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To examine the association of (1) high and low blood pressure (BP) and (2) antihypertensive (AH) drug use with incident frailty.We conducted a secondary analysis of data from the Multidomain Alzheimer Preventive Trial (MAPT), in which 1394 non-frail community-dwelling participants aged ≥70 years were followed up for 5 years. BP was measured once at baseline in a lying position using a validated electronic device. High BP was defined as systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg, and low BP as systolic BP ≤ 110 mm Hg and/or diastolic BP ≤ 70 mm Hg. AH drugs were assessed at baseline and classified according to the Anatomical Therapeutic Chemical (ATC) code.Incident frailty over the 5 years was assessed using the Fried phenotype. Cox proportional hazards models were used for the analyses.Low BP was associated with a greater risk of frailty (HR = 1.43, 95% CI [1.07-1.92], p = 0.02) after adjustment for age, sex, education, AH drug use, BMI, diabetes, ischemic heart disease, congestive heart failure, AF, stroke, MAPT randomization group, sit-to-stand chair test and pre-frailty. Participants with low BP and those on two or more AH drugs were at the greatest risk of frailty. Neither high BP (HR = 0.84, 95% CI [0.63-1.22], p = 0.24) nor AH drug use (HR = 1.21, 95% CI [0.89-1.64], p = 0.22) was independently associated with incident frailty.Low BP could be used as a new marker for identifying older adults at higher risk of frailty.gov registration number: NCT00672685.

Aim: Oral anticoagulants are the first-line drugs for treating thrombotic disorders related to nonvalvular atrial fibrillation and for treating deep vein thrombosis, diseases that increase in prevalence with age. Older patients have a greater risk of thrombotic and hemorrhagic events and are more prone to drug interactions. Given this backdrop, we wanted to determine the factors associated with the prescription of direct oral anticoagulants and vitamin K antagonists in older patients. Methods: We performed a cross-sectional observational study using a hospital prescription database. The study population consists of 405 older patients who were given oral anticoagulants. The 2 variables of interest were the prescription of 1 of the 2 classes of oral anticoagulants (direct oral anticoagulants vs vitamin K antagonists) and appropriateness of oral anticoagulant prescribing according to Summary of Product Characteristics (potentially inappropriate vs appropriate). Results: The factors associated with direct oral anticoagulant prescribing were the female gender (odds ratio [OR]: 1.87, 95% confidence interval [CI]: 1.22-2.88) and initiation during hospital stay (OR: 2.56, 95% CI: [1.52-4.32]). Stage 4 and 5 chronic kidney diseases (OR: 0.39, 95% CI: [0.19-0.79] and OR: 0.07, 95% CI: [0.01-0.53]) were factors favoring vitamin K antagonist prescription. Being 90 years of age or more (OR: 2.05, 95% CI: [1.06-3.98]) was a factor for potentially inappropriate anticoagulant prescribing. The gastroenterology department (OR: 2.91, 95% CI: [1.05-8.11]) was associated with potentially inappropriate anticoagulant prescribing. Conclusions: Direct oral anticoagulants are the drugs of choice for anticoagulant treatment, including in older adults. The female gender and the initiation during hospital stay increased the chances of being prescribed a direct oral anticoagulant in older adults. Stage 4 and 5 chronic kidney disease increased the likelihood of having a vitamin K antagonist prescribed. Our study also revealed a persistence of potentially inappropriate oral anticoagulant prescriptions in older patients.

International audience

To investigate the impact of visit-to-visit systolic blood pressure variability (BPV), diastolic BPV, mean arterial pressure variability, and pulse pressure variability on cognitive decline and incident dementia in noninstitutionalized patients aged ≥65 years. A total of 3319 subjects from the S.AGES (Sujets AGÉS—Aged Subjects) cohort underwent clinical examinations every 6 months during 3 years. Variability was evaluated using standard deviation (SD), coefficient of variation, average real variability, successive variation, variation independent of mean, and residual SD. Cognition was assessed using the Mini-Mental State Examination and dementia with the Diagnostic Statistical Manual of Mental Disorders. Linear mixed models and Cox proportional hazards models were used. Higher systolic BPV was associated with poorer cognition independently of baseline SBP: adjusted 1-SD increase of coefficient of variation: β (SE)=−0.12 (0.06), P =0.04. Similar results were observed for diastolic BPV and mean arterial pressure variability: β (SE)=−0.20 (0.06), P P =0.02). Among the 3319 subjects, 93 (2.8%) developed dementia. Higher systolic BPV was associated with greater dementia risk (adjusted 1-SD increase of coefficient of variation: hazard ratios=1.23 [95% CI, 1.01–1.50], P =0.04). Similar results were found for diastolic BPV and mean arterial pressure variability ( P

Polysaccharidic scaffolds hold great hope in regenerative medicine, however their sterilization still remains challenging since conventional methods are deleterious. Recently, electron beams (EB) have raised interest as emerging sterilization techniques. In this context, the aim of this work was to study the impact of EB irradiations on polysaccharidic macroporous scaffolds. The effects of continuous and pulsed low energy EB were examined on polysaccharidic or on polyelectrolyte complexes (PEC) scaffolds by SEC-MALLS, FTIR and EPR. Then the scaffolds’ physicochemical properties: swelling, architecture and compressive modulus were investigated. Finally, sterility and in vitro biocompatibility of irradiated scaffolds were evaluated to validate the effectiveness of our approach. Continuous beam irradiations appear less deleterious on alginate and chitosan chains, but the use of a pulsed beam limits the time of irradiation and better preserve the architecture of PEC scaffolds. This work paves the way for low energy EB tailor-made sterilization of sensitive porous scaffolds.

Background The computerization of prescriptions with a computerized physician order entry contributes to securing the error-free drug supply, but is not risk-free. Objective: To determine the impact of a computerized physician order entry system on prescribing errors immediately after its implementation and 1 year later. Setting The Cardiology and Diabetology Departments at Toulouse University Hospital, France. Method The prescriptions were analysed by pharmacists over three 30-day periods for 3 consecutive years (N: computerization period, N - 1, N + 1). For each identified error, the prescriber was informed by a pharmaceutical intervention. The pharmaceutical interventions were counted and arranged according to the classification by the French Society of Clinical Pharmacy. Their average numbers and clinical impacts were compared for each period using t-tests and Kruskal-Wallis tests. Main outcome measure The average numbers of pharmaceutical interventions. Results In total, 12.1 pharmaceutical interventions per 100 patient days were done during the N - 1 period, 14.1 during N and 9.6 during N + 1. Among those, 3.6 (N) and 2.1 (N + 1) were related to the computerization itself, and 10.5 (N) and 7.5 (N + 1) were not. The average number of computerization-related pharmaceutical interventions significantly decreased from N to N + 1 (p = 0.04). The average number of classic interventions decreased from N - 1 to N + 1 (p = 0.02). The clinical impacts of the computerization related errors were similar to those of other errors. Conclusion The implementation of the computerized physician order entry induced the appearance of specific computerized-related errors, but the number of classic errors decreased. The entry-system related errors were not more severe than other errors, and the number decreased after 1 year.

Dental caries is defined as a pathological breakdown of the tooth. It is an infectious phenomenon involving a multifactorial aetiology. The impact of drugs on cariogenic risk has been poorly investigated. In this study, we identified drugs suspected to induce dental caries as adverse drug reactions (ADRs) and then studied a possible pathogenic mechanism for each drug that had a statistically significant disproportionality. We extracted individual case safety reports of dental caries associated with drugs from VigiBase® (the World Health Organization global individual case safety report database). We calculated disproportionality for each drug with a reporting odds ratio (ROR) and 99% confidence interval. We analysed the pharmacodynamics of each drug that had a statistically significant disproportionality. In VigiBase®, 5229 safety reports for dental caries concerning 733 drugs were identified. Among these drugs, 88 had a significant ROR, and for 65 of them (73.9%), no information about dental caries was found in the summaries of the product characteristics, the Micromedex® DRUGDEX, or the Martindale databases. Regarding the pharmacological classes of drugs involved in dental caries, we identified bisphosphonates, atropinic drugs, antidepressants, corticoids, immunomodulating drugs, antipsychotics, antiepileptics, opioids and β2-adrenoreceptor agonist drugs. Regarding possible pathogenic mechanisms for these drugs, we identified changes in salivary flow/composition for 54 drugs (61.4%), bone metabolism changes for 31 drugs (35.2%), hyperglycaemia for 32 drugs (36.4%) and/or immunosuppression for 23 drugs (26.1%). For nine drugs (10.2%), the mechanism was unclear. We identified 88 drugs with a significant positive disproportionality for dental caries. Special attention has to be paid to bisphosphonates, atropinic drugs, immunosuppressants and drugs causing hyperglycaemia.

BACKGROUND: Our objective was to investigate the impact of both prevalent and incident hypertension on cognition in middle-aged individuals followed up for 10 years and to explore the extent to which blood pressure control by antihypertensive drugs could modify this relationship. METHOD: Three thousand, two hundred and one participants from the Vieillissement Sante Travail (Aging, Health and Work) (VISAT) cohort study, aged 32, 42, 52 and 62 years at baseline were followed up 5 and 10 years later. Blood pressure, antihypertensive medication use as well as memory and speed cognitive performances were assessed at baseline and follow-up. Linear mixed models were used for analyses. RESULTS: At 10-year follow-up, compared with nonhypertensive participants, prevalent hypertensive individuals showed poorer global cognitive performances (beta = -2.99 +/- 0.96, P = 0.002 for participants aged 32 or 42 years at baseline and beta = -5.94 +/- 1.00, P < 0.001 for those aged 52 or 62). Patients with incident hypertension had poorer global cognitive performances over time compared with patients without hypertension. When considering prevalent hypertension and blood pressure control status by antihypertensive therapy, untreated and uncontrolled hypertension were associated with poorer cognitive performances than controlled and no hypertension (untreated hypertension compared with no hypertension: beta = -5.51 +/- 0.75, P < 0.001; uncontrolled hypertension compared with no hypertension: beta = -6.13 +/- 1.40, P < 0.001). CONCLUSION: Our findings showed that both prevalent and incident hypertension are associated with poorer global cognitive function in middle-aged individuals and suggested a potential preventive effect of antihypertensive therapy on cognition. Thus, for brain functioning, heightened efforts to detect hypertension and adequately treat it are of critical importance.

Summary Introduction Faced with the increasing number of pharmaceutical products on the market, several pharmacovigilance notifications regarding confusion between look-alike and sound-alike drugs have been reported. This study of perception among patients, family physicians and pharmacists aims to evaluate drug identification factors and the risk of errors of confusion for patients. Material and methods Patients were systematically approached in randomly selected pharmacies within the Midi-Pyrenees region in France and invited to complete a questionnaire. Two other questionnaires were respectively sent to family physicians and pharmacists in the same region asking for their opinion on patients’ perception of the identification of prescribed medicines. Results Of the 768 patients interviewed, most report identifying their medications by name (brand name: 50%; generic: 21%), while a smaller number cite physical appearance (box: 16%, tablet: 7% and blister packaging: 3%). In practice the factors considered most likely to cause confusion by patients relate to drug appearance (look-alike tablets: 28%, look-alike boxes: 20% and look-alike blister packaging: 13%). In contrast, look-alike and sound-alike names (generic and brand names combined) were cited in 31% of cases. Physicians (n = 345) and pharmacists (n = 198) understimate that patients identify their treatment by name (physicians: 46%; pharmacists: 26% vs. patients: 71%), reporting instead that problems arise mainly from the appearance of medicines (physicians: identification: 52% and risk factors for confusion: 74%; pharmacists: identification: 74% and risk factors for confusion: 83%; versus patients: identification: 26%; risk factors for confusion: 61%). Discussion Our study highlights the critical role of medication name in identifying drugs among patients. However, confusion of look-alike tablets or pills figures prominently among fears surrounding medication errors. Despite several notifications of pharmacovigilance, this issue appears to be underestimated within the body of medical literature. Proper identification of medicines by patients is essential to improving medication safety and therapeutic compliance. Concrete measures can be undertaken to reach this goal.

To investigate the association between pulse wave velocity, intima-media thickness, carotid artery diameter, carotid plaques, and conversion from mild cognitive impairment to dementia. Three hundred and seventy-five elderly ambulatory subjects with mild cognitive impairment were followed yearly to examine potential conversion to dementia. Vascular function was assessed by carotid-femoral pulse wave velocity. Vascular structure was evaluated by intima-media thickness, carotid artery diameter, and carotid plaques using an ultrasonographic assessment of carotid arteries. One hundred and five patients (28%) converted to dementia during a mean follow-up period of 4.5 years. Higher pulse wave velocity was associated with greater risk of conversion to dementia (1-SD increase of pulse wave velocity: hazard ratio, 1.33; 95% CI, 1.04–1.71; P =0.02) independently of age, sex, educational level, systolic blood pressure, cardiovascular diseases, body mass index, calcium channel blockers intake, Mini–Mental State Examination at baseline, and apoE ε4 status. Intima-media thickness, carotid plaques, and carotid artery diameter did not predict conversion to dementia (1-SD increase of intima-media thickness: hazard ratio, 0.93; 95% CI, 0.73–1.18; P =0.55; presence of carotid plaques: hazard ratio, 1.08; 95% CI, 0.62–1.87; P =0.79; 1-SD increase of carotid artery diameter: hazard ratio, 1.08; 95% CI, 0.89–1.31; P =0.44). Pulse wave velocity was associated with conversion to dementia, whereas intima-media thickness, carotid plaques, or carotid artery diameter were not after controlling for age and other confounding factors. Arterial stiffness could identify mild cognitive impairment patients at higher risk of dementia and may be a therapeutic target to delay or prevent the onset of dementia.

Objectif. Decrire les facteurs associes a la prescription d’anticoagulants oraux directs (AOD). Methode. Cohorte de patients de rythmologie du Centre Hospitalier Universitaire de Toulouse, traites par anticoagulants oraux dans le cadre d’une fibrillation atriale (FA). Une regression logistique a permis de decrire les facteurs associes a la prescription d’AOD et ceux associes a l’arret de l’anticoagulant. Resultats. Parmi les 140 patients inclus, 92 etaient traites par anti-vitamines K (AVK) et 48 par AOD. Les facteurs associes a la prescription d’AOD etaient un diagnostic de FA recent, la prise anterieure d’AVK et l’absence d’anti-agregants plaquettaires (AAP). L’arret de l’anticoagulant (n = 24) etait associe a la prise d’AOD. Conclusion. Les AOD sont moins prescrits que les AVK chez les patients sous AAP. L’ international normalized ratio (INR) est equilibre chez la majorite des patients sous AVK etant passes aux AOD. Une etude plus puissante permettrait de confirmer le profil de prescription des AOD.

Rationale, aims and objectives Hospital clinical pharmacists are involved in teaching students during professional internship. Organization between the unit care and the pharmacy place is complicated. This study evaluated the effectiveness of two pharmaceutical teams: an experienced pharmacist in the pharmacy place, reachable by phone (team 1) or an experienced pharmacist in the ward, near patients and students (team 2). Methods Pharmaceutical interventions were collected during two successive time periods, each of 6 months in a 15-bed unit (neurology). During the first time period, prescriptions were analyzed by the student (resident) in the ward and experienced pharmacist in the pharmacy place. During the second time period, prescriptions were analyzed by both experienced pharmacist and the resident in the ward. We compared the number, the type, the approval of pharmaceutical interventions and the medication reconciliation activities. Proportions were compared by a chisquared test (or Fisher exact test) as well as the quantitative value was calculated by a Student test. Results ‘Mentoring and supervising’ students in the ward increased significantly the number of pharmaceutical interventions (PI; 104 interventions for 1408 analyzed prescriptions (7.4%) by the students in the ward and 317 interventions for 1391 (22.8%) by both the experienced pharmacist and the students in the ward (P = 0.002). Furthermore, specific interventions from medication reconciliation were significantly increased by the presence of experienced pharmacist in the ward (0.96% vs. 8.83% P = 0.018). Conclusion Effectiveness of clinical pharmacists can be improved by the presence of experienced pharmacist at patients’ bedside, near students.

Resume Introduction L’accident vasculaire cerebral (AVC) est une pathologie de survenue brutale, responsable d’un grand nombre de handicaps, de demences et de deces dans les pays occidentaux. Le traitement de reference de la prevention secondaire, essentiel pour diminuer le risque de recidive, est l’acetylsalycilate de lysine ou aspirine. En cas de fibrillation atriale (FA), les anticoagulants sont indiques. En 2012, l’extension de l’autorisation de mise sur le marche (AMM) des nouveaux anticoagulants oraux (communement appeles NOAC), plus precisement les anticoagulants oraux directs (AOD) dans la prevention des AVC chez les patients adultes atteints de FA non valvulaire, a entraine une progression des prescriptions d’AOD et notamment de dabigatran et rivaroxaban. Devant le risque iatrogene hemorragique, une information du patient, un accompagnement a la prescription et a l’analyse pharmaceutique ainsi qu’un suivi dans le temps, paraissent indispensables conformement au plan national pour la securite des patients (PNSP 2013–2017). Methodes Des outils ont ete elabores par les medecins de l’unite neurovasculaire (UNV) du CHU Toulouse Purpan, en collaboration avec les pharmaciens cliniciens, grâce a un partenariat avec les equipes d’education therapeutique de cardiologie et de medecine vasculaire. Les sources bibliographiques validees sont les recommandations des caracteristiques des produits, les avis de transparence de la Haute Autorite de sante (HAS) et les communications de l’Agence nationale de la securite du medicament (ANSM). Les documents ont ete valides par la Commission des medicaments et des dispositifs medicaux steriles (COMEDIMS) et une diffusion est prevue sur le site de l’Agence regionale de sante (ARS). Resultats Les outils crees sont des brochures informatives personnalisees pour le patient servant de support a l’entretien pharmaceutique, un tableau d’aide a la prescription et a l’analyse pharmaceutique dans le but de lutter contre l’iatrogenie medicamenteuse et un feuillet d’enregistrement permettant de realiser un suivi a plus long terme des patients. Conclusion Ce travail pluridisciplinaire a pour but de prevenir l’iatrogenie medicamenteuse et de promouvoir le bon usage du medicament. Il resulte et concretise une bonne integration des pharmaciens cliniciens dans une UNV.

International audience; Rationale, aim, and objective: There are several ways to establish an accurate medication list in the hospital admission medication reconciliation (MedRec). The challenge for MedRec lies in the availability, reliability, and completeness of the data used. In France, the Electronic Pharmaceutical Record (ePR) was developed to register each medication taken by ambulatory patients, primarily to make dispensation in community pharmacies safe. We evaluated the suitability of this tool in the MedRec when patients were admitted to the hospital. Method: We conducted a 6-month pilot study of 249 MedRec files from a hospital diabetology department. The analysis was supplemented by the ePR for any patient for whom this information was recorded. The study evaluated the ePR as a new MedRec tool, as well as the clinical impact (CI) of the new data collected. Results: The ePR was contributory for 28% of the patients. Discrepancies were associated with polypharmacy, most of which had a CI = 1. Medication omission was the most frequently found discrepancy (72%), but self-medication (8%) and lack of medication adherence (9%) were also observed. Conclusion: This tool provided added value for reconciliation, as it quickly identifies regular medications, adherence, and self-medication behaviour. The ePR is essential for conducting a thorough MedRec.

Peripheral serotonin (5-HT) has been involved in adverse cardiac remodeling and valve fibrosis. The peripheral levels of 5-HT mainly depend on its release from activated platelets and degradation by monoamine oxidase A (MAO-A). The SERAOPI study investigated the relationship between arterial serotoninergic system, degree of platelet activation and cardiac remodeling, in patients with aortic valve stenosis (AS). Thirty patients with severe AS and 15 control subjects underwent transthoracic echocardiography, radial, and aortic arterial blood sampling. Measurements of 5-HT and its MAO-A-dependent degradation product, 5-HIAA, were performed by HPLC. Arterial platelet activation was assessed by flow cytometry analysis of platelet surface expression of P-selectin and activated integrin GPIIb/IIIa. Activated platelets and arterial plasma 5-HT increased in AS patients as compared to control subjects (P-selectin 1.08 ± 0.2MFI vs. 0.49 ± 0.1MFI, P = 0.04; GPIIb/IIIa 0.71 ± 0.1MFI vs. 0.35 ± 0.1MFI; P = 0.0015 and arterial plasma 5-HT 11.55 ± 1.6 nM vs. 6.18 ± 0.7 nM, P = 0.028, respectively). Moreover, 5-HT was strongly correlated to left ventricular hypertrophy assessed by echocardiography. The correlation was independent of cardiovascular risk comorbidities and others echocardiographic AS parameters. Finally, plasma 5-HIAA increased in AS patients (74.64 ± 9.7 nM vs. 37.16 ± 4.1 nM; P = 0.0002) indicating a higher 5-HT degradation rate by MAO-A. Platelet activation, arterial circulating serotonin, and serotonin degradation increased in patients with AS. These observations suggest that the serotoninergic system may contribute to the pathogenesis of AS including valve fibrosis and adverse ventricular remodeling. Am. J. Hematol. 90:15–19, 2015. © 2014 Wiley Periodicals, Inc.

Resume Objectif Les evolutions de consommation de cocaine ainsi que le manque de recommandations officielles pour la prise en charge medicamenteuse font de cette toxicomanie un probleme preoccupant. Les substances coupantes de la cocaine en proportion grandissante dans les differentes formes existantes ne sont pas denuees d’effet. Les medecins doivent agir en prenant en compte la globalite du tableau clinique en essayant de comprendre la part de telle ou telle substance. Materiel et methode Cette revue de la litterature permet de mettre en evidence la difficulte de la prise en charge de cette toxicomanie. Les principales substances coupantes sont detaillees avec leurs effets notables en fonction de leurs voies d’administration. Les grands principes de la prise en charge aigue et chronique feront l’objet d’un paragraphe distinct en fonction des cibles pharmacologiques ainsi que les moyens medicamenteux dont le corps medical dispose. Conclusion et discussion Un tableau recapitulatif est propose pour la pratique clinique afin de lister l’ensemble des domaines medicaux qui peuvent etre atteints autant par les effets de la cocaine que par les principales substances coupantes et les investigations medicales ou surveillances a faire qui en decoulent. Enfin, sont evoquees les autres prises en charge non medicamenteuses et les nouveaux outils pour les evaluer.

Resume Objectif Utilisation de deux techniques complementaires pour evaluer l’observance des patientes aux antiosteoporotiques. Methodes Etude transversale monocentrique realisee sur une periode de 6 mois chez les patientes d’une pharmacie de Midi-Pyrenees, traitees par medicaments antiosteoporotiques. L’observance a ete estimee en croisant 2 techniques (autoquestionnaire patient et mesure du medication possession ratio ). Une analyse statistique descriptive et une modelisation par regression logistique pour identifier les facteurs associes a un defaut d’observance ont ete realisees. Resultats En utilisant deux techniques evaluant l’observance au medicament des patientes, le defaut d’observance etait compris entre 14 et 55 %. L’observance etait meilleure chez les patientes ayant recu des conseils dietetiques ou une information sur l’interet d’une activite physique, et moins bonne chez les patientes menopausees depuis moins de 23 ans. Conclusion Croiser plusieurs techniques evaluant l’observance des patientes a leur medicament permet de mieux identifier les patientes presentant un defaut d’observance.

International audience; Controlling microarchitecture in polymer scaffolds is a priority in material design for soft tissue applications. This paper reports for the first time the elaboration of alginate foam-based scaffolds for mesenchymal stem cell (MSC) delivery and a comparative study of various surfactants on the final device performance. The use of surfactants permitted to obtain highly interconnected porous scaffolds with tunable pore size on surface and in cross-section. Their mechanical properties in compression appeared to be adapted to soft tissue engineering. Scaffold structures could sustain MSC proliferation over 14 days. Paracrine activity of scaffold-seeded MSCs varied with the scaffold structure and growth factors release was globally improved in comparison with control alginate scaffolds. Our results provide evidence that exploiting different surfactant types for alginate foam preparation could be an original method to obtain biocompatible scaffolds with tunable architecture for soft tissue engineering.

Implantation of adrenal medullary bovine chromaffin cells (BCC), which synthesize and secrete a combination of pain-reducing neuroactive compounds including catecholamines and opioid peptides, has been proposed for the treatment of intractable cancer pain. Macro- or microencapsulation of such cells within semi-permeable membranes is expected to protect the transplant from the host's immune system. In the present study, we report the viability and functionality of BCC encapsulated into microcapsules of alginate-poly-L-lysine (PLL) with a liquefied inner core. The experiment was carried out during 44 days. Empty microcapsules were characterized in terms of morphology, permeability, and mechanical resistance. At the same time, the viability and functionality of both encapsulated and nonencapsulated BCC were evaluated in vitro. We obtained viable BCC with excellent functionality: immunocytochemical analysis revealed robust survival of chromaffin cells 30 days after isolation and microencapsulation. HPLC assay showed that encapsulated BCC released catecholamines basally during the time course study. Taken together, these results demonstrate that viable BCC can be successfully encapsulated into alginate-PLL microcapsules with a liquefied inner core.

Adrenal medullary chromaffin cells synthetize and secrete a combination of pain-reducing neuroactive compounds including catecholamines and opioid peptides. Previous reports have shown that implantation of chromaffin cells into the spinal subarachnoid space can reduce both acute and chronic pain in several animal models. We recently demonstrated that human chromaffin cell grafts in the cerebrospinal fluid (CSF) could alleviate intractable cancer pain after failure of systemic opiates. However, wider application of this approach was limited by the limited availability of allogeneic donor material. Alternatively, chromaffin cells from xenogeneic sources such as bovine adrenal medulla were successful in the experimental treatment of pain, but recent concern over risk of prion transmission precluded use of bovine grafts in human clinical trials. The objective of the present study was to investigate the possibility of developing a new xenogeneic porcine source of therapeutic chromaffin cells because this strategy is currently considered the safest for transplantation in man. In the present study, we report the isolation and the characterization of primary porcine chromaffin cells (PCC) compared to bovine cells. We show, for the first time, that these cells grafted in the rat subarachnoid space can attenuate pain-related behaviors as assessed by the formalin test, a model of tonic pain. Moreover, in addition to behavioral studies, immunohistochemical analysis revealed robust survival of chromaffin cells 35 days after transplantation. Taken together, these results support the concept that porcine chromaffin cells may offer an alternative xenogeneic cell source for transplants delivering pain-reducing neuroactive substances.

Describing the factors associated with direct oral anticoagulants (DOA) prescription in patients with atrial fibrillation (AF).This study was performed in Toulouse on a cohort of patients received in rhythmology consultation, treated with vitamin K antagonists (VKA) or DOA for AF. A multivariate model was performed using logistic regression to describe the factors associated with DOA prescription and secondly, those associated with discontinuation of the anticoagulant.Among the 140 patients included, 96 (66%) were treated with VKA and 48 (34%) with DOA. Recent AF diagnosis (OR 7.52, 95% CI [2.41;23.29], p = 0.001), previous exposure to VKA (OR 17.11, 95% CI [4.48;60.91], p0.001), and no current exposure to anti-platelet agents (APA) (OR 7.69, 95% CI [1.22; 50.00], p = 0.030) were associated to DOA prescription. Discontinuation of the anticoagulant (n=24) was associated to DOA intake (OR 2.71, 95% CI [1.21; 6.08], p = 0.016).DOA are less prescribed than VKA in patients treated with APA. DOA switch to VKA was not systematic in patients diagnosed for a long time. However, international normalized ratio (INR) values were stable in most of patients treated with VKA at the switching to DOA. A more powerful study would confirm the factors associated with DOA prescription.

A number of pre-clinical studies have demonstrated the value of adrenal medullary allografts in the management of chronic pain. The present longitudinal survey studied 15 patients transplanted for intractable cancer pain after failure of systemic opioids due to the persistence of undesirable side-effects. Before inclusion, all the patients had their pain controlled by daily intrathecal (I-Th) morphine administration. The main evaluation criteria of analgesic activity of the chromaffin cell allograft was the complementary requirement of analgesics and in particular the consumption of I-Th morphine required to maintain effective pain control. Out of the 12 patients who profited from enhanced analgesia with long-term follow-up (average 4.5 months), five no longer required the I-Th morphine (with prolonged interruption of systemic opioids as well), two durably decreased I-Th morphine intake and five were stabilized until the end of their follow-up. Durable decline and stabilization were interpreted as indicative of analgesic activity by comparison with the usual dose escalation observed during disease progression. In most cases, we noted a relationship between analgesic responses and CSF met-enkephalin levels. The results of this phase II open study demonstrate the feasibility and the safety of this approach using chromaffin cell grafts for long-term relief of intractable cancer pain. However, while analgesic efficacy was indicated by the reduction or stabilization in complementary opioid intake, these observations will need to be confirmed in a controlled trial in a larger series of patients.

To use two different techniques to assess adherence of patients treated with antiosteoporotic drug.This monocentric transversal study was performed on a 6 months period, on patients of a single French pharmacy treated with antiosteoporotic drugs. Adherence was assessed crossing 2 techniques (patient autoquestionnaire and medication possession ratio measurement). Statistical analysis consisted in a description of the population study and a multivariate logistic regression to identify the factors associated with a lack of observance.Using the two techniques, the lack of adherence was estimated to be between 14 and 55%. Adherence was better in patients who were given dietetic advice or information about the usefulness of physical activity and worse in patients who reached menopause less than 23 years ago.A better identification of patients with a lack of observance is possible by crossing several techniques to assess adherence of the patient to his antiosteoporotic drug.

Despite the success of alginate scaffolds and mesenchymal stem cells (MSCs) therapy in cardiac failure treatment, the impact of the physicochemical environment provided by alginate matrices on cell behavior has never been investigated. The purpose of this work was double: to determine the alginate composition influence on ( 1 ) encapsulated rat MSC viability, paracrine activity, and phenotype in vitro and ( 2 ) cardiac implantability and in vivo biocompatibility of patch shape scaffolds. Two alginates, differing in composition and thus presenting different mechanical properties when hydrogels, were characterized. In both cases, encapsulated MSC viability was maintained at around 75%, and their secretion characteristics were retained 28 days postencapsulation. In vivo study revealed a high cardiac compatibility of the tested alginates: cardiac parameters were maintained, and rats did not present any sign of infection. Moreover, explanted hydrogels appeared surrounded by a vascularized tissue. However, scaffold implantability was highly dependent on alginate composition. G-type alginate patches, presenting higher elastic and Young moduli than M-type alginate patches, showed a better implantation easiness and were the only ones that maintained their shape and morphology in vivo. As a consequence of alginate chemical composition and resulting hydrogel structuration, G-type alginate hydrogels appear to be more adapted for cardiac implantation.

Mesenchymal stem cells (MSCs) may be used as a cell source for cell therapy of solid organs due to their differentiation potential and paracrine effect. Nevertheless, optimization of MSC-based therapy needs to develop alternative strategies to improve cell administration and efficiency. One option is the use of alginate microencapsulation, which presents an excellent biocompatibility and an in vivo stability. As MSCs are hypoimmunogenic, it was conceivable to produce microparticles with [alginate-poly-l-lysine-alginate (APA) microcapsules] or without (alginate microspheres) a surrounding protective membrane. Therefore, the aim of this study was to determine the most suitable microparticles to encapsulate MSCs for engraftment on solid organ. First, we compared the two types of microparticles with 4 × 106 MSCs/ml of alginate. Results showed that each microparticle has distinct morphology and mechanical resistance but both remained stable over time. However, as MSCs exhibited a better viability in microspheres than in microcapsules, the study was pursued with microspheres. We demonstrated that viable MSCs were still able to produce the paracrine factor bFGF and did not present any chondrogenic or osteogenic differentiation, processes sometimes reported with the use of polymers. We then proved that microspheres could be implanted under the renal capsule without degradation with time or inducing impairment of renal function. In conclusion, these microspheres behave as an implantable scaffold whose biological and functional properties could be adapted to fit with clinical applications.

A new method is described for encapsulation of living cells. PC12 rat adrenal pheochromocytoma cells, which have been shown to synthesize, store and release dopamine were employed. The particles are made first and the cells then incorporated in a gentle mechanical procedure. The morphology (by light and electron microscopic observation), stability, rheology, texture and permeability of these microcapsules provided by Kappa Biotech were investigated. Membrane permeability studies demonstrated exclusion of 69,000 Da human serum albumin, but equilibrium of D-glucose and inulin was within 24h, indicating a molecular weight cut-off in the 5000-70,000 Da range. The viability and the function of the encapsulated cells were evaluated by measuring the spontaneous release of dopamine by high performance liquid chromatography with electrochemical detection. The results show that dopamine-secreting cells can be sequestered in a semi-permeable capsule and still display good viability and proliferation for at least 1 month.

Adrenal medullary (AM) tissue transplantation into the central nervous system has been reported as a potential source of opioid peptides and catecholamines, which have analgesic effects useful in the control of chronic pain. Clinical trials, involving allogeneic graft of whole tissue explants into the subarachnoid space of the lumbar spinal cord, have already been reported. The aim of the present study was to determine whether adhesion and function of AM explants were related in some extent and how this relationship could account for improvement of AM tissue in terms of analgesic activity before grafting. Our experiments demonstrated a significant correlation between the adherent state of AM organoids during culture and a sustained secretion of Met-enkephalin and catecholamines by chromaffin cells (CC). These findings suggest that optimal culture condition for AM organoid adhesion can be defined for maintenance of tissue, prior to transplantation. Using immunocytochemistry, flow cytometry, and ELISA assays we showed that different cell adhesion molecules (CAMs) and extracellular matrix ECM proteins were expressed and released by AM cells during culture. Adherent AM organoids expressed increased levels of specific neural CAMs (NCAM and HNK-1 epitope) and integrin chains (beta1, alpha1, alpha2, alpha4, alpha5) and deposited markedly higher levels of fibronectin, but also laminin and collagen IV. Those molecules and probably adhesion processes they control might be involved in the maintenance of the CC-secreting neuroendocrine phenotype through cellular signaling pathways.

Intracerebroventricular morphine analgesic for the treatment of cancer pain was administered, using implanted access ports, in 82 patients from 1984 to January 1994. All of the patients who were selected for treatment were no longer responsive and had developed drug side effects to oral or parenteral opiates in varying doses (60-400 mg/d). The mean follow-up was 66 days (range, 12-443 d) for this series of 82 patients. The effective control of pain was achieved in nearly all of the patients, with only two failures. During the treatment, the daily morphine doses were moderately increased. The initial doses of morphine were a mean of 0.30 mg (range, 0.10-2 mg), and the final doses were a mean of 2.5 mg (range, 0.10-60 mg). The results show that the ratio of the terminal dose to the initial dose increased more rapidly for patients who had a follow-up of over 60 days. However, the increase seems to have been because of the progress of the disease rather than because of drug tolerance.