Peripheral Delta Opioid Receptors Mediate Formoterol Anti-allodynic Effect in a Mouse Model of Neuropathic Pain.

Neuropathic pain is a challenging condition for which current therapies often remain unsatisfactory. Chronic administration of β2 adrenergic agonists, including formoterol currently used to treat asthma and chronic obstructive pulmonary disease, alleviates mechanical allodynia in the sciatic nerve cuff model of neuropathic pain. The limited clinical data currently available also suggest that formoterol would be a suitable candidate for drug repurposing. The antiallodynic action of β2 adrenergic agonists is known to require activation of the delta-opioid (DOP) receptor but better knowledge of the molecular mechanisms involved is necessary. Using a mouse line in which DOP receptors were selectively ablated in neurons expressing Nav1.8 sodium channels (DOP cKO), we showed that these DOP peripheral receptors were necessary for the antiallodynic action of the β2 adrenergic agonist formoterol in the cuff model. Using a knock-in mouse line expressing a fluorescent version of the DOP receptor fused with the enhanced green fluorescent protein (DOPeGFP), we established in a previous study, that mechanical allodynia is associated with a smaller percentage of DOPeGFP positive small peptidergic sensory neurons in dorsal root ganglia (DRG), with a reduced density of DOPeGFP positive free nerve endings in the skin and with increased DOPeGFP expression at the cell surface. Here, we showed that the density of DOPeGFP positive free nerve endings in the skin is partially restored and no increase in DOPeGFP translocation to the plasma membrane is observed in mice in which mechanical pain is alleviated upon chronic oral administration of formoterol. This study, therefore, extends our previous results by confirming that changes in the mechanical threshold are associated with changes in peripheral DOP profile. It also highlights the common impact on DOP receptors between serotonin noradrenaline reuptake inhibitors such as duloxetine and the β2 mimetic formoterol.journal article20192020 02 14importe

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Salmonella enterica SUBSP. Enterica et Campylobacter SPP. dans la filière avicole Sénégalaise (impact sur la santé publique)

Les salmonelles et les campylobacters sont les bactéries les plus fréquemment impliquées dans les toxi-infections alimentiares collectives dans les pays développés et sont particulièrement graves chez les personnes vulnérables. Dans les pays en développement comme le Sénégal, les données sur l'impact de ces bactéries sur la santé publique font défaut. Or, avec le développement exponentiel de l'aviculture, des informations précises sont nécessaires pour permettre aux autorités publiques de prendre les mesures idoines pour maîtriser ces risques ; d'autant que les produits alimentaires issus de la filière "poulet de chair" représentent un risque de contamination important. Une meilleure connaissance de l'épidémiologie de ces bactéries tout au long de la filière permet d'identifier ces mesures. Les facteurs de risque mis en évidence relèvent des bonnes pratiques hygiéniques mais aussi de pratiques spécifiques au mode de production sénégalais. Les similarités génétiques entre les souches isolées chez le poulet et l'homme montrent que la viande de volaille peut constituer une source potentielle de contamination. La diminution de la sensibilité de ces bactéries aux antibiotiques peut s'avérer un autre problème émergent de santé publiqueLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Un nouveau regard médical sur la plainte douloureuse chronique

Bien que des descriptions de patients affectés de douleurs chroniques existent depuis des siècles dans la littérature, leur prise en charge ne différait pas de celle des patients atteints de douleurs aiguës. Il a fallu attendre le milieu du 20e siècle pour que le statut de ces patients soit reconnu ; en l’absence de « preuves objectives » bon nombre d’entre eux étaient rejetés par les médecins qu’ils confrontaient aux limites de leur savoir biomédical. Les progrès récents de la recherche ont contribué à porter un nouveau regard sur les patients douloureux chroniques. On sait aujourd’hui que : 1/ tous les individus n’ont pas les mêmes voies nociceptives ; 2/ il existe une plasticité de ce signal d’alarme qui dépend de ce que vit le sujet et qui en garde une trace mnésique ; 3/ que la douleur qui dure modifie profondément les connexions cérébrales, perturbe l’analyse de toutes les perceptions, et conduit à un état dépressif ; 4/ que certaines de ces perturbations sont réversibles par des traitements.Although descriptions of chronic pain patients exist for long time in the literature, their treatment was not adequate. It was in the mid-twentieth century that the status of those patients was recognized. In the absence of “objective evidence” many of them were rejected by the doctors confronted with the limits of their biomedical knowledge. The recent advances in research in mechanisms involved in the emergence and perpetuation of chronic pathological pain, contributes to a new look on chronic pain patients. We now know that: 1/ all individuals do not have the same nociceptive pathways; 2/ there is a plasticity of those pathways signal that depends on what the subject lives and who keeps a memory sometimes of what his ancestors lived; 3/ long-lasting pain profoundly modifies the brain connections, disrupts the analysis of all the perceptions and leads to depression; 4/ some of these disturbances are reversible by