Novel locally active estrogens accelerate cutaneous wound healing-part 2

Estrogen deprivation is associated with delayed healing, while estrogen replacement therapy (ERT) accelerates acute wound healing and protects against development of chronic wounds. However, current estrogenic molecules have undesired systemic effects, thus the aim of our studies is to generate new molecules for topic administration that are devoid of systemic effects. Following a preliminary study, the new 17β-estradiol derivatives 1 were synthesized. The estrogenic activity of these novel compounds was evaluated in vitro using the cell line ERE-Luc B17 stably transfected with an ERE-Luc reporter. Among the 17β-estradiol derivatives synthesized, compounds 1e and 1f showed the highest transactivation potency and were therefore selected for the study of their systemic estrogenic activity. The study of these compounds in the ERE-Luc mouse model demonstrated that both compounds lack systemic effects when administered in the wound area. Furthermore, wound-healing experiments showed that 1e displays a significant regenerative and anti-inflammatory activity. It is therefore confirmed that this class of compounds are suitable for topical administration and have a clear beneficial effect on wound healing

La struttura e le attività del SSN

Il capitolo fornisce una visione d’insieme del Servizio Sanitario Nazionale (SSN) italiano, della sua organizzazione e delle sue attività, con un’attenzione particolare ai cambiamenti che ne hanno caratterizzato l’evoluzione negli ultimi anni

Gli Ospedali di Comunità: quali prospettive alla luce del PNRR?

L’obiettivo del presente capitolo è quello di approfondire ulteriormente l’analisi rispetto a quanto emerso nel precedente capitolo sugli OdC pubblicato nel Rapporto OASI 2021 (ibid.), indagando l’evoluzione e le progettualità previste nel breve e medio periodo per queste strutture alla luce delle indicazioni di sviluppo contenute nel PNRR. In particolare, vengono analizzate le priorità strategiche, le vocazioni produttive e i modelli di servizio, il target di utenza e la tipologia di bisogni da soddisfare, la tipologia di personale clinico e amministrativo coinvolto, la dotazione tecnologica e i modelli di integrazione e interconnessione con gli altri servizi e setting di cura e assistenza, sia territoriali che ospedalieri

La struttura e le attività del SSN

Il capitolo dipinge un quadro complessivo del Servizio Sanitario Nazionale (SSN) italiano, della sua organizzazione e delle sue attività, con un’attenzione particolare ai cambiamenti che ne hanno caratterizzato l’evoluzione negli ultimi anni

Gli ospedali di comunità in Italia: passato, presente e futuro

Il presente capitolo approfondisce il tema degli ospedali di comunità (OdC) attraverso un’analisi approfondita dell’esistente, concentrandosi prima sul contesto internazionale per poi analizzare quello nazionale, con una mappatura aggiornata degli OdC presenti nel nostro Paese e la presentazione di otto casi studio, condotti in sei regioni differenti

Il PNRR e i sistemi sanitari regionali: modelli di governance e processi di change management

Il Capitolo si focalizza sul modo in cui, i diversi sistemi sanitari regionali (SSR), si sono occupati della gestione del PNRR, adottando una duplice prospettiva di indagine: i) da una parte si intende studiare il modello di governance scelto dai diversi SSR; ii) dall’altra è obiettivo del lavoro approfondire se i SSR hanno interpretato la gestione del PNRR esclusivamente come un programma di spesa o anche come un’opportunità per un’azione di change management. In particolare, il Capitolo analizza le attività di programmazione relative alle Case di Comunità (CdC), sia in termini di programmazione della spesa che la ri-progettazione dei modello di assistenza territoriale, attraverso la metodologia dei casi studio che sono i SSR di: Campania, Emilia Romagna, Lazio, Lombardia e Molise. Dalle analisi emerge la necessità di rafforzare i livelli regionali, in termini di numerosità e competenze. Il PNRR, sia nel programma di spesa che nella riforma dei servizi territoriali, comporta un incremento delle responsabilità e delle attività del livello regionale, necessario, da un lato, per programmare e realizzare gli investimenti e, dall’altro, per guidare un processo di trasformazione dei servizi e sviluppo delle competenze. In secondo luogo, il contributo suggerisce l’importanza di curare le interdipendenze fra il programma di spesa e il processo di change management mentre i SSR stanno realizzando i due interventi con gruppi di lavoro e tempistiche differenti. In questo caso sorge il rischio che gli investimenti su una singola CdC vengano programmati prima di averne definito la vocazione strategica e i servizi offerti e, di conseguenza, che tali investimenti risultino disfunzionali. Rischi che potrebbero essere mitigati promuovendo delle forme di coordinamento fra i gruppi di lavoro che stanno guidando i due interventi

Beta Cell Hubs Dictate Pancreatic Islet Responses to Glucose

N.R.J. was supported by a Diabetes UK RW and JM Collins Studentship (12/0004601). J.B. was supported by a European Foundation for the Study of Diabetes (EFSD) Albert Renold Young Scientist Fellowship and a Studienstiftung des deutschen Volkes PhD Studentship. D.T. was supported by an Advanced Grant from the European Research Commission (268795). G.A.R. was supported by Wellcome Trust Senior Investigator (WT098424AIA) and Royal Society Wolfson Research Merit Awards, and by MRC Programme (MR/J0003042/1), Biological and Biotechnology Research Council (BB/J015873/1), and Diabetes UK Project (11/0004210) grants. G.A.R. and M.W. acknowledge COST Action TD1304 Zinc-Net. D.J.H. was supported by Diabetes UK R.D. Lawrence (12/0004431), EFSD/Novo Nordisk Rising Star and Birmingham Fellowships, a Wellcome Trust Institutional Support Award, and an MRC Project Grant (MR/N00275X/1) with G.A.R. D.J.H and G.A.R. were supported by Imperial Confidence in Concept (ICiC) Grants. J.F. was supported by an MRC Programme grant (MR/L02036X/1). L.P. provided human islets through collaboration with the Diabetes Research Institute, IRCCS San Raffaele Scientific Institute (Milan), within the European islet distribution program for basic research supported by JDRF (1-RSC-2014-90-I-X). P.M. and M.B. were supported by the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 155005 (IMIDIA), resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution, and by the Italian Ministry of University and Research (PRIN 2010-2012). D.B. and E.B. provided human islets through the European Consortium for Islet Transplantation sponsored by JDRF (1-RSC-2014-100-I-X)

Multicentre, randomised, open-label, phase IV-III study to evaluate the efficacy of cloxacillin plus fosfomycin versus cloxacillin alone in adult patients with methicillin-susceptible Staphylococcus aureus bacteraemia: study protocol for the SAFO trial

Introduction: Methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia is a frequent condition, with high mortality rates. There is a growing interest in identifying new therapeutic regimens able to reduce therapeutic failure and mortality observed with the standard of care of beta-lactam monotherapy. In vitro and small-scale studies have found synergy between cloxacillin and fosfomycin against S. aureus. Our aim is to test the hypothesis that cloxacillin plus fosfomycin achieves higher treatment success than cloxacillin alone in patients with MSSA bacteraemia. Methods: We will perform a superiority, randomised, open-label, phase IV-III, two-armed parallel group (1:1) clinical trial at 20 Spanish tertiary hospitals. Adults (≥18 years) with isolation of MSSA from at least one blood culture ≤72 hours before inclusion with evidence of infection, will be randomly allocated to receive either cloxacillin 2 g/4-hour intravenous plus fosfomycin 3 g/6-hour intravenous or cloxacillin 2 g/4-hour intravenous alone for 7 days. After the first week, sequential treatment and total duration of antibiotic therapy will be determined according to clinical criteria by the attending physician. Primary endpoints: (1) Treatment success at day 7, a composite endpoint comprising all the following criteria: patient alive, stable or with improved quick-Sequential Organ Failure Assessment score, afebrile and with negative blood cultures for MSSA at day 7. (2) Treatment success at test of cure (TOC) visit: patient alive and no isolation of MSSA in blood culture or at another sterile site from day 8 until TOC (12 weeks after randomisation). We assume a rate of treatment success of 74% in the cloxacillin group. Accepting alpha risk of 0.05 and beta risk of 0.2 in a two-sided test, 183 subjects will be required in each of the control and experimental groups to obtain statistically significant difference of 12% (considered clinically significant). Ethics and dissemination: Ethical approval has been obtained from the Ethics Committee of Bellvitge University Hospital (AC069/18) and from the Spanish Medicines and Healthcare Product Regulatory Agency (AEMPS, AC069/18), and is valid for all participating centres under existing Spanish legislation. The results will be presented at international meetings and will be made available to patients and funders

Signalisation redox au cours du développement et de la régénération chez l'adulte

In the recent years it is becoming evident that reactive oxygen species (ROS) are not only deleterious compounds that induce damage of biological molecules, but are also important molecules that can mediate different signaling pathways. Controlled ROS, and in particular H2O2, levels have been found to be involved in the regenerative process of different species. We then focused on the regulation of H2O2 signaling during regeneration of the adult zebrafish caudal finand we showed that nerves control H2O2 levels both in normal tissue and after lesioning; this process is mediated by Schwann cells, through Shh signaling. In addition, there is also a reciprocal action of H2O2 on nerve growth, suggesting the presence of a positive feedback loop.Redox levels are highly dynamic not only during regeneration, but also during development. We then looked at the role of H2O2 during morphogenesis and more specifically, its impact on axonal growth and its relationship with Shh signaling. We found that reduction of H2O2 levels, normally very high during morphogenesis, impairs axon projections and that this effect can be rescued by the activation of Shh signaling. Moreover, we found that different redox levels modify the intracellulardistribution of Shh protein and also its extracellular availability. These results further strengthen the relationship between H2O2 and Shh signaling pathways.It is widely accepted that targets of redox signaling include proteins whose activity is dependent on an active cysteine because the oxidative status of this amino acid can be modified by H2O2 levels.The process of S-acylation, which is very important for both the processes of axonal projections growth and Shh signaling, consists in the covalent attachment of a fatty acid, often palmitate, to a cysteine sulphur and it is then a possible target of ROS signaling. We asked whether a relationship between H2O2 levels and protein S-palmitoylation could exist and we found that augmentation of H2O2 levels downregulates the S-palmitoylation process. The relevance of this observation iscurrently being tested in vivo.Ces dernières années, il est apparu que les espèces réactives de l'oxygène (ROS) ne sont pas seulement des substances délétères qui induisent des dommages de molécules biologiques, mais qu’elles sont également impliquées dans la signalisation cellulaire. Des niveaux contrôlés de H2O2 sont en particulier impliqués dans le processus de régénération chez différentes espèces. Nous avons donc étudié la régulation de la signalisation de H2O2 au cours de régénération de la nageoire caudale chez le poisson zèbre adulte. Nous avons montré que les nerfs contrôlent les niveaux de H2O2 à la fois dans les tissus normaux et après blessure; ce processus est médié par les cellules de Schwann qui expriment Shh. En plus, H2O2 stimule la croissance des nerfs, ce qui suggère la présence d'une boucle de rétrocontrôle positif.Les niveaux redox sont très dynamiques non seulement lors de la régénération, mais aussi au coursdu développement. Nous avons ensuite examiné le rôle de H2O2 pendant la morphogenèse et plusprécisément, son impact sur la croissance axonale et sa relation avec la signalisation Shh. Nous avons constaté que la réduction des niveaux de H2O2, normalement très élevé au cours de la morphogenèse, altère les projections axonales et que cet effet peut être sauvé par l'activation de la voie de signalisation de Shh.Les cibles de la signalisation redox comprennent des protéines dont l'activité est dépendante d'une cystéine, car l'état d'oxydation de cet acide aminé peut être modifié par les niveaux de H2O2. Le processus de S-acylation, qui est très important pour le processus de croissance des projections axonales et pour la voie de signalisation de Shh, consiste en la fixation covalente d'un acide gras, souvent le palmitate, au group sulfurique d’une cysteine et il est donc une cible potentielle de signalisation de ROS. Nous avons mis en évidence une corrélation entre le niveau de palmitoylationd’une protéine et les niveaux de H2O2 dans la cellule. La pertinence de cette observation estactuellement testée in vivo

I minori delle scuole secondarie di I grado

Il saggio esemplificata un welfare inclusivo, capace di promuovere mobilità sociale, nel caso delle scuole aperte per le medie (secondarie di I grado), disegnando la strategia, il format dei servizi, la sostenibilità economica, gli attori partner, il modello di governanc