[From medication reconciliation to shared medication review: Pilot study integrating support for community pharmacists within a pharmaceutical care pathway]. / De la conciliation médicamenteuse au bilan partagé de médication : étude pilote intégrant un accompagnement des pharmaciens d'officine au sein d'un parcours de soins pharmaceutiques.

INTRODUCTION: Medication reconciliation at hospital and the shared medication review are two complementary activities for securing the medication management of the elderly patient. We are experimenting with a pharmaceutical care pathway including a support approach to promote continuity between these two activities and the initiation of shared medication review. MATERIALS AND METHODS: An admission and discharge medication reconciliation has been set up in a geriatric follow-up care and rehabilitation service. A drug assessment was also carried out during the hospital stay. Support for community pharmacists following conciliation was provided by phone calls. Medication discrepancies at admission and discharge, pharmaceutical interventions (PI) as well as satisfaction and difficulties encountered by community pharmacists were collected. RESULTS: Thirty-three patients were included in the study. On admission, 33% of patients had an unintentional discrepancy and 15% on discharge. On average 1.15 PI per patient were notified. The support was propounded to 13 pharmacists. Eight pharmacists (62%) accepted it. Among them, 5 (62.5%) had never performed a medication review. Lack of time was the main difficulty encountered by pharmacists. DISCUSSION AND CONCLUSION: Our pathway enables to integrate hospital and primary care activities and specifically support the delicate transition between them. This enables to facilitate the implementation of these activities and to maintain a relevant and secure continuity of pharmaceutical care.

Drug-related problems among older patients: Analysis of 8 years of pharmacist's interventions.

OBJECTIVES: To analyse the most frequent DRP over time and pharmacists' interventions made among older patients aged over 75 years old. DRP between older patients and younger patients aged 18 to 74 years and between older patients treated in geriatric wards or not were also compared. METHODS: A cross-sectional observational study conducted on DRP detected by pharmacists at the university hospital centre of Lyon and prospectively recorded in the Act-IP© database from January 2008 to December 2015. RESULTS: A total of 56,223 DRP were investigated - 19,056 in older patients and 37,167 in younger patients. A supratherapeutic dosage was mainly reported (22.4% in older patients vs. 19.0% in younger patient) and pharmacists made interventions mostly to adjust dosage (27.3% vs. 24.2%). Physicians' acceptance was significantly lower in older patients (57.1% vs. 64.3%). DRP associated to a drug included a supratherapeutic use of acetaminophen (5.2% vs. 3.8%) and hypnotics (4.0% vs. 1.4%), medication in cardiology used without indication (1.4% vs. 0.2%) and underuse of vitamin D (1.2% vs. 0.1%). Supratherapeutic dosages were more significantly detected with a lower overall physicians' acceptance in older patients treated in general wards. CONCLUSIONS: This study highlights the specificity of DRP among older patients and encourages health care professionals to remain especially alert regarding older patients treated in general wards. These findings can contribute to define or adjust training needs and quality indicators to improve the daily practices of health care professionals.

Nb and Cu co-doped (La,Sr)(Co,Fe)O3: a stable electrode for solid oxide cells.

Solid oxide cells (SOCs) are electrochemical devices that convert the chemical energy of a fuel into electricity. With regard to electrodes, the development of materials with mixed conduction properties is a key issue for improving the performance of SOCs at high temperatures. New Cu and Nb co-doping La1-x Sr x Fe y Co1-y O3-δ (LSCF) materials were studied as electrode materials on yttria-stabilized zirconia (YSZ) supports. The results show that Cu0.05 + Nb0.05 co-doped LSCF maintains a stable cubic structure even after several heat treatments and has better conductivity than a classically used LSCF.

Pharmacists' interventions on prescription problems in one French community pharmacy: A prospective pilot study.

OBJECTIVES: While many international studies widely describe pharmacists' interventions (PIs) on drug-related problems (DRP) in community pharmacies, in France, these activities are underreported. The aim of this study is to describe the PI rate, given as the number of interventions in among all prescriptions reviewed during the study period. MATERIAL AND METHODS: This study was conducted in one French rural community pharmacy during a 7-month period. Age, sex, type of prescriber, type of problems, intervention and the outcome were prospectively recorded. PIs were prospectively formalized and classified using the validated tool from the French Society of Clinical Pharmacy. In addition, all interventions were reviewed by an independent pharmacist. RESULTS: Among the 20,238 prescriptions, n=211 pharmacists' interventions on 159 prescriptions (0.79%) were performed. Prescriptions were ordered by general practitioners in 78.6%. The most common DRP were the improper prescription (30.8%), a drug or medical device not received by the patient (21.8%, all linked to drug shortages) or a dosage problem (18.9%). Antibiotics were the most common drugs involved in DRP (13.3%). The main PI were the drug switch/establishment of a therapeutic alternative (38.4%), dose adjustment (25.6%) and optimization of the dispensing/administration modalities (25.1%). The overall acceptance rate of PIs was 93.4%. CONCLUSION: We found a PI rate, as well as acceptance rate by prescribers, in the same range than as reported in studies performed in other countries. A consequent large part percentage of PIs can be classified as "administrative". This first prospective French study needs to be further supported by multi-site studies.

[Hospital pharmacy residency in France in 2014: to a recognition of the specialization?]. / L'internat en pharmacie hospitalière en France à l'horizon 2014 : vers une formation reconnue ?

The current format of French residency in hospital pharmacy was created in 1983 and is a 4-year specialized training. So far, training has not been recognized as a prerequisite for hospital pharmacy practice. Since 2011, pharmacy residents and hospital pharmacists representative structures have lobbied for that recognition and the government has worked in that direction. The ideology of the concept was validated after a period of probation and the regulatory procedure began late 2012. Two key elements were initially identified as obstacles: first the European legislation on recognition of professional qualifications and then the fear that there might not be enough hospital pharmacists trained in order to complete the care missions in hospital pharmacies in France. The European legislation has now been amended in order to recognize professional qualifications and a demographic analysis of hospital pharmacists leads to the conclusion that these items are no longer obstacles. In 2014, hospital pharmacy residency, through the Specialized Studies degree, should be recognized as a prerequisite for hospital pharmacy practice.

A detailed field-based evaluation of naphthenic acid mobility in groundwater.

An anaerobic plume of process-affected groundwater was characterized in a shallow sand aquifer adjacent to an oil sands tailings impoundment. Based on biological oxygen demand measurements, the reductive capacity of the plume is considered minimal. Major dissolved components associated with the plume include HCO(3), Na, Cl, SO(4), and naphthenic acids (NAs). Quantitative and qualitative NA analyses were performed on groundwater samples to investigate NA fate and transport in the subsurface. Despite subsurface residence times exceeding 20 years, significant attenuation of NAs by biodegradation was not observed based on screening techniques developed at the time of the investigation. Relative to conservative tracers (i.e., Cl), overall NA attenuation in the subsurface is limited, which is consistent with batch sorption and microcosm studies performed by other authors. Insignificant biological oxygen demand and low concentrations of dissolved As (<10 microg L(-1)) in the plume suggest that the potential for secondary trace metal release, specifically As, via reductive dissolution reactions driven by ingress of process-affected water is minimal. It is also possible that readily leachable As is not present in significant quantities within the sediments of the study area. Thus, for similar plumes of process-affected groundwater in shallow sand aquifers which may occur as oil sands mining expands, a reasonable expectation is for NA persistence, but minimal trace metal mobilization.

A Phase II study targeting amyloid-beta with 3APS in mild-to-moderate Alzheimer disease.

BACKGROUND: As a potential disease-modifying treatment for Alzheimer disease (AD), 3-amino-1-propanesulfonic acid (3APS) is a compound that binds to amyloid beta (Abeta), a toxic protein known to aggregate, leading to amyloid plaque deposition in the brain. METHODS: We assessed the safety, tolerability, and pharmacokinetic/pharmacodynamic effect of 3APS in a randomized, double-blind, placebo-controlled Phase II study in which 58 subjects with mild-to-moderate AD were randomly assigned to receive placebo or 3APS 50, 100, or 150 mg BID for 3 months. At the end of the double-blind phase, 42 of these subjects entered an open-label phase in which they received 3APS 150 mg BID for 17 months. Assessments included plasma and CSF 3APS concentrations, CSF levels of Abeta (Abeta(40) and Abeta(42)), and total tau, as well as cognitive (Alzheimer's Disease Assessment Scale-cognitive subscale, Mini-Mental State Examination) and clinical (Clinical Dementia Rating scale-Sum of Boxes) measures. RESULTS: 3APS had no significant impact on vital signs or laboratory test values. The most frequent side effects were nausea, vomiting, and diarrhea, which were intermittent and mild to moderate in severity. Seven 3APS-treated subjects discontinued because of side effects (all causalities) over the course of the study, and there were no 3APS-related serious adverse events. 3APS crossed the blood-brain barrier, and dose-dependently reduced CSF Abeta(42) levels after 3 months of treatment. There were no psychometric score differences between groups over the 3-month double-blind period. CONCLUSION: Long-term administration of 3-amino-1-propanesulfonic acid is safe, tolerated and reduces CSF Abeta(42) levels in patients with mild-to-moderate Alzheimer disease.

Fibro-osseous proliferation in the sternums and femurs of female B6C3F1, C57black and CD-1 mice: a comparative study.

Sternums and femurs from B6C3F1, C57black and CD-1 mice, used as controls in carcinogenicity studies, were microscopically examined for the presence of fibro-osseous proliferation (syn. hyperostosis, myelofibrosis, osteofibrosis). The uterus, vagina and ovaries of the same animals were microscopically examined, particularly for the morphological changes indicative of hyperestrogenism. The incidences of each finding in each strain were compared using a chi square test to detect any interstrain variations of statistical significance. Despite the markedly high incidence of endometrial cystic hyperplasia, vaginal epithelial cell hyperplasia and hyperkeratosis, which are morphological changes indicative of hyperestrogenism in all three strains of mice, the incidence of fibro-osseous proliferation in B6C3F1 mice was markedly higher than in the other two strains and statistically significant. This could be explained by a more sustained and higher level of endogenous estradiol in B6C3F1 mice, as brought into evidence by the markedly high, and stastically significant, incidence of follicular development/atresia, with cystic formation, in the ovaries of this strain. However, genetic factors that could determine the general predisposition to fibro-osseous proliferation in B6C3F1 mice cannot be ruled out.

Selective modulation of chemokinesis, degranulation, and apoptosis in eosinophils through the PGD2 receptors CRTH2 and DP.

BACKGROUND: PGD(2) is the major prostanoid released by mast cells during an allergic response. Its role in the allergic response, however, remains unclear. OBJECTIVE: Because the accumulation of eosinophils is a feature of allergic reactions, we investigated the role of PGD(2) in the modulation of eosinophil function. METHODS: Circulating human eosinophils were isolated and challenged with PGD(2). The effects of PGD(2) on various eosinophil functions were then analyzed. RESULTS: PGD(2) binds with high affinity preferentially to 2 receptors, DP and chemoattractant receptor-homologous molecule expressed on T(H)2 cells (CRTH2). We show that both DP and CRTH2 are detectable on circulating eosinophils. We demonstrate that PGD(2) (1-10 nmol/L) induces a rapid change in human eosinophil morphology and an increase in chemokinesis and promotes eosinophil degranulation. These effects are induced by the CRTH2-selective agonist 13-14-dihydro-15-keto-PGD(2) (DK-PGD(2)) but not by the DP-selective agonist BW245C. These results suggest a role for CRTH2 in the modulation of eosinophil movement and in triggering the release of cytotoxic proteins. Finally, we demonstrate that BW245C, but not DK-PGD(2), can delay the onset of apoptosis in cultured eosinophils, presumably through interaction with DP. CONCLUSION: These data support the hypothesis that PGD(2) controls eosinophil functions through 2 pharmacologically distinct receptors with independent functions. Blockade of PGD(2)-mediated effects on human eosinophils may reduce the damage caused by these cells during an allergic response, but inhibition of both receptors may be required.

Glycosaminoglycan mimetics: a therapeutic approach to cerebral amyloid angiopathy.

Amyloid deposits characteristic of cerebral amyloid angiopathy lead to vessel rupture and intracerebral hemorrhage. Proteoglycans associate with the amyloid fibril deposits and are thought to play a role in the polymerization of amyloid proteins and the propagation of the deposition process. A series of low molecular weight anionic compounds was developed to mimic the glycosaminoglycan moieties of these proteoglycans. These compounds were tested in different in vitro systems to determine their anti-Abeta amyloid activity. Specific compounds were identified as being anti-fibrillogenic and protective against Abeta-induced cvtotoxicity. Such compounds also did not show intrinsic cellular toxicity could cross the blood-brain barrier (BBB) in vivo, and showed a good safety profile following chronic' exposure. Molecules showing an anti-amyloid profile combined with the ability to cross the BBB represent promising therapeutics for CAA.

Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695.

We have created early-onset transgenic (Tg) models by exploiting the synergistic effects of familial Alzheimer's disease mutations on amyloid beta-peptide (Abeta) biogenesis. TgCRND8 mice encode a double mutant form of amyloid precursor protein 695 (KM670/671NL+V717F) under the control of the PrP gene promoter. Thioflavine S-positive Abeta amyloid deposits are present at 3 months, with dense-cored plaques and neuritic pathology evident from 5 months of age. TgCRND8 mice exhibit 3,200-4,600 pmol of Abeta42 per g brain at age 6 months, with an excess of Abeta42 over Abeta40. High level production of the pathogenic Abeta42 form of Abeta peptide was associated with an early impairment in TgCRND8 mice in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months of age. Notably, learning impairment in young mice was offset by immunization against Abeta42 (Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., Mount, H. T. J., Nixon, R. A., Mercken, M., Bergeron, C., Fraser, P. E., St. George-Hyslop, P., and Westaway, D. (2000) Nature 408, 979-982). Amyloid deposition in TgCRND8 mice was enhanced by the expression of presenilin 1 transgenes including familial Alzheimer's disease mutations; for mice also expressing a M146L+L286V presenilin 1 transgene, amyloid deposits were apparent by 1 month of age. The Tg mice described here suggest a potential to investigate aspects of Alzheimer's disease pathogenesis, prophylaxis, and therapy within short time frames.

Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain.

Huntington disease is a devastating neurodegenerative disease caused by the expansion of a polymorphic glutamine tract in huntingtin. The huntingtin interacting protein (HIP-1) was identified by its altered interaction with mutant huntingtin. However, the function of HIP-1 was not known. In this study, we identify HIP-1 as a proapoptotic protein. Overexpression of HIP-1 resulted in rapid caspase 3-dependent cell death. Bioinformatics analyses identified a novel domain in HIP-1 with homology to death effector domains (DEDs) present in proteins involved in apoptosis. Expression of the HIP-1 DED alone resulted in cell death indistinguishable from HIP-1, indicating that the DED is responsible for HIP-1 toxicity. Furthermore, substitution of a conserved hydrophobic phenylalanine residue within the HIP-1 DED at position 398 eliminated HIP-1 toxicity entirely. HIP-1 activity was found to be independent of the DED-containing caspase 8 but was significantly inhibited by the antiapoptotic protein Bcl-x(L), implicating the intrinsic pathway of apoptosis in HIP-1-induced cell death. Co-expression of a normal huntingtin fragment capable of binding HIP-1 significantly reduced cell death. Our data identify HIP-1 as a novel proapoptotic mediator and suggest that HIP-1 may be a molecular accomplice in the pathogenesis of Huntington disease.

Role of protein kinase C-alpha in the control of infection by intracellular pathogens in macrophages.

The protein kinase C (PKC) family regulates macrophage function involved in host defense against infection. In this study, we investigated the role of macrophage PKC-alpha in the uptake and subsequent fate of Leishmania donovani promastigotes and Legionella pneumophila infections. To this end, we used clones of the murine macrophage cell line RAW 264.7 overexpressing a dominant-negative (DN) mutant of PKC-alpha. While phagocytosis of L. donovani promastigotes was not affected by DN PKC-alpha overexpression, their intracellular survival was enhanced by 10- to 20-fold at 48 h postinfection. Intracellular survival of a L. donovani mutant defective in lipophosphoglycan repeating units synthesis, which normally is rapidly degraded in phagolysosomes, was enhanced by 100-fold at 48 h postinfection. However, IFN-gamma-induced leishmanicidal activity was not affected by DN PKC-alpha overexpression. Similar to macrophages from genetically resistant C57BL/6 mice, control RAW 264.7 cells were not permissive for the intracellular replication of Legionella pneumophila. In contrast, DN PKC-alpha-overexpressing RAW 264.7 clones were phenotypically similar to macrophages from genetically susceptible A/J mice, as they allowed intracellular replication of L. pneumophila. Permissiveness to L. pneumophila was not the consequence of a general defect in the microbicidal capacities because killing of a temperature-sensitive mutant of Pseudomonas aeruginosa was normal in DN PKC-alpha-overexpressing RAW 264.7 clones. Collectively, these results support a role for PKC-alpha in the regulation of innate macrophage functions involved in the control of infection by intracellular parasites.

Interactions of CD45-associated protein with the antigen receptor signaling machinery in T-lymphocytes.

CD45 is a transmembrane protein tyrosine phosphatase playing an essential role during T-cell activation. This function relates to the ability of CD45 to regulate p56(lck), a cytoplasmic protein tyrosine kinase necessary for T-cell antigen receptor (TCR) signaling. Previous studies have demonstrated that CD45 is constitutively associated in T-lymphocytes with a transmembrane molecule termed CD45-AP (or lymphocyte phosphatase-associated phosphoprotein). Even though the exact role of this polypeptide is unclear, recent analyses of mice lacking CD45-AP have indicated that its expression is also required for optimal T-cell activation. Herein, we wished to understand better the function of CD45-AP. The results of our studies showed that in T-cells, CD45-AP is part of a multimolecular complex that includes not only CD45, but also TCR, the CD4 and CD8 coreceptors, and p56(lck). The association of CD45-AP with TCR, CD4, and CD8 seemed to occur via the shared ability of these molecules to bind CD45. However, binding of CD45-AP to p56(lck) could take place in the absence of other lymphoid-specific components, suggesting that it can be direct. Structure-function analyses demonstrated that such an interaction was mediated by an acidic segment in the cytoplasmic region of CD45-AP and by the kinase domain of p56(lck). Interestingly, the ability of CD45-AP to interact with Lck in the absence of other lymphoid-specific molecules was proportional to the degree of catalytic activation of p56(lck). Together, these findings suggest that CD45-AP is an adaptor molecule involved in orchestrating interactions among components of the antigen receptor signaling machinery. Moreover, they raise the possibility that one of the functions of CD45-AP is to recognize activated Lck molecules and bring them into the vicinity of CD45.

Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation.

The amyloid-beta precursor protein (APP) is directly and efficiently cleaved by caspases during apoptosis, resulting in elevated amyloid-beta (A beta) peptide formation. The predominant site of caspase-mediated proteolysis is within the cytoplasmic tail of APP, and cleavage at this site occurs in hippocampal neurons in vivo following acute excitotoxic or ischemic brain injury. Caspase-3 is the predominant caspase involved in APP cleavage, consistent with its marked elevation in dying neurons of Alzheimer's disease brains and colocalization of its APP cleavage product with A beta in senile plaques. Caspases thus appear to play a dual role in proteolytic processing of APP and the resulting propensity for A beta peptide formation, as well as in the ultimate apoptotic death of neurons in Alzheimer's disease.

Caspases cleave focal adhesion kinase during apoptosis to generate a FRNK-like polypeptide.

Focal adhesion kinase (Fak) is a non-receptor protein-tyrosine kinase that stimulates cell spreading and motility by promoting the formation of contact sites between the cell and the extracellular matrix (focal adhesions). It suppresses apoptosis by transducing survival signals that emanate from focal adhesions via the clustering of transmembrane integrins by components of the extracellular matrix. We demonstrate that Fak is cleaved by caspases at two distinct sites during apoptosis. The sites were mapped to DQTD772, which was preferentially cleaved by caspase-3, and VSWD704, which was preferentially cleaved by caspase-6 and cytotoxic T lymphocyte-derived granzyme B. The cleavage of Fak during apoptosis separates the tyrosine kinase domain from the focal adhesion targeting (FAT) domain. The carboxyl-terminal fragments that are generated suppress phosphorylation of endogenous Fak and thus resemble a natural variant of Fak, FRNK, that inhibits Fak activity by preventing the localization of Fak to focal adhesions. The cleavage of Fak by caspases may thus play an important role in the execution of the suicide program by disabling the anti-apoptotic function of Fak. Interestingly, rodent Fak lacks an optimal caspase-3 consensus cleavage site although it is cleaved in murine cells undergoing apoptosis at an upstream site. This appears to be the first example of a caspase substrate where the cleavage sites are not conserved between species.