Effects of sacubitril-valsartan on remodelling, fibrosis and mitochondria in a murine model of isoproterenol-induced left ventricular dysfunction

Background: Sacubitril/valsartan has been demonstrated to promote left ventricular (LV) reverse remodelling and improve outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). Its molecular and tissue effects have not been fully elucidated yet, due to the paucity of preclinical studies, mostly based on ischaemic models. We aimed to evaluate the effects of sacubitril/valsartan on LV remodelling, myocardial fibrosis and mitochondrial biology in a murine model of non-ischaemic LV dysfunction. Methods: Adult transgenic male mice with cardiac-specific hyperaldosteronism (AS mice) received subcutaneous isoproterenol injections to induce LV systolic dysfunction. After 7 days, mice were randomized to a 2-week treatment with saline (ISO-AS n = 15), valsartan (ISO + V n = 12) or sacubitril/valsartan (ISO + S/V n = 12). Echocardiography was performed at baseline, at day 7, and after each of the 2 weeks of treatment. After sacrifice at day 21, histological and immunochemical assays were performed. A control group of AS mice was also obtained (Ctrl-AS n = 8). Results: Treatment with sacubitril/valsartan, but not with valsartan, induced a significant improvement in LVEF (p = 0.009 vs ISO-AS) and fractional shortening (p = 0.032 vs ISO-AS) after 2- week treatment. In both ISO + V and ISO + S/V groups, a trend toward reduction of the cardiac collagen 1/3 expression ratio was detected. ISO + V and ISO + S/V groups showed a significant recovery of mitochondrial morphology and inner membrane function meant for oxidative phosphorylation. Conclusion: In a murine model of non-ischaemic HF, sacubitril/valsartan proved to have beneficial effects on LV systolic function, and on cardiac energetics, by improving mitochondrial activity

Studio di coorte sull’incidenza dei decubiti al calcagno in pazienti immobilizzati da gesso agli arti inferiori presso l’Istituto Ortopedico Rizzoli e dei possibili fattori di rischio

Introduzione. La lesione da decubito, in particolare al calcagno, può rappresentare una complicanza da immobilizzazione per apparecchio gessato. Obiettivo. Indagare l’incidenza delle complicanze cutanee tardive (in particolare la lesione da decubito al calcagno) da apparecchio gessato e valutare eventuali fattori di rischio. Materiali e metodi. Sono stati monitorati per 16 mesi tutti i pazienti consecutivi, provenienti da tre reparti, a cui veniva applicato un apparecchio gessato agli arti inferiori. I fattori di rischio sono stati identificati dall’infermiere addetto al confezionamento del gesso e la gravità della lesione stadiata con la scala NPUAP, al momento dell’asportazione del gesso, dall’infermiere del reparto o dell’ambulatorio. Risultati. Sono stati arruolati 216 pazienti. Il 17.6% (38/216) ha avuto una lesione da decubito: 16/124 (13%) nei reparti ortopedici e 22/92 (24%) nei reparti oncologici. Sono risultati fattori di rischio all’analisi multivariata, l’essere sottoposti a trattamenti con farmaci antiblastici (p=0.033; OR=2.61) (la sola patologia oncologica non aumentava il rischio rispetto alla popolazione ortopedica generale); l’avere la cute arrossata prima dell’applicazione dell’apparecchio gessato (p=0.001; OR=4.44) e l’avere accusato disturbi dopo l’applicazione (p=0.000; OR=7.86). Le lesioni erano prevalentemente di 1° grado e solo il 2.4% (6/216) erano di II grado o superiore. L’estensione e la durata del gesso, il materiale con cui viene confezionato, e l’aver subito un intervento chirurgico non sono risultati fattori di rischio statisticamente significativi. Conclusioni. Le lesioni da decubito da gesso sono una complicanza relativamente frequente in particolare in alcune popolazioni a rischio che devono tenere immobilizzati gli arti inferiori. La conoscenza del rischio di base e l’identificazione di specifici fattori di rischio possono permettere l’identificazione e lo studio di misure preventive per migliorare l’assistenza a questa specifica popolazione

Recent advances in electronics and software for the METIS coronagraph aboard solar orbiter

METIS is a visible and UV externally inversely occulted coronagraph selected to fly aboard the Solar Orbiter space mission. Thanks to its own capabilities and exploiting the peculiar opportunities offered by the SO mission profile, the instrument will address some of the still open issues in understanding the physics driving the observed processes in the corona and characterizing the slow and fast components of the solar wind. Recently the METIS design went thorough a significant revision involving the overall electronics configuration and software functionalities, comprehensive of descoping of some features but also aiming at the improvement of the instrument\u2019s reliability. As a result the electronics architecture has been simplified enabling an effective cold-strapped redundancy scheme of some subsystems, while the preliminary SW database has been defined as well. We also identified the scientific processing algorithms implementing the instrument functionalities and the imagecompression capabilities able to match the selected HW resources providing an optimal compromise between complexity and compression ratio. This paper describes the revised electronics and software design developed in order to maximize the overall scientific returns with the updated instrument configuration approaching the Phases C/D of the project

The transitioning from conventional therapy to biological treatment in psoriatic patients: STRATOS, a project of Marche Region

STRATOS is the acronym of the "STRuctured Approach to the Treatment of psOriatic patientS". The optimization of the psoriasis's therapeutic management is one of the most important goals for dermatologists. According to Mrowietz's consensus report, the transitioning from conventional therapy to biological therapy is mainly due to the lack/loss of efficacy and/or for safety reasons. The aim of the manuscript was to describe the principal results obtained by the Dermatologic Clinic of Polytechnic University of Marche Region and the Units of Dermatology of the Marche Region applying, in our regional reality, Mrowietz's protocol for the daily management of patients with moderate-to-severe plaque

A pharmacogenetic study for clinical outcomes of high-risk stage II and stage III colon cancer patients Treated with oxaliplatin and fluoropyrimidines adjuvant chemotherapy

Background:  single nucleotide polymorphisms (SNPs) can predict treatment dose and safety of chemotherapeutic agentsi n different subgroups of cancer patients. We investigated 17 SNPs in 11 genes involved in the DNA repair, drug metabolism and as drug targets :TS, MTHFR, ERCC1, XRCC1, XRCC3, XPD, GSTT, GSTP, GSTM, ABCC1, ABCC2.    Material and methods:  TOSCA was a non-profit, Italian, multicentre, randomized, non-inferiority phase III study conducted in high-risk stage II and stage III colorectal cancer patients treated with 6 or 3 months of FOLFOX-4 or XELOX adjuvant chemoterapy. Patients who signed the informed consent were prospectively accrued in this ancillary study. Patients were genotyped by classical methods. The primary and secondary endpoints were relapse free survival (RFS) and overall survival (OS), respectively. Univariate and multivariate Cox proportional hazard models were used. Results:  524 patients were enrolled in this study (from July 2007 to October 2011), Eight patients were excluded from analysis due to major violation and 4 never started treatment. . 185 and 188 patients were treated with FOLFOX-4, 68 and 71 with XELOX in 6-month and in 3-month arm, respectively. Allele frequencies of all SNPs were consistent with Hardy-Weinberg equilibrium.  82(16%) progression and 71(14%) deaths were observed. Progression or deaths occurred in 106(21%) patients. The XRCC1 rs25487 G>A shortened significantly RFS (adjusted HR [AA vs GG] 2.02; 95%CI 1.15-3.56; p=0.015) and OS (adjusted HR[AA vs GG] 3.07; 95%CI 1.57-5.99; p=0.001). Interactions between SNPs and treatment duration were detected. In detail, 3-month treatment was correlated with a shorter RFS for patients with G allele in XPD rs13181 T>G and for patients with CC genotype (vs TC+TT) in ERCC1 rs11675 T>C. A better RFS and OS were identified in patients treated for 3 months with GG genotype for ABCC2 rs4148386 A>G. Finally, the GG genotype in ABCC2 rs1885301G>A increased OS in patients treated with 3 months treatment. Conclusions:  XRCC1 rs25487 G>A produced remarkable differences in RFS and OS in the studied population. Additional functional SNPs involved in the DNA repair pathways may engage a clinical impact according to the duration of the adjuvant chemotherapy program. These findings may impact on the overall chemotherapy treatment strategy of colon cancer patients. Additional prospective studies are warranted for confirming this associations and after adjustment for tumor-related prognostic factors