Sintesi di nuovi ligandi della Glicoproteina-P a struttura Ariletilanilinica per lo sviluppo di traccianti per la PET

Le ATP-binding cassette transporters (trasportatori ABC),fanno parte di una superfamiglia proteica molto diffusa in diversi tipi di organismi: dai procarioti all’uomo. In quest’ultimo,derivano dall’espressione di 49 geni dai quali si originano ben 7 sottoclassi : ABC-A G. Sono proteine transmembrana,che sono in grado di regolare il passaggio di diverse tipologie di sostanze attraverso queste barriere. Per poter svolgere tale funzione, necessitano di una fonte energetica,la quale è costituita dall’ATP (adenosina trifosfato) e dalla sua successiva idrolisi. Per questo motivo,questi trasportatori sono,a tutti gli effetti,delle “pompe di membrana”. Possiamo,inoltre,operare una loro suddivisione anche in base alla direzione secondo la quale le sostanze vengono trasportate,abbiamo : • Importatori • Esportatori/Efflussori Gli Importatori sono presenti solo nei Procarioti. Invece,negli Eucarioti,si riscontra la esclusiva presenza degli Esportatori. Quest’ultimi,esercitano una funzione protettiva contrastando l’accumulo di moltissime tipologie di sostanze potenzialmente pericolose o per un determinato distretto fisiologico o per la sopravvivenza della singola cellula. Ne consegue che posseggano la capacità di interagire con una vasta gamma di substrati,strutturalmente e funzionalmente,molto diversi fra loro : dai metaboliti ai lipidi,dagli steroli ai farmaci. Grazie a questa capacità,si riscontra la loro presenza all’interno di numerosissime membrane di diversi distretti biologici,come : -Barriera Emato-Encefalica (BEE) -Placenta -Intestino -Stomaco -Fegato Essendo proteine trasportatrici,è pacifico che influenzino o siano coinvolte direttamente anche nella regolazione di molti processi cellulari. Questo ha fatto sì che,col tempo,siano state sempre di più oggetto di studi e ricerca. Fra queste, particolare interesse,lo ha suscitato la ABC-B1,altresì nota come Glicoproteina-P (P-gp),soprattutto a causa del suo ruolo in alcune patologie neuro-degenerative (Parkinson,Alzheimer) e tumorali. In questo senso,l’aspetto sul quale la ricerca si sta concentrando negli ultimi anni,è,oltre alla caratterizzazione delle sue funzioni e della sua struttura,la valutazione della sua espressione in condizioni normali e patologiche. Potenzialmente,potrebbe rappresentare uno dei bersagli principali,sia per quanto riguarda la diagnosi che il trattamento,di tali patologie. I vantaggi,teorici,che si potrebbero riscontrare sono svariati e riguardano : la maggiore capacità di diagnosi delle patologie,l’aumento della biodisponibilità dei farmaci,i migliori risultati terapeutici,la riduzione delle dosi,la riduzione della probabilità che insorgano effetti collaterali e fenomeni di resistenza ai farmaci,l’aumento della qualità di vita dei pazienti e la riduzione della spesa farmaceutic

Impact of structural features of very thin stents implanted in unprotected left main or coronary bifurcations on clinical outcomes

Objectives: To evaluate the independent clinical impact of stent structural features in a large cohort of patients undergoing unprotected left main (ULM) or coronary bifurcation percutaneous coronary intervention (PCI) with a range of very thin strut stents. Background: Clinical impact of structural features of contemporary stents remains to be defined. Methods: All consecutive patients enrolled in the veRy thin stents for patients with left mAIn or bifurcatioN in real life (RAIN) registry were included. The following stent structural features were studied: antiproliferative drugs (everolimus vs. sirolimus vs. zotarolimus), strut material (platinum-chromium vs. cobalt-chromium), polymer (bioresorbable vs. durable), number of crowns (<8 vs. ≥8) and number of connectors (<3 vs. ≥3). For small diameter stents (≤2.5 mm), struct thickness (74 vs. 80/81 μm) was also tested. Target lesion failure (TLF), a composite of target lesion revascularization and stent thrombosis, was the primary endpoint. Multivariate analysis was performed with Cox regression models. Results: Out of 2,707 patients, 110 (4.1%) experienced a TLF event after 16 months (12–18). After adjustment for confounders, an increased number of connectors (adjusted hazard ratio [adj-HR] 0.62, 95% confidence interval (CI) 0.39–0.99, p =.04) reduced risk of TLF, driven by stents with ≥2.5 mm diameter (HR 0.54, 95% CI 0.32–0.93, p =.02). This independent relationship was lost for stents with diameter <2.5 mm, where only strut thickness appeared to impact. Conversely, no independent relationship of polymer type, number of crowns, and the specific limus-family eluted drug with outcomes was observed. Conclusions: Among a range of contemporary very thin stent models, an increased number of connectors improved device-related outcomes in this investigated high-risk procedural setting

Daily risk of adverse outcomes in patients undergoing complex lesions revascularization: a subgroup analysis from the RAIN-CARDIOGROUP VII study (veRy thin stents for patients with left mAIn or bifurcatioN in real life)

Introduction: Percutaneous coronary intervention (PCI) for complex lesions, including unprotected left main (ULM) and bifurcations, is gaining a relevant role in treating coronary artery disease with good outcomes, also thanks to new generation stents. The daily risk of adverse cardiovascular events and their temporal distribution after these procedures is not known.Methods: All consecutive patients presenting with a critical lesion of ULM or bifurcation treated with very thin struts stents, enrolled in the RAIN-Cardiogroup VII study, were analyzed. The daily risk of major acute cardiovascular events (MACE), target lesion revascularization (TLR) and stent thrombosis (ST) and their temporal distribution in the first year of follow-up was the primary endpoint. Differences among subgroups (ULM, patient presentation, kind of stent polymer) were the secondary endpoint.Results: 2745 patients were included, mean age 68 ± 11 years, 33.3% diabetics, 54.5% had an acute coronary syndrome (ACS); 88.5% of treated lesions were bifurcations, 27.2% ULM. Average daily risk was 0.022% for MACE, 0.005% for TLR and 0.004% for ST, in the first year. Bimodal distribution of adverse events, especially TLR, with an early peak in the first 50 days and a late one after 150 days, was observed. Patients with ULM presented a significantly higher daily risk of events, and ACS patients presented higher MACE risk. No difference emerged according to the type of stent polymer.Conclusions: The daily risk of adverse events in the first year after complex PCI in our study is acceptably low. PCI on ULM carries a higher risk of complications

Incidence of adverse events at 3 months versus at 12 months after dual antiplatelet therapy cessation in patients treated with thin stents with unprotected left main or coronary bifurcations

Incidence and predictors of adverse events after dual antiplatelet therapy (DAPT) cessation in patients treated with thin stents (<100 microns) in unprotected left main (ULM) or coronary bifurcation remain undefined. All consecutive patients presenting with a critical lesion of an ULM or involving a main coronary bifurcation who were treated with very thin strut stents were included. MACE (a composite end point of cardiovascular death, myocardial infarction [MI], target lesion revascularization [TLR], and stent thrombosis [ST]) was the primary endpoint, whereas target vessel revascularization (TVR) was the secondary endpoint, with particular attention to type and occurrence of ST and occurrence of ST, CV death, and MI during DAPT or after DAPT discontinuation. All analyses were performed according to length of DAPT dividing the patients in 3 groups: Short DAPT (3-months), intermediate DAPT (3 to 12 months), and long DAPT (12-months). A total of 117 patients were discharged with an indication for DAPT ≤3 months (median 1: 1 to 2.5), 200 for DAPT between 3 and 12 months (median 8: 7 to 10), and 1,958 with 12 months DAPT. After 12.8 months (8 to 20), MACE was significantly higher in the 3-month group compared with 3 to 12 and 12-month groups (9.4% vs 4.0% vs 7.2%, p ≤0.001), mainly driven by MI (4.4% vs 1.5% vs 3%, p ≤0.001) and overall ST (4.3% vs 1.5% vs 1.8%, p ≤0.001). Independent predictors of MACE were low GFR and a 2 stent strategy. Independent predictors of ST were DAPT duration <3 months and the use of a 2-stent strategy. In conclusion, even stents with very thin strut when implanted in real-life ULM or coronary bifurcation patients discharged with short DAPT have a relevant risk of ST, which remains high although not significant after DAPT cessation

The management of intra-abdominal infections from a global perspective : 2017 WSES guidelines for management of intra-abdominal infections

Intra-abdominal infections (IAIs) are common surgical emergencies and have been reported as major contributors to non-trauma deaths in the emergency departments worldwide. The cornerstones of effective treatment of IAIs are early recognition, adequate source control, and appropriate antimicrobial therapy. Prompt resuscitation of patients with ongoing sepsis is of utmost important. In hospitals worldwide, non-acceptance of, or lack of access to, accessible evidence-based practices and guidelines result in overall poorer outcome of patients suffering IAIs. The aim of this paper is to promote global standards of care in IAIs and update the 2013 WSES guidelines for management of intra-abdominal infections.Peer reviewe

2019 update of the WSES guidelines for management of Clostridioides (Clostridium) difficile infection in surgical patients

In the last three decades, Clostridium difficile infection (CDI) has increased in incidence and severity in many countries worldwide. The increase in CDI incidence has been particularly apparent among surgical patients. Therefore, prevention of CDI and optimization of management in the surgical patient are paramount. An international multidisciplinary panel of experts from the World Society of Emergency Surgery (WSES) updated its guidelines for management of CDI in surgical patients according to the most recent available literature. The update includes recent changes introduced in the management of this infection.Peer reviewe

WSES/GAIS/WSIS/SIS-E/AAST global clinical pathways for patients with skin and soft tissue infections

Skin and soft-tissue infections (SSTIs) encompass a variety of pathological conditions that involve the skin and underlying subcutaneous tissue, fascia, or muscle, ranging from simple superficial infections to severe necrotizing infections. Together, the World Society of Emergency Surgery, the Global Alliance for Infections in Surgery, the Surgical Infection Society-Europe, The World Surgical Infection Society, and the American Association for the Surgery of Trauma have jointly completed an international multi-society document to promote global standards of care in SSTIs guiding clinicians by describing reasonable approaches to the management of SSTIs. An extensive non-systematic review was conducted using the PubMed and MEDLINE databases, limited to the English language. The resulting evidence was shared by an international task force with different clinical backgrounds.Peer reviewe

WSES/GAIS/SIS-E/WSIS/AAST global clinical pathways for patients with intra-abdominal infections

Intra-abdominal infections (IAIs) are common surgical emergencies and have been reported as major contributors to non-trauma deaths in hospitals worldwide. The cornerstones of effective treatment of IAIs include early recognition, adequate source control, appropriate antimicrobial therapy, and prompt physiologic stabilization using a critical care environment, combined with an optimal surgical approach. Together, the World Society of Emergency Surgery (WSES), the Global Alliance for Infections in Surgery (GAIS), the Surgical Infection Society-Europe (SIS-E), the World Surgical Infection Society (WSIS), and the American Association for the Surgery of Trauma (AAST) have jointly completed an international multi-society document in order to facilitate clinical management of patients with IAIs worldwide building evidence-based clinical pathways for the most common IAIs. An extensive non-systematic review was conducted using the PubMed and MEDLINE databases, limited to the English language. The resulting information was shared by an international task force from 46 countries with different clinical backgrounds. The aim of the document is to promote global standards of care in IAIs providing guidance to clinicians by describing reasonable approaches to the management of IAIs.Peer reviewe