Impact of prolonged antihypertensive duration of action on predicted clinical outcomes in imperfectly adherent patients: comparison of aliskiren, irbesartan and ramipril.

Background: Most patients miss occasional doses of antihypertensives. The use of 'forgiving' drugs (i.e. drugs with duration of action longer than the 24-h dosing interval) may allow an adequate blood pressure (BP) reduction to be maintained despite missed doses. Aim:To quantify the effects of adherence level and duration of action on estimated mean systolic BP (SBP) reduction and cardiovascular disease (CVD) risk. Method:For 1250 patients, we simulated 256-day dosing histories with realistically distributed drug holidays based on a study of electronically monitored dosing records. Adherence was set to the desired level by altering the proportion of doses missed. Mean office SBP-lowering effect (aliskiren 300 mg, -14.1 mmHg; irbesartan 300 mg, -13.3; ramipril 10 mg, -10.1 mmHg) and the rate of SBP increase after stopping treatment (off-rate; aliskiren, 1.0 mmHg/day; irbesartan, 3.6 mmHg/day; ramipril, 4.0 mmHg/day) were taken from the results of a randomised, double-blind trial. SBP was averaged over time and patient to estimate mean reductions in SBP and 10-year CVD risk (Framingham risk equation, baseline absolute 10-year CVD risk: 27%). Results:Predicted reductions in SBP and CVD risk with aliskiren were larger and less affected by imperfect adherence than the reductions with irbesartan or ramipril. For aliskiren, reducing adherence from 90% to 60% led to a predicted rise in SBP of 1.0 mmHg and three additional CVD events per 1000 treated patients; larger predicted differences were observed for irbesartan (2.5 mmHg; 7.5 events/1000 treated patients) and ramipril (2.2 mmHg; 6.7 events/1000 treated patients). Conclusion:To offset the effects of imperfect adherence, a common challenge with antihypertensives, for better BP management it may be prudent to prescribe 'forgiving' drugs.

Place des antiarthrosiques symptomatiques d'action lente dans l'arthrose (sulfate de chondroïtine, glucosamine, acide hyaluronique) [Role of slow-acting anti-arthritic agents in osteoarthritis (chondroitin sulfate, glucosamine, hyaluronic acid)].

Osteoarthritis (OA) is one of the major causes of pain and of outpatient's clinics. 15 years ago, physiopathology of OA and its potential therapeutic targets were announced to be better understood, but the results of therapeutic trials were finally not as convincing as expected. Slow Acting Drugs (SADs) are part of the treatments evaluated in OA. Even if evidence based medicine is low, positive effects of SADs have been observed. We can reasonably propose these treatments for a short test period. It can sometimes enable us to decrease the dosage of others treatment such as NSAIDs. In any case, the physician must properly inform the patient about products available in Switzerland and must be aware of degrees of purity and costs of the products available on the intemet.

Role of the GNOM gene in Arabidopsis apical-basal patterning--From mutant phenotype to cellular mechanism of protein action.

How the apical-basal axis of polarity is established in embryogenesis is still a mystery in plant development. This axis appeared specifically compromised by mutations in the Arabidopsis GNOM gene. Surprisingly, GNOM encodes an ARF guanine-nucleotide exchange factor (ARF-GEF) that regulates the formation of vesicles in membrane trafficking. In-depth functional analysis of GNOM and its closest relative, GNOM-LIKE 1 (GNL1), has provided a mechanistic explanation for the development-specific role of a seemingly mundane trafficking regulator. The current model proposes that GNOM is specifically involved in the endosomal recycling of the auxin-efflux carrier PIN1 to the basal plasma membrane in provascular cells, which in turn is required for the accumulation of the plant hormone auxin at the future root pole through polar auxin transport. Thus, the analysis of GNOM highlights the importance of cell-biological processes for a mechanistic understanding of development.

Molecular mechanisms of action of herbal antifungal alkaloid berberine, in Candida albicans.

Candida albicans causes superficial to systemic infections in immuno-compromised individuals. The concomitant use of fungistatic drugs and the lack of cidal drugs frequently result in strains that could withstand commonly used antifungals, and display multidrug resistance (MDR). In search of novel fungicidals, in this study, we have explored a plant alkaloid berberine (BER) for its antifungal potential. For this, we screened an in-house transcription factor (TF) mutant library of C. albicans strains towards their susceptibility to BER. Our screen of TF mutant strains identified a heat shock factor (HSF1), which has a central role in thermal adaptation, to be most responsive to BER treatment. Interestingly, HSF1 mutant was not only highly susceptible to BER but also displayed collateral susceptibility towards drugs targeting cell wall (CW) and ergosterol biosynthesis. Notably, BER treatment alone could affect the CW integrity as was evident from the growth retardation of MAP kinase and calcineurin pathway null mutant strains and transmission electron microscopy. However, unlike BER, HSF1 effect on CW appeared to be independent of MAP kinase and Calcineurin pathway genes. Additionally, unlike hsf1 null strain, BER treatment of Candida cells resulted in dysfunctional mitochondria, which was evident from its slow growth in non-fermentative carbon source and poor labeling with mitochondrial membrane potential sensitive probe. This phenotype was reinforced with an enhanced ROS levels coinciding with the up-regulated oxidative stress genes in BER-treated cells. Together, our study not only describes the molecular mechanism of BER fungicidal activity but also unravels a new role of evolutionary conserved HSF1, in MDR of Candida.

Développement durable et urbanisme de projet : une nouvelle configuration de l'action publique

La notion de développement durable structure le débat contemporain sur les finalités et les instruments des politiques publiques. La montée en puissance des préoccupations environnementales et de qualité des cadres de vie déplace les enjeux traditionnels de l'aménagement. Cette refonte s'inscrit dans une prise de conscience de la transversalité des problèmes de développement territorial. Une attention accrue est aussi portée aux acteurs et à leur participation invitant à repenser les articulations entre les élus, l'administration et la société civile. L'aménagement du territoire est à un tournant. La complexité accrue du champ décisionnel liée à la multiplicité des objectifs à prendre en compte, à la diversification des acteurs concernés, mais aussi à l'interférence des échelles de gouvernance bouscule les pratiques professionnelles. Cette note vise à montrer les principaux changements observés au cours des dernières années. Elle met l'accent sur la redéfinition des objectifs et des instruments d'aménagement et l'émergence des nouvelles pratiques de conduite de projets.

Action publique concertée et gestion des sports de nature : une ethnographie participative au Conseil général du Bas-Rhin

En France, la décentralisation et la territorialisation de l'action publique ont fait des sports de nature un objet d'action publique légitime en donnant naissance à de nouveaux outils de management public dédiés à la concertation et à la planification des usages de la nature. Nés de l'article 52 de la Loi sur le sport modifiée en 2000, la Commission Départementale des Espaces, Sites et Itinéraires relatifs aux sports de nature (CDESI) et le Plan Départemental des Espaces Sites et Itinéraires relatifs aux sports de nature (PDESI) sont des outils de concertation territoriale dédiés à la gestion publique des sports de nature au niveau départemental. Un enjeu de ce travail tient à l'appréhension des transformations de l'action publique en s'attachant à l'étude des dispositifs de concertation sur les sports de nature. Un deuxième enjeu de ce travail s'attache à mettre en évidence les effets de la concertation en analysant les interactions et les différents modes d'engagements des acteurs au cours de la « chose publique en train de se faire » (Cefaï, 2002). Les acteurs s'engagent non seulement dans la concertation comprise comme une activité sociale faite d'interactions, mais ils s'engagent également dans la concertation en tant que processus d'action publique. Aussi, un autre enjeu de ce travail est d'appréhender les effets de la concertation par une analyse processuelle des engagements (Fillieule, 2004) des acteurs et des organisations. En mobilisant les outils conceptuels de la sociologie interactionniste, de la sociologie pragmatique, ainsi que de la sociologie structuraliste, l'analyse des situations interactionnelles a notamment permis d'identifier les procédures de cadrage et les techniques dramaturgiques mises en oeuvre par les interactants, ainsi que les répertoires argumentatifs mobilisés par ces acteurs pendant l « 'épreuve » de la concertation. Les confrontations des points de vue et les justifications des prises de positions des acteurs peuvent faire évoluer la configuration initiale des jeux d'acteurs même si, pour certains, ces changements ne restent parfois qu'éphémères. Les organisations s'engagent dans la concertation en fonction de la revendication d'une légitimité qui est à comprendre comme une forme militantisme institutionnel s'articulant autour de la valorisation d'une expertise militante, environnementale, institutionnelle, ou encore de leur statut de partenaire institutionnel. In France, decentralization and territorialization of public action have made outdoor sports become an object of public policies justifiable by giving birth to new tools of public management dedicated to the public consultation, the dialogue, and the planning of the uses of the landscapes. Indeed, born of article 52 of the Law on sport modified in 2000, the Departmental committee for Spaces, Sites and Routes relative to natural sports ( CDESI) and the Departmental Plan of Spaces Sites and Routes relative to natural sports ( PDESI) are governance tools dedicated to the public management of outdoor sports for counties. A challenge of this work is to understand the changes of public policy by focusing on the study of mechanisms for consultation on outdoor sports. A second item of this work is to highlight the effects of cooperation by focusing on the analysis of interactions and actor's commitments during the "public thing in the making" (Cefaï, 2002). Actors commit themselves not only in the dialogue included as a social activity made by interactions, but they also take part to the dialogue included as a process of public action. Also, another issue of this work is to understand the effects of consultation by a processual approach of individual commitments (Fillieule, 2004) of actors and organizations. Using the conceptual tools of symbolic interactionism, pragmatic sociology, and structuralist sociology, the analysis of interactional situations has highlighted the framing work and procedures implemented by the interactants, as well as the dramaturgical techniques and argumentative directories which, they mobilize during the "test" of the consultation. Confrontation of viewpoints and justifications of interactants' positions can evolve from their initial configuration sets, even if for some of them these changes are sometimes ephemeral. Organizations involve themselves according to demands of legitimacy which, are to understand as a shape institutional militancy articulating around the valuation of a militant, environmental, institutional expertise, or still around their status of institutional partner.

A CT-based study investigating the relationship between pedicle screw placement and stimulation threshold of compound muscle action potentials measured by intraoperative neurophysiological monitoring.

PURPOSE: Neurophysiological monitoring aims to improve the safety of pedicle screw placement, but few quantitative studies assess specificity and sensitivity. In this study, screw placement within the pedicle is measured (post-op CT scan, horizontal and vertical distance from the screw edge to the surface of the pedicle) and correlated with intraoperative neurophysiological stimulation thresholds. METHODS: A single surgeon placed 68 thoracic and 136 lumbar screws in 30 consecutive patients during instrumented fusion under EMG control. The female to male ratio was 1.6 and the average age was 61.3 years (SD 17.7). Radiological measurements, blinded to stimulation threshold, were done on reformatted CT reconstructions using OsiriX software. A standard deviation of the screw position of 2.8 mm was determined from pilot measurements, and a 1 mm of screw-pedicle edge distance was considered as a difference of interest (standardised difference of 0.35) leading to a power of the study of 75 % (significance level 0.05). RESULTS: Correct placement and stimulation thresholds above 10 mA were found in 71 % of screws. Twenty-two percent of screws caused cortical breach, 80 % of these had stimulation thresholds above 10 mA (sensitivity 20 %, specificity 90 %). True prediction of correct position of the screw was more frequent for lumbar than for thoracic screws. CONCLUSION: A screw stimulation threshold of >10 mA does not indicate correct pedicle screw placement. A hypothesised gradual decrease of screw stimulation thresholds was not observed as screw placement approaches the nerve root. Aside from a robust threshold of 2 mA indicating direct contact with nervous tissue, a secondary threshold appears to depend on patients' pathology and surgical conditions.