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Purpose This study aims to provide real-world data about starting-dose of NOACs and dose- adjustment in patients with AF. In fact, even if new oral anticoagulation agents (NOACs) have a predictable effect without need for regular monitoring, dose-adjustments should be performed according to the summary of product information and international guidelines. Methods We employed the Italian Medicines Agency monitoring registries comprising data on a nationwide cohort of patients with AF treated with NOACs from 2013 to 2018. Logistic regression analysis was used to evaluate the determinants of dosage choice. Results During the reference period, treatment was commenced for 866539 patients. Forty-five percent of the first prescriptions were dispensed at a reduced-dose (dabigatran 60.3%, edoxaban 45.2%, apixaban 40.9%, rivaroxaban 37.4%). The prescription of reduced-dose was associated with older age, renal disease, bleeding risk and the concomitant use of drugs predisposing to bleeding, but not with CHA₂DS₂-VASc and HAS-BLED. A relative reduction of the proportion of patients treated with low-dosages was evident overtime for dabigatran and rivaroxaban; whereas prescription of low-dose apixaban and edoxaban increased progressively among elderly patients. Conclusions Evidence based on real-world data shows a high frequency of low-dose prescriptions of NOACs in AF patients. Except for older age, renal disease, bleeding risk and the concomitant use of drugs predisposing to bleeding, other factors that may determine the choice of reduced-dose could not be ascertained. There may be potential under-treatment of AF patients, but further evaluation is warranted.

Computer Aided Diagnosis (CAD) systems can support physicians in classifying different kinds of breast cancer, liver cancer and blood tumours also revealed by images acquired via Computer Tomography, Magnetic Resonance, and Blood Smear systems. In this regard, this survey focuses on papers dealing with the description of existing CAD frameworks for the classification of the three mentioned diseases, by detailing existing CAD workflows based on the same steps for supporting the diagnosis of these tumours. In detail, after an appropriate acquisition of the images, the fundamental steps carried out by a CAD framework can be identified as image segmentation, feature extraction and classification. In particular, in this work, specific CAD frameworks are considered, where the task of feature extraction is performed by using both traditional handcrafted strategies and Convolutional Neural Networks-based innovative methodologies, whereas the final supervised pattern classification is based on neural/non-neural machine learning methods. The cited methodology is focused on sharing and reviewing an amount of specific works. Then, the performance of three selected case studies are carefully reported, designed with the aim of showing how final outcomes can vary according to different choices in each step of the adopted workflow. More in detail, these case studies concern with breast images acquired by Tomosynthesis and Magnetic Resonance, hepatocellular carcinoma images acquired by Computed Tomography and enhanced by a triphasic protocol with a contrast medium, peripheral blood smear images for cellular blood tumours and are used to compare their performance.

Heart failure (HF) prevalence is increasing among the aging population, and the mortality rate remains unacceptably high despite improvements in therapy. Myocardial ischemia (MI) and, consequently, ischemia/reperfusion injury (IRI), are frequently the basis of HF development. Therefore, cardioprotective strategies to limit IRI are mandatory. Nanocarriers have been proposed as alternative therapy for cardiovascular disease. Controlled reoxygenation may be a promising strategy. Novel nanocarriers, such as cyclic nigerosyl-nigerose (CNN), can be innovative tools for oxygen delivery in a controlled manner. In this study we analyzed new CNN-based formulations as oxygen nanocarriers (O2-CNN), and compared them with nitrogen CNN (N2-CNN). These different CNN-based formulations were tested using two cellular models, namely, cardiomyoblasts (H9c2), and endothelial (HMEC) cell lines, at different concentrations. The effects on the growth curve during normoxia (21% O2, 5% CO2 and 74% N2) and their protective effects during hypoxia (1% O2, 5% CO2 and 94% N2) and reoxygenation (21% O2, 5% CO2 and 74% N2) were studied. Neither O2-CNN nor N2-CNN has any effect on the growth curve during normoxia. However, O2-CNN applied before hypoxia induces a 15–30% reduction in cell mortality after hypoxia/re-oxygenation when compared to N2-CNN. O2-CNN showed a marked efficacy in controlled oxygenation, which suggests an interesting potential for the future medical application of soluble nanocarrier systems for MI treatment.

Doxorubicin (DOX) is an anthracycline widely used in cancer therapy and in particular in breast cancer treatment. The treatment with DOX appears successful, but it is limited by a severe cardiotoxicity. This work evaluated the in vitro and in vivo anticancer effect of a new formulation of &beta, cyclodextrin nanosponges containing DOX (BNS-DOX). The BNS-DOX effectiveness was evaluated in human and mouse breast cancer cell lines in vitro in terms of effect on cell growth, cell cycle distribution, and apoptosis induction, and in vivo in BALB-neuT mice developing spontaneous breast cancer in terms of biodistribution, cancer growth inhibition, and heart toxicity. BNS-DOX significantly inhibited cancer cell proliferation, through the induction of apoptosis, with higher efficiency than free DOX. The breast cancer growth in BALB-neuT mice was inhibited by 60% by a BNS-DOX dose five times lower than the DOX therapeutic dose, with substantial reduction of tumor neoangiogenesis and lymphangiogenesis. Biodistribution after BNS-DOX treatment revealed a high accumulation of DOX in the tumor site and a low accumulation in the hearts of mice. Results indicated that use of BNS may be an efficient strategy to deliver DOX in the treatment of breast cancer, since it improves the anti-cancer effectiveness and reduces cardiotoxicity.

Chemoresistance represents one of the main obstacles in treating several types of cancer, including bladder and ovarian cancers, and it is characterized by an increase of cellular antioxidant potential. Nrf2 and YAP proteins play an important role in increasing chemoresistance and in inducing antioxidant enzymes. It has been reported that Ailanthone (Aila), a compound extracted from the Ailanthus Altissima, has an anticancer activity toward several cancer cell lines, including chemoresistant cell lines. We have examined the effect of Aila on proliferation, migration and expression of Nrf2 and YAP proteins in A2780 (CDDP-sensitive) and A2780/CP70 (CDDP-resistant) ovarian cancer cells. Furthermore, to clarify the mechanism of Aila action we extended our studies to sensitive and CDDP-resistant 253J-BV bladder cancer cells, which have been used in a previous study on the effect of Aila. Results demonstrated that Aila exerted an inhibitory effect on growth and colony formation of sensitive and CDDP-resistant ovarian cancer cells and reduced oriented cell migration with higher effectiveness in CDDP resistant cells. Moreover, Aila strongly reduced Nrf2 and YAP protein expression and reduced the expression of the Nrf2 target GSTA4, and the YAP/TEAD target survivin. In CDDP-resistant ovarian and bladder cancer cells the intracellular oxidative stress level was lower with respect to the sensitive cells. Moreover, Aila treatment further reduced the superoxide anion content of CDDP-resistant cells in correlation with the reduction of Nrf2 and YAP proteins. However, Aila treatment increased Nrf2 and YAP mRNA expression in all cancer cell lines. The inhibition of proteolysis by MG132, a proteasoma inhibitor, restored Nrf2 and YAP protein expressions, suggesting that the Aila effect was at post-translational level. In accordance with this observation, we found an increase of the Nrf2 inhibitor Keap1, a reduction of p62/SQSTM1, a Nrf2 target which leads Keap1 protein to the autophagic degradation, and a reduction of P-YAP. Moreover, UCHL1 deubiquitinase expression, which was increased in bladder and ovarian resistant cells, was down-regulated by Aila treatment. In conclusion we demonstrated that Aila can reduce proliferation and migration of cancer cells through a mechanism involving a post translational reduction of Nrf2 and YAP proteins which, in turn, entailed an increase of oxidative stress particularly in the chemoresistant lines.

Background Analyzing the data of the International Register of Open Abdomen (IROA), the feasibility of open abdomen treatment has been demonstrated at every age. This new analysis on the IROA database investigates the risk factors for mortality in elderly patients treated with open abdomen for intra-abdominal infection. Methods Data were derived from the IROA, a prospective observational international cohort study that enrolled patients treated with open abdomen worldwide. A univariate analysis of potential risk factors was performed. Inclusion criteria were patients older than 65 years and treated with open abdomen for intra-abdominal infection. End point was overall mortality, calculated within 30 days after open abdomen management, after 1-month and 1-year follow-up. Results A total of 116 patients was analyzed with mean age of 76 ± 7 years. Definitive closure was achieved in 93 patients (93/116, 80.2%) for a mean open abdomen duration of 5.0 ± 5.0 days. Complicated patients were 101 (101/116, 87.1%) for a total of 201 complications. Overall, 62 out of 116 patients (53.4%) died: 23 patients (23/62, 37.1%) during open abdomen management, 29 patients (46.8%) within 30 days after abdominal closure, 9 patients (14.5%) after 1-month follow-up, and 1 patient (1.6%) after 1-year follow-up. Age did not affect mortality (75 ± 6 years in alive patients versus 77 ± 7 years in dead patients, p = 0.773). Definitive abdominal closure was the most important factor to prevent mortality. Conclusions This study confirmed that age alone cannot be considered a determinant for death, even in elderly patients managed with open abdomen for severe intra-abdominal infection.

13 p.-7 fig.-1 tab., Inducible T-cell costimulator (ICOS) upon binding to its ligand (ICOSL) mediates adaptive immunity and antitumor response. Thus, antitumor therapies targeting the ICOS/ICOSL pathway hold great promise for cancer treatment. In this regard, ICOSL triggering by a soluble recombinant form of ICOS (ICOS-Fc) hampered adhesiveness and migration of dendritic, endothelial, and tumor cells in vitro. Furthermore, in vivo treatment with ICOS-Fc previously showed the capability to inhibit lung metastatization of ICOSL+ B16-F10 melanoma cells when injected intravenously in mice, but it failed to block the growth of established subcutaneous B16-F10 murine tumors. Thus, we asked whether passive targeting of solid tumors with ICOS-Fc-loaded biocompatible and biodegradable nanoparticles (NPs) could instead prove effectiveness in reducing tumor growth. Here, ICOS-Fc was loaded in two types of polymer nanoparticles, i.e. cross-linked β-cyclodextrin nanosponges (CDNS) and poly(lactic-co-glycolic acid) (PLGA) NPs and in vitro characterized. In vivo experiments showed that treatment of C57BL6/J mice with ICOS-Fc loaded into the two nanoformulations inhibits the growth of established subcutaneous B16-F10 tumors. This anticancer activity appears to involve both anti-angiogenic and immunoregulatory effects, as shown by decreased tumor vascularization and downmodulation of IL-10 and Foxp3, two markers of regulatory T cells (Tregs). Overall, the substantial in vivo anticancer activity of ICOS-Fc-loaded CDNS and PLGA NPs against different components of the tumor microenvironment makes these nanoformulations attractive candidates for future combination cancer therapy., This work was supported by the Associazione Italiana Ricerca sul Cancro (IG 20714, AIRC, Milano), Fondazione Amici di Jean (Torino), and Fondazione Cariplo (2017–0535).

Background Superficial erosion currently causes at least one-third of acute coronary syndromes (ACS), and its incidence is increasing. Yet, the underlying mechanisms in humans are still largely unknown. Objectives The authors sought to assess the role of hyaluronan (HA) metabolism in ACS. Methods Peripheral blood mononuclear cells were collected from ACS (n = 66), stable angina (SA) (n = 55), and control (CTRL) patients (n = 45). The authors evaluated: 1) gene expression of hyaluronidase 2 (HYAL2) (enzyme degrading high-molecular-weight HA to its proinflammatory 20-kDa isoform) and of CD44v1, CD44v4, and CD44v6 splicing variants of HA receptor; and 2) HYAL2 and CD44 protein expression. Moreover, they compared HYAL2 and CD44 gene expression in ACS patients with plaque erosion (intact fibrous cap and thrombus) and in ACS patients with plaque rupture, identified by optical coherence tomography analysis. Results Gene expression of HYAL2, CD44v1, and CD44v6 were significantly higher in ACS as compared with SA (p = 0.003, p Conclusions HYAL2 and CD44v6 splicing variants seem to play an important role in ACS, in particular when associated with plaque erosion. After further validation, HYAL2 might represent a potentially useful biomarker for the noninvasive identification of this mechanism of coronary instability.

Purpose Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma often refractory to currently available treatments (immuno-chemotherapy/autologous-stem-cell-transplantation-ASCT). Recently, new cell therapies have been approved for patients failing two conventional treatments, CAR-T (Chimeric-Antigen-Receptor-T-cell), committing payers in planning and implementing their use. We aim to define, using Real World Data (RWD), a reproducible procedure that allows identification of CAR-T target population for DLBCL. Methods Through the linking of electronic healthcare datasets (EHD), we identified patients with non-Hodgkin's Lymphoma (NHL), resident in Lazio region (2010-2015), aged ≥20 years. DLBCL patients were followed using pathological anatomy (PA) reports, up to 3 years. To be defined as relapsed after two treatment lines, patients must have had new chemotherapy and/or NHL hospitalization after ASCT or at the end of the second chemotherapy. The incident rate of second relapse (R2-rate) was extended to the population without PA reports. Result NHL incident patients were 7384, 68% presented a PA report and, 29% of these had DLBCL codes. Patients who relapsed after two treatment lines were 47 (39%) in the subgroup of patients who received ASCT and 138 (41%) in that with second chemotherapy treatment. Patients in the two subgroups were very different in terms of age and comorbidity. The annual incident number of DLBCL was estimated to be 329 which multiplied by R2-rate (13.7%) gives 45 patients per year eligible for CAR-T. Discussion This study shows how RWD allows the identification of a target population with new advanced therapies. This approach is rigorous, transparent and verifiable over time.

Background Assessment and rating of Parkinson’s Disease (PD) are commonly based on the medical observation of several clinical manifestations, including the analysis of motor activities. In particular, medical specialists refer to the MDS-UPDRS (Movement Disorder Society – sponsored revision of Unified Parkinson’s Disease Rating Scale) that is the most widely used clinical scale for PD rating. However, clinical scales rely on the observation of some subtle motor phenomena that are either difficult to capture with human eyes or could be misclassified. This limitation motivated several researchers to develop intelligent systems based on machine learning algorithms able to automatically recognize the PD. Nevertheless, most of the previous studies investigated the classification between healthy subjects and PD patients without considering the automatic rating of different levels of severity. Methods In this context, we implemented a simple and low-cost clinical tool that can extract postural and kinematic features with the Microsoft Kinect v2 sensor in order to classify and rate PD. Thirty participants were enrolled for the purpose of the present study: sixteen PD patients rated according to MDS-UPDRS and fourteen healthy paired subjects. In order to investigate the motor abilities of the upper and lower body, we acquired and analyzed three main motor tasks: (1) gait, (2) finger tapping, and (3) foot tapping. After preliminary feature selection, different classifiers based on Support Vector Machine (SVM) and Artificial Neural Networks (ANN) were trained and evaluated for the best solution. Results Concerning the gait analysis, results showed that the ANN classifier performed the best by reaching 89.4% of accuracy with only nine features in diagnosis PD and 95.0% of accuracy with only six features in rating PD severity. Regarding the finger and foot tapping analysis, results showed that an SVM using the extracted features was able to classify healthy subjects versus PD patients with great performances by reaching 87.1% of accuracy. The results of the classification between mild and moderate PD patients indicated that the foot tapping features were the most representative ones to discriminate (81.0% of accuracy). Conclusions The results of this study have shown how a low-cost vision-based system can automatically detect subtle phenomena featuring the PD. Our findings suggest that the proposed tool can support medical specialists in the assessment and rating of PD patients in a real clinical scenario.

Riccardo Di Domenicantonio,1 Francesco Trotta,1 Silvia Cascini,1 Nera Agabiti,1 Anna Kohn,2 Antonio Gasbarrini,3 Marina Davoli,1 Antonio Addis1 1Department of Epidemiology, Lazio Regional Health Service, Rome, Italy; 2IBD Unit, AO San Camillo Forlanini, Rome, Italy; 3Department of Internal Medicine, Agostino Gemelli University Hospital, Catholic University of Sacred Heart, Rome, Italy Background: The comparison of effectiveness and safety of anti-tumor necrosis factor-alpha agents for the treatment of inflammatory bowel disease (IBD) is relevant for clinical practice and stakeholders. Objective: The objective of this study was to compare the risk of abdominal surgery, steroid utilization, and hospitalization for infection in Crohn’s disease (CD) or ulcerative colitis (UC) patients newly treated with infliximab (IFX) or adalimumab (ADA). Methods: A retrospective population-based cohort study was performed using health information systems data from Lazio region, Italy. Patients with CD or UC diagnosis were enrolled at first prescription of IFX or ADA during 2008–2014 (index date). Only new drug users were followed for 2 years from the index date. IFX versus ADA adjusted hazard ratios were calculated applying “intention-to-treat” approach, controlling for several characteristics and stratifying the analysis on steroid use according to previous drug utilization. Sensitivity analyses were performed according to “as-treated” approach, adjusting for propensity score, censoring at switching or discontinuation, and evaluating different lengths of follow-up periods. Results: We enrolled 1,432 IBD patients (42% and 83% exposed to IFX for CD and UC, respectively). In both diseases, treatment effects did not differ in any outcome considered, and sensitivity analyses confirmed the results from the main analysis. Conclusion: In our population-based cohort study, effectiveness and safety data in new users of ADA or IFX with CD or UC were comparable for the outcomes we tested. Keywords: biologics, real-world effectiveness, inflammatory bowel disease

Aims In patients with acute coronary syndrome (ACS), the higher activity of effector T-cells suggests that mechanisms involving adaptive immunity dysregulation might play a role in coronary instability. The shedding of the functional CD31 domain 1–5 leads to uncontrolled lymphocyte activation. In experimental models, matrix metalloproteinase-9 (MMP-9) has been implicated in endothelial CD31 cleavage. Interestingly, higher serum levels of MMP-9 have been observed in ACS. We aim to investigate the mechanisms underlying CD31 dysregulation in ACS. Methods and results To assess CD31 cleavage on CD4+ T-cells, we analysed by flow cytometry CD4+ T-cells of 30 ACS, 25 stable angina (SA) patients, and 28 controls (CTRL) using two different CD31 antibodies that specifically recognize domain 1–5 or the non-functional membrane-proximal domain 6. The ratio between the domains was significantly lower in ACS than in SA and CTRL (P = 0.002 ACS vs. SA; P = 0.002 ACS vs. CTRL). After stimulation with anti-CD3/CD28, the 1–5/6 domain ratio was significantly lower in ACS than in SA (P = 0.005). ELISA of supernatants obtained from T-cell receptor-stimulated CD4+ T-cells showed higher production of MMP-9 in ACS than in SA (P

Several Erythropoiesis-stimulating agents (ESAs) are available to treat anemia in patients with chronic kidney disease (CKD). Questions about the comparability of such therapeutic options are not purely a regulatory or economical matter. Appropriate use of originator or biosimilar in these patients need to be supported by clinical data. Regarding the prevention of blood transfusion, reduction of fatigue, breathlessness and mortality or cardiovascular events, a summary of the comparative efficacy and safety data of these drugs is lacking. We performed a systematic literature search of CENTRAL, PubMed, and Embase through November 11, 2015. Our inclusion criteria encompassed randomized, controlled clinical trials that evaluated the comparative effectiveness of different ESAs originators and/or biosimilar. The considered participants were adults aged 18 years or older with anemia due to CKD. The overall quality of evidence was assessed using the GRADE system. We identified 30 eligible studies including 7843 patients with CKD, and 21/30 studies included patients using hemodialysis or peritoneal dialysis. Compared with ESA biosimilars, epoetin α did not statistically differ for any of the ten measured outcomes. The quality of evidence varied from low to very low. In the comparison between epoetin α vs. darbepoetin α, no differences were observed for all outcomes, but blood transfusions showed favorable results for darbepoetin α: RR 2.18 (1.31–3.62). The quality of evidence varied from low to very low. No differences were observed between epoetin β and methoxy polyethylene glycol-epoetin β, and between darbepoetin α and methoxy polyethylene glycol-epoetin β, the quality of evidence varied from moderate to very low. Data from 31 included studies allowed to pool data in meta-analysis related to four different comparisons and eleven outcome measures. Nevertheless, only one result was statistically significant in favor of darbepoetin α in the comparison with epoetin α concerning blood transfusions. For all the other outcomes and comparisons, we did not find any differences in terms of efficacy and security between the EPO considered. The quality of evidence is quite low, and further research could change these results. Further high quality studies examining the comparative effectiveness of ESAs need to be conducted.

Background Epicardial adipose tissue (EAT) has a close functional and anatomic relationship with epicardial coronary arteries. Accumulating evidence suggests that host microbiome alterations may play a role in several inflammatory/immune disorders, triggering a robust proinflammatory response also involving interleukin-1β (IL-1β) and the NALP3 inflammasome. In the current study, we explore the hypothesis that in patients with non-ST elevation acute coronary syndrome (ACS), EAT contains potentially pro-atherosclerotic bacteria that might elicit inflammasome activation. Methods EAT samples were obtained during coronary artery bypass grafting from ACS ( n =18) and effort stable angina (SA; n =16) patients, and as controls, from patients with angiographically normal coronary arteries undergoing surgery for mitral insufficiency (MVD; n =13). In all patients, NALP3 and proIL-1β mRNA expressions were evaluated with qRT-PCR. In 3 patients from each group, EAT microbiota composition was determined using next-generation sequencing technologies. Results In EAT, mRNA expression of both NALP3 and pro-IL1β was significantly higher in ACS than in SA and MVD ( P =0.028 and P =0.005, respectively). A broad range of bacterial species ( n =76) was identified in both ACS and SA, with different predominant species. In contrast, microbial DNA was barely observed in MVD. Conclusions Our study demonstrated the presence of bacterial DNA directly into EAT, surrounding diseased coronary arteries, of patients with ACS. Furthermore, ACS is associated with NALP3/inflammasome pathway activation in EAT. Our data suggest that the EAT environment is susceptible to microbial colonization that might stimulate a proinflammatory response. These findings add new elements to the pathogenesis of ACS and suggest novel therapeutic targets.

Introduction and objective: Computer Aided Decision (CAD) systems based on Medical Imaging could support radiologists in grading Hepatocellular carcinoma (HCC) by means of Computed Tomography (CT) images, thus avoiding medical invasive procedures such as biopsies. The identification and characterization of Regions of Interest (ROIs) containing lesions is an important phase allowing an easier classification in two classes of HCCs. Two steps are needed for the detection of lesioned ROIs: a liver isolation in each CT slice and a lesion segmentation. Materials and methods: Materials consist in abdominal CT hepatic lesion from 18 patients subjected to liver transplant, partial hepatectomy, or US-guided needle biopsy. Several approaches are implemented to segment the region of liver and, then, detect the lesion ROI. Results: A Deep Learning approach using Convolutional Neural Network is followed for HCC grading. The obtained good results confirm the robustness of the segmentation algorithms leading to a more accurate classification.

Background Current guidelines recommend prophylaxis with granulocyte colony-stimulating factors (G-CSFs) for patients with cancer who are at greater risk of febrile neutropenia (FN) while receiving chemotherapy. G-CSF biosimilars are available and represent a savings opportunity; however, their uptake has thus far been low. Objective Our objective was to evaluate prescribing patterns for G-CSFs in the prevention of chemotherapy-related FN and to evaluate the impact of regional guidance on G-CSF prescription. Methods We conducted an observational drug-utilization study in the Lazio region of Italy using the Electronic Therapeutic Plan Registry, which collects information on G-CSF prescriptions reimbursed by the regional health service. This registry includes information on demographics, tumour, indication for G-CSF use and previous G-CSF exposure. All therapeutic plans (TPs) registered from 1 July 2015 to 30 June 2016 were selected. A pharmaceutical policy intervention was implemented in November 2015. We evaluated temporal trends regarding G-CSF substances and compared the frequency of TPs for each G-CSF substance during the pre- and post-intervention periods. Results A total of 7082 TPs were eligible for the analysis, corresponding to 6592 patients. The frequency of TPs prescribed after the intervention indicated a significant increase in the use of a filgrastim biosimilar (% difference: 14.4; p

Background: Open abdomen is the cornerstone of damage control strategies in acute care and trauma surgery. The role of BMI has not been well investigated. The aim of the study was to assess the role of BMI in determining outcomes after open abdomen. Methods: This is an analysis of patients recorded into the International Register of Open Abdomen; patients were classified in two groups according to BMI using a cutoff of 30 kg/m2. The primary outcome was in-hospital mortality; secondary outcomes were primary fascia closure rate, length of treatment, complication rate, entero-atmospheric fistula rate and length of ICU stay. Results: A total of 591 patients were enrolled from 57 centers, and obese patients were 127 (21.5%). There was no difference in mortality between the two groups; complications developed during the open treatment were higher in obese patients (63.8% vs. 53.4%, p = 0.038) while post-closure complications rate was similar. Obese patients had a significantly longer duration of the open treatment (9.1 ± 11.5 days vs. 6.3 ± 7.5 days; p = 0,002) and lower primary fascia closure rate (75.5% vs. 89.5%; p < 0,001). No differences in fistula rate were found. There was a linear correlation between the duration of open abdomen and the BMI (Pearson’s linear correlation coefficient = 0,201; p < 0,001). Conclusions: Open abdomen in obese patients seems to be safe as in non-obese patients with similar mortality; however, in obese patients the length of open abdomen is significantly higher with higher complication rate, longer ICU length of stay and lower primary fascia closure rate. Trial registration number: ClinicalTrials.gov, Identifier: NCT02382770.

The traditional diagnosis of Parkinson’s disease (PD) aims to assess several clinical manifestations, and it is commonly based on medical observations. However, an overall evaluation is extremely difficult due to the large variety of symptoms that affect PD patients. Furthermore, the traditional PD assessment is based on visual subjective observation of different motor tasks. For this reasons, an automatic system could be able to automatically assess and rate the PD and objectively evaluate the performed motor tasks. Such system could then support medical specialists in the assessment and rating of PD patients in a real clinical scenario. In this work, we developed multi-modal tool suite able to extract and process meaningful features from different motor tasks by means of two main experimental set-ups. In detail, we acquired and evaluated the motor performance acquired during the finger tapping, the foot tapping and the hand writing exercises. Several sets of features have been extracted from the acquired signals and used to both successfully classify a subject as PD patient or healthy subject, and rate the disease among PD patients.

Blepharospasm (BSP) is an adult-onset focal dystonia with phenomenologically heterogeneous effects, including, but not limited to, blinks, brief or prolonged spasms, and a narrowing or closure of the eyelids. In spite of the clear and well-known symptomatology, objectively rating the severity of this dystonia is a rather complex task since BSP symptoms are so subtle and hardly perceptible that even expert neurologists can rate the gravity of the pathology differently in the same patients. Software tools have been developed to help clinicians in the rating procedure. Currently, a computerised video-based system is available that is capable of objectively determining the eye closure time, however, it cannot distinguish the typical symptoms of the pathology. In this study, we attempt to take a step forward by proposing a neural network-based software able not only to measure the eye closure, time but also to recognise and count the typical blepharospasm symptoms. The software, after detecting the state of the eyes (open or closed), the movement of specific facial landmarks, and properly implementing artificial neural networks with an optimised topology, can recognise blinking, and brief and prolonged spasms. Comparing the software predictions with the observations of an expert neurologist allowed assessment of the sensitivity and specificity of the proposed software. The levels of sensitivity were high for recognising brief and prolonged spasms but were lower in the case of blinks. The proposed software is an automatic tool capable of making objective 'measurements' of blepharospasm symptoms.

The effectiveness of the tiotropium Respimat® formulation in routine clinical practice is still an open issue due to concern about the generalizability of the Tiotropium Safety and Performance in Respimat® (TIOSPIR) trial findings. Our aim was to compare the incidence of acute respiratory events between new users of tiotropium Respimat® and HandiHaler®. The study population comprised patients aged ≥45 years resident in two Italian regions who received a first tiotropium prescription (HandiHaler® or Respimat®) between 1 July 2011 and 30 November 2013. The cohort was identified within the database of drug prescriptions reimbursed by the Italian National Health Service. Clinical outcomes were obtained from hospital records. The primary outcome was the first hospitalization for respiratory events, including chronic obstructive pulmonary disease (COPD) exacerbation, respiratory failure, hypoxemia/hyperventilation and pneumonia, during the exposure period. The hazard ratios were estimated for the propensity score matched groups with Cox regression. After matching, 31,334 patients with incident tiotropium prescriptions were included. Similar incidence rates of the primary outcome between the Respimat® and HandiHaler® users were identified (adjusted hazard ratio 0.95, 95% CI 0.84–1.07). No differences emerged in the subgroup analyses conducted according to the baseline characteristics of the tiotropium users. This study confirms the findings observed in the TIOSPIR trial in a more heterogeneous population that included patient subgroups with severe respiratory disease and unstable COPD.

Osteoporosis-related fractures are a growing public health concern worldwide due to high societal and economic burden. The study aims to assess trends in incidence rates of hip and distal femoral fractures and in the use of anti-osteoporosis drugs in Italy between 2007 and 2017. Patients with hip and distal femoral fractures (ICD-9-CM codes 820.x and 821.x) were identified in the Italian National Hospital Discharge Database while anti-osteoporosis medication data were retrieved from the National Observatory on the Use of Medicines Database. A joinpoint regression analysis was performed to identify the years where the trends in incidence rates of hip and distal femoral fractures changed significantly; the average annual percentage change for the period of observation was estimated. Hospitalizations for femoral fractures were 991,059, of which 91.4% were hip fractures and 76.5% occurred in women. Age-standardized hip fractures rate per 100,000 person-years decreased both in women (-8.7%; from 789.9 in 2007 to 721.5 in 2017) and in men (-4.3%; from 423.9 to 405.6), while the rate of distal femoral fractures increased by 23.9% in women (from 67.78 to 83.95) and 22.7% in men (from 27.76 to 34.06). These changes were associated with an increment in the use of anti-osteoporosis drugs from 2007 to 2011 (from 9.1 to 12.4 DDD/1000 inhabitants/day), followed by a plateau in the period 2012-2017. The use of bisphosphonates increased progressively from 2007 to 2010 (from 8.2 to 10.5 DDD/1000 inhabitants/day), followed by a plateau and then decreased from 2015 onwards. The decreasing trend of hip fractures could be related to a major intake of anti-osteoporosis medications while the increment of distal femoral fractures might be due to population aging and to the use of bisphosphonates and denosumab. Further research is needed to identify and implement interventions to prevent hip and distal femoral fractures.

Introduction: Hypertrophic osteoarthropathy (HOA) is an orphan disease characterized by digital clubbing, periostitis of tubular bones and arthralgia/arthritis. The disease may be classified as primary or secondary. Pulmonary and other intra-thoracic diseases are the cause of more than 90% of the secondary forms.Areas covered: The diagnosis is generally based on the presence of a triad of symptoms including digital clubbing, periostitis of the distal end of the tubular bones and painful swelling of the limbs, associated with bilateral and symmetrical arthritis in the large joints. Radiographic evaluation is the assessment reference for the diagnosis.Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) seem to be the key mediators in the pathogenesis of this disorder. Treatment and prognosis depend on the HOA underlying cause. In some cases, treatment of associated malignancy can solve or improve clubbing. Bisphosphonates may have a role for the symptomatic treatment ...

Camptothecin (CPT), a pentacyclic alkaloid, is an inhibitor of DNA Topoisomerase-I and shows a wide spectrum of anti-cancer activities. The use of CPT has been hampered by poor aqueous solubility and a high degradation rate. Previously, it has been reported that CPT encapsulated in β-cyclodextrin-nanosponges (CN-CPT) overcomes these disadvantages and improves the CPT's inhibitory effect on DU145 prostate tumor cell lines, and PC-3 growth in vitro. This work extends these observations by showing that CN-CPT significantly inhibits the adhesion and migration of these tumor cells and their STAT3 phosphorylation. The anti-adhesive effect is exerted also in human endothelial cells, in which CN-CPT also inhibits the angiogenic activity as assessed by the tubulogenesis and sprouting assays. Finally, CN-CPT substantially delays the growth of PC-3 cell engraftment in SCID mice in vivo without apparent toxic effects. These results support the use of β-cyclodextrin nanosponge nanotechnology as a potential nanocarrier for delivery of anticancer drugs in the treatment of prostate cancers.

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia associated with an increased risk of stroke and thromboembolism. Anticoagulation with Vitamin K antagonists (VKAs) or with novel oral anti-coagulants (NOACs) represents the cornerstone of the pharmacological treatment to reduce the risk of thromboembolism. This study aims to provide real-world data from a whole large European country about NOAC use in “non-valvular atrial fibrillation” (NVAF). Methods: We analysed the Italian Medicines Agency (AIFA) monitoring registries collecting data of a nationwide cohort of patients with “NVAF” treated with NOACs. Using logistic regression analysis, baseline characteristics and treatment discontinuation information were compared among initiators of the 4 NOACs. Results: In the reference period, the NOAC database collected data for 683,172 patients. The median age was 78 years with 19.5% aged 85 or older. Overall, the treatments were in accordance with guidelines. About 1/3 of patients switched from a prior VKA treatment; in the 72.3% of cases, these patients had a labile International Normalized Ratio (INR) at first prescription. The most prescribed NOAC was rivaroxaban, followed by apixaban, dabigatran and edoxaban. Conclusions: This study is the largest European real-world study ever published on NOACs. It includes all Italian patients treated with NOACs since 2013 accounting for about 1/3 of subjects with AF. The enrolled population consisted of very elderly patients, at high risk of ischemic adverse events. The AIFA registries are consolidated tools that guarantee the appropriateness of prescription and provide important information for the governance of National Health System by collecting real-world data. Keywords: Monitoring registries, Real world data, NOACs, AF, Appropriateness

There is an increasing interest in the use of Gait Analysis (GA) in Parkinson’s Disease (PD), however no one has previously investigated what are the principal trends on the main applications of quantitative GA in studies involving this neurological disorder. We performed a systematically literature search for articles published through 2013 to present using three electronic databases. We retrieved 76 articles that met the inclusion criteria and identified four main research areas which refers to GA for: pathophysiological mechanisms underlying PD; assessment tool for treatment outcomes; automatic recognition of PD symptoms and algorithms for classification between PD patients and healthy subjects.

Background Ailanthone (Aila) is a natural active compound isolated from the Ailanthus altissima, which has been shown to possess an “in vitro” growth-inhibitory effect against several cancer cell lines. Advanced bladder cancer is a common disease characterized by a frequent onset of resistance to cisplatin-based therapy. The cisplatin (CDDP) resistance is accompanied by an increase in Nrf2 protein expression which contributes to conferring resistance. Recently, we demonstrated a cross-talk between Nrf2 and YAP. YAP has also been demonstrated to play an important role in chemoresistance of bladder cancer. Purpose We analyzed the antitumor effect of Aila in sensitive and CDDP-resistant bladder cancer cells and the molecular mechanisms involved in Aila activity. Study design Sensitive and CDDP-resistant 253J B-V and 253J bladder cancer cells, intrinsically CDDP-resistant T24 bladder cancer cells and HK-2 human renal cortex cells were used. Cells were treated with diverse concentrations of Aila and proliferation, cell cycle, apoptosis and gene expressions were determined. Methods Aila toxicity and proliferation were determined by MTT and colony forming methods, respectively. Cell cycle was determined by cytofluorimetric analysis through PI staining method. Apoptosis was detected using Annexin V and PI double staining followed by quantitative flow cytometry. Expressions of Nrf2, Yap, c-Myc, and house-keeping genes were determined by western blot with specific antibodies. Cell migration was detected by wound healing and Boyden chamber analysis. Results Aila inhibited the growth of sensitive and CDDP-resistant bladder cancer cells with the same effectiveness. On the contrary, the growth of HK-2 cells was only slightly reduced by Aila. Cell cycle analysis revealed an accumulation of Aila-treated bladder cancer cells in the G0/G1 phase. Interestingly, Aila strongly reduced Nrf2 expression in these cell lines. Moreover, Aila significantly reduced YAP, and c-Myc protein expression. The random and the oriented migration of bladder cancer cells were strongly inhibited by Aila treatment, in particular in CDDP-resistant cells. Conclusion Aila inhibited proliferation and invasiveness of bladder cancer cells. Its high effectiveness in CDDP resistant cells could be related to the inhibition of Nrf2, YAP, and c-Myc expressions. Aila could represent a new tool to treating CDDP-resistant bladder cancers.

Osteoporosis is characterized by low Bone Mineral Density (BMD). This illness has a highcost impact in all developed countries. In this work, we propose a supervised approach to classify the BMD status of post-menopausal women based on an experimental non-invasive analysis of static and dynamic baropodometry. A questionnaire on nutritional habits and lifestyle and previous fractures was drawn up. Sixty women in amenorrhea > 12 months and age > 45 years were included and divided in 3 groups (Normal, Osteopenic and Osteoporotic) according to T-score values. Those with neurological or musculoskeletal disorders, history of vestibulopathies, uncorrected visual deficit or drug use were excluded. Static and Dynamic Baropodometry was performed to all the enrolled women and a preliminary processing was carried on to select the most relevant features via Principal Component Analysis (PCA). Subsequently, two supervised classifiers based on the selected 27 features were designed and tested and their results were discussed as a promising tool for screening subjects suffering from both bone and muscle functional decline.

Patients suffering from Parkinson’s Disease (PD) are characterized by an abnormal handwriting activity since they have difficulties in motor coordination and a decline in cognition. In this paper, we propose a model-free technique for differentiating PD patients from healthy subjects by using a handwriting analysis tool based on biometric signals (e.g., surface ElectroMyoGraphy, pen pressure, etc.) and an Artificial Intelligence-based classifier. Experimental tests have been carried on with both healthy and PD subjects to identify the most representative features, the best writing patterns and the best AI-based classification approach between Artificial Neural Network (ANN) and Support Vector Machine (SVM) in terms of accuracy and repeatability. Finally, the obtained results are reported and discussed to infer some important properties on writing patterns, classification approaches and the role of muscular activities on the handwriting analysis applied to neurodegenerative disease research.

Intrinsic or acquired chemoresistance represents the main obstacle to the successful treatment of cancer patients. Several mechanisms are involved in multidrug resistance: decreased uptake of hydrophilic drugs, increase of energy dependent efflux, alteration of the redox state, alteration of apoptotic pathways, and modification of the tumor microenvironment. In recent years, several types of nanoparticles have been developed to overcome these obstacles and improve the accumulation and release of drugs at the pathological site. In this review we describe the main mechanisms involved in multidrug resistance and the nanovehicles which have been proposed to target specific aspects of this phenomenon.

When diagnosing Parkinson’s disease (PD), medical specialists normally assess several clinical manifestations of the patient and rate a severity level according to established criteria. They refer to the Movement Disorder Society – sponsored revision of Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), the most widely adopted scale for rating PD. Since gait patterns differ between healthy elders and those with PD, we implement a simple, low-cost clinical tool that can extract kinematic and postural features through Microsoft Kinect v2 sensor to classify and rate PD. Thirty participants were enrolled for the purpose of the present study: sixteen PD patients, rated according to MDS-UPDRS Part IV for motor complications, and fourteen healthy paired subjects. Several gait cycles were extracted for each patient to improve the reliability of the methods and sixteen kinematic and postural features were considered. After preliminary feature selection, several classifier families were trained (both Support Vector Machine, SVM, and Artificial Neural Networks, ANN) and evaluated for the best solution. Results showed that the ANN classifier performed the best by reaching 89,40% of accuracy with only nine features in diagnosis PD and 95,02% of accuracy with only six features in rating PD severity.

Assessment and rating of Parkinson’s Disease (PD) are commonly based on the medical observation of several clinical manifestations, including the analysis of motor activities. In particular, medical specialists refer to the Movement Disorder Society – sponsored revision of Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), the most widely used scale for rating PD. The UPDRS scale also considers the observation of some subtle motor phenomena that are either difficult to capture with human eyes or subjectively considerate abnormal. In this scenario, an automatic system able to capture the considered motor exercises and rate the PD severity could be used as a support system for the healthcare sector. In this work, we implemented a simple and low-cost clinical tool that can extract motor features of two main exercises required by the UPDRS scale (the finger tapping and the foot tapping) to classify and rate the PD severity. Sixty two participants were enrolled for the purpose of the present study: thirty three PD patients and twenty nine healthy paired subjects. Results showed that an SVM using the features extracted by both considered exercises was able to classify healthy subjects and PD patients with great performances by reaching 87.1% of accuracy. The results of the classification between mild and moderate PD patients indicated that the foot tapping features were the most representative ones to discriminate (81.0% of accuracy). We can conclude that developed tool can support medical specialists in the assessment and rating of PD patients in a real clinical scenario.

The incidence of heart failure (HF) is increasing worldwide and myocardial infarction (MI), which follows ischemia and reperfusion (I/R), is often at the basis of HF development. Nanocarriers are interesting particles for their potential application in cardiovascular disease. Impaired drug delivery in ischemic disease is challenging. Cyclodextrin nanosponges (NS) can be considered innovative tools for improving oxygen delivery in a controlled manner. This study has developed new α-cyclodextrin-based formulations as oxygen nanocarriers such as native α-cyclodextrin (α-CD), branched α-cyclodextrin polymer (α-CD POLY), and α-cyclodextrin nanosponges (α-CD NS). The three different α-CD-based formulations were tested at 0.2, 2, and 20 µg/mL to ascertain their capability to reduce cell mortality during hypoxia and reoxygenation (H/R) in vitro protocols. H9c2, a cardiomyoblast cell line, was exposed to normoxia (20% oxygen) or hypoxia (5% CO2 and 95% N2). The different formulations, applied before hypoxia, induced a significant reduction in cell mortality (in a range of 15% to 30%) when compared to samples devoid of oxygen. Moreover, their application at the beginning of reoxygenation induced a considerable reduction in cell death (12% to 20%). α-CD NS showed a marked efficacy in controlled oxygenation, which suggests an interesting potential for future medical application of polymer systems for MI treatment.

Objectives To evaluate the benefit/risk profile of epoetin α biosimilar with the erythropoiesis-stimulating agents (ESAs) originators when administered to naive patients from clinical practice. Design Population-based observational cohort study. Setting All residents in the Lazio Region, Italy, with chronic kidney disease (CKD) or cancer retrieved from the Electronic Therapeutic Plan (ETP) Register for ESA between 2012 and 2014. Participants Overall, 13 470 incident ESA users were available for the analysis, 8161 in the CKD and 5309 in the oncology setting, respectively. Interventions ESAs identified through the ATC B03XA were divided into 3 groups: (1) biosimilars; (2) epoetin α originator and (3) other originators. Patients were exposed to ESAs from the date of activation of the ETP, until the end of a 6-month follow-up period. Outcome measures Effectiveness (all-cause mortality and blood transfusion) and safety (major cardiovascular events, blood dyscrasia). A composite outcome including all-cause mortality, blood transfusion and major cardiovascular events was predefined. HRs of any outcome were estimated through Cox regression. Results We found no differences between patients on biosimilars or all originators with regard to the risk estimates of all-cause mortality, blood transfusion, major cardiovascular events and blood dyscrasia in the CKD setting. The composite outcome confirmed these results (biosimilars vs epoetin α originators: adjusted HR=1.02, 95% CI 0.78 to 1.33; biosimilars vs other originators: adjusted HR=1.09, 95% CI 0.85 to 1.41). Comparable risk estimates were observed between biosimilars and all originators in the oncology setting. Conclusions In both settings, our findings are suggestive of no difference between biosimilars and originators on relevant effectiveness and safety outcomes. This study may contribute to settling future drug policy for the health services and provides reassurance on the approval pathway for biosimilars. The oncology setting merits further research, taking into account tumour types, tumour stage and anticancer chemotherapy administered.

Computer Aided Decision (CAD) systems based on Medical Imaging could support radiologists in grading Hepatocellular carcinoma (HCC) by means of Computed Tomography (CT) images, avoiding that patient undergo any medical invasive procedures such as biopsies. The individuation and characterization of Regions of Interest (ROIs) containing lesions is an important phase that enables an easier classification between two classes of HCCs. Two phases are needed for the individuation of lesioned ROIs: a liver isolation in each CT slice, and a lesion segmentation. Ultimately, all individuated ROIs are described by morphological features and, finally, a feed-forward supervised Artificial Neural Network (ANN) is used to classify them. Testing determined that the ANN topologies found through an evolutionary strategy showed a high generalization on the mean performance indices regardless of applied training, validation and test sets, showing good performances in terms of both accuracy and sensitivity, permitting a correct grading of HCC lesions.

In this paper, we propose a deep learning approach for breast lesions classification, by processing breast images obtained using an innovative acquisition system, the Tomosynthesis, a medical instrument able to acquire high-resolution images using a lower radiographic dose than normal Computed Tomography (CT). The acquired images were processed to obtain Regions Of Interest (ROIs) containing lesions of different categories. Subsequently, several pre-trained Convolutional Neural Network (CNN) models were evaluated as feature extractors and coupled with non-neural classifiers for discriminate among the different categories of lesions. Results showed that the use of CNNs as feature extractor and the subsequent classification using a non-neural classifier reaches high values of Accuracy, Sensitivity and Specificity.

Handwriting analysis represents an important research area in different fields. From forensic science to graphology, the automatic dynamic and static analyses of handwriting tasks allow researchers to attribute the paternity of a signature to a specific person or to infer medical and psychological patients’ conditions. An emerging research field for exploiting handwriting analysis results is the one related to Neurodegenerative Diseases (NDs). Patients suffering from a ND are characterized by an abnormal handwriting activity since they have difficulties in motor coordination and a decline in cognition.

The most common methods used by neurologist to evaluate Parkinson’s Disease (PD) patients are rating scales, that are affected by subjective and non-repeatable observations. Since several research studies have revealed that walking is a sensitive indicator

Background: No definitive data about open abdomen (OA) epidemiology and outcomes exist. The World Society of Emergency Surgery (WSES) and the Panamerican Trauma Society (PTS) promoted the International Register of Open Abdomen (IROA). Methods: A prospective observational cohort study including patients with an OA treatment. Data were recorded on a web platform (Clinical Registers (R)) through a dedicated website: www.clinicalregisters.org. Results: Four hundred two patients enrolled. Adult patients: 369 patients; Mean age: 57.39 +/- 18.37; 56% male; Mean BMI: 36 +/- 5.6. OA indication: Peritonitis (48.7%), Trauma (20.5%), Vascular Emergencies/Hemorrhage (9.4%), Ischemia (9.1%), Pancreatitis (4.2%), Post-operative abdominal-compartment-syndrome (3.9%), Others (4.2%). The most adopted Temporary-abdominal-closure systems were the commercial negative pressure ones (44.2%). During OA 38% of patients had complications; among them 10.5% had fistula. Definitive closure: 82.8%; Mortality during treatment: 17.2%. Mean duration of OA: 5.39(+/- 4.83) days; Mean number of dressing changes: 0.88(+/- 0.88). After-closure complications: (49.5%) and Mortality: (9%). No significant associations among TACT, indications, mortality, complications and fistula. A linear correlationexists between days of OA and complications (Pearson linear correlation = 0.326 p

Keratoconus is a bilateral progressive corneal disease characterized by thinning and apical protrusion; its early diagnosis is fundamental since it allows one to treat this rare disease by cross-linking approach, thus preventing a major corneal deformation and avoiding more invasive and risky surgical therapies, such as cornea transplant. Ophthalmology improvements have allowed a more rapid, precise and painless acquisition of corneal biometric parameters which are useful to evaluate alterations and abnormalities of eye’s outer structure. This paper presents a study about Keratoconus diagnosis based on a machine learning approach using corneal physical and morphological parameters obtained through Precisio™ tomographic examination. Artificial Neural Networks (ANNs) have been used for classification; in particular, a mono-objective Genetic Algorithm has been used to obtain the best topology for the neural classifiers for different input datasets obtained from features ranking. High levels of accuracy (higher than 90%) have been reached for all types of classification; in particular, binary classification has showed the best discrimination capability for Keratoconus identification.

Introduction and objective: Computer Aided Decision (CAD) systems based on Medical Imaging could support radiologists in grading Hepatocellular carcinoma (HCC) by means of Computed Tomography (CT) images, avoiding medical invasive procedures such as biopsies. The identification and characterization of Regions of Interest (ROIs) containing lesions is an important phase allowing an easier classification in two classes of HCCs. Two steps are needed for the detection of lesioned ROIs: a liver isolation in each CT slice and a lesion segmentation.

Anaplastic carcinoma of the thyroid (ATC) is a lethal human malignant cancer with median survival of 6 months. To date, no treatment has substantially changed its course, which makes urgent need for the development of novel drugs or novel formulations for drug delivery. Nanomedicine has enormous potential to improve the accuracy of cancer therapy by enhancing availability and stability, decreasing effective doses and reducing side effects of drugs. Camptothecin (CPT) is an inhibitor of DNA topoisomerase-I with several anticancer properties but has poor solubility and a high degradation rate. Previously, we reported that CPT encapsulated in β-cyclodextrin-nanosponges (CN-CPT) increased solubility, was protected from degradation and inhibited the growth of prostate tumor cells both in vitro and in vivo. The aim of this study was to extend that work by assessing the CN-CPT effectiveness on ATC both in vitro and in vivo. Results showed that CN-CPT significantly inhibited viability, clonogenic capacity and cell-cycle progression of ATC cell lines showing a faster and enhanced effect compared to free CPT. Moreover, CN-CPT inhibited tumor cell adhesion to vascular endothelial cells, migration, secretion of pro-angiogenic factors (IL-8 and VEGF-α), expression of β-PIX, belonging to the Rho family activators, and phosphorylation of the Erk1/2 MAPK. Finally, CN-CPT significantly inhibited the growth, the metastatization and the vascularization of orthotopic ATC xenografts in SCID/beige mice without apparent toxic effects in vivo. This work extends the previous insight showing that β-cyclodextrin-nanosponges are a promising tool for the treatment of ATC.

Introduction: SAPHO syndrome is an inflammatory disorder including axial and peripheral skeletal manifestations frequently associated with different forms of skin pustulosis and other neutrophilic ...

The pathogenesis of ankylosing spondylitis (AS) is mainly characterized by inflammation in the axial skeleton initially dominated by mononuclear cell infiltrates and by increased number of osteoclasts (OCs) combined by an enhanced osteoblast activity leading to excessive bone apposition. The complexity of AS pathogenetic pathways has so far prevented the development of an adequate definitive therapy. Among the most studied targets for assessing therapeutic effectiveness, there are the OCs, the primary bone resorbing cells. Here, we investigated spontaneous and induced osteoclastogenesis in peripheral blood mononuclear cells (PBMCs) from AS patients, in order to explore the relation between osteoclastogenesis and disease activity. In addition, we tested the susceptibility of OCs from AS patients to undergo apoptosis investigating their response to Emblica officinalis plant extracts, previously characterized by us as apoptotic inducer in OCs. We found that PBMCs from AS are more susceptible to spontaneous osteoclastogenesis than the PBMCs from control samples, and that the osteoclastogenic potential was significantly associated with high ASDAS among AS patients with bone marrow edema. In addition, after treatment with E. officinalis extracts, normal OCs underwent apoptosis, but OCs from AS patients showed a strong resistance to apoptotic stimulus. We found that OCs from AS patients, unlike OCs from healthy individuals, express high levels of survival signals including Bcl-XL and Survivin, but do not express Bim proapoptotic protein. Our data demonstrate that AS OCs present qualitative peculiarity: this may help in identifying an effective strategy to prevent bone changes in AS before structural modifications have occurred.

Background Study to investigate the intussusception incidence background in the pediatric population and its temporal trend in Italy. Methods A cross-sectional study was conducted on the pediatric population aged 0 to 15 years, in the period 1 January 2002 to 31 December 2012. Intussusception cases were identified using the national hospital discharge database. The annual intussusception incidence, the incidence rate ratios (IRRs) and the related 95 % confidence Intervals (CI) were calculated. Results The overall intussusception incidence rate was 21 per 100,000 children aged ≤15 years, and was higher among boys than girls. The highest intussusception incidence rate occurred in infants

Background Kawasaki disease is a complex and potentially serious condition. It has been observed in temporal relation to immunisation. Methods We conducted a systematic literature review using various reference sources to review the available evidence published in the literature. Results We identified twenty seven publications reporting a temporal association between immunisation and Kawasaki disease. We present a systematic review of data drawn from randomised controlled trials, observational studies, case series and reports, and reviews. Overall there was a lack of standardised case definitions, making data interpretation and comparability challenging. Conclusions Although a temporal relationship between immunisation and Kawasaki disease is suggested, evidence for an increased risk or a causal association is lacking. Implementation of a standardised Kawasaki disease case definition would increase confidence in the findings and add value to future studies of pre- or post-licensure vaccine safety studies.

Neuropsychiatric (NP) involvement in Systemic Lupus Erythematosus (SLE), can be a severe and troubling manifestation of the disease that heavily impacts patient’s health, quality of life and disease outcome. It is one of the most complex expressions of SLE which can affect central, peripheral and autonomous nervous system. Complex interrelated pathogenetic mechanisms, including genetic factors, vasculopathy, vascular occlusion, neuroendocrine-immune imbalance, tissue and neuronal damage mediated by autoantibodies, inflammatory mediators, blood brain barrier dysfunction and direct neuronal cell death can be all involved. About NPSLE a number of issues are still matter of debate: from classification and burden of NPSLE to attribution and diagnosis. The role of neuroimaging and new methods of investigation still remain pivotal and rapidly evolving as well as is the increasing knowledge in the pathogenesis. Overall, two main pathogenetic pathways have been recognized yielding different clinical phenotypes: a predominant ischemic-vascular one involving large and small blood vessels, mediated by aPL, immune complexes and leuko-agglutination which it is manifested with more frequent focal NP clinical pictures and a predominantly inflammatory-neurotoxic one mediated by complement activation, increased permeability of the BBB, intrathecal migration of autoantibodies, local production of immune complexes and pro-inflammatory cytokines and other inflammatory mediators usually appearing as diffuse NP manifestations. In the attempt to depict a journey throughout NPSLE from diagnosis to a reasoned therapeutic approach, classification, epidemiology, attribution, risk factors, diagnostic challenges, neuroimaging techniques and pathogenesis will be considered in this narrative review based on the most relevant and recent published data.

Multicentric reticulohistiocytosis (MRH) and fibroblastic rheumatism (FR) are uncommon disorders with similar joint and skin manifestations. They are usually included among the non-Langerhans histiocytoses, but recent insights drive some criticism. The diagnosis is often challenging and must be confirmed by the histological typical features. If the skin manifestations are missing, the arthritic complaints may be confused with those of other rheumatic disorders. In these cases, only a careful clinical and radiological evaluation leads to the correct diagnosis. The natural course of the diseases may rapidly develop into disabling manifestations, making an aggressive treatment strongly recommendable. There is emerging evidence that anti-tumour necrosis factor-α agents and bisphosphonates are promising drugs for MRH, while a course of methotrexate and steroids seems to be the best option for FR. Finally, the clinician should be aware that in many cases MRH, but not FR, is associated with a large number of systemic manifestations and with malignancy. This eventuality must be accurately ruled out.

Objectives Adult-onset Still's disease (AOSD) is a potentially crippling or life-threatening rare disease that may be self-limited, intermittent, and chronic. Clinical predictors of outcome are still lacking, as is information on the rate of progress of its chronic course. The main objective is to identify factors that improve our ability to predict the course of AOSD, and factors associated with the rate of progress of its chronic course. A comparison with the literature is included. Methods A retrospective cohort observational study conducted at the tertiary-referral Rheumatology Unit in Ferrara, Italy. Results Seventy-six patients (44 females and 32 males) referred to the Unit and who satisfied the criteria for AOSD were identified. Our findings on white AOSD patients are largely compatible with those previously published. Ferritin level, as well disease activity score (DAS 28 ), is associated with the rate of progression of the articular manifestations of the disease. A polyarthritis persisting over 6 months is associated with the development of a chronic articular course, irrespective of the size of the involved joints. Conclusions Ferritin, being associated with the course of AOSD, could play a role in the diagnosis of the disease. Together with DAS 28 , it might also serve as a useful predictor for the rate of progress of the chronic course of the disease, as measured with simple erosion narrowing score.