Dose-dependent pharmacokinetics of ropivacaine in anesthetized rabbits : absence of changes in protein binding

Objective: The primary objectives of this study were to investigate the in vivo pharmacokinetics and in vitro plasma protein binding of ropivacaine at the concentration range observed after intravenous administration of different doses in anesthetized rabbits. Study design: Prospective experimental study Animals: Thirteen New Zealand White rabbits Methods: Rabbits were anesthetized with isoflurane. Different doses (0.62 to 6.52 mg/kg) of 0.5 % plain ropivacaine hydrochloride were administered and arterial blood sampled at frequent intervals up to 10 hours. Ropivacaine plasma concentrations were determined by high performance liquid chromatography. Pharmacokinetic analysis of individual data sets was performed using non-compartmental approach to calculate area under the plasma concentration–time curve from time zero to infinity (AUC0–inf). In vivo pharmacokinetics linearity was verified using analyses of variance for between group comparisons of the effect of dose on the AUC0–inf normalized by the dose. A population pharmacokinetic model was developed to describe ropivacaine disposition after intravenous administration in the linear range of dose in anesthetized rabbits. Determination of protein binding was performed, under controlled temperature and pH conditions, in plasma samples spiked extemporaneously with 3 H-ropivacaine and unlabeled ropivacaine (2.5 and 3500 ng/ml) using an ultrafiltration method. Results: At intravenous doses higher than 3.67 mg/kg, dose-dependent changes in ropivacaine systemic clearance were observed. In contrast, protein binding was found to be concentration independent in the tested range. Conclusions and clinical relevance: In anesthetized rabbits, saturation of ropivacaine plasma protein binding is not the mechanism responsible for the pharmacokinetic nonlinearity of ropivacaine observed at intravenous doses higher than 3.67 mg/kg. Disposition parameters obtained in our study will enable accurate characterization of ropivacaine pharmacokinetics after a peripheral nerve block

Nucleus accumbens D1- and D2-expressing neurons control the balance between feeding and activity-mediated energy expenditure

Accumulating evidence points to dysregulations of the Nucleus Accumbens (NAc) in eating disorders (ED), however its precise contribution to ED symptomatic dimensions remains unclear. Using chemogenetic manipulations in male mice, we found that activity of dopamine D1 receptor-expressing neurons of the NAc core subregion facilitated effort for a food reward as well as voluntary exercise, but decreased food intake, while D2-expressing neurons have opposite effects. These effects are congruent with D2-neurons being more active than D1-neurons during feeding while it is the opposite during running. Chronic manipulations of each subpopulations had limited effects on energy balance. However, repeated activation of D1-neurons combined with inhibition of D2-neurons biased behavior toward activity-related energy expenditure, whilst the opposite manipulations favored energy intake. Strikingly, concomitant activation of D1-neurons and inhibition of D2-neurons precipitated weight loss in anorexia models. These results suggest that dysregulations of NAc dopaminoceptive neurons might be at the core of EDs

La Convention sur la diversité des expressions culturelles quinze ans après : une mise en oeuvre effective d’un instrument juridique faiblement contraignant

La Convention sur la protection et la promotion de la diversité des expressions culturelles (Convention de 2005) est adoptée par la Conférence générale de l’UNESCO à Paris le 20 octobre 2005. Les objectifs que se fixent les Parties incluent la reconnaissance de la nature spécifique – économique et culturelle – des activités, biens et services culturels, la réaffirmation de leur droit souverain d’adopter et de mettre en oeuvre les politiques et mesures qu’elles jugent appropriées pour la protection et la promotion de la diversité des expressions culturelles, ainsi que le renforcement de la coopération internationale afin de parvenir à des échanges culturels plus équilibrés. Attendue comme une réponse à l’échec de l’exception culturelle survenu dans les années 90, la Convention de 2005 est cependant critiquée au lendemain de son adoption en raison de son faible niveau de contrainte. Or, quinze ans plus tard, un examen de la pratique des Parties permet de dresser un bilan positif de la mise en oeuvre de ce traité dont les engagements outrepassent largement le cadre de la relation entre le commerce et la culture. Les données recueillies grâce à la performance des mécanismes de suivi démontrent en effet que les Parties s’appuient abondamment sur la Convention de 2005 pour mener diverses initiatives en vue d’atteindre les objectifs de ce traité. Ces actions, qui traduisent des changements opérés par les États sur leur propre territoire ou dans les relations qu’ils entretiennent entre eux, sont le reflet de l’effectivité de cet instrument juridique pourtant faiblement contraignant.The Convention on the Protection and Promotion of the Diversity of Cultural Expressions (2005 Convention) was adopted by UNESCO’s General Conference in Paris on October 20, 2005. The objectives taken on by the Parties include acknowledging the specific nature—economic and cultural—of cultural activities, goods and services, the reaffirmation of their sovereign right to adopt or implement the policies and measures they deem appropriate for the protection and the promotion of the diversity of cultural expressions, as well as reinforcing international cooperation in order to achieve more balanced cultural exchanges. Seen as a response to the failure of the cultural exception of the 90s, the 2005 Convention is nevertheless criticized soon after its adoption due to its low level of constraint. However, 15 years later, an overview of the Parties’ practices results in a positive assessment of the implementation of this treaty for which the commitments largely exceed the framework of the relation between commerce and culture. The data collected due to the performance of the follow-up mechanisms indeed demonstrates that the Parties rely abundantly on the 2005 Convention to undertake diverse initiatives aimed at achieving the treaty’s objectives. These actions, translating changes operated by states on their own territories or within the relations they maintain with one another, are indicative of the effectivity of this legal instrument that is only weakly binding.La Convención sobre la Protección y Promoción de la Diversidad de las Expresiones Culturales (Convención de 2005) fue adoptada por la Conferencia General de la UNESCO en París el 20 de octubre de 2005. Los objetivos establecidos por las Partes incluyen el reconocimiento de la naturaleza específica – económica y cultural – de actividades, bienes y servicios culturales, la reafirmación del derecho soberano de las partes a adoptar e implementar las políticas y medidas que estimen convenientes para la protección y promoción de la diversidad de las expresiones culturales, así como el fortalecimiento de la cooperación internacional para lograr intercambios culturales más equilibrados. No obstante, la Convención de 2005, que se esperaba como respuesta al fracaso de la excepción cultural que se produjo en la década de 1990, fue criticada después de su adopción debido a su bajo nivel de obligaciones jurídicas. Sin embargo, quince años después, un examen de la práctica de las Partes permite hacer una valoración positiva de la implementación de este tratado, cuyos compromisos van mucho más allá de la relación entre comercio y cultura. Los datos recopilados a través de los mecanismos de monitoreo demuestran que las Partes dependen en gran medida de la Convención de 2005 para llevar a cabo diversas iniciativas que buscan lograr los objetivos de este tratado. Estas acciones, que reflejan cambios realizados por los Estados en su propio territorio o en las relaciones que mantienen entre sí, reflejan la efectividad de este instrumento legal a pesar de su débil carácter vinculante

When low level of constraint and effectiveness go hand in hand: The example of the 2005 Convention

International audienceThe year 2022 marks 15 years since the entry into force of the United Nations Educational, Scientific and Cultural Organization's 2005 Convention on the Protection and Promotion of the Diversity of Cultural Expressions. Among its objectives, this treaty aims at acknowledging the specific nature - economic and cultural - of cultural activities, goods, and services, reaffirming the sovereign right of states to adopt or implement measures they deem appropriate for the protection and the promotion of the diversity of cultural expressions as well as reinforcing international cooperation for more balanced cultural exchanges. Since its adoption, this treaty has been criticized for its low level of constraint. However, data collected over the years show that parties rely extensively on the Convention to undertake diverse initiatives to achieve the treaty's objectives. Based on concrete examples, this article aims to show that the effectivity of a legal instrument does not only rely on its degree of constraint but also on other factors, including monitoring mechanisms put in place in the context of its implementation

La Convention sur la diversité des expressions culturelles quinze ans après : une mise en œuvre effective d’un instrument juridique faiblement contraignant

The Convention on the Protection and Promotion of the Diversity of Cultural Expressions (2005 Convention) was adopted by UNESCO’s General Conference in Paris on October 20, 2005. The objectives taken on by the Parties include acknowledging the specific nature— economic and cultural— of cultural activities, goods and services, the reaffirmation of their sovereign right to adopt or implement the policies and measures they deem appropriate for the protection and the promotion of the diversity of cultural expressions, as well as reinforcing international cooperation in order to achieve more balanced cultural exchanges. Seen as a response to the failure of the cultural exception of the 90s, the 2005 Convention is nevertheless criticized soon after its adoption due to its low level of constraint. However, 15 years later, an overview of the Parties’ practices results in a positive assessment of the implementation of this treaty for which the commitments largely exceed the framework of the relation between commerce and culture. The data collected due to the performance of the follow-up mechanisms indeed demonstrates that the Parties rely abundantly on the 2005 Convention to undertake diverse initiatives aimed at achieving the treaty’s objectives. These actions, translating changes operated by states on their own territories or within the relations they maintain with one another, are indicative of the effectivity of this legal instrument that is only weakly binding.La Convention sur la protection et la promotion de la diversité des expressions culturelles (Convention de 2005) est adoptée par la Conférence générale de l’UNESCO à Paris le 20 octobre 2005. Les objectifs que se fixent les Parties incluent la reconnaissance de la nature spécifique – économique et culturelle – des activités, biens et services culturels, la réaffirmation de leur droit souverain d’adopter et de mettre en oeuvre les politiques et mesures qu’elles jugent appropriées pour la protection et la promotion de la diversité des expressions culturelles, ainsi que le renforcement de la coopération internationale afin de parvenir à des échanges culturels plus équilibrés. Attendue comme une réponse à l’échec de l’exception culturelle survenu dans les années 90, la Convention de 2005 est cependant critiquée au lendemain de son adoption en raison de son faible niveau de contrainte. Or, quinze ans plus tard, un examen de la pratique des Parties permet de dresser un bilan positif de la mise en oeuvre de ce traité dont les engagements outrepassent largement le cadre de la relation entre le commerce et la culture. Les données recueillies grâce à la performance des mécanismes de suivi démontrent en effet que les Parties s’appuient abondamment sur la Convention de 2005 pour mener diverses initiatives en vue d’atteindre les objectifs de ce traité. Ces actions, qui traduisent des changements opérés par les États sur leur propre territoire ou dans les relations qu’ils entretiennent entre eux, sont le reflet de l’effectivité de cet instrument juridique pourtant faiblement contraignant.La Convención sobre la Protección y Promoción de la Diversidad de las Expresiones Culturales (Convención de 2005) fue adoptada por la Conferencia General de la UNESCO en París el 20 de octubre de 2005. Los objetivos establecidos por las Partes incluyen el reconocimiento de la naturaleza específica – económica y cultural – de actividades, bienes y servicios culturales, la reafirmación del derecho soberano de las partes a adoptar e implementar las políticas y medidas que estimen convenientes para la protección y promoción de la diversidad de las expresiones culturales, así como el fortalecimiento de la cooperación internacional para lograr intercambios culturales más equilibrados. No obstante, la Convención de 2005, que se esperaba como respuesta al fracaso de la excepción cultural que se produjo en la década de 1990, fue criticada después de su adopción debido a su bajo nivel de obligaciones jurídicas. Sin embargo, quince años después, un examen de la práctica de las Partes permite hacer una valoración positiva de la implementación de este tratado, cuyos compromisos van mucho más allá de la relación entre comercio y cultura. Los datos recopilados a través de los mecanismos de monitoreo demuestran que las Partes dependen en gran medida de la Convención de 2005 para llevar a cabo diversas iniciativas que buscan lograr los objetivos de este tratado. Estas acciones, que reflejan cambios realizados por los Estados en su propio territorio o en las relaciones que mantienen entre sí, reflejan la efectividad de este instrumento legal a pesar de su débil carácter vinculante.Guèvremont Véronique, Varin Clémence. La Convention sur la diversité des expressions culturelles quinze ans après : une mise en œuvre effective d’un instrument juridique faiblement contraignant. In: Revue Québécoise de droit international, volume 32-2, 2019. pp. 1-27

Les nouveaux modes d’intervention de l’État visant à protéger et à promouvoir la diversité des expressions culturelles sur les plateformes numériques

International audienceLa culture a toujours entretenu des rapports étroits avec la technique. A ce titre, le numérique a une influence certaine tant dans la définition des objets culturels (jeux vidéo, créations générées par une intelligence artificielle...) que dans leur diffusion, impliquant même parfois la mise en place de nouveaux équilibres. Cet ouvrage constitue les actes du colloque annuel du Master 2/LLM Propriété intellectuelle fondamentale et technologies numériques (Université Paris-Sud/Paris-Saclay et Université Laval) et offre ainsi une lecture franco-québécoise des enjeux liés à la culture (au sens large) dans l’environnement numérique

Contribution of BKCa channels to vascular tone regulation by PDE3 and PDE4 is lost in heart failure

International audienceAims: Regulation of vascular tone by 3',5'-cyclic adenosine monophosphate (cAMP) involves many effectors including the large conductance, Ca2+-activated, K+ (BKCa) channels. In arteries, cAMP is mainly hydrolyzed by type 3 and 4 phosphodiesterases (PDE3, PDE4). Here, we examined the specific contribution of BKCa channels to tone regulation by these PDEs in rat coronary arteries, and how this is altered in heart failure (HF).Methods and results: Concomitant application of PDE3 (cilostamide) and PDE4 (Ro-20-1724) inhibitors increased BKCa unitary channel activity in isolated myocytes from rat coronary arteries. Myography was conducted in isolated, U46619-contracted coronary arteries. Cilostamide (Cil) or Ro-20-1724 induced a vasorelaxation that was greatly reduced by iberiotoxin (IBTX), a BKCa channel blocker. Ro-20-1724 and Cil potentiated the relaxation induced by the β-adrenergic agonist isoprenaline (ISO) or the adenylyl cyclase activator L-858051 (L85). IBTX abolished the effect of PDE inhibitors on ISO but did not on L85. In coronary arteries from rats with HF induced by aortic stenosis, contractility and response to acetylcholine were dramatically reduced compared with arteries from sham rats, but relaxation to PDE inhibitors was retained. Interestingly, however, IBTX had no effect on Ro-20-1724- and Cil-induced vasorelaxations in HF. Expression of the BKCa channel α-subunit, of a 98 kDa PDE3A and of a 80 kDa PDE4D were lower in HF compared with sham coronary arteries, while that of a 70 kDa PDE4B was increased. Proximity ligation assays demonstrated that PDE3 and PDE4 were localized in the vicinity of the channel.Conclusion: BKCa channels mediate the relaxation of coronary artery induced by PDE3 and PDE4 inhibition. This is achieved by co-localization of both PDEs with BKCa channels, enabling tight control of cAMP available for channel opening. Contribution of the channel is prominent at rest and on β-adrenergic stimulation. This coupling is lost in HF

Cutibacterium acnes Biofilm Study during Bone Cells Interaction

International audienceCutibacterium acnes is an opportunistic pathogen involved in Bone and Prosthesis Infections (BPIs). In this study, we observed the behavior of commensal and BPI C. acnes strains in the bone environment through bacterial internalization by osteoblast-like cells and biofilm formation. For the commensal strains, less than 1% of the bacteria were internalized; among them, about 32.7 ± 3.9% persisted intracellularly for up to 48 h. C. acnes infection seems to have no cytotoxic effect on bone cells as detected by LDH assay. Interestingly, commensal C. acnes showed a significant increase in biofilm formation after osteoblast-like internalization for 50% of the strains (2.8-fold increase). This phenomenon is exacerbated on a titanium support, a material used for medical devices. For the BPI clinical strains, we did not notice any increase in biofilm formation after internalization despite a similar internalization rate by the osteoblast-like cells. Furthermore, fluorescent staining revealed more live bacteria within the biofilm after osteoblast-like cell interaction, for all strains (BPIs and commensal). The genomic study did not reveal any link between their clinical origin and phylotype. In conclusion, we have shown for the first time the possible influence of internalization by osteoblast-like cells on commensal C. acnes

Raspberry consumption : identification of distinct immune-metabolic response profiles by whole blood transcriptome profiling

Background. Numerous studies reported that diets rich in phenolic compounds are beneficial to human health, especially for immune-metabolic conditions, yet these effects and underlying mechanisms are not well defined. Objectives. The main goal of this study was to investigate the architecture of the inter-individual variability of the immune-metabolic response to raspberry consumption, by identifying distinct subgroups of participants sharing similar transcriptomic signatures. Methods. The 24 participants assigned to the treated arm of a randomized controlled trial, and at risk of developing metabolic syndrome, received 280g/day of frozen raspberries for 8 weeks. RNAseq data from whole blood assessed at weeks 0 and 8 were used to identify sub-groups of responses to raspberry consumption, by using partial least-squares discriminant analysis (PLS-DA) and hierarchical clustering. Changes in clinical features, metabolic parameters, plasma metabolites and gut metagenomics were compared between the resulting sub-groups. Results. Transcriptomic-based clustering regrouped the initial 24 study participants into two significantly different sub-groups of response to raspberry consumption, with 13 participants being defined as responders and 11 as non-responders. Following raspberry consumption, a significant decrease in plasma triglycerides, total-cholesterol and C-reactive protein was found in the responder sub-group, as compared to the non-responder sub-group. Two major components composed respectively of 100 and 220 genes were further identified by sparse PLS-DA as those better discriminating responders and non-responders. Functional pathways related to cytokine production, leukocyte activation and immune response were significantly enriched with discriminant genes. Factor analysis revealed that the first metabolomic factor mostly composed of decreasing triglycerides and increasing phosphatidylcholines was significantly higher in responders, as compared to non-responders. Analysis of gut metagenomic data revealed differences between responders and non-responders prior to the intervention and distinct modulations, notably regarding Firmicutes and Actinobacteria phyla. Conclusions. The discrimination analysis carried out in the present study based on transcriptional changes following raspberry consumption was able to identify two divergent sub-groups of participants, which were further identified as responders and non-responders, according to their immune-metabolic and gut metagenomic responses. In the context of precision nutrition, this holistic approach represents a promising framework to tackle the issue of inter-individual variability in the understanding of the impact of foods or nutrients on immune-metabolic health