplementation. Il est necessaire de realiser une prise en charge multidisciplinaire du patient avec des controles precoces et reguliers.

Ligaments are strong bands of connective tissue which display high resistance to tension, allowing joint stability. However, sudden twisting motion and excessive stretching are causes of sprains. Medical managements involve initial symptomatic treatment and secondary rehabilitation regimen, without beneficial effect regarding the mechanical properties of the tissue. In fact, ligaments never recover their initial resistance to load tension. In this article, we reviewed the macroscopic and biochemical characteristics of normal and injured ligaments, with a special emphasis on the role of cytokines and growth factors during the healing process, and on the beneficial effect of a moderate exercise on the scar formation. Indeed, recent data highlighted: (1) the role of both IL-1 beta and bFGF during the inflammatory state to promote fibroblast and endothelial cell migration into the wound; (2) VEGF helped capillary growth during the proliferative state; (3) whereas TGF beta expression resulted in the deposition of a disorganised fibrotic extracellular matrix. In contrast, mechanical stimulation during a moderate exercise inhibited TGF beta expression, improving the deposition of specific collagen network and the overall ligament healing process.

International audience

Objective : to evaluate the ability of T2 mapping on an 8.5T imager to characterize morphologically and quantitatively spontaneous repair of rat patellar cartilage following full thickness defect. Methods : Patellar cartilage defects were created in 24 rats knees on D0. Eight rats per time-point were killed on D20, D40 and D60 after surgery. T2 maps of repair tissue in patellar defects were obtained from eight different axial spin echo images on an 8.5T imager. Global, superficial and deep T2 values were evaluated in spontaneous repair tissues (3×8 right patellae) vs the opposite patellae (3×8 left patellae) of the same animals. MR data were compared with macroscopic and histological studies. Results : T2 map was able to identify morphologically three types of repair tissue observed macroscopically and histologically: ‘ total ', ‘ partial ' and ‘ hypertrophic ' repair tissue. ‘ Total ' and ‘ partial ' repair tissues were characterized by global T2 values almost similar to controls, whereas ‘hypertrophic' repair tissues were characterized by T2 global values higher than controls. Zonal variation between superficial and deep T2 values observed in controls was not depicted in repair tissue before D60. Conclusion : T2 map is able to characterize quantitatively and qualitatively rat patellar cartilage repair, and thus can be promoted, as a non invasive technique, in clinical longitudinal studies of articular cartilage repair.

Introduction Paracetamol, the highest over-the-counter (OTC) selling drug in France, has become the first cause of acute hepatic failure [1] . Patient's knowledge of paracetamol has to date only been assessed in hospitalized patients. We aimed to assess good use and knowledge of paracetamol in patients in a realistic setting of self-medication in our region. Methods We conducted a prospective observational study in randomly selected community pharmacies of Metz (France) agglomeration. Patients coming to buy OTC paracetamol for themselves or their family had to answer to an anonymous auto-questionnaire. After being asked about gender, age, weight, parenthood and chronic disease, the patient had to answer to 14 items about paracetamol indications, recommended maximal dose per intake and maximal daily dose, delay between 2 doses, consequences of overdosage and alcohol intake, and the need to adapt dosage to the body weight. The patient also had to identify drugs containing paracetamol among 6 usual drugs; and finally to tell how he gets information and circumstances that can lead him to stop self-medication and visit his general practitioner. Responses were individually and concomitantly analyzed through 3 scores: good use (5 points; good user if > 3), overdosage (4 points; positive if ≤ 3) and knowledge (9 points; good knowledge if > 6). Univariate and multivariate analysis were performed with SAS, version 9.3 (SAS Institute, Cary, NC). Results Twenty-four community pharmacies participated and 302 individual questionnaires were collected. Most of patients (84.4%) could be considered as “good users”. Independent factors of good use were a good knowledge of paracetamol (OR = 5.3; p Conclusion Patients should be better informed about hepatotoxicity of paracetamol to warrant a better safety of its consumption by self-medication. Pharmacists and physicians have to remind patients the risk factors of unintentional overdose and liver toxicity and not hesitate to check if the patient may be at risk for overdosage. Package leaflets should also to be more informative.

We report the assessment of motor and sensory behaviors using an electrophysiologic and an histologic approach, in a rat model of cisplatin peripheral neuropathy. Cisplatin was injected intraperitoneally one (3 mg/ kg), two (2 mg/kg), or three (1 mg/kg) times a week up to a cumulative dose of 15 or 20 mg/kg. With regard to nociceptive signs, we observed mechanical and thermal (cold stimuli) hyperalgesia and allodynia associated with minor motor disorders for the 3 mg/kg dose. Peripheral nerve conduction velocities were decreased in the cisplatin-(3 mg/kg) treated group. In addition, the histologic approach revealed that large axons were more frequently affected than the small ones, and nonmyelinated axons were unaffected. However, even in the most severe cases, myelin sheaths remained within normal limits. This animal model of nociceptive neuropathy would be suitable to study the pathophysiologic mechanisms of neuropathic pain and to test potential neuroprotective agents.

RESUME Les formes familiales de chondrocalcinoses articulaires sont une maladie chronique caracterisee par des acces articulaires aigus, la presence de cristaux de pyrophosphate de calcium dihydrate dans le liquide synovial, le cartilage et les tissus peri-articulaires et, sur les radiographies, une incrustation calcique des cartilages et fibrocartilages de l’organisme. Nous avons etudie une famille alsacienne dans laquelle la transmission est autosomique dominante. L’analyse genetique entreprise a permis de montrer, comme dans les familles anglaises et argentines, une liaison avec le bras court du chromosome 5p, suggerant qu’une anomalie d’un gene situe dans cette region pourrait etre impliquee dans ces formes familiales.

This work describes a new animal model of neuropathic pain produced by the single intraperitoneal administration of Taxol (32 mg/kg) to male Sprague-Dawley rats. During the course of the experiment, the clinical status of the rats remained satisfactory and motor function was not altered. A number of classical behavioural tests of nociception as well as histological and electrophysiological investigations were performed. Taxol administration produced an important and rapidly developing mechanical hyperalgesia, a thermal hypoalgesia but no mechanical or thermal allodynia. Degenerative changes were observed in the sciatic nerve, the nerve fibres in the paw subcutaneous tissue and in the lumbar spinal cord. When Taxol or vehicle (a mix of Cremophor and ethanol) were repeatedly injected once a week for 5 weeks, similar nociceptive disorders were observed in addition to a decrease in peripheral nerve conduction velocity. The selective dysfunction of high-diameter myelinated fibres observed after one single administration of Taxol (32 mg/kg) may be attributable to paclitaxel-induced neuropathy, however other mechanisms causing neurochemical dysfunction must also be involved.

Resume Nous rapportons le cas d’un homme de 80 ans, traite par levofloxacine pour un episode de surinfection bronchique, qui a developpe des ruptures tendineuses multiples, d’evolution favorable en neuf mois. La presence de facteurs de risque tels qu’un âge avance, une insuffisance respiratoire chronique et une corticotherapie par voie nasale semblent avoir favorise cet effet indesirable.

L’ingenierie tissulaire du cartilage vise a produire un implant cartilagineux similaire au tissu natif a partir de biomateriaux colonises par des cellules. Les cellules souches mesenchymateuses (CSMs) semblent etre de meilleures candidates que les chondrocytes autologues en raison de leur facilite d’acces, de leurs capacites d’expansion in vitro, et de differenciation. Differentes sources de CSMs sont disponibles la moelle osseuse, le tissu adipeux, la gelee de Wharton ou la membrane synoviale. L’objectif de notre etude etait d’etudier les capacites de differenciation chondrogenique des CSMs issues de la membrane synoviale humaine (CSMs MS) pour la production d’un implant cartilagineux en comparaison avec les CSMs issues de la moelle osseuse humaine (CSMs MO). Lors des phases d’expansion, les expressions des marqueurs de surface des CSMs MS et des CSMs MO ont ete etudiees par cytometrie en flux. Ensuite, les CSMs MS et CSMs MO ont ete ensemencees individuellement dans des biomateriaux a base de collagene et cultivees pendant 28 jours dans des milieux enrichis en facteurs de croissance (TGF-B1 et ou BMP-2). L’activite mitochondriale, le taux d’expression des genes d’interet du cartilage, des genes osteogeniques et fibrotiques, ainsi que la qualite de la matrice synthetisee ont ete evalues dans les implants cartilagineux obtenus. Les deux types cellulaires presentaient un pourcentage de cellules positives CD73 superieur a 95 %. En revanche, des differences ont ete observees pour l’expression du marqueur CD90 (55 % pour les CSMs MS contre 23 % pour les CSMs MO) et du marqueur CD105 (superieur a 95 % pour les CSMs MO avec une baisse a 70 % pour les CSMs MS). Au sein des implants cartilagineux, les CSMs MS ont fait preuve d’une activite mitochondriale similaire a celle des CSMs MO. Les conditions TGF-B1 seul et TGF-B1 + BMP-2 ont permis une differenciation chondrogenique des CSMs MS et des CSMs MO. L’expression des genes d’interet du cartilage (COL2A1, SOX 9, ACAN) a ete augmentee et etait similaire entre les deux types cellulaires etudies. En revanche, l’expression de certains genes hypertrophiques et ou osteogeniques etait diminuee pour les CSMs MS (COL1A1, COL10A1, RUNX2). La quantite de glycosaminoglycannes sulfates synthetises etait identique entre les types cellulaires. La matrice extracellulaire synthetisee au sein des implants etait riche en proteoglycannes et en collagene de type 2 et aucune derive osteogenique n’a ete observee. Les CSMs MS representent donc une source cellulaire alternative aux potentialites chondrogeniques moins propices a la differenciation terminale osseuse par rapport aux CSMs MO.

As zymosan-induced arthritis in rats combines dual activation of early prostaglandindependent processes (edema, fever, pain) and IL-1 related effects on cartilage metabolism, we compared the respective influences of indomethacin (IMT) and dexamethasone (DEX) on its course. Different parameters were assessed: knee swelling, febrile response, loss of activity, cartilage metabolism and histology. DEX improved all these parameters, while IMT exerted only light beneficial effects on fever and knee swelling without obvious beneficial influence on cartilage metabolism and histological lesions. These results suggest that anti-inflammatory activities of DEX and IMT are due to interferences with different pathways during zymosan-induced arthritis in rats.

Resolution of racemic tiaprofenic acid (TA) has been performed using immobilized human serum albumin as the stationary phase. The eluent was phosphate buffer—acetonitrile—n-octanoic acid (90:10:0.015, v/v). Detection was achieved at 305 nm. The pharmacokinetics of the enantiomers were studied following oral administration into humans and after subcutaneous injection in rats. Plasma concentrations of (+)-TA were much greater than those of (−)-TA. For the rat, the pharmacokinetic parameters between (−)-TA and (+)-TA were all statistically different (p

International audience; The systemic effects of human recombinant Interleukin-1 beta (HrIL-1 beta) on hindpaw edema were determined in arthritis induced by human native type II collagen (CII) with muramyl dipeptide (MDP) both injected on day 0. Daily treatment with HrIL-1 beta (0.2 microgram sc) pretreatment, from D-1 (the day before MDP and CII were injected) to D3 significantly delayed the secondary inflammation in the uninjected left hindpaw, whereas the same treatment from D6 to D10 at the end of the "primary" inflammation, enhanced the volume of the left hindpaw. Treatment from D13 to D17 did not affect the "secondary" edema in the left hindpaw. Thus, HrIL 1 beta administration produces pro- or anti-inflammatory effects on a developing polyarthritis depending on when treatment is started and is most effective as an anti-inflammatory molecule when started at the peak of the the inflammatory reaction, as previously described. In view of these early findings, we have compared the effect of adding HrIL-1 beta along with MDP in the sensitization procedure on the time-course of CII-induced arthritis. No adjuvant effect of HrIL-1 beta was observed. On the contrary, HrIL-1 beta significantly decreased the signs of inflammation in the injected hindpaw during the secondary inflammation. In addition, the immune response to type II collagen was less in the group receiving HrIL-1 beta, maybe because of nonspecific increase of antigen clearance. On the other hand, the MDP sensitization procedure enhanced the incidence of CII arthritis and significantly worsened the clinical parameters in both primary and secondary inflammations.

World Congress of the Osteoarthritis-Research-Society-International (OARSI), Paris, FRANCE, APR 24-27, 2014; International audience; no abstract

The binding of the non-steroidal anti-inflammatory drug indomethacin to proteins in human cerebrospinal fluid (CSF), drawn during lumbar puncture from 10 patients affected by lumbosciatica, was measured by equilibrium dialysis and spectrofluorimetry. Similar binding studies on human serum albumin solutions (0.5 and 1 g/L) were performed using the same techniques. The mean binding percentage of indomethacin determined by equilibrium dialysis was 40%. The results obtained by both techniques allowed us to conclude that the binding of indomethacin in CSF was essentially due to albumin.

Serum hyaluronic acid (HA) may provide a good marker for the severity of joint disease in the rat since a positive correlation was observed in experimental models of arthritis. However, little is known about its physiological variation in rats. In the present work, we do not find any circadian rhythm of HA in healthy Sprague-Dawley rats in contrast to that observed in humans, whose serum levels vary during daytime. Furthermore, the influence of blood sampling conditions on HA concentrations was evaluated in conscious animals and by using different anesthetics. The greater reproducibility for the assay of HA is observed with the intracardiac puncture under ether inhalation. Blood sample collection in the absence of anesthesia leads to a significant increase in serum levels of HA, which could be attributed partly to enhanced joint movements generated by psychological stress.