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Introduction Interleukin 17 is a proinflammatory cytokine considered to play a significant role in the immunopathogenesis of many chronic immune-mediated disorders. Interleukin 17 inhibitors provide an excellent treatment option for patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis. However, Interleukin 17 inhibitors have been suspected of worsening or triggering new-onset inflammatory bowel disease. Areas covered A literature search was conducted until March 2021 to investigate reporting prevalence, and characteristics of all gastroenterological adverse events in patients treated with Interleukin 17 inhibitors. One hundred and six clinical randomized trials were included, involving 40,053 patients. Inflammatory bowel disease cases were reported in 0.4% of patients exposed to Interleukin 17 inhibitors. The most frequent other gastrointestinal adverse events were diarrhea (2.5%), nausea or vomiting (0.7%), and gastroenteritis (0.2%). Sixty-one uncontrolled or retrospective studies were included, involving 16,791 patients. Sixty (0.36%) inflammatory bowel disease cases were reported, 0.6% of patients reported other gastrointestinal adverse events. Expert opinion Interleukin 17 inhibitors are safe and effective in the treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis. Low incidence rate of developing new-onset inflammatory bowel disease or exacerbating preexisting inflammatory bowel disease with anti-IL-17 agents has been reported. Clinicians should be aware of the possibility of these concerns when considering this therapy.

Aims: Baclofen is widely used for spastic disorders, and most recently for addictive disorders. The first signals of baclofen abuse occurred in the last decade. This study aims to assess the motives, diversion sources and routes of administration associated with the non-medical use of baclofen and examine health problems related to the non-medical use of baclofen. Methods: Spontaneous reports of baclofen abuse reported to the addictovigilance center of East France were analyzed. A literature search was simultaneously conducted using PubMed®, Web of Sciences®, and Google Scholar® databases. Both searches were performed in February 2021 without a time limit. Results: Forty-six cases were analysed (33-from the literature review and 13-from addictovigilance base). Baclofen’s non-medical use mainly affected male subjects with addictive history, but cases of primary abuse in subjects without any substance abuse history were also observed. Euphoria search was the most common reason for misuse. Route of administration included oral, snorting and sublingual use. Physicians were a common source for misused baclofen, but cases involving illegal sources were also observed. Most of the patients misusing baclofen presented serious complications, mainly represented by neurological and respiratory disturbances. Physical and psychological dependence to baclofen was observed in three persons. Conclusion: Although baclofen abuse remains relatively infrequent or (most likely) underestimated, this study helped to confirm the intrinsic abuse potential of baclofen and make visible the baclofen-abuse-related health harms. Careful consideration and benefit-risk analysis should be employed when prescribing baclofen, and emergency departments should be aware of baclofen dangers in abuse situations.

International audience; Background: 3D printing has become a promising tool for cartilage engineering, combining 3D deposition of cells seeded in supporting biomaterials. Objective: Our goal was to evaluate the chondrogenic properties of three different bioinks, seeded with human bone marrow mesenchymal stem cells (bMSCs). Methods: The three different tested bioinks are seeded with 2 × 106 cells/mL bMSCs. The bioink#1 is composed of gelatin, fibrinogen, and very low viscosity alginate. The bioink#2 has the same composition, excepted for the alginate that is a low viscosity one. The bioink#3 is manufactured by CELLINK®. The cartilaginous substitutes were cultivated for 28 days in the presence of ITS vs TGF-ß1. The extracellular matrix synthesis is evaluated at D28 by histology (Hematoxylin-Eosin-Saffron & Alcian Blue) and immunostaining (type II collagen). Results: The bioink#1 better promoted type II collagen synthesis, although the three bioink were equipotent in terms of proteoglycan content. Despite its universal characteristics, the bioink#3 failed to encourage the hyaline-like matrix synthesis. Conclusion: The bioink#1 containing gelatin, fibrinogen, and very low viscosity seems to be the fittest of the three bio-inks to obtain a cartilaginous substitute presenting a remarkable matrix synthesis. This study confirms the importance of the choice of bioink for cartilage engineering.

Worldwide, the consumption of dietary supplements for the enhancement of sexual performance is common. Consumers are generally fond of these products because they often want to avoid drugs, preferring "natural" than "chemical" solutions. This is challenging, as many of these supplements labelled "herbal" or "natural" are actually adulterated with drugs, mainly phosphodiesterase-5 inhibitors. This phenomenon is facilitated by fewer demanding regulations for marketing supplements. Thus, consumers may be widely exposed to serious adverse events, such as acute liver injury, kidney failure, pulmonary embolism, stroke or even death. We aim to warn physicians about this issue. This multidisciplinary review simultaneously deals with clinical consequences of this phenomenon, analytical toxicology, and regulation. Indeed, after outlining this worldwide issue and highlighting that a drug-adulterated dietary supplement is actually a falsified drug, we discuss its main contributing factors. Then, we describe some examples of adverse events of which a case of sildenafil-tadalafil-induced ischaemic stroke that benefited medical care in our hospital. Furthermore, we present some means to avoid adulteration and discuss their limitations that may be explained by the heterogeneity of the regulation of dietary supplements between countries. Doing so, we point out the requirement of a global harmonization of this regulation for an efficient eradication of this public health threat. Meanwhile, dietary supplements should be considered adulterated until proven otherwise. Thus, we encourage physicians to investigate these products in the drug histories of their patients, especially when clinical conditions cannot be explained by classical aetiologies.

Cancer develops resistance to treatments through many mechanisms. Single-cell analyses reveal the intratumor heterogeneity and dynamic relationships between cancer cell subpopulations. These analyses also highlight that various mechanisms of resistance may coexist in a given tumor. Studies have unraveled how the microenvironment affects tumor response to treatments and how cancer cells may adapt to these treatments. Though challenging, individualized treatment based on the molecular characterization of the tumor should become the new standard of care. In the meantime, the success rate of clinical trials in oncology remains dramatically low. There is a need to do better and improve the predictability of preclinical models. This requires innovative changes in ex vivo models and the culture system currently being used. An innovative ligand design is also urgently needed. The limited arsenal of medicinal chemistry reactions and the biases of scaffold selection favor structurally similar compounds with linear shapes at the expense of disc and spherical shapes, which leave a large chemical shape space untouched. In this regard, venoms have received increasing interest as a wellspring for drug candidates. Overall, the characterization of tumor heterogeneity has contributed to advancing our understanding of the mechanisms that underlie cancer resistance to treatments. Targeting these mechanisms will require setting key milestones to significantly improve the translatability of preclinical studies to the clinic with the hope of increasing the success rate of clinical trials.

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.

International audience

Background: Liver toxicity during immune checkpoint inhibitor treatment is mostly due to immune mediated hepatitis. Viral hepatitis, as well as auto-immune or metabolic hepatitis, are considered as exclusion criteria for ICI induced immune hepatitis diagnosis. However, considering the high prevalence of viral hepatitis B infection and the increasing prescription of immune checkpoint inhibitors, their use in patients with HBV chronic viral infection may be common, even more if patients are treated for hepatocellular carcinoma. Few clinical studies directly deal with the risk of HBV reactivation during ICI therapy and real-life data is currently based on five reported cases of HBV reactivation, one with fatal outcome. In this review, we summarize the current available clinical information about HBV reactivation risk during ICI treatment, its hypothetic mechanism, and propose practical recommendations about verifying and monitoring HBV status throughout the treatment.

Resume Objectif L’objectif de cette etude etait de realiser un etat des lieux des usages, mesusages et des cas d’abus/dependance avec les formes non injectables de fentanyl (forme de fentanyl transdermique et formes de fentanyl transmuqueuses) en France. Methode La consommation problematique de la forme de fentanyl transdermique et des formes de fentanyl transmuqueuses a ete evaluee en utilisant une approche combinant plusieurs sources d’information : (i) notifications spontanees (NotS) recensees sur 6 ans (2010–2015) pour la forme transdermique et sur 3 ans (2013–2015) pour les formes transmuqueuses rapportees aux reseaux de pharmacosurveillance et (ii) donnees des enquetes specifiques du reseau francais d’addictovigilance recensees sur 6 ans (2010–2015). Resultats Au total, 147 NotS ont ete recensees pour la forme de fentanyl transdermique et 109 NotS pour les formes de fentanyl transmuqueuses. Les profils mis en evidence dans les cas d’addictovigilance different en fonction de la forme galenique. Pour la forme de fentanyl transdermique, 2 profils : 1/recherche d’effets antalgiques (74 %) : femmes (61 %), âge median 47 ans, antecedents d’abus et/ou psychiatriques (46 %), traitees pour des douleurs chroniques d’origine non cancereuse (93 %), 2/recherche d’effets psychiques positifs autres qu’antalgiques (26 %) : hommes (82 %), âge median 32 ans, antecedents addictifs et/ou psychiatriques (87 %), obtention illegale (60 %). Pour les formes de fentanyl transmuqueuses, 1 seul profil : femmes (52 %), âge median 48 ans, antecedents d’abus (24 %) et psychiatriques (28 %), indications hors autorisation de mise sur le marche (AMM) [72 %] (indication hors cancer et/ou patients sans traitement de fond). Le mesusage des formes de fentanyl transmuqueuses comporte un risque eleve d’effets indesirables : ceux deja connus des opioides, parfois letaux, (syndrome de sevrage, depression respiratoire et du systeme nerveux central,…) mais aussi des reactions graves au niveau du site d’administration (buccal ou nasal). Pour la forme de fentanyl transdermique, 27 cas d’intoxications, dont 25 graves, lors d’une consommation problematique ont ete signales. A noter, 19 cas de deces impliquant les deux formes de fentanyl ont ete mis en evidence (2 pour les formes de fentanyl transmuqueuses et 17 concernant la forme de fentanyl transdermique). Conclusion Nos resultats rapportent un mesusage important et preoccupant des formes de fentanyl transmuqueuses avec une large utilisation hors AMM et egalement une dependance primaire au fentanyl, quelle que soit la forme galenique, chez des patients traites pour des douleurs chroniques d’origine non cancereuse. Devant les risques importants du fentanyl, il est necessaire de poursuivre la surveillance du mesusage, en particulier, grâce aux activites du reseau francais d’addictovigilance permettant une analyse multisource des informations concernant les cas d’abus, de mesusage et de dependance.

Introduction Teledermoscopy using smartphone-based applications is becoming more and more important in a setting of increasing frequency of skin cancer and difficult access to specialized care. The TELESPOT project aimed to provide rapid diagnosis and speed up patient flow between primary healthcare centers and a tertiary care center in Belgium. The aim of the present study is to describe the development of an in-house smartphone-based dermoscopy application, evaluate its real-life value in a series of primary healthcare centers, and present preliminary diagnostic data. Methods Modified Likert scales were used to assess patient and general practitioner (GP) satisfaction rates for the system. Furthermore, a total of 105 photographic and dermoscopic images were acquired in a series of 80 patients at participating centers. Results Overall, patient and GP satisfaction levels were 89% and 94%, respectively. High-priority management was recommended in 7.6% of cases (8/105: 3 basal cell carcinoma, 1 primary cutaneous B-cell lymphoma, 1 Spitz melanocytic nevus, 1 congenital nevus, 1 in situ melanoma, and 1 invasive melanoma, proven by histology). Conclusions The primary healthcare centers were highly satisfied with the TELESPOT project in terms of user-friendliness, efficacy, and reliability as well as in providing a reinforced image of first-line medicine efforts in combating skin cancer.

Several gastrointestinal symptoms and chronic inflammatory bowel diseases (IBDs) have been reported after therapy with IL-17 inhibitors. To date, however, no study has shown a clear association between these drugs and IBD onset. We searched on Vigibase, the worldwide pharmacovigilance database, to investigate reporting prevalence, characteristics, and prognosis of all gastroenterological adverse events in patients treated with IL-17 inhibitors. In total, 1,129 gastrointestinal Individual Case Safety Reports (ICSRs) were identified, including 850 IBD (42.5% Crohn's disease, 31.9% ulcerative colitis, and 25.6% undifferentiated IBD) and 279 colitis (mainly undifferentiated colitis (79.2%), and microscopic colitis (10.4%)). ICSRs were associated with secukinumab (SEC, 83.6%) or ixekizumab (IXE, 16.3%), whereas only one colitis occurred with brodalumab (0.1%). Most IBD and colitis cases were detected within 6 months from therapy start in both the SEC (68.8% and 73.5%) and IXE groups (100% and 66.7%). Patients' outcomes were reported in 428 ICSRs (37.9%). Complete or ongoing recovery from symptoms was detected in about two-thirds of patients experiencing IBD (59.5%) or colitis (64.2%), whereas in the other cases, there was no recovery (33.9% and 29.5%) or there were sequelae (5.4% and 4.2%). Fatal events occurred in four patients (1.2%) in the IBD group (3 after SEC and on1e with IXE) and two SEC-treated subjects in the colitis group (2.1%). Treatment with IL-17 inhibitors is associated with a relevant number of exacerbations and new onset of IBD and colitis. Careful evaluation of gastrointestinal symptoms and the monitoring of intestinal inflammatory biomarkers should be recommended before prescribing these drugs.

Immunotherapy with immune checkpoint inhibitors (ICIs) for cancer has become increasingly prescribed in recent years. Indeed, it is used to treat both solid and hematological malignancies due to their considerable potential in treating melanoma, non-small cell lung and other cancers. Immune-mediated related adverse endocrine toxicity, and especially thyroiditis, is seen as a growing problem needing specific screening and management. This study aims at describing thyroid dysfunctions induced by the ICIs marketed in France, which are registered in the French Pharmacovigilance database. This database was queried for nivolumab, pembrolizumab, and ipilimumab-induced adverse drug reactions reported before April 30, 2017. Both a pharmacologist and an endocrinologist have reviewed each case to select only those of peripheral thyroiditis (thyrotoxicosis and hypothyroidism). During this period, 110 thyroiditis following ICI therapy were reported. Sex/ratio was around one. Most of the cases (47.2%) were asymptomatic. Although some thyrotoxicosis cases were severe, no orbitopathy was reported. Hypothyroidism and thyrotoxicosis were equally described. Antithyroid antibodies were positive in only 16% patients. The ultrasonography was informative in 19% patients. Levothyroxine supplementation was necessary in 57% patients, leading to 19% recovery. With a dedicated optimized management, most of the cases did not require immunotherapy discontinuation. Finally, immune-mediated related thyroiditis is increasing due to a wider prescription of ICI therapy in various cancer conditions and systematic screening. Often asymptomatic, they lead to a local activation accompanied by hormonal deficiency in the long run. It is necessary to carry out an early and sustained multidisciplinary screening to allow immunotherapy continuation.

Nicorandil-induced ulcers remain often poorly recognised, with a late diagnosis and an inadequate management. We aimed to provide a clinical overview of the 148 spontaneously reported cases of nicorandil-induced ulcers to the French pharmacovigilance network between 2005 and 2014 and to complete this picture with worldwide published cases over the same period. Spontaneously reported nicorandil-induced ulcers were mainly mucosal (oral and anal) with a previous trauma in 23·0% of patients, revealed by a severe complication in 12·8% of cases. The mean cumulative dose of nicorandil was higher in serious cases. The median delay between the start of nicorandil use and the onset of the ulcer was 23·4 months, and after the ulcer was diagnosed, the median time to incriminate nicorandil was still 3·3 months, being shorter for mucosal ulcerations than for cutaneous ulcerations (5·2 versus 14·0 months, P = 0·001). The anatomic distribution in the 199 published cases differed slightly, but delays were similar. The hypothesis of mechanism becomes more precise, leaving no doubt about the necessity to discontinue the treatment. Practitioners need to be aware that nicorandil-induced ulcers can occur in many locations, possibly multiple and complicated, and should be simply managed by discontinuing treatment with no further reintroduction of nicorandil.

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.

International audience

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

This study investigated the relationship of oxytocin (OT) to chondrogenesis and osteoarthritis (OA). Human bone marrow and multipotent adipose-derived stem cells were cultured in vitro in the absence or presence of OT and assayed for mRNA transcript expression along with histological and immunohistochemical analyses. To study the effects of OT in OA in vivo, a rat model and a human cohort of 63 men and 19 women with hand OA and healthy controls, respectively, were used. The baseline circulating OT, interleukin-6, leptin, and oestradiol levels were measured, and hand X-ray examinations were performed for each subject. OT induced increased aggrecan, collagen (Col) X, and cartilage oligomeric matrix protein mRNA transcript levels in vitro, and the immunolabelling experiments revealed a normalization of Sox9 and Col II protein expression levels. No histological differences in lesion severity were observed between rat OA groups. In the clinical study, a multivariate analysis adjusted for age, body mass index, and leptin levels revealed a significant association between OA and lower levels of OT (odds ratio = 0.77, p = 0.012). Serum OT levels are reduced in patients with hand OA, and OT showed a stimulatory effect on chondrogenesis. Thus, OT may contribute to the pathophysiology of OA.

Amiodarone treatment is contraindicated during breastfeeding. As the regional pharmacovigilance centre, we were contacted for information relative to the possibility of breastfeeding after single intravenous administration of 450 mg amiodarone to a breastfeeding woman. A monitoring of amiodarone concentration in plasma and milk was performed in the mother. At day 4, milk concentration of amiodarone reached a peak (233 μg/L) and milk to plasma ratio was determined to 3.5. Milk concentration was still detectable at day 10 (132 μg/L). The maximal relative infant dose was estimated to be 0.6% of the maternal weight-adjusted dosage, corresponding to 0.18% of the usual posology used in children by parenteral route. The review of the literature retrieved one publication suggesting that a single intravenous administration of 150 mg of amiodarone to a mother represents a negligible infant risk based on low breast milk concentration. The French National Pharmacovigilance database query did not disclose any case of side effects during breastfeeding after a single dose of amiodarone. A very limited exposition of breastfed newborns to amiodarone, as well as a low risk of side effects, is expected after a single administration of amiodarone to their mothers.

International audience

Purpose The aim of this work is to compare the energy response of a scintillating fiber to that of standard detectors used for dose monitoring in Computed Tomography (CT) and confirm the validity of Plastic Scintillating Detectors in CT dosimetry. We also seek to model the scintillating fiber response in realistic irradiation conditions for future applications on a complete dose measurement system. For this, we have modeled an X-ray generator emission and validated the model using its measured X-rays spectrum. Materials and methods Irradiations were performed in an X-ray generator at voltage varying from 80 to 140 kV. The Plastic Scintillating Detector (PSD) was compared with a pencil ion chamber and Thermo-Luminescent Detectors (TLD). Monte Carlo simulations of each detector response were compared to measurements in order to validate the simulation in a simple case. Results The Monte Carlo simulations reproduced accurately the response of each detector with less than 3% and 5% of difference for the ion chamber and the TLDs respectively. When comparing the PSD with the two standard detectors, we observed that while the plastic scintillator detector and the ion chamber responses presented less than 5% discrepancy, they both were very different than TLDs response on the whole investigated energy range. The Monte Carlo simulation of the PSD reproduced accurately the response of the plastic scintillating detector with less than 3% of difference. Conclusion The X-ray spectrum has been accurately measured which allowed to successfully reproduce the energy response of the PSD using Monte Carlo simulations. Although this study proved that the scintillating fibers energy response is appropriate for CT dose measurement, further experiments must be performed in clinical conditions.

Aseptic meningitis associates a typical clinical picture of meningitis with the absence of bacterial or fungal material in the cerebrospinal fluid. Drug-induced aseptic meningitis (DIAM) may be due to two mechanisms: (i) a direct meningeal irritation caused by the intrathecal administration of drugs and (ii) an immunologic hypersensitivity reaction to a systemic administration. If the direct meningeal irritation allows a rather easy recognition, the immunologic hypersensitivity reaction is a source of challenging diagnostics. DIAM linked to a systemic treatment exerts typically an early onset, usually within a week. This period can be shortened to a few hours in case of drug rechallenge. The fast and spontaneous regression of clinical symptoms is usual after stopping the suspected drug. Apart from these chronological aspects, no specific clinical or biological parameters are pathognomonic. CSF analysis usually shows pleiocytosis. The proteinorachia is increased while glycorachia remains normal. Underlying pathologies can stimulate the occurrence of DIAM. Thus, systemic lupus erythematosus appears to promote DIAM during NSAID therapy, especially ibuprofen-based one. Similarly, some patients with chronic migraine are prone to intravenous immunoglobulin-induced aseptic meningitis. DIAM will be mainly evoked on chronological criteria such as rapid occurrence after initiation, rapid regression after discontinuation, and recurrence after rechallenge of the suspected drug. When occurring, positive rechallenge may be very useful in the absence of initial diagnosis. Finally, DIAM remains a diagnosis of elimination. It should be suggested only after all infectious causes have been ruled out.

International audience; Opioid antagonists such as naltrexone and nalmefene are used in drug therapy for alcoholism. Nalmefene, approved in Europe in February 2013 for the reduction of alcohol consumption, is used in patients with alcohol dependence. We report 11 cases of opioid withdrawal syndrome after a single dose of nalmefene in patients usually treated with methadone, buprenorphine, but also with fentanyl or loperamide. Nalmefene is both a partial agonist and an antagonist of opioid receptors. Regarding to its opioid antagonist activity, nalmefene is contraindicated in patients with an opioid treatment. Therefore, when prescribing or delivering nalmefene, healthcare professionals need to be vigilant about any type of opioid exposure, even masked or hidden, to avoid these potential life-threatening syndromes.

Resume Introduction Le paracetamol est la substance active la plus impliquee dans les intoxications medicamenteuses volontaires et involontaires. Neanmoins, sa mise a disposition hors officine, via la grande distribution, est actuellement debattue en France. Methode Nous avons realise une evaluation prospective de la connaissance, de l’usage et du risque de surdosage en paracetamol a l’aide d’un questionnaire autoadministre dans la patientele de cabinets de medecine generale de la zone urbaine de Metz Metropole, entre mai 2015 et fevrier 2016. La prevalence des patients en risque potentiel de surdosage involontaire a ete estimee par methode de capture-recapture. Resultats Parmi les 819 patients ayant repondu, 17,9 % avaient une connaissance satisfaisante et 20,3 % etaient a risque de surdosage potentiel, majoritairement des patients âges de plus de 55 ans ou appartenant aux categories socioprofessionnelles des ouvriers et des inactifs. Un bon score de connaissance etait un facteur protecteur du risque de surdosage ( p Conclusion La dispensation du paracetamol hors des pharmacies d’officine ne saurait etre recommandee en l’etat. Des campagnes d’information sont necessaires pour limiter le risque de surdosage involontaire et de ses consequences hepatotoxiques.

International audience

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).

The System for Continuous Observation of Rodents in Home-cage Environment (SCORHE) was developed to demonstrate the viability of compact and scalable designs for quantifying activity levels and behavior patterns for mice housed within a commercial ventilated cage rack. The SCORHE in-rack design provides day- and night-time monitoring with the consistency and convenience of the home-cage environment. The dual-video camera custom hardware design makes efficient use of space, does not require home-cage modification, and is animal-facility user-friendly. Given the system's low cost and suitability for use in existing vivariums without modification to the animal husbandry procedures or housing setup, SCORHE opens up the potential for the wider use of automated video monitoring in animal facilities. SCORHE's potential uses include day-to-day health monitoring, as well as advanced behavioral screening and ethology experiments, ranging from the assessment of the short- and long-term effects of experimental cancer treatments to the evaluation of mouse models. When used for phenotyping and animal model studies, SCORHE aims to eliminate the concerns often associated with many mouse-monitoring methods, such as circadian rhythm disruption, acclimation periods, lack of night-time measurements, and short monitoring periods. Custom software integrates two video streams to extract several mouse activity and behavior measures. Studies comparing the activity levels of ABCB5 knockout and HMGN1 overexpresser mice with their respective C57BL parental strains demonstrate SCORHE's efficacy in characterizing the activity profiles for singly- and doubly-housed mice. Another study was conducted to demonstrate the ability of SCORHE to detect a change in activity resulting from administering a sedative.

BACKGROUND Studies of mechanisms mediating resistance to chemotherapy led to the discovery of the multidrug transporter ABCB1 (ATP-binding cassette, subfamily B, member 1), often expressed in leukemic cells of patients with acute myeloid leukemia (AML). Most clinical trials evaluating the strategy of inhibiting efflux-mediated chemotherapeutic resistance have been unsuccessful, clearly indicating the need for a better approach. METHODS This study investigated the clinical relevance of 380 genes whose expression has been shown to affect the response to chemotherapy, mostly through in vitro studies, in 11 paired samples obtained at AML diagnosis and at relapse. The expression profiling of these 380 genes was performed using TaqMan-based quantitative reverse-transcription polymerase chain reaction. Patients had a median age of 58 years at diagnosis, a median duration of complete remission of 284.5 days, and a median overall survival of 563 days. Cytogenetic abnormalities were detected at diagnosis in 4 patients, whereas 5 displayed a normal karyotype and 2 were not investigated. RESULTS Hierarchical clustering shows that samples taken at diagnosis and relapse clustered in pairs for 6 patients of the 11 studied, suggesting recurrence of the same leukemic blast, whereas for the other 5 patients, the data indicate their relapse blasts arose from different origins. A patient-by-patient analysis of the paired samples led to the striking observation that each had a unique gene signature representing different mechanisms of resistance. CONCLUSIONS The data underline the need for personalized molecular analysis to tailor treatment for patients with AML. Cancer 2013;119:3076—3083. © 2013 American Cancer Society.

Introduction Nalmefene (NMF – SELINCRO®), a drug for alcohol withdrawal management (AWM), is both a partial agonist and an antagonist of opioids receptors. Inherent to the latter activity, NMF is contra-indicated in patients with opioid treatment. However, despite this contra-indication, cases of opioid withdrawal syndrome (OWS) in patients treated with opioid maintenance therapy (OMT) are reported [1] , [2] . We aim to report 2 additional cases. Cases description A 46 and a 34-year-old men, with a history of alcoholism and opioid dependence, had OMT with methadone since a few years and were prescribed NMF. Thirty minutes after their single first dose of NMF, they experienced nausea, diarrhoea, vomiting and psychomotor excitement. First patient also had clonus, abundant sweating and anxiety. Both were transferred to the emergency department where OWS was diagnosed. They both received intravenous morphine, plus oxazepam (first patient) or a mix of benzodiazepines and neuroleptics (second patient). On the following day, first patient still presented digestive symptoms leading to hypokalaemia. A symptomatic treatment was initiated, morphine was stopped and methadone was reintroduced. He totally recovered on the 3rd day and was discharged. The second patient was transferred into intensive care unit (ICU) as he required intubation and sedation. Two days later, morphine was stopped and methadone was reintroduced. The patient had totally recovered and was discharged two days later. Discussion–conclusion Our two cases must be added to the nine other recently reported cases of OWS soon after a single first NMF intake in opioid dependent patients [1] , [2] . This condition always required hospitalization and sometimes ICU stay. No patient died. The summary of product characteristics of Selincro® has been updated in July 2015 with a clearer additional assertion to emphasize the need for healthcare professionals to be aware of their patients’ opioid consumption, especially OMT, before prescribing or delivering NMF. As co-existence of alcoholism and OMT is not rare, healthcare professionals really need to be vigilant about the contra-indication of NMF in patients under OMT.

Objective To examine the secular trend of hip fracture incidence in Belgium between 2000 and 2007 and the concomitant change in the prescriptions of antiosteoporosis medications. Methods The incidence of hip fractures and the number of prescriptions were determined using national databases. A logistic regression including years and 5-year age range was performed to assess the secular trend of hip fracture incidence, and Pearson's correlation coefficient was calculated to examine the relationship between hip fracture incidence and the prescriptions of antiosteoporosis medications. Results The annual number of hip fractures increased in Belgium from 13,512 in 2000 to 14,744 in 2007, with a more marked increased in men (20.4%) than in women (5.7%). The age-adjusted incidence of hip fractures was significantly decreased by 1.12% per year in women, but declined nonsignificantly by 0.34% per year in men. An increase in the prescriptions of antiosteoporosis medications in women was observed during the same time period. Conclusion Despite an increase in the number of hip fractures in Belgium between 2000 and 2007, there was a significant decrease in age-adjusted incidence in women but not in men. Although our results suggest that the decrease may be related to the extent of antiosteoporosis medications, a causal relationship cannot be ascertained and many other factors may have contributed to the decrease in age-adjusted incidence.

Purpose We highlight the risk associated with acetaminophen misuse in patients having dental pain in France based on a series of cases of unintentional acetaminophen overdose reported by the Emergency Dental Service of Nancy over a 9-month period. Methods Data were collected by querying the French Pharmacovigilance database. Each retrieved clinical data were reviewed by a clinician. Results Thirteen cases of acetaminophen overdose were reported to the Regional Pharmacovigilance Center of Lorraine, Nancy, France. Most cases (10/13) concerned men aged 20–40 years old. Mild, unspecific clinical symptoms were observed in seven of 13 patients. The median value of the supposed ingested dose was 137 mg/kg/24 h. Liver enzyme activity was tested in 10 patients and was abnormal in four patients. N-acetylcysteine treatment was administered to four patients. Conclusions We propose that even patients with mild clinical symptoms with a supposed ingested dose of acetaminophen greater than 150 mg/kg/24 h should be referred to an emergency department and that liver enzyme activity should be analyzed. No case of liver failure was observed during our short survey. However, hepatotoxicity of repeated supratherapeutic ingestion of acetaminophen was suspected in four patients. Patients and practitioners should thus be better informed about the risk of unintentional acetaminophen overdose following supratherapeutic acetaminophen ingestion. Copyright © 2011 John Wiley & Sons, Ltd.

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.

Background Systemic inflammation such as rheumatoid arthritis (RA) and Crohn's disease (CD) may be responsible for vascular comorbidity. TNF-alpha blockade was expected to lower these comorbidities but several cases of arterial and venous thromboembolic events (TE) have been reported. Objectives The aim of this work was to study retrospectively the main characteristics of spontaneously notified TNF-alpha blockers related TE over a 7-year period. Methods TE related to infliximab, etanercept and adalimumab spontaneously notified to the French adverse drug reporting system database between January 2000 and December 2006 were analyzed. Separate analysis of arterial TE and venous TE was performed. Risk factors for each category of TE were assessed with consensual criteria. Results 85 TE were analyzed, representing 4.5% of all the spontaneously notified adverse reactions of the 3 TNF-alpha blockers in the database. 42 were arterial events and 43 were venous events. The incidence was not significantly different between the 3 TNF-alpha blockers. Mean delay of TE onset after treatment initiation was 10.6 months. It was significantly shorter for etanercept (6.1 months, p=0.001) especially for venous TE (2.4 months). 16 among the 42 patients with arterial TE had 2 or more risk factors whereas 39 among the 43 patients with venous TE had no RF or only one. Most of patients (79/85) received concomitant systemic corticosteroids and/or methotrexate and/or COX-2 selective inhibitors. 23 patients had been investigated for autoimmunity, 13 had antinuclear and/or antiphospholipid antibodies. Main limitations of this study were underreporting and heterogeneous report contents. Conclusion Despite its limitations, this study suggests that venous TE could be favoured by TNF-alpha blockers therapy since they occurred in patients with no or few risk factors for venous thrombosis. However, this needs to be more evaluated by controlled studies.

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.

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Vincristine (VCT) is a neurotoxic agent and also a substrate of multidrug resistance (MDR) transporters such as P-glycoprotein (P-gp) and MDR-associated proteins 1 and 2 (MRP1 and MRP2). These proteins are expressed in the central and peripheral nervous systems (CNS and PNS) and normally protect these structures against the harmful effects of VCT. The aim of this study was to elucidate the paradoxical relation between the MDR transporters and the VCT neurotoxicity. With a validated rat model of VCT-induced neuropathy, (1) the expressions of mdr1a (P-gp), mdr1b (P-gp), mrp1 (MRP1), and mrp2 (MRP2) genes were assessed by quantitative real-time polymerase chain reaction, and (2) the transporter activity was monitored using a radioactive tracer, (99m)Tc-sestamibi, in the CNS and PNS. The results showed higher expression of mdr1a and mdr1b genes (x3 and x35, respectively) in the brain than in the spinal ganglia in both control and treated animals. Transporter activity was higher (x10) in the CNS than in the PNS. Hence, P-gp protection may be lower in the PNS than in the CNS, and this may be responsible for the peripheral neurotoxicity of P-gp substrates. VCT treatment increased expression of the mdr1a gene in the CNS and PNS (both x1.7), mrp1 gene in the PNS (x1.7), and transporter activity in both the CNS and the PNS (x4 and x8, respectively). This transporter induction may induce adverse effects when analgesic drugs are administered to treat neuropathic pain.

Background and aims: Our aim was to provide age- and sex-stratified prevalence estimates of physical disabilities and handicap in the general Belgian population. Methods: A cross-sectional and demographically representative health interview survey was conducted nationwide in Belgium in 1997. The 8836 persons aged 15 years and over who answered the health interview were included in this study. Seventeen items from the survey encompassing main activities of daily living (ADL) and confining were analyzed. To provide prevalence estimates as detailed as possible, neither aggregation nor dichotomization were applied. Results: Women consistently reported more disability than men: mobility (p

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.

Objective To evaluate the ability of 55-MHz quantitative ultrasound (US) to detect the in vivo effects of experimental arthritis, as well as those of two antiinflammatory drugs, naproxen (NPX) and dexamethasone (DEX), on cartilage and subchondral bone. Methods Arthritis was induced in both knees of 108 rats by intraarticular injection of zymosan (ZYM). Two groups of arthritic rats (n = 36 per group) were treated daily with either NPX (10 mg/kg/day) or DEX (0.1 mg/kg/day). Using a 3-dimensional US microscope, patellae were explored in vitro on days 5, 14, and 21 after injections. US assessment included the analysis of quantitative indices of local modifications involving cartilage and bone: integrated reflection coefficient (IRC) from the cartilage surface and apparent integrated backscatter from the cartilage internal structure (cartilage matrix) (AIBcartilage) and the cartilage–bone interface (AIBbone). Results ZYM induced articular surface fibrillation that resulted in a decrease in IRC at all times (P < 0.02) and in an increase in AIBbone on days 5 and 14 (P < 0.005). Fibrillation was not changed by NPX administration, while it disappeared following DEX treatment. Cartilage–bone interface alterations were prevented by DEX and partially compensated for by NPX. Cartilage matrix echogenicity decreased with time in all groups due to maturation (P < 0.05), except in DEX-treated rats. Conclusion Quantitative 55 MHz US allowed detection of early cartilage and bone lesions due to experimental arthritis, and also allowed detection of the effects of antiinflammatory drugs. NPX seemed to have an effect on subchondral bone lesions, but not on cartilage. DEX appeared to repair articular surface and bone, but prevented animal growth and cartilage maturation.

To investigate the usefulness of magnetic resonance (MR) T2 mapping in characterizing the evolution of cartilage matrix content and thickness during the maturation and aging process.Patellae from four groups of rats aged 4 weeks, 8 weeks, 4 months, and more than 6 months ("old rats") were studied ex vivo with an 8.5-T microimager. T2 values were calculated on transverse rat patellar sections and displayed with a color scale (the T2 map) on a pixel-by-pixel basis. Biochemical and histologic studies were performed to evaluate the influence of proteoglycans and collagen contents on T2 values of the patellar cartilage.On the T2 map, the maturation process until 10 weeks was characterized by a decrease in T2 values and in cartilage thickness. The biochemical data revealed a global decrease in proteoglycans and a progressive global increase in collagen content, whereas the histologic study revealed subtle zonal variation in matrix constituents with depth. As aging progressed, the T2 values were low, without important variations, whereas the global cartilage thickness decreased. The cartilage matrix became globally more fibrotic, especially in the deepest zone. Biochemical analysis revealed that collagen content was more determinant of MR signal intensity than was proteoglycans content during maturation and aging.T2 mapping allows characterization of variations in cartilage matrix constituents and thickness.

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.