Platelet activation and arterial peripheral serotonin turnover in cardiac remodeling associated to aortic stenosis.

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.

[Factors Associated with Direct Oral Anticoagulants versus Vitamin K Antagonists in Patients with Non-valvular Atrial Fibrillation]. / Facteurs associés à la prescription d'anticoagulants oraux directs versus anti-vitamines K dans la fibrillation atriale non valvulaire.

OBJECTIVE: Describing the factors associated with direct oral anticoagulants (DOA) prescription in patients with atrial fibrillation (AF). METHOD: 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. RESULTS: 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], p<0.001), 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). DISCUSSION: 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.

[The lack of adherence to antiosteoporotic drugs: crossing methods, the key to adherence measurement?]. / Défaut d'observance aux médicaments antiostéoporotiques: croisement de deux techniques, la clef pour l'évaluation de l'observance ?

OBJECTIVE: To use two different techniques to assess adherence of patients treated with antiosteoporotic drug. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Blood pressure, antihypertensive drugs, and incident frailty: The Multidomain Alzheimer Preventive Trial (MAPT).

OBJECTIVES: To examine the association of (1) high and low blood pressure (BP) and (2) antihypertensive (AH) drug use with incident frailty. STUDY DESIGN: 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. MAIN OUTCOME MEASURES: Incident frailty over the 5 years was assessed using the Fried phenotype. Cox proportional hazards models were used for the analyses. RESULTS: 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. CONCLUSIONS: Low BP could be used as a new marker for identifying older adults at higher risk of frailty. CLINICALTRIALS: gov registration number: NCT00672685.

Low-energy electron beam sterilization of solid alginate and chitosan, and their polyelectrolyte complexes.

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.

Factors Associated With the Choice of Oral Anticoagulant Class in the Older Patients: An Observational Study.

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.

Visit-to-Visit Blood Pressure Variability Is Associated With Cognitive Decline and Incident Dementia: The S.AGES Cohort.

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: ß (SE)=-0.12 (0.06), P=0.04. Similar results were observed for diastolic BPV and mean arterial pressure variability: ß (SE)=-0.20 (0.06), P<0.001 for both. Higher pulse pressure variability was no longer associated with cognitive function after adjustment for age, except with residual SD (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<0.01). Pulse pressure variability was not associated with dementia risk. Beyond hypertension, higher BPV is a major clinical predictor of cognitive impairment and dementia. Further studies are needed to assess whether controlling BP instability could be a promising interventional target in preserving cognition among older adults.

Medication prescribing errors: a pre- and post-computerized physician order entry retrospective study.

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.

Alginate-chitosan PEC scaffolds: A useful tool for soft tissues cell therapy.

In this study we evaluate macroporous scaffolds made of alginate-chitosan polyelectrolyte complexes (PEC) as tools to optimize the results of soft tissues cell therapy. Cell therapy using mesenchymal stem cells (MSC) has become attractive for tissue repair and regeneration in a number of acute and chronic injuries. Unfortunately their low retention and/or survival after injection limit their beneficial effects. A biomaterial-assisted implantation, providing cells a three-dimensional (3D) microenvironment is a promising strategy. To this purpose, we designed a family of PEC scaffolds, and studied if they could meet the requirement of such application. Xray tomography showed that all PEC scaffolds present an interconnected macroporosity, and both rheology and tensile measurements reveal optimized mechanical properties (higher storage moduli and Young moduli) compared to alginate reference scaffolds. In vitro assays demonstrated their ability to allow MSC retention (higher than 90%), long-term viability and FGF2 secretion. Then, we used a skeletal muscle implantation model to assess the biological response to scaffolds graft, and showed that they support in vivo vascular formation within the implant-derived tissue. The combination of alginate/chitosan PEC scaffolds architecture and angiogenic potential make them appear as interesting tools to optimize MSC therapy results in soft tissues.

Drug identification by the patient: Perception of patients, physicians and pharmacists.

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-Pyrénées 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.

Blood pressure and cognitive performances in middle-aged adults: the Aging, Health and Work longitudinal study.

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 Santé 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 (ß = -2.99 ±â€Š0.96, P = 0.002 for participants aged 32 or 42 years at baseline and ß = -5.94 ±â€Š1.00, 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: ß = -5.51 ±â€Š0.75, P < 0.001; uncontrolled hypertension compared with no hypertension: ß = -6.13 ±â€Š1.40, 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.

The Electronic Pharmaceutical Record: A new method for medication reconciliation.

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.

Pulse Wave Velocity Is Associated With Greater Risk of Dementia in Mild Cognitive Impairment Patients.

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.

Correction to: Drug-Induced Dental Caries: A Disproportionality Analysis Using Data from VigiBase.

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.

Drug-Induced Dental Caries: A Disproportionality Analysis Using Data from VigiBase.

INTRODUCTION: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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 ß2-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. CONCLUSION: 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.

Elaboration and evaluation of alginate foam scaffolds for soft tissue engineering.

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.

Mentoring and supervising clinical pharmacist students at patients' bedside: which benefits?

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.

Human chromaffin cell graft into the CSF for cancer pain management: a prospective phase II clinical study.

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.

Evaluation of polyelectrolyte complex-based scaffolds for mesenchymal stem cell therapy in cardiac ischemia treatment.

Three-dimensional (3D) scaffolds hold great potential for stem cell-based therapies. Indeed, recent results have shown that biomimetic scaffolds may enhance cell survival and promote an increase in the concentration of therapeutic cells at the injury site. The aim of this work was to engineer an original polymeric scaffold based on the respective beneficial effects of alginate and chitosan. Formulations were made from various alginate/chitosan ratios to form opposite-charge polyelectrolyte complexes (PECs). After freeze-drying, the resultant matrices presented a highly interconnected porous microstructure and mechanical properties suitable for cell culture. In vitro evaluation demonstrated their compatibility with mesenchymal stell cell (MSC) proliferation and their ability to maintain paracrine activity. Finally, the in vivo performance of seeded 3D PEC scaffolds with a polymeric ratio of 40/60 was evaluated after an acute myocardial infarction provoked in a rat model. Evaluation of cardiac function showed a significant increase in the ejection fraction, improved neovascularization, attenuated fibrosis as well as less left ventricular dilatation as compared to an animal control group. These results provide evidence that 3D PEC scaffolds prepared from alginate and chitosan offer an efficient environment for 3D culturing of MSCs and represent an innovative solution for tissue engineering.

Alginate scaffolds for mesenchymal stem cell cardiac therapy: influence of alginate composition.

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.