Development of new in vitro models based on the use of electrospun scaffolds and their imaging by multiphoton microscopy coupled with fluorescence lifetime imaging microscopy

2016 - 2017In this thesis, new possible applications of electrospun scaffolds are presented. Besides, the interaction of human dermal fibroblasts (HDFs) with the materials has been investigated using multiphoton microscopy (MPM) coupled with fluorescence lifetime imaging microscopy (FLIM), using a non-invasive, marker-free approach. In the first part of the thesis, pure poly-L-lactide (PLA) scaffolds were obtained and characterized as delivery systems for Diclofenac sodium salt (DCF) and a synthetically obtained prodrug of it for the treatment of actinic keratosis. The Diclofenac prodrug was obtained via solid phase peptide synthesis using a versatile, clean, high yielding procedure. Besides, the drug encapsulation and its release from the scaffold could be imaged using MPM. Moreover, when working with the unmodified DCF we were able to control the release profile by adding small amounts of dimethyl sulfoxide. The DCF-loaded scaffold was used as a delivery system to induce in vitro cell death in HDFs. The target cells were imaged using MPM coupled with FLIM, using a non-invasive, marker-free in vitro model to investigate drug effects. In the last part of the thesis, we produced and characterized different hybrid gelatin/PLA scaffolds. In this case, the goal was to obtain well-blended scaffolds with tunable properties, such as porosity, hydrophobicity and wettability... [edited by Author]XXX cicl

Pruritus in chronic plaque psoriasis: a questionnaire-based study on 230 Italian patients

In the past, several textbooks defined psoriasis as a non-pruritic dermatosis, but the most recent data in the literature emphasizes the high frequency of pruritus in psoriasis and its impact on the quality of life of patients with psoriasis.Aim of this study was to explore the sensory and affective dimensions of pruritus as well as to assess the impact of itch on quality of life and to evaluate the influence of lifestyles, habits, and various anti-pruritic therapies on pruritus in a large group of psoriatic subjects. The structured Yosipovitch itch questionnaire was given to 240 psoriatic patients. 230 patients returned a complete and detailed questionnaire. Pruritus was referred to by 80% of the patients. Psoriasis area and severity index (PASI) was significantly higher in itching-patients (P=0.04). In half of the patients, itching appeared daily, particularly in the evening. Significant aggravating factors of pruritus were stress, skin dryness, hot water, sweating, elevated ambient temperature, exercise, abundant meals, bad moods, lying position, and contact with clothes. Cold water is the only factor that showed to significantly relieve the pruritus. Anti-pruritic therapies had limited effect.Pruritus is a common, bothersome, and poorly responsive symptom in patients with psoriasis.</p

Simultaneous presence of Brugada and overgrowth syndromes

In the present article, we describe the case of a 21-year-old male presenting to the Emergency Department following a syncopal episode. Physical examination revealed a distinctive facial appearance in the context of an overgrowth syndrome. Also, an ajmaline test was performed because of the evidence of an incomplete right bundle branch block with ST-T segment elevation in the right precordial derivations, revealing a type-1 Brugada electrocardiographic pattern. Considering the high cardiovascular risk phenotype, the patient underwent subcutaneous cardiac defibrillator implantation. The subsequent comprehensive genomic testing analysis led to the diagnosis of a variant of an uncertain significance of the nuclear receptor binding SET domain protein 1 (NSD1) gene and a heterozygous mutation of the calsequestrin 2 (CASQ2) gene. NSD1 gene alterations are usually responsible for the Sotos syndrome, characterized by distinctive facial appearance, learning disability, and overgrowth, in addition to cardiac anomalies, ranging from single self-limiting alterations to more severe, complex cardiac abnormalities. On the contrary, a compound heterozygous or homozygous alteration of the CASQ2 gene is usually associated with catecholaminergic polymorphic ventricular tachycardia; however, the significance of a merely heterozygous alteration in CASQ2 gene, as in the present case report, is not yet clear. In conclusion, to the best of our knowledge, this is the first description of the coexisting presence of Brugada and overgrowth syndromes in a single patient

A New Orbiting Deployable System for Small Satellite Observations for Ecology and Earth Observation

In this paper, we present several study cases focused on marine, oceanographic, and atmospheric environments, which would greatly benefit from the use of a deployable system for small satellite observations. As opposed to the large standard ones, small satellites have become an effective and affordable alternative access to space, owing to their lower costs, innovative design and technology, and higher revisiting times, when launched in a constellation configuration. One of the biggest challenges is created by the small satellite instrumentation working in the visible (VIS), infrared (IR), and microwave (MW) spectral ranges, for which the resolution of the acquired data depends on the physical dimension of the telescope and the antenna collecting the signal. In this respect, a deployable payload, fitting the limited size and mass imposed by the small satellite architecture, once unfolded in space, can reach performances similar to those of larger satellites. In this study, we show how ecology and Earth Observations can benefit from data acquired by small satellites, and how they can be further improved thanks to deployable payloads. We focus on DORA—Deployable Optics for Remote sensing Applications—in the VIS to TIR spectral range, and on a planned application in the MW spectral range, and we carry out a radiometric analysis to verify its performances for Earth Observation studies

A multicenter randomized phase 4 trial comparing sodium picosulphate plus magnesium citrate vs. polyethylene glycol plus ascorbic acid for bowel preparation before colonoscopy. The PRECOL trial

Background: Adequate bowel preparation before colonoscopy is crucial. Unfortunately, 25% of colonoscopies have inadequate bowel cleansing. From a patient perspective, bowel preparation is the main obstacle to colonoscopy. Several low-volume bowel preparations have been formulated to provide more tolerable purgative solutions without loss of efficacy. Objectives: Investigate efficacy, safety, and tolerability of Sodium Picosulphate plus Magnesium Citrate (SPMC) vs. Polyethylene Glycol plus Ascorbic Acid (PEG-ASC) solutions in patients undergoing diagnostic colonoscopy. Materials and methods: In this phase 4, randomized, multicenter, twoarm trial, adult outpatients received either SPMC or PEG-ASC for bowel preparation before colonoscopy. The primary aims were quality of bowel cleansing (primary endpoint scored according to Boston Bowel Preparation Scale) and patient acceptance (measured with six visual analogue scales). The study was open for treatment assignment and blinded for primary endpoint assessment. This was done independently with videotaped colonoscopies reviewed by two endoscopists unaware of study arms. A sample size of 525 patients was calculated to recognize a difference of 10% in the proportion of successes between the arms with a two-sided alpha error of 0.05 and 90% statistical power. Results: Overall 550 subjects (279 assigned to PEG-ASC and 271 assigned to SPMC) represented the analysis population. There was no statistically significant difference in success rate according to BBPS: 94.4% with PEG-ASC and 95.7% with SPMC (P = 0.49). Acceptance and willing to repeat colonoscopy were significantly better for SPMC with all the scales. Compliance was less than full in 6.6 and 9.9% of cases with PEG-ASC and SPMC, respectively (P = 0.17). Nausea and meteorism were significantly more bothersome with PEG-ASC than SPMC. There were no serious adverse events in either group. Conclusion: SPMC and PEG-ASC are not different in terms of efficacy, but SPMC is better tolerated than PEG-ASC. SPMC could be an alternative to lowvolume PEG based purgative solutions for bowel preparation

A randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in the treatment of patients with metastatic colorectal cancer-OBELICS (Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme).

BACKGROUND: Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy. METHODS/DESIGN: OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80% statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [(18)F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project. DISCUSSION: Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response. EudraCT Number: 2011-004997-27 TRIAL REGISTRATION: ClinicalTrials.gove number, NCT01718873

Role of continuous glucose monitoring in diabetic patients at high cardiovascular risk. an expert-based multidisciplinary delphi consensus

Background: Continuous glucose monitoring (CGM) shows in more detail the glycaemic pattern of diabetic subjects and provides several new parameters (“glucometrics”) to assess patients’ glycaemia and consensually guide treatment. A better control of glucose levels might result in improvement of clinical outcome and reduce disease complications. This study aimed to gather an expert consensus on the clinical and prognostic use of CGM in diabetic patients at high cardiovascular risk or with heart disease. Methods: A list of 22 statements concerning type of patients who can benefit from CGM, prognostic impact of CGM in diabetic patients with heart disease, CGM use during acute cardiovascular events and educational issues of CGM were developed. Using a two-round Delphi methodology, the survey was distributed online to 42 Italian experts (21 diabetologists and 21 cardiologists) who rated their level of agreement with each statement on a 5-point Likert scale. Consensus was predefined as more than 66% of the panel agreeing/disagreeing with any given statement. Results: Forty experts (95%) answered the survey. Every statement achieved a positive consensus. In particular, the panel expressed the feeling that CGM can be prognostically relevant for every diabetic patient (70%) and that is clinically useful also in the management of those with type 2 diabetes not treated with insulin (87.5%). The assessment of time in range (TIR), glycaemic variability (GV) and hypoglycaemic/hyperglycaemic episodes were considered relevant in the management of diabetic patients with heart disease (92.5% for TIR, 95% for GV, 97.5% for time spent in hypoglycaemia) and can improve the prognosis of those with ischaemic heart disease (100% for hypoglycaemia, 90% for hyperglycaemia) or with heart failure (87.5% for hypoglycaemia, 85% for TIR, 87.5% for GV). The experts retained that CGM can be used and can impact the short- and long-term prognosis during an acute cardiovascular event. Lastly, CGM has a recognized educational role for diabetic subjects. Conclusions: According to this Delphi consensus, the clinical and prognostic use of CGM in diabetic patients at high cardiovascular risk is promising and deserves dedicated studies to confirm the experts’ feeling

Erythropoietin in amyotrophic lateral sclerosis: a multicentre, randomised, double blind, placebo controlled, phase III study

OBJECTIVE: To assess the efficacy of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS). METHODS: Patients with probable laboratory-supported, probable or definite ALS were enrolled by 25 Italian centres and randomly assigned (1:1) to receive intravenous rhEPO 40,000 IU or placebo fortnightly as add-on treatment to riluzole 100 mg daily for 12 months. The primary composite outcome was survival, tracheotomy or &gt;23 h non-invasive ventilation (NIV). Secondary outcomes were ALSFRS-R, slow vital capacity (sVC) and quality of life (ALSAQ-40) decline. Tolerability was evaluated analysing adverse events (AEs) causing withdrawal. The randomisation sequence was computer-generated by blocks, stratified by centre, disease severity (ALSFRS-R cut-off score of 33) and onset (spinal or bulbar). The main outcome analysis was performed in all randomised patients and by intention-to-treat for the entire population and patients stratified by severity and onset. The study is registered, EudraCT 2009-016066-91. RESULTS: We randomly assigned 208 patients, of whom 5 (1 rhEPO and 4 placebo) withdrew consent and 3 (placebo) became ineligible (retinal thrombosis, respiratory insufficiency, SOD1 mutation) before receiving treatment; 103 receiving rhEPO and 97 placebo were eligible for analysis. At 12 months, the annualised rate of death (rhEPO 0.11, 95% CI 0.06 to 0.20; placebo: 0.08, CI 0.04 to 0.17), tracheotomy or &gt;23 h NIV (rhEPO 0.16, CI 0.10 to 0.27; placebo 0.18, CI 0.11 to 0.30) did not differ between groups, also after stratification by onset and ALSFRS-R at baseline. Withdrawal due to AE was 16.5% in rhEPO and 8.3% in placebo. No differences were found for secondary outcomes. CONCLUSIONS: RhEPO 40,000 IU fortnightly did not change the course of ALS

Discordant Results with Pimecrolimus 1% Cream in the Treatment of Plasma Cell Balanitis

Plasma cell balanitis of Zoon is a chronic, benign, inflammatory dermatosis of the glans penis and prepuce. The exact aetiology is unknown. The treatments described to date have provided only partially successful results. Recently, several reports of plasma cell balanitis successfully treated with calcineurin inhibitors have been published. We report 3 cases of plasma cell balanitis refractory to several treatments with steroids and antifungals treated with pimecrolimus 1% cream applied twice daily: 1 patient had a complete resolution, 1 patient had a marked response but relapsed during the treatment and the last patient had a partial response due to the development of a side effect that precociously required to stop the treatment. One patient referred a slight pruritus after the first applications of the cream that spontaneously disappeared after a few minutes. Additional experiences are needed to determine if topical pimecrolimus is an effective and safe treatment for plasma cell balanitis