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Non-cancer pain of the locomotor apparatus is the main symptom justifying referral to a rheumatologist with potential introduction of opioids, leading to addiction if misused. The objective was to evaluate the impact of a personalized pharmaceutical plan on patients' knowledge of their opioid treatment and its duration. This prospective non-randomized pilot study was conducted during 7 months with standardized data collected in a French rheumatology department. Patients with rheumatic diseases and non-cancer pain requiring opioid treatment were included. The intervention group had a 30-min opioid-targeted pharmaceutical interview and received a full medication plan and the control group received usual care. A total of 17 patients were included in the intervention group and 18 in the control group. Among patients in the intervention group, only 6 (35%) knew that immediate-release opioids have a rapid and short action, 9 (53%) were worried about taking opioids, and 13 (76%) reported that they would refer to the information document provided if side effects occurred. A trend toward a shorter duration of treatment was observed in the study group (HR = 1.87, 95% CI 0.93 to 3.76, p = 0.08), but this trend was attenuated when adjusting on hospital duration (HR = 1.53, 95% CI 0.74 to 3.15, p = 0.25). This pilot study provides preliminary evidence on the role of the clinical pharmacist in the management of non-cancer pain with strong opioids. Clinical benefits will be assessed in a randomized study. Key Points • Knowledge of opioids is insufficient in rheumatology patients with non-cancer pain. • Pharmaceutical interviews may improve patients' knowledge of opioids.

Resume Introduction Dans un contexte d’amelioration continue de la qualite, une optimisation de l’accueil et de la prise en charge medicamenteuse des patients ambulatoires est engagee au secteur des retrocessions de notre pharmacie. Afin d’evaluer les besoins en formation des preparateurs en pharmacie hospitaliere (PPH), un audit a ete realise. Materiel et methode Les retrocessions menees par les PPH du service pendant 9 semaines ont ete auditees. Les informations collectees etaient : la presentation du PPH au patient, la duree de l’entretien, la notion d’instauration ou de renouvellement, les outils utilises lors de la retrocession, et les explications donnees au patient sur son traitement. Les PPH ont evalue leur dispensation sur une echelle de Likert de 1 a 5 et les patients leur satisfaction sur une echelle de 1 a 4. Resultats Cent retrocessions ont ete auditees. Les outils etaient utilises dans 52 % des instaurations et 11 % des renouvellements de traitement. Concernant les instaurations, les modalites d’administration etaient expliquees a chaque fois, contrairement au delai de renouvellement (57 %), aux effets indesirables (47 %) ou encore aux modalites de conservation (9,5 %). Lors des renouvellements, la tolerance etait abordee dans 34 % et l’adhesion dans 19 % des dispensations. Les PPH ont estime etre a l’aise (4,4/5). Les patients ont note leur satisfaction entre 3/4 et 3,9/4. Conclusion Plusieurs axes d’amelioration ressortent de cette enquete. La formation complementaire des PPH devra inclure la communication aupres des patients ambulatoires. Cette demarche s’inscrit dans le cadre de la certification ISO 9001 obtenue en 2019 pour le service des retrocessions.

Une etude a ete realisee aupres d’etudiants en maieutique pour evaluer l’interet d’une salle de naissance virtuelle dans laquelle des erreurs pouvant entrainer un risque pour la patiente ou le soignant ont ete volontairement inserees. Les outils suscitant une participation active des apprenants et utilisant des pedagogies numeriques innovantes presentent des atouts en termes d’attractivite et de motivation.

Resume Objectif Comparaison des interventions pharmaceutiques (IP) realisees par un pharmacien integre dans l’equipe medicale de medecine interne (analyse de niveau 3) par rapport a une analyse centralisee en pharmacie a usage interieur (PUI). Materiel et methode Une comparaison prospective est realisee durant 17 jours. Les prescriptions ont ete analysees simultanement par deux internes en pharmacie. Les parametres evalues ont inclus le nombre, la nature, la classe pharmacologique, l’impact clinique estime des IP et l’acceptation par le prescripteur. Resultats Les 180 prescriptions analysees ont fait l’objet de 121 IP. L’analyse de niveau 3 a produit 51 % d’IP supplementaires. La nature et le type d’IP etaient repartis de facon globalement homogene (p Discussion L’analyse integree au sein du service permet la production de certaines IP specifiques et ameliore la pertinence de l’analyse, notamment pour les IP a fort impact clinique. L’acces a une information plus complete du pharmacien present dans l’unite de soins explique cet etat de fait. Conclusion La connaissance des specificites de l’analyse au sein d’un service de soins est un atout pour le pharmacien clinicien conduisant a une meilleure efficacite.

This work aimed to assess treatment adherence in rheumatoid arthritis patients with several tools and to identify factors associated with poor adherence.Between February and December 2015, 183 patients were included in this cross-sectional study. A homemade 23-item self-questionnaire was filled by patients during an outpatient consultation or a day hospitalization stay. Morisky Medication Adherence Scale (MMAS)-4, MMAS-8 and Girerd scores were extracted from this homemade questionnaire. Medication possession ratio (MPR) was then calculated. For identification of factors associated with nonadherence, patients were divided in two groups according to MMAS-8 results differentiating patients with good or bad adherence to treatments.Of the 183 patients, 59% received a combination of biologic and conventional synthetic disease-modifying drugs, 22% a biological treatment alone, and 19% a conventional DMARD alone. Respectively, 3%, 10%, and 7% were considered as low adherent according to MMAS-4, MMAS-8, and Girerd scores. MPR was calculated for 84/183 patients; 23% were low adherent. The need for a help in preparing the drugs (p = 0.05; OR = 6.12; 95% CI: 0.86 to 268.90) and concomitant diabetes (p0.001; OR = 0.045, 95% CI: 0.001 to 0.299) was higher in patients with good adherence. Presence of a patient's relative reminding to take medications was associated with low adherence (p = 0.002; OR = 4.32, 95% CI: 1.41 to 13.11).This study highlighted the difficulty of assessing treatment adherence in rheumatoid arthritis patients despite four different tools. Objective measures by MPR indicated a higher proportion of poor adherent patients than self-questionnaires.Key Points• Proportion of patients considered as low adherent ranged from 3 to 27% according to the method of evaluation.• The use of a pillbox and/or the preparation of drugs by a patient's relative was associated with good adherence.• The presence of a patient's relative reminding to take medication was associated with low adherence.

Background: Prolonged air leak (PAL) is the most common complication after lung resection. Several surgical sealants have been developed to reduce PAL, including fibrin-based (FS), polyethylene glycol-based (PEGS) and polyglycolic acid-based (PGAS) sealants. In this work we report our experience of surgical sealant use after robot-assisted lung resection. Methods: A 7-year retrospective study was conducted, including patients who had robot-assisted lobectomy or segmentectomy. Data were collected using a prospective national database. The use of surgical sealants was recorded in traceability sheets. Results: PAL occurred in 60 of the 299 patients included. American Society of Anesthesiologists score (ASA) and index of prolonged air leak (IPAL) were higher for patients with sealants. In this group, operative time, chest drain duration and length of stay were significantly longer. PAL occurrence was significantly associated to sealant in univariate analysis (Odds ratio =1.88, 95% CI: 1.07 to 3.36, P=0.03) but the association was slightly decreased when adjusting on IPAL and ASA score (Odds ratio =1.70, 95% CI: 0.94 to 3.10, P=0.08). Comparing sealants, more segmentectomies were performed in patients with PGAS (P=0.0013) and their operative time was shorter (P=0.0002). PAL occurrences were not different. Length of stay (P=0.0045) and operative time (P=0.0002) were longer in patients with PEGS who had more postoperative complications (P=0.024). Conclusions: This study did not identify a positive effect of surgical sealants for preventing PAL. However it highlighted the need to rationalize their use.

Resume Malgre la diffusion du concept, des methodes, puis, l’inscription dans les textes qui fondent notre exercice professionnel, le developpement de la pharmacie clinique dans les differentes structures de soins en France ne s’est pas fait de maniere synchrone, selon le meme deploiement, la meme priorisation des activites, les memes moyens et la meme vitesse. Une raison est, sans doute, le temps incompressible qu’il faut pour que les mentalites evoluent, les pratiques s’installent sur le terrain et les experimentations prennent corps. A un moment donne de ce processus, le role d’une societe savante est de proposer une reflexion sur un modele de pratique permettant d’homogeneiser sur le territoire, l’offre de services cliniques de l’equipe pharmaceutique. Cet article a cette ambition. C’est le fruit d’un travail collectif de la Societe francaise de pharmacie clinique. Le modele propose comporte 3 types de prestations, s’inscrivant dans un contexte organisationnel impose (modele statique) et/ou une notion de parcours (modele dynamique) : 1. dispensation ; 2. bilan de medication ; 3. plan pharmaceutique personnalise. Cette version de modele est amenee a evoluer au gre du niveau de competences des pharmaciens, des experiences des equipes pharmaceutiques et du niveau d’integration de l’activite au sein des parcours de soins, tout ceci sous contraintes organisationnelles, reglementaires et financieres.

Dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban are direct oral anticoagulants (DOACs). Their inter-individual variability in pharmacodynamics and pharmacokinetics (transport and metabolism) is high, and could result from genetic polymorphisms. As recommended by the French Network of Pharmacogenetics (RNPGx), the management of some treatments in cardiovascular diseases (as antiplatelet agents, oral vitamin K antagonists, and statins) can rely on genetic testing in order to improve healthcare by reducing therapeutic resistance or toxicity. This paper is a review of association studies between single nucleotide polymorphisms (SNPs) and systemic exposure variation of DOACs. Most of the results presented here have a lot to do with some SNPs of CES1 (rs2244613, rs8192935, and rs71647871) and ABCB1 (rs1128503, rs2032582, rs1045642, and rs4148738) genes, and dabigatran, rivaroxaban, and apixaban. Regarding edoxaban and betrixaban, as well as SNPs in the CYP3A4 and CYP3A5 genes, literature is scarce, and further studies are needed.

Nicardipine is an antihypertensive drug that may be used off-label by oral route to treat hypertension in children. Currently commercially available tablets are inappropriate for oral use in children and manufactured hard capsules are not suitable for easy dose individualization to achieve target blood pressure. We aimed to fulfill this lack of appropriate dose forms by developing an oral liquid formulation of nicardipine. We compounded an extemporaneous 2 mg/mL nicardipine solution in InOrpha® vehicle for oral use with 1% polysorbate 80. A HPLC-MS/MS stability-indicating method was developed and validated. The stability was assessed under room temperature and refrigerated storage conditions. Nicardipine concentration remained above 95% of the initial concentration for 90 days in both storage conditions, without apparition of degradation products. Organoleptic parameters, pH, osmolality, viscosity and density were assessed and remained stable throughout storage. A uniformity of content was maintained before and after agitation of the packaging bottles. Mass uniformity of delivered doses was also ensured. Finally, the formulation met the Pharmacopoeia specifications for microbiological contaminations. In this study we report a compounded formulation of nicardipine for oral use in pediatrics. This solution, which could be easily manufactured, is being used in our hospital. Pharmacological and clinical parameters including bioavailability, pharmacokinetics, efficacy and tolerance remain to be assessed.

The primary objective was to evaluate the impact of an in-department pharmacist on the prevention of drug iatrogenesis in a rheumatology department. Secondary objectives were to determine (i) if medication history discrepancies were detected more frequently in the elderly or not, and (ii) if the mean number of treatments at admission had an impact on the number of medication history discrepancies.Implementation of a clinical-pharmacy program based on medication reconciliation and medication review of prescription for all patients admitted to a rheumatology department between January and June 2017. The analytical approach was mainly descriptive and data were expressed as mean ± standard deviation (i.e., number of treatments at admission, number of medication reconciliations) and as proportions (i.e., acceptance rate, impact). Chi-squared tests and Student's test were performed to determine if there was a significant difference in outcomes.Three hundred twelve patients were included in the study, 517 medication history discrepancies in 243 (77.8%) patients and 196 pharmaceutical interventions in 133 (42.6%) patients. A significant difference was found in the number of medication history discrepancies and pharmaceutical interventions between the two age groups and in the mean number of treatments at admission between patients with or without medication history discrepancies. 15.4% of study patients had major medication history discrepancies and major pharmaceutical interventions. All patients and practitioners reported the usefulness of an in-department pharmacist.This program was found effective in terms of safety and improvement in the continuity of care. Key Points • This clinical-pharmacy program with an in-department pharmacist had a positive impact on the prevention of drug iatrogenesis in one rheumatology department. • 15.4% (n = 48) of study patients had major medication history discrepancies and major pharmaceutical interventions. • All practitioners and patients were satisfied with this clinical-pharmacy program.

International audience

OBJECTIVES The objective of this study was to assess the learning curve (LC) of robot-assisted lung segmentectomy and to evaluate hospital-related costs. METHODS We conducted a retrospective study of Robot-assisted thoracic surgery (RATS) segmentectomies performed by 1 surgeon during 5 years. Perioperative and medical device data were collected. The LC, based on operating time, was assessed by Cumulative SUM analysis and an exponential model. Cost of care was estimated using the French National Cost Study method. RESULTS One hundred and two RATS segmentectomies were included. The LC was completed at ∼30 procedures according to both models without significant difference in patients’ characteristics before or after the LC. Mean operative time decreased from 136 min [95% confidence intervals (CI) 124–149] for the first 30 procedures to 97 min (95% CI 88–107) for the last 30 procedures. Mean length of stay decreased non-significantly (P = 0.10 for linear trend) from 8.1 days (95% CI 6.1–11.0) to 6.2 days (95% CI 4.9–7.9). The overall costs for the last 30 procedures as compared with the first 30 did not significantly decrease in the primary economic analysis but significantly decreased (P = 0.02) by €1271 (95% CI −2688 to +108, P = 0.02 for linear trend) after exclusion of 1 outlier (hospitalization-related costs > €10 000). After exclusion of this outlier, costs related to EndoWrist® instruments significantly decreased by €−135 (95% CI −220 to −35, P = 0.004), whereas costs related to clips decreased non-significantly (P = 0.28). CONCLUSIONS The LC was completed at ∼30 procedures. Inexperienced surgeons may have higher procedure costs, related to consumable medical devices and operating time.

Essentials The C‐terminal domain of the fibrinogen α chain (αC domain) is implicated in different severe diseases via clotting abnormalities or amyloid deposits.Certain anomalies of the fibrinogen molecule lead to amyloid deposits in the kidney, inducing renal insufficiency.In contrast, in Alzheimer's disease, fibrinogen is normal, but due to an inflammatory process, fibrinogen crosses into the brain and interacts with Aβ, leading to formation of pathological deposits. Abstract Fibrinogen, involved in coagulation, is a soluble protein composed of two sets of disulfide‐bridged Aα, Bβ, and γ‐chains. In this review, we present the clinical implications of the αC domain of the molecule in Alzheimer's disease, hereditary renal amyloidosis and a number of thrombotic and hemorrhagic disorders. In Alzheimer's disease, amyloid beta peptide (Aβ) is increased and binds to the αC domain of normal fibrinogen, triggering increased fibrin(ogen) deposition in patients’ brain parenchyma. In hereditary renal amyloidosis, fibrinogen is abnormal, with mutations located in the fibrinogen αC domain. The mutant αC domain derived from fibrinogen degradation folds incorrectly so that, in time, aggregates form, leading to amyloid deposits in the kidneys. In these patients, no thrombotic tendency has been observed. Abnormal fibrinogens with either a point mutation in the αC domain or a frameshift mutation resulting in absence of a part of the αC domain are often associated with either thrombotic events or bleeding. Mutation of an amino acid into cysteine (as in fibrinogens Dusart and Caracas V) or a frameshift mutation yielding an unpaired cysteine in the αC domain is often responsible for thrombotic events. Covalent binding of albumin to the unpaired cysteine via a disulphide bridge leads to decreased accessibility to the fibrinolytic enzymes, hence formation of poorly degradable fibrin clots, which explains the high incidence of thrombosis. In contrast, anomalies due to a frameshift mutation in the αC connector of the molecule, provoking deletion of a great part of the αC domain, are associated with bleeding.

Resume Objectifs Evaluer l’interet du passage d’un anti-TNFα a un autre chez des patients atteints de polyarthrite rhumatoide (PR) en fonction du motif de changement (echec primaire, echappement ou intolerance) et en fonction du sens de rotation [anticorps monoclonal (mAc) vers recepteur (sR) ou sR vers le mAc]. Methodes Entre 2000 et 2008, 356 patients atteints de PR ont recu un anti-TNFα [infliximab (IFX), etanercept (ETA) ou adalimumab (ADA)]. L’activite de la maladie etait evaluee de facon standardisee au cours de cette etude retrospective. Les donnees demographiques, cliniques et biologiques etaient recueillies a l’introduction du premier anti-TNFα et au moins 6 mois plus tard pour evaluer la reponse a cet anti-TNFα en fonction des criteres de reponse EULAR. Un echec primaire, un echappement ou une intolerance au premier anti-TNFα induisait le passage a un autre anti-TNFα, dont la reponse etait evaluee 6 mois plus tard. Un score de propension mesurait ensuite toute interaction avec les variables de depart. Resultats Parmi les 356 patients atteints de PR, 38 sont passes de l’IFX ou de l’ADA a l’ETA, 26 de l’ETA a l’IFX ou de l’ADA, et 8 d’un mAc (IFX ou ADA) a l’autre. Les parametres cliniques des switchers (patients ayant change d’anti-TNFα) et non-switchers etaient comparables. Les switchers changeaient de biomedicaments en raison d’un echec primaire (36,1 %), d’un echappement (33,3 %), ou d’une intolerance (30,6 %), sans afference entre ces sous-groupes. Quels que soient la raison du changement ou le sens de la rotation, les patients repondaient davantage au second anti-TNFα qu’au premier (p Conclusion Le passage d’un TNFα a un autre est plus souvent benefique pour les patients atteints de PR quand on passe d’un mAc au sR dirige contre un anti-TNFα.

Introduction et but de l’etude La vitamine D est essentielle dans la prevention des chutes et dans la prise en charge de pathologies osseuses. La HAS ainsi que l’Assurance Maladie recommandent le dosage de la vitamine D dans les situations suivantes : patient a risque de chutes a repetition (dont patients denutris severes), medicaments inducteurs de carence, osteomalacie, rachitisme, transplante renal, chirurgie bariatrique. La supplementation en vitamine D fait l’objet de recommandations et semble insuffisante en medecine de ville. Le statut vitaminique D des patients (identification des situations avec une indication au dosage et supplementation) est-il re evalue en medecine aigue et quelle est la place des patients denutris severes qui releveraient d’une evaluation du statut vitaminique ? Materiel et methodes Il s’agit d’une etude observationnelle retrospective. Les criteres d’inclusion sont les patients sortis de 2 services de medecine aigue (medecine interne et geriatrie) du 01/12/18 au 31/12/18. Les patients deja supplementes ont ete analyses de facon independante. Les criteres d’exclusion sont les deces et l’hypercalcemie vraie. Parmi les patients a risque de chutes repetees ont ete differencies les chuteurs averes definis par au moins deux chutes au cours des 12 derniers mois des patients denutris severe. Le dosage de vitamine D, la supplementation en vitamine et ses modalites etaient recueillis. Resultats et analyse statistique Nous avons etudies 238 dossiers patients. Vingt deux patients ont ete exclus (21 deces et 1 hypercalcemie). La moyenne d’âge 85 ans (± 0 ans ; Sex ratio 78/138). 187/216 (87 %) patients relevaient d’une supplementation. Dans ce groupe, 43/187 (23 %) etaient deja supplementes a l’entree. Parmi les 144/187 (77 %) non supplementes en ville : 72/144 (50 %) avaient une indication au dosage de vitamine D : risque de chutes a repetition chez 72/72 (100 %) dont 39/72 (54 %) chuteurs averes et 33/72 (46 %) denutris severes. Aucun de ces 72 patients n’a beneficie du dosage recommande. La place des patients denutris severe represente 33/144 (23 %) des patients necessitant une supplementation. 72/144 (50 %) n’avaient pas d’indication au dosage mais etaient soit osteoporotiques, soit âges de plus de 65 ans et en perte d’autonomie avec une exposition solaire insuffisante relevant d’une supplementation trimestrielle. Seuls 33/187 (18 %) ont beneficie de vitamine D a la sortie, de galeniques et posologies diverses. Pour 23/43 (53 %) des patients deja supplementes, la vitamine D n’a pas ete reconduite. Parmi les patients non supplementes en ville, seuls 13/144 (9 %) ont beneficie d’une introduction de vitamine D. Conclusion Nos resultats montrent que la reevaluation du statut vitaminique D et la prescription de vitamine D semblent tres insuffisants en medecine hospitaliere aigue mais egalement en medecine de ville. Une sensibilisation sur cette thematique est necessaire, surtout chez le patient a risque de chute et notamment les denutris severes.

Introduction Le risque d’accident medicamenteux pour une population polypathologique et polymediquee, souvent âgee, constitue un enjeu de prise en charge. La conciliation medicamenteuse d’entree (CME) menee de facon pluridisciplinaire apporte une securite dans la prise en charge des patients. Au sein de 2 services de medecine interne polyvalente et de medecine aigue geriatrique (105 lits), une activite de CME est realisee quotidiennement. Le but de cette etude etait d’evaluer l’interet clinique de la CME. Patients et methodes Etude retrospective des erreurs medicamenteuses (EM) relevees lors des CME realisees de novembre 2018 a avril 2019 (160 jours), priorisees par les medecins pour les patients a risque, realisees par les externes en pharmacie et validees par un binome pharmacien/medecin. Cotation de l’impact clinique potentiel (ICP) des EM selon l’echelle clinique CLEO, par deux professionnels, separement, en aveugle, en 4 categories : erreurs nuisibles (−1 C), de nulles a moyennes (0 C, 1 C, 2 C), de majeures a vitales (3 C, 4 C) ou non evaluables (NE). Resultats Trois cent quatre-vingt CME ont ete realisees, soit une couverture de 28 % (âge moyen 82 ± 11,5 ans). Cent cinquante et un EM ont ete relevees pour 119 patients soit 0,4 EM par patient concilie. Le retour systematique aux medecins a conduit a 80 (53 %) corrections et 71 (47 %) justifications. Cent trente-trois EM (88 %) cotees identiquement par le pharmacien et le medecin. Neuf EM (6 %) cotees avec un IC plus important par le pharmacien et 9 (6 %) par le medecin. Parmi les EM cotees a l’identique, 29 (22 %) avaient un ICP « majeur a vital ». Elles concernaient notamment 7 antiglaucomateux, 6 antiagregants plaquettaires, 4 anticoagulants, 1 anti-hormone (Ormandyl®), 1 antineoplasique (Hydrea®). Conclusion Les erreurs medicamenteuses etaient frequentes et evaluees souvent consensuellement par le pharmacien et le medecin, avec un impact clinique potentiel souvent « majeur a vital ». Les classes medicamenteuses concernees etaient parfois inhabituelles. L’interet clinique de la CME est confirme et renforce la securisation de la prescription medicale, a fortiori lorsque le pharmacien est present dans le service. La realisation d’une cotation prospective de l’impact clinique potentiel constitue un objectif futur a developper.

Introduction La vitamine D est essentielle dans la prevention des chutes et dans la prise en charge de pathologies osseuses. La HAS ainsi que l’Assurance Maladie recommandent le dosage de la vitamine D dans les situations suivantes : patient a risque de chutes a repetition (dont patients denutris severes), medicaments inducteurs de carence, osteomalacie, rachitisme, transplante renal, chirurgie bariatrique. La supplementation en vitamine D fait l’objet de recommandations nationales et semble insuffisante en medecine de ville. L’objectif de cette etude etait de determiner si le statut vitaminique D des patients (supplementation et dosage de la vitamine D) etait reevalue lors de l’hospitalisation. Patients et methodes Etude observationnelle retrospective. Tous les patients hospitalises dans 2 services de medecine aigue (medecine interne et geriatrie) en decembre 2018 ont ete inclus. Les malades decedes au cours de l’hospitalisation ou avec une hypercalcemie ont ete exclus. Les patients deja supplementes ont ete analyses de facon independante. Le dosage de vitamine D, la supplementation en vitamine et ses modalites etaient recueillis. Resultats Deux cent seize patients ont ete inclus et 22 non inclus (21 deces et 1 hypercalcemie). Âge moyen 85 ± 10 ans ; sex-ratio 78/138. Cent quatre-vingt-sept sur 216 (87 %) patients relevaient d’une supplementation. Dans ce groupe, 43/187 (23 %) etaient deja supplementes a l’entree. Parmi les 144/187 (77 %) non supplementes en ville : 72/144 (50 %) avaient une indication au dosage de vitamine D (risque de chutes a repetition chez 72/72 [100 %] dont 39/72 [54 %] chuteurs averes et 33/72 [46 %] denutris severes). Aucun de ces 72 patients n’a beneficie du dosage recommande. Soixante-douze sur 144 (50 %) n’avaient pas d’indication au dosage mais etaient soit osteoporotiques, soit âges de plus de 65 ans et en perte d’autonomie avec une exposition solaire insuffisante relevant d’une supplementation trimestrielle. Seuls 33/187 (18 %) ont beneficie de vitamine D a la sortie, de galeniques et posologies diverses. Pour 23/43 (53 %) des patients deja supplementes, la vitamine D n’a pas ete reconduite. Parmi les patients non supplementes en ville, seuls 13/144 (9 %) ont beneficie d’une introduction de vitamine D. Conclusion Nos resultats montrent que la reevaluation du statut vitaminique D et la prescription de vitamine D semblent tres insuffisantes en medecine hospitaliere aigue mais egalement en medecine de ville. Une sensibilisation sur cette thematique est indispensable a fortiori chez les patients a risque de chutes.

Pentoxifylline (PTX), a xanthine family molecule and simvastatin (SIM), an anti-hypercholesterolemic agent, have recently been considered as sensitizers to chemotherapy and radiotherapy. The present in vitro study evaluated their antitumor synergistic effects on MDA‑MB‑231 breast cancer cells characterized by the triple‑negative phenotype (TNP). The anti-proliferative effects of these two agents were evaluated by MTT and clonogenic assays. Cell cycle progression was examined using propidium iodide staining. Apoptosis was investigated by Annexin V labeling, and by examining caspase 3 activity and DNA fragmentation. Autophagic vesicles and reactive oxygen species (ROS) levels were monitored by flow cytometry. Western blot analysis was performed to evaluate molecular targets. Our results revealed that when used alone, PTX and SIM exerted antitumor effects. Nevertheless, used in combination, the inhibition of cell proliferation was synergistically superior (80% vs 42%) than that observed following treatment with each agent alone after 48 h. PTX alone (0.5 mM) induced both apoptosis (25%) and autophagy (25%); however, when used in combination with SIM (0.5 µM), the balance between these processes was disrupted and the cells underwent apoptosis (>65%) as opposed to autophagy (

International audience; Objectives : To evaluate the benefits for rheumatoid arthritis (RA) patients of switching from one tumor necrosis factor inhibitor (TNFi) to another based on reason for change (primary failure, escape or intolerance) and molecule-switching order.Methods : Between 2000 and 2008, 356 RA patients prescribed a TNFi (infliximab [IFX], etanercept [ETA] or adalimumab [ADA]) and undergoing standardized evaluation were included in this retrospective study. Detailed demographic, clinical and biological data were collected before first biologic use and ≤ 6 months later to evaluate response based on EULAR-criteria. Primary failure, escape or intolerance of first TNFi triggered switch to another TNFi, the response of which was evaluated 6 months later. Propensity score then measured any interaction with baseline variables.Results : Of the 356 RA patients, 38 switched from IFX/ADA to ETA, 26 from ETA to IFX/ADA, and eight from one monoclonal antibody (mAb; IFX/ADA) to another. Clinical parameters for switchers and non-switchers were comparable. Switchers changed therapies because of primary failure (36.1%), escape (33.3%), or intolerance (30.6%), with no difference found in these subgroups. More switchers responded to the second TNFi than the first (P < 0.01), respectively, regardless of switch (ETA to IFX/ADA: 50 vs. 23.1% [P < 0.05]; IFX/ADA to ETA: 57.9 vs. 15.8% [P < 0.001]) or reason for changing. In addition, DAS28 decreased more with the second antagonist (P < 0.001) and regardless of molecules switched (P < 0.01). Survival of the second TNFi was significantly longer with switch from mAb to the soluble receptor than vice versa (P < 0.05).Discussion : Overall, any switching from one TNFi to another, especially mAb to soluble receptor, was often beneficial for RA patients.

The practice of crushing drugs is very common in geriatric units. In 2009 a first study, performed in all geriatric units of a university hospital, showed that numerous errors were made during prescription, preparation and administration. The aim of this second prospective study was to assess the impact of regional and national recommendations in the same geriatric units. A survey of 719 patients (85.3 ± 6.7 years) was performed in 2013. For each patient who received crushed drugs, we recorded the reason the drugs were crushed, pharmacological classes, galenic presentations and the technique used for preparation and administration. Results were compared to the previous study. The number of patients receiving drugs after crushing was significantly lower than in the previous study (22.9% vs. 32.3%, P < 0.001). The number of crushed drugs was lower too (594 per 165 patients vs. 966 per 224 patients (P < 0.01). The main indication for crushing drugs remained swallowing disorders. The dosage form prevented crushing in 24.9% of drugs (vs. 42.0% in 2009, P < 0.001), but the drugs generally remained crushed all together. A mortar was used less often (38.6% vs. 92.6%, P < 0.001), with preference for individual-specific cups (56.1%). Mortars were more often cleaned between each patient (56.0% vs. 11.6%). The vehicle was more often neutral (water 88.5% vs. 5.7%, P < 0.001). This second study shows that regional and national recommendations have led to an overall improvement of practices for crushing drugs. Technical improvements are still possible, in association with appropriate pharmacological studies.

Objectives Minimally invasive procedures are used for the surgical treatment of lung cancer. Two techniques are proposed: video-assisted thoracic surgery or robotic-assisted thoracic surgery. Our goal was to study the economic impact of our long-standing program for minimally invasive procedures for major lung resection. Methods We conducted a single-centre, 1-year prospective cost study. Patients who underwent lobectomy or segmentectomy were included. Patient characteristics and perioperative outcomes were collected. Medical supply expenses based on the microcosting method and capital depreciation were estimated. Total cost was evaluated using a national French database. Results One hundred twelve patients were included, 57 with and 55 without robotic assistance. More segmentectomies were performed with robotic assistance. The median length of stay was 5 days for robotic-assisted and 6 days for video-assisted procedures (P = 0.13). The duration of median chest drains (4 days, P = 0.36) and of operating room time (255 min, P = 0.55) was not significantly different between the groups. The overall conversion rate to thoracotomy was 9%, significantly higher in the video-assisted group than in the robotic group (16% vs 2%, P = 0.008). No difference was observed in postoperative complications. The cost of most robotic-assisted procedures ranged from €10 000 to €12 000 (median €10 972) and that of most video-assisted procedures ranged from €8 000 to €10 000 (median €9 637) (P = 0.007); median medical supply expenses were €3 236 and €2 818, respectively (P = 0.004). The overall mean cost of minimally invasive techniques (€11 759) was significantly lower than the mean French cost of lung resection surgical procedures (€13 424) (P = 0.001). Conclusions The cost at our centre of performing minimally invasive surgical procedures appeared lower than the cost nationwide. Robotic-assisted thoracic surgery demonstrated acceptable additional costs for a long-standing program.

Resume En cas de difficultes pour avaler, l’ecrasement ou l’ouverture des medicaments est une pratique courante. Si l’administration necessite une modification de la forme galenique, il convient de (re)evaluer le traitement. La Societe francaise de pharmacie clinique a realise un guide informant sur la possibilite d’ecraser ou d’ouvrir un medicament a partir d’elements pharmacocinetiques et galeniques et/ou de proposer des alternatives.

Resume Propos Les troubles de deglutition ou du comportement genent frequemment l’administration des medicaments chez les malades âges. Le recours a l’ecrasement des medicaments est frequent avec des pratiques non validees. L’objectif de cette premiere etude prospective, menee par un groupe multidisciplinaire sur l’ensemble des lits de geriatrie du CHU de Rouen, etait d’analyser la pratique de l’ecrasement des medicaments de leur prescription a leur administration afin d’envisager des mesures correctives. Methodes Une enquete a ete menee en juin 2009 aupres de 683 malades de plus de 65 ans hospitalises dans 23 unites de geriatrie. Lorsqu’un malade recevait des medicaments apres ecrasement, il etait enregistre le motif de l’ecrasement, les medicaments et formes galeniques concernes et les techniques de preparation et d’administration. Resultats Deux cent vingt et un patients (32,3 %) (85,5 ± 6,5 ans, femmes 74,2 %) recevaient 1528 medicaments (6,9 ± 4 par patient) dont 966 (63,2 %) apres ecrasement (comprimes ou contenu de gelules ouvertes), principalement le matin (50,4 %). Les motifs principaux d’ecrasement etaient les troubles de la deglutition puis les troubles psycho-comportementaux. Quarante-deux pour cent des 966 medicaments ecrases avaient une forme galenique contre-indiquant l’ecrasement. Les medicaments d’un meme malade etaient ecrases ensemble pres de trois fois sur quatre et melanges a des vehicules divers pour l’administration. Le materiel utilise (mortier, 92,6 %) etait souvent commun pour plusieurs patients (59,4 %). Les medicaments etaient administres immediatement apres la preparation dans 83,5 % des cas, mais avec d’importantes variations quant aux heures d’administration. Conclusion L’ecrasement des medicaments expose a des risques iatrogenes et des risques professionnels. Des recommandations regionales puis nationales ont ete elaborees pour corriger les dysfonctionnements lies a cette pratique.

Seeking to improve ovarian cancer therapy, we compared biological characteristics of the moderately-aggressive OVCAR-3 cell line with two highly aggressive ovarian cancer cell populations: the SK-OV-3 cell line, and HASCJ primary cells isolated from the ascitic fluid of a patient with FIGO stage IV ovarian cancer. Secretion of angiogenic factors was not discriminative, whereas cell invasion through Matrigel and vasculogenic mimicry were much greater in the more aggressive cells. Among 10 agents tested for their ability to decrease cancer cell aggressivity using these two models, inhibitors of Stat3, IGF-IR and Rho GTPase were found to be the most promising.

Introduction Le controle des prescriptions chez les sujets âges est un enjeu majeur. En effet, le taux d’evenements iatrogenes augmente avec l’âge, du fait de la polymedication, des facteurs de fragilite, des infections intercurrentes. Or, la pathologie iatrogene entraine outre les consequences directes de l’evenement (mortalite de 1 a 5 %), une perte d’autonomie liee a l’hospitalisation difficilement reversible, dommageable pour la population âgee. Patient(e)/patient(e)s L’objectif de cette etude etait de realiser un bilan de l’analyse pharmaceutique des prescriptions pour en extraire des messages cles a transmettre ensuite aux prescripteurs de l’etablissement concernant les situations a risque les plus frequentes chez les personnes âgees. Nous avons etudie l’ensemble des interventions pharmaceutiques (IP) tracees par la pharmacie entre le 15 novembre 2016 et le 14 fevrier 2017, realisees dans les services de medecine interne et de geriatrie aigue du CHU (221 lits). Nous avons cible les patients de plus de 70 ans. Les IP ont ete codees selon la classification de la Societe francaise de pharmacie clinique qui regroupe les IP en fonction du type de problematique releve en vue d’une exploitation statistique. Resultats Sur la periode, 210 IP ont ete realisees dont 153 directement dans les services de soins (analyse de niveau 3) et 57 de facon centralisee a partir de la pharmacie (analyse de niveau 2). Les interventions les plus frequentes correspondaient aux surdosages ou contre-indications lies au terrain physiopathologique (78 IP), notamment l’adaptation a la fonction renale (36 IP) (amoxicilline, allopurinol, paracetamol) et le respect des posologies specifiques aux personnes âgees (zopiclone 7 IP, paracetamol 6 IP). Les IP correspondant a l’adaptation de la voie d’administration concernaient principalement les prescriptions de paracetamol en intraveineux associees a des traitements par voie orale (12 P). L’association de benzodiazepines ou la presence d’un anxiolytique a longue duree d’action etaient egalement recurrentes. Les interactions medicamenteuses ( n = 23) regroupaient principalement l’association de medicaments donnant des torsades de pointes (8 IP) (hydrozyzine, tiapride, escitalopram) ainsi que l’absorption concomitante de medicaments reduisant l’absorption gastro-intestinale (alginate, sels de fer, resines) avec des antibiotiques ou des antihypertenseurs (6 IP). Enfin, certaines pathologies chroniques n’etaient pas traitees (28 IP), par exemple les carences en vitamine D chez l’insuffisant renal chronique a risque de fracture. Conclusion Le type d’IP retrouve est fortement influence par l’informatisation des prescriptions. En effet, le logiciel du CHU propose aux prescripteurs, pour les principales molecules referencees a la pharmacie, des posologies et des plans de prises type ainsi qu’une premiere analyse des interactions medicamenteuses contre-indiquees et deconseillees. Neanmoins, l’analyse manuelle des prescriptions est toujours essentielle pour tenir compte du terrain physiopathologique du patient. L’analyse des IP illustre les pathologies chroniques dont sont victimes les personnes âgees notamment l’insuffisance renale, l’etat anxieux ou depressif. Les specificites de cette population doivent ainsi etre prises compte lors de la prescription.

Angiogenesis is thought to be involved in the development of acute leukemia (AL). We investigated whether bone marrow stromal cells (BMSCs) derived from stem cells might be responsible for the increase in microvascular density (MVD), and compared 13 bone marrow samples from AL patients with 23 samples from patients in complete remission (controls). We demonstrated that AL-derived BMSC secreted more insulin growth factor-1 (IGF-1) and SDF-1alpha than controls. In addition, in contrast to normal adherent BMSCs, adherent BMSCs derived from CD133+/CD34+ stem cells from AL patients were able to form capillary-like structures ('vasculogenic mimicry') on Matrigel. The increase in vasculogenic mimicry occurred through PI3 kinase and rho GTPase pathway as inhibitors of these signaling pathways (wortmannin and GGTI-298, respectively) were able to reduce or prevent capillary tube formation. In normal BMSC, addition of exogenous IGF-1 generated capillary-like tubes through the same pathway as observed spontaneously in AL-derived BMSC. The involvement of IGF-1 in the mimicry process was confirmed by the addition of a neutralizing antibody against IGF-1R or a IGF-1R pathway inhibitor (picropodophyllin). In conclusion, AL-derived BMSC present functional abnormalities that may explain the increase in MVD in the bone marrow of AL patients.

SummaryThe aims of this case-control study were to identify in vitamin K antagonist (VKA)-treated unselected patients, factors associated with international normalised ratio (INR) values: (i) greater than 6.0.;and (ii) ranging from 4.0 to 6.0 complicated with bleeding. We also assessed VKA-related morbidity in these patients. During a two-month period, 4,188 consecutive and unselected patients were referred to our Emergency Department. At admission, the medical records of each patient and two age- and sex-matched controls were reviewed for: both duration and indication of VKA therapy, previous medical history of VKA-related haemorrhage, underlying co-morbidities, concomitant medications other than VKA, duration of hospitalization and deaths’ causes. Of these 4,188 subjects,50 case-patients (1.19%) were identified; both case-patients and controls did not differ as regards indications and patterns of VKA therapy. Interestingly, two-thirds of case-patients were women, suggesting that female gender may be a risk factor of VKA over-coagulation onset. We identified the following risk factors of VKA over-coagulation: previous medical history of INR levels over therapeutic range, therapy with antibiotics, amiodarone and proton pump inhibitors, as well as fever. A total of 88% of case-patients were hospitalized; mean duration of patients’ hospitalization was seven days [range:1–56 days];no patient died from major bleeding. Our study underscores that it is of utmost importance to consider the strength of indication before starting VKA therapy, as this therapy has been responsible for as high as 1.19% of admissions in unselected subjects referred to an Emergency Department. Our data therefore suggest that internists should be aware of VKA-related high morbidity, particularly in situations at risk of VKA over-coagulation.

International audience; Multiple drug resistance remains an unsolved problem in cancer therapy. A previous study has demonstrated that the chemotherapeutic drug doxorubicin (Dox) induced upregulation of P-glycoprotein in endothelial cells, resulting in a 20-fold increase in drug resistance and reduced efficiency of doxorubicin treatment in a mouse tumor model. In the present study, the cross-resistance and sensitivity of HMECd1 and HMECd2 established cell lines to anti-angiogenic drugs, particularly sunitinib, was explored. The results revealed that Dox treatment induced a significant increase in the breast cancer resistance protein (ABCG2) gene transcription and protein expression. This increase gave rise to a 4- to 5-fold increase in the half maximal inhibitory concentration of the HMECd1 and HMECd2 cells in response to sunitinib treatment in vitro. Functionally, the role of ABCG2 in the resistance to sunitinib was confirmed by the use of the ABCG2 inhibitors fumitremorgin C and diethylstilbestrol, which blocked cell resistance. The present study indicates that endothelial cells exhibit cross-resistance between cytotoxic drugs and anti-angiogenic drugs. This suggests that multiple drug resistance induced by chemotherapy in endothelial cells may affect the efficiency of anti-angiogenic drugs.

Limin Huang,1,* Chaoquan Hu,2,* Mélanie Di Benedetto,3 Rémi Varin,4 Jielin Liu,2,3 Li Wang,3 Jean-Pierre Vannier,4 Jian Jin,3,5 Anne Janin,3,6,7 He Lu,3,6 Hong Li4 1Department of Oncology, People’s Hospital of Guizhou Province, Guiyang, People’s Republic of China; 2Department of Surgery, Affiliated Hospital, Guiyang Medical University, Guiyang, People’s Republic of China; 3INSERM UMR-S 1165, Paris, France; 4MERCI (EA 3829), Faculté de Médecine et de Pharmacie, Université de Rouen, Rouen, France; 5School of Medicine and Pharmaceutics, Jiangnan University, Wuxi, People’s Republic of China; 6Université Paris Diderot, Laboratoire de Pathologie, Paris, France; 7AP-HP-Hôpital Saint-Louis, Laboratoire de Pathologie, Paris, France *These authors contributed equally to this studyAbstract: Multiple drug resistance is still an unsolved problem in cancer therapy. Our previous study demonstrated that the chemotherapeutic drug doxorubicin (Dox) induced upregulation of P-glycoprotein (P-gp) in endothelial cells, resulting in a 20-fold increase in drug resistance and reduced efficiency of Dox treatment in a mice tumor model. In this study, we exposed human microvascular endothelial cells (HMEC-1) to sunitinib, a tyrosine kinase receptor inhibitor, to induce drug resistance. The results show that sunitinib treatment induced multiple drug resistance in these cells. They became resistant not only to sunitinib but also to Dox, paclitaxel, and vinblastine. Significant increases in P-gp (9.3-fold), ABCG2 (breast cancer resistance protein, 1.9-fold), and multidrug resistance-associated protein 1 (2.7-fold) gene transcription were found by quantitative polymerase chain reaction quantification, and their protein expression was confirmed by Western blot. These increases gave rise to an approximately five-fold increase in half maximal inhibitory concentration in these cells in response to sunitinib treatment in vitro. The inhibitors of adenosine triphosphate-binding cassette transporters did not reverse the drug resistance in sunitinib-resistant HMEC-1 cells, assumedly because of a blockage of the pump function caused by sunitinib. Our study indicates that the antiangiogenic drug sunitinib induces multiple drug resistance in endothelial cells. The induction of adenosine triphosphate-binding cassette transporters seems not to be responsible for observed multiple drug resistance, and the underlying mechanisms remain unknown.Keywords: drug resistance, endothelial cells, cancer therapy, ABC family, sunitinib

Mesenteric ischemia/reperfusion occurring during hemorrhagic shock and resuscitation (H/R) induces a systemic inflammatory response and damages endothelial cells. Our aim was to investigate whether H/R affects selectively mesenteric vascular reactivity and the roles of free radicals and inducible nitric oxide (NO) synthase (iNOS) in these changes. Rats subjected to H (30 min)/R (60 min) in the presence or absence of the free radical scavenger N-2 mercaptopropionyl glycine (MPG), or the specific inhibitor of iNOS [(3) N-(3-aminomethyl)benzyl) acetaminide; 1400W] were studied. Saline requirements to maintain systemic blood pressure during R (53.4 +/- 5.2 mL/kg/h) were reduced by MPG (26.2 +/- 3.1) and 1400W (37.5 +/- 4.1). H/R reduced maximal mesenteric arteries relaxation to acetylcholine (sham: 70% +/- 5%, H/R: 21% +/- 3%) and this impairment was prevented by MPG (66% +/- 10%) and reduced by 1400W (49% +/- 9%). H/R did not affect the endothelium-independent relaxations. Maximal responses to phenylephrine were reduced in mesenteric arteries by H/R (3.6 +/- 0.5 mN/mm vs. sham 6.5 +/- 0.5), this impairment was prevented by 1400W and MPG. No impaired response to acetylcholine was detected in skeletal muscle arteries. H/R was associated with an increased production of TNF-alpha (169 +/- 8.5 ng/mL vs. sham 38 +/- 5 ng/mL), and this was reduced to 75 +/- 8 ng/mL in MPG-treated rats. Total intestinal content of iNOS mRNA was also increased by H/R and this increase was partly reduced by treatment with MPG. H/R induces an early and selective mesenteric endothelial cell dysfunction through a mechanism that involves oxygen-derived free radicals and NO produced by iNOS. H/R is associated with a mesenteric hyporeactivity through an induction of NOS and may be prevented by scavenging free radicals. This early impairment in endothelial function is associated with a local inflammatory response.

Voltage-gated Na+ channels (VGSCs) are highly expressed in several types of carcinomas including breast, prostate and lung cancers as well as in mesothelioma and cervical cancers. Although the VGSCs activity is considered crucial for the potentiation of cancer cell migration and invasion, the mechanisms responsible for their functional expression and regulation in cancer cells remain unclear. In the present study, the role of the small GTPase RhoA in the regulation of expression and function of the Nav1.5 channel in the breast cancer cell lines MDA-MB 231 and MCF-7 was investigated. RhoA silencing significantly reduced both Nav1.5 channel expression and sodium current indicating that RhoA exerts a stimulatory effect on the synthesis of an active form of Nav1.5 channel in cancer cells. The inhibition of Nav1.5 expression dramatically reduced both cell invasion and proliferation. In addition, a decrease of RhoA protein levels induced by Nav1.5 silencing was observed. Altogether, these findings revealed: i) the key role of the small GTPase RhoA in upregulation of Nav1.5 channel expression and tumor aggressiveness, and ii) the existence of a positive feedback of Nav1.5 channels on RhoA protein levels. journal article research support, non-u.s. gov't 2014 Feb 2013 12 10 imported

Background —Chronic heart failure (CHF) impairs the endothelium-dependent, flow-mediated dilation (FMD) of small arteries. However, whether chronic angiotensin-converting enzyme (ACE) inhibition affects the impairment of FMD in CHF is unknown. We investigated the effects of long-term ACE inhibition on the FMD of peripheral arteries in rats with CHF and the mechanism(s) involved. Methods and Results —FMD was assessed in isolated, perfused gracilis muscle arteries from sham-operated, and untreated or ACE inhibitor-treated (perindopril 2 mg · kg −1 · day −1 for 10 weeks) rats with CHF (coronary artery ligation). The role of nitric oxide (NO), prostaglandins, and free radicals was assessed by pretreating the vessels with the NO synthase inhibitor N W -nitro- l -arginine, the cyclooxygenase inhibitor diclofenac, or the free radical scavenger N-2-mercaptopropionyl-glycine (MPG). Endothelial NO synthase mRNA expression was determined by reverse transcriptase polymerase chain reaction. In animals with hemodynamic and echographic signs of CHF, FMD was converted into vasoconstriction, and this was prevented by ACE inhibition. FMD of arteries from sham-operated or ACE inhibitor–treated CHF rats was abolished by N W -nitro- l -arginine. In untreated CHF rats, FMD was increased by diclofenac and MPG. In contrast, in arteries from ACE inhibitor–treated rats, neither diclofenac nor MPG affected FMD. In parallel, ACE inhibition prevented the reduction of endothelial NO synthase mRNA by CHF. Conclusions —In CHF, ACE inhibition normalized NO-dependent dilatation and suppressed the production of vasoconstrictor prostanoid(s), resulting in improved FMD. The improvement of FMD might contribute to the beneficial effects of ACE inhibition during CHF.

Background —Flow-mediated dilatation (FMD) of the peripheral arteries may be impaired in chronic heart failure (CHF), and this could contribute to the increased peripheral resistance and exercise intolerance that occur with this disease. Physical exercise improves the FMD of large conduit arteries in CHF, but whether a similar impairment also occurs in smaller arteries is unknown. The mechanisms of the changes in FMD after CHF or exercise are also unknown. Methods and Results —FMD was assessed in isolated, perfused, and preconstricted gracilis muscle arteries from sham-operated rats or CHF rats (coronary artery ligation) who were either sedentary or exercised (30-minute swimming period twice a day for 10 weeks, starting 7 days after ligation). In animals with hemodynamic and echographic signs of CHF, FMD was abolished and converted into vasoconstriction (percent change in diameter after 370 μL/min flow: sham, 42±5%; CHF, −4±3%; P P N ω -nitro- l -arginine (L-NA) but unaffected by the cyclooxygenase inhibitor diclofenac or the free radical scavenger N-(2-mercaptopropionyl)-glycine (MPG). In arteries from sedentary CHF rats, FMD was not modified by L-NA, but it was partially restored by diclofenac or MPG. In exercised CHF rats, FMD was abolished by L-NA and only moderately improved by diclofenac or MPG. Likewise, endothelial nitric oxide synthase mRNA expression (determined by reverse transcription polymerase chain reaction at the level of the gracilis muscle) was reduced by CHF, and this was prevented by exercise. Conclusions —CHF abolishes the FMD of small arteries by impairing the nitric oxide pathway, increasing oxidant stress, and releasing a prostanoid-contracting factor. Exercise partially restores FMD by increasing expression of endothelial nitric oxide synthase and preventing the production of vasoconstrictor prostanoids and free radicals. Such restoration of FMD might contribute to the increase in exercise capacity after physical exercise in CHF.

Background Rho GTPases are involved in cellular functions relevant to cancer. The roles of RhoA and Rac1 have already been established. However, the role of Rac3 in cancer aggressiveness is less well understood. Methods This work was conducted to analyze the implication of Rac3 in the aggressiveness of two breast cancer cell lines, MDA-MB-231 and MCF-7: both express Rac3, but MDA-MB-231 expresses more activated RhoA. The effect of Rac3 in cancer cells was also compared with its effect on the non-tumorigenic mammary epithelial cells MCF-10A. We analyzed the consequences of Rac3 depletion by anti-Rac3 siRNA. Results Firstly, we analyzed the effects of Rac3 depletion on the breast cancer cells’ aggressiveness. In the invasive MDA-MB-231 cells, Rac3 inhibition caused a marked reduction of both invasion (40%) and cell adhesion to collagen (84%), accompanied by an increase in TNF-induced apoptosis (72%). This indicates that Rac3 is involved in the cancer cells’ aggressiveness. Secondly, we investigated the effects of Rac3 inhibition on the expression and activation of related signaling molecules, including NF-κB and ERK. Cytokine secretion profiles were also analyzed. In the non-invasive MCF-7 line; Rac3 did not influence any of the parameters of aggressiveness. Conclusions This discrepancy between the effects of Rac3 knockdown in the two cell lines could be explained as follows: in the MDA-MB-231 line, the Rac3-dependent aggressiveness of the cancer cells is due to the Rac3/ERK-2/NF-κB signaling pathway, which is responsible for MMP-9, interleukin-6, -8 and GRO secretion, as well as the resistance to TNF-induced apoptosis, whereas in the MCF-7 line, this pathway is not functional because of the low expression of NF-κB subunits in these cells. Rac3 may be a potent target for inhibiting aggressive breast cancer.

Introduction Defective thrombolysis, a thrombotic risk factor, can be attributed to the formation of a compact clot poorly accessible to fibrinolytic enzymes. Venous thrombi, rich in red blood cells (RBCs), and arterial thrombi containing various amounts of RBCS, plasma and whole blood (WB) clot permeability and degradability were compared. The effect of rivaroxaban, a potent direct factor Xa inhibitor, was also evaluated. Materials and Methods Fibrin permeability was determined by flow measurement through the clot. Clot degradability was evaluated by the amount of D-dimer generated by clot perfusion with plasminogen and tissue plasminogen activator. Fibrin clot structure was assessed by confocal microscopy. Results WB clot permeability (KS) and degradability were 6.7- and 38-fold lower, respectively, compared with plasma clots. This is attributed to 1) occlusion of fibrin pores by RBCs and 2) a consistent increase in thrombin generation due to platelets and RBCs inducing formation of a tighter clot. Rivaroxaban added to plasma or WB before clotting, in reducing thrombin generation, led to the formation of a looser clot that is more degradable by fibrinolytic enzymes. Permeability and degradability of whole blood clots formed in the presence of rivaroxaban were very similar to those of plasma clots. Conclusion The resistance to fibrinolysis of WB clots was reduced considerably when clots were formed with rivaroxaban. These results may have implications for the development of antithrombotic agents.