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Introduction In a context of financial constraints, an appropriate and efficient resource allocation represents the main issue of health care governance at any level of health decision-making processes. In these circumstances continuously monitoring how the resources are allocated, to make the necessary changes in a timely and efficient manner, is unavoidable. In this perspective, the Medicines Utilisation Monitoring Centre (OsMed), placed at Italian Medicines Agency (AIFA), develops and publishes the National Report on Medicines Use. It also provides with an updated overview on the Italian pharmaceutical market in relation to policies, data of inpatient and outpatient consumption as well as expenditure. Methods Data from the Medicines Utilisation Monitoring Centre, stated by a National Law in 1998, were used to describe the main figures on the Italian national pharmaceutical expenditure. Results In 2018 the overall Italian pharmaceutical expenditure (public and private) was 29.1 billion euro, almost the same as the previous year (-0.1%). The public outpatient expenditure amounted to 12.4 billion euro, corresponding to a decrease of 4% compared to 2017, while the inpatient public expenditure observed an increase. The total private expenditure, including the cost-sharing and pharmaceuticals directly paid by patients increased by 3.8% compared to 2017 (amounting to 8.4 billion euro). In 2018 the total consumption, including INHS and private purchase, was 1,571.5 DDDs per every 1,000 inhabitants per day. Conclusions The Report aims to provide a common and comprehensive information base to equally support the local policies interventions. This document has been subject to a constant evolution in order to meet the evolving information needs.

Recently, promising strategies of plexes include the complexation of nucleic acids with lipids (lipoplexes) and different kinds of polymers (polyplexes) for delivery of actives and genetic material in abnormal conditions like cancer, cystic fibrosis and genetic disorders. The present review article focuses on the comparative aspects of lipoplexes and polyplexes associated with molecular structure, cellular transportation and formulation aspects. The major advantages of lipoplexes and polyplexes over conventional liposomes involve non-immunogenic viral gene transfer, facile manufacturing and preservation of genetic material encapsulated within the nanocarriers. Lipoplexes and polyplexes enhance the transfection of DNA into the cell by stepwise electrostatic cationic-anionic interaction with DNA backbones. The ease and cost-effective formation of complexes extend their applications in the treatment of cancer and genetic disorders. Lipoplexes and polyplexes necessitate intensive research in the fields of quality, toxicity and methods of preparation for commercialization.

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.

Cancer treatment strategy requires the employment of drug delivery systems to overcome the barriers in current chemotherapies. Cyclodextrin nanosponges (CDNSs) which have been studying since 2006 in the pharmaceutical field, would be a candidate in advancing medical treatments, such as cancer therapy. These nano-systems encompass many properties that may lead to their usage as anticancer carriers but they need to be analyzed in depth. The purpose of this review is to demonstrate the research works that have been studied about the vehicle and compare it with a commercialized one, liposome. Here, both of the nano-systems were analyzed about the in-vitro and in-vivo properties, capacity of macromolecules encapsulation, and applications in 3-D printing technology. This comparison revealed that most of the CDNSs’ characteristics are in line with the liposomes in cancer treatment, but it deserves further experiments and studies for the future. More investigation may result in better function of the mentioned vehicles. Therefore, promoted drug efficacy with minimal side effects would be reached. Generally, research works about CDNSs are in progress and they deserve to reach the trade market shortly.

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.

Bio-based substances (BBS) obtained from composted urban biowaste and nanosponges obtained from β-cyclodextrins (βCD) were used as green source to produce biochar via pyrolysis performed under mild conditions. Pyrolysis conditions were optimized by means of TGA analysis, and different temperatures of pyrolysis were investigated. The resulting carbonaceous materials were characterized with several physicochemical techniques (elemental analysis, FTIR spectroscopy, XRD, SEM, surface area analysis, and zeta potential measurements). Additionally, the adsorption capacity of such materials was tested toward the removal of charged dyes from aqueous environment. Isothermal experiments carried out at circumneutral pH indicated an important charge-selectivity, which encourages their use as sustainable alternative materials in wastewater purification treatments. Moreover, the analysis of the adsorption capacity as a function of specific surface area of materials suggests the strategy to obtain carbonaceous solids with enhanced capacity in capture of polar molecules.

The design and structural optimisation of a novel polysaccharide-based nanomaterial for the controlled and sustained release of doxorubicin are here reported. A cross-linked polymer was obtained by reacting a tetraglucose, named cyclic nigerosyl-1-6-nigerose (CNN), with pyromellitic dianhydride. The cross-linking reaction formed solid nanoparticles, named nanosponges, able to swell as a function of the pH. Nanoparticle sizes were reduced using High Pressure Homogenization, to obtain uniform nanosuspensions. Doxorubicin was incorporated into the CNN-nanosponges in a good extent. DSC and solid state NMR analyses proved the drug interaction with the polymer matrix. In vitro studies demonstrated pH-dependent slow and prolonged release kinetics of the drug from the nanoformulation. Doxorubicin-loaded CNN-nanosponges were easily internalized in A2780 cell line. They might considered an intracellular doxorubicin reservoir, able to slowly release the drug over time. CNN-nanosponges may be promising biocompatible nanocarriers for the sustained delivery of doxorubicin with potential localised application in cancer treatments.

Pedestrian detection and tracking have become an important field in the computer vision research area. This growing interest, started in the last decades, might be explained by the multitude of potential applications that could use the results of this research field, e.g. robotics, entertainment, surveillance, care for the elderly and disabled, and content-based indexing. In this survey paper, vision-based pedestrian detection systems are analysed based on their field of application, acquisition technology, computer vision techniques and classification strategies. Three main application fields have been individuated and discussed: video surveillance, human-machine interaction and analysis. Due to the large variety of acquisition technologies, this paper discusses both the differences between 2D and 3D vision systems, and indoor and outdoor systems. The authors reserved a dedicated section for the analysis of the Deep Learning methodologies, including the Convolutional Neural Networks in pedestrian detection and tracking, considering their recent exploding adoption for such a kind systems. Finally, focusing on the classification point of view, different Machine Learning techniques have been analysed, basing the discussion on the classification performances on different benchmark datasets. The reported results highlight the importance of testing pedestrian detection systems on different datasets to evaluate the robustness of the computed groups of features used as input to classifiers.

In this work, the interaction between Kynurenic acid (KYNA) and several natural and modified cyclodextrins (CDs) is carried out. Among all the CD tested, HPβ-CD showed the strongest complexation constant (KF), with a value of 270.94 ± 29.80 M−1. Between natural (α- and β-) CDs, the complex of KYNA with β-CD was the most efficient. The inclusion complex of KYNA with CDs showed a strong influence of pH and temperature. The KF value decreased at high pH values, when the pKa was passed. Moreover, an increase of the temperature caused a decrease in the KF values. The thermodynamic parameters of the complexation (ΔH°, ΔS° and ΔG°) were studied with negative entropy, enthalpy and spontaneity of the process at 25 °C. Moreover, the inclusion complex was also characterized using FTIR and TGA. Finally, molecular docking calculations provided different interactions and their influence in the complexation constant.

Ailanthone, a quassinoid from Ailanthus altissima (Mill.) Swingle, is a natural herbicide, whose use is limited by its low persistence and rapid degradation in organic substrates. Dextrin-based nanosponges (NSs) are polymers with a cage-like structure that can complex several molecules, acting as carriers or protectors. Their encapsulation efficiency can be exploited in numerous applications. Hence this study explored at first the biological activity of eight different dextrin-based NSs, synthesized with 1,1′-carbonyldiimidazole (CDI) or pyromellitic dianhydride (PYRO) (αNS-CDI, βNS-CDI, γNS-CDI, LC NS-CDI, αNS-PYRO, βNS-PYRO, γNS-PYRO, and LC NS-PYRO), towards two model species (Lepidium sativum L. and Raphanus sativus L.) in filter paper under controlled conditions in laboratory. Then, the selected dextrin-based NSs were loaded with ailanthone and applied in the concentration of 7.5 or 30 mg L−1 of ailanthone in pre-emergence on the same species, initially on filter paper and subsequently on cultivation substrate for horticulture. In all three bioassays, the number of germinated seeds and the length of developed roots and hypocotyls were evaluated. In the first bioassay, the results showed that five dextrin-based NSs promoted the germination and root elongation, thus counteracting the herbicidal effect of ailanthone. Hence, three selected formulations (αNS-CDI, γNS-CDI, and LC NS-CDI) were loaded with ailanthone, with γNS-CDI providing the highest loading capacity (1.36%) and encapsulation efficiency (55.15%). In the second bioassay, the phytotoxic activity of ailanthone was strengthen by dextrin-based NSs, always stronger by at least 58% than the pure compound across 30 days in paper, without differences between formulations. In the third bioassay, loading ailanthone in γNS-CDI also prolonged its herbicidal activity, still reducing to only 20% the germination and growth of garden cress and radish 30 and 20 days after treatment, respectively. Overall, results demonstrated that dextrin-based nanosponges can be proposed as suitable carriers in the formulation of ailanthone-based herbicide. Their use both increased and extended the phytotoxic activity of ailanthone, leading to the possibility of reducing the amount applied for each treatment, or reducing the number of herbicide treatments.

β-Cyclodextrin polymer, namely nanosponges (NSs), were synthesized using two cross-linkers: 1,1′-carbonyldiimidazole (CDI) and pyromellitic dianhydride (PMDA). The synthesized NSs were complexed with N,N-diethyl-meta-toluamide (DEET) and, after complex characterization, the NSs cross-linked with CDI were found more effective than those cross-linked with PMDA in terms of encapsulation efficiency and loading capacity. The CDI-NSs were dispersed in a polyacrylic resin, which was thermally polymerized on a polyester fabric surface. The fabric functionalization was evaluated through quantification of DEET extracted from the polyester fabrics, before and after three washing cycles. The results showed that encapsulation into NSs prolongs the persistence of DEET on polyester fabrics.

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.

This study was developed inside the European Project Life "Clean up" (LIFE 16 ENV/ES/000169) to search for suitable adsorbents to purify treated water from emerging pollutants. Notably, among pollutants, the attention was focused on Ciprofloxacin removal, selecting as recyclable adsorbent Cyclodextrin-based nanosponges, characterized by using FTIR-ATR, DSC, TG, SEM, EDX, gas-volumetric analysis, and XRD analyses. Indeed, the in-batch adsorption process was quite complete removing, in a few minutes, 90% of the pollutant from water, with a maximum adsorption capacity of 2 mg/g. A better comprehension of the adsorption mechanism was obtained by studying the effect of various experimental parameters on the process, i.e. ionic strength, pH values, adsorbent/pollutant ratio, and temperature values. The thermodynamics (?G°0), the adsorption isotherms (Langmuir, Freundlich, Temkin, and Dubinin-Radushkevich), and kinetics of the process were also investigated. In particular, the applicability of all the proposed isotherms, except the Langmuir model, was observed, and the finding highlighted the heterogeneous character of the adsorption process. The pseudo-second-order kinetic model well described the process and the application of the Weber-Morris model suggested that two main consecutive steps constituted the adsorption. Despite the relatively low adsorption capacity, desorption experiments, recycling 80% of the pollutant for each cycle, were performed, and for the purpose, 0.1 M NaCl was used, lowering the environmental impact. Moreover, other contaminants, such as Diclofenac, Carbendazim, Furosemide, and Sulfamethoxazole were successfully removed from the water, also if present in a quaternary mixture, opening the possibility to use this adsorbent for real water treatments.

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.

We present a numerical platform named Structured and Unstructured grid Relocatable ocean platform for Forecasting (SURF). The platform is developed for short-time forecasts and is designed to be embedded in any region of the large-scale Mediterranean Forecasting System (MFS) via downscaling. We employ CTD data collected during a campaign around the Elba island to calibrate and validate SURF. The model requires an initial spin up period of a few days in order to adapt the initial interpolated fields and the subsequent solutions to the higher-resolution nested grids adopted by SURF. Through a comparison with the CTD data, we quantify the improvement obtained by SURF model compared to the coarse-resolution MFS model.

Several reports indicate that chemo-resistant cancer cells become highly adapted to intrinsic oxidative stress by up-regulating their antioxidant systems, which causes an increase of intracellular GSH content. Doxorubicin is one of the most widely used drugs for tumor treatment, able to kill cancer cells through several mechanisms. However, doxorubicin use is limited by its toxicity and cancer resistance. Therefore, new therapeutic strategies able to reduce doses and to overcome chemo-resistance are needed. A new class of glutathione-responsive cyclodextrin nanosponges (GSH-NS), is able to release anticancer drugs preferentially in cells having high GSH content. Doxorubicin-loaded GSH-NS, in the cancer cells with high GSH content, inhibited clonogenic growth, cell viability, topoisomerase II activity and induced DNA damage with higher effectiveness than free drug. Moreover, GSH-NS reduced the development of human tumor in xenograft models more than free drug. These characteristics indicate that GSH-NS can be a suitable drug delivery carrier for future applications in cancer therapy.

The biological activity of extracts from Ailanthus altissima is mainly due to the presence of ailanthone, a compound belonging to the quassinoid class. Recently, attention has been paid to its strong cytostatic activity. However, the extraction of ailanthone is based on very long and demanding procedures, which keep the price of the commercial product very high. Thus, the development of selective adsorbents for the purification of ailanthone from A. altissima leaves extracts could help in reduce the costs of production. In this work, we describe the rational design of a molecularly imprinted polymer selective for ailanthone based on the screening of a 96-members not-imprinted polymeric library to rapidly identify pre-polymerization mixtures able to generate MIPs with enhanced binding properties. A 4-vinylpyridine-co-trimethylolpropane trimethacrylate polymer showed high binding towards ailanthone. It was used to prepare an imprinted polymer with acetonitrile showed interesting binding affinity (Keq = 18.3 × 103 L mol−1), high imprinting factor (IF = 3.8) and fast binding kinetics (kass = 0.390 min−1, kdis = 0.021 mol L−1 min−1). The imprinted polymer was used to develop a successful purification protocol of extracts from Ailanthus altissima leaves. The purification was based on the combination of a preliminary clean-up of Soxhlet extracts onto a reverse phase-C18 cartridge and the subsequent isolation of ailanthone by a molecularly imprinted solid phase extraction. This approach allowed efficiently purifying the ailanthone contained in aqueous or methanolic Soxhlet extracts with high yields compared to the quantities reported in literature (water: 0.756 ± 0.027 mg g−1; methanol: 0.770 ± 0.030 mg g−1). Moreover, it allows processing sample volumes up to 15 mL without significant losses of the target compound.

The complexation of the bioactive compound oxyresveratrol (OXY) with a polymer called cyclodextrin-based nanosponge (CD-NS) and its application was studied.A new methodology is used to calculate, an apparent inclusion complex constant (KFapp) between a ligand and CD-NSs. Moreover, the KFapp of resveratrol was also evaluated and compared. The complex of OXY with the nanosponge β-CDI 1:4, was studied in vitro using DSC, TGA and FTIR techniques and its drug loading and release behavior were studied. An in vitro digestion showed higher protection of OXY complexed than free OXY. The bioactivity enhancing capacity of OXY was also studied against prostate (PC-3) and colon (HT-29 and HCT-116) cancer cell lines, where it showed stronger cell viability inhibition than the free drug. The findings as a whole represent a new opportunity for studying the complexation of drugs in CD-NSs and the use of oxyresveratrol as an ingredient in nutraceutical products.

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

BackgroundCritical impairment of adaptive immune response has been observed in patients with acute coronary syndromes (ACS) with reduced expansion of regulatory T cells (Treg) and enhanced effector T-cell responsiveness, both associated with poorer outcomes.ObjectivesThis study investigated the mechanisms underlying T-cell dysregulation in ACS.MethodsWe evaluated both early and downstream T-cell receptor activation pathways after ex vivo stimulation with anti-CD3 and anti-CD28 crosslink in CD4+ T cells from 20 patients with non-ST-segment elevation myocardial infarction (NSTEMI), 20 with stable angina (SA), and 20 controls. We reassessed 10 NSTEMI and 10 SA patients after 1 year.ResultsPhospho-flow analysis revealed reduced phosphorylation of the zeta-chain–associated protein kinase of 70 kDa at the inhibitory residue tyrosine 292, enhancing T-cell activation, in NSTEMI helper T cells versus SA and controls (each, p < 0.001), resulting from increased expression of the protein tyrosine phosphatase, nonreceptor type, 22 (PTPN22) (p < 0.001 for both comparisons), persisting at follow-up. We also observed reduced phosphorylation (p

Background The process leading to a regulatory outcome is guided by factors both related and unrelated to the data package, defined in this analysis as ‘formal and informal factors’, respectively. The aim of this qualitative study was to analyse which formal and informal factors drive the decision-making process of the European Medicines Agency (EMA) and Food and Drug Administration (FDA) regulators with regard to anticancer drugs, using in-depth semi-structured interviews with regulators of the two agencies. Methods In line with the theory and practice of qualitative research, no set sample size was defined a priori. Respondent enrolment continued until saturation and redundancy were reached. Data were collected through means of in-depth semi-structured interviews conducted either in a face-to-face setting or via Skype® with each regulator. The interviews were audio-recorded and verbatim transcribed. The analysis was manually carried out on the transcribed text. Data were independently coded and categorized by two researchers. Interpretation of the findings emerged through a process of triangulation between the two. Results Seven EMA and six FDA regulators, who had extensive experience with making decisions about anticancer medicines, were interviewed between April and June 2012. There is an open dialogue between the FDA and EMA, with the two moving closer and exchanging information, not opinions. Differences in decision-making between the agencies may be due to a different evaluation of end points. Different interaction modalities with industry and patients represent an additional source of divergence with a potential impact on decision-making. The key message of our respondents was that the agencies manage uncertainty in a different way: unlike the EMA, the FDA has a prevailing attitude to take risks in order to guarantee quicker access to new treatments. Conclusions Although formal factors are the main drivers for regulatory decisions, the influence of informal factors plays an important role in the drug evaluation process.

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.

Investigations of the effect of the β-cyclodextrin-based nanosponge-1-methylcyclopropene (1-MCP) complex (β-CD-NS complex) on six ethylene-sensitive cut flowers were performed. Anemone coronaria L. multicolor, Ranunculus asiaticus L. ‘Minou Abrown’, Helianthus annuus L. ‘Sunrich Orange’, Rosa hybrida L. ‘Jupiter’, Paeonia lactiflora L. ‘Sarah Bernhardt’, and Papaver nudicaule L. multicolor underwent four different treatments: a vase placement in a suspension of β-CD-NS complex (0.25 μL L −1 ), exposure to gaseous 1-MCP (0.25 μL L −1 ) for 6 h, exposure to exogenous ethylene (1 ± 0.2 μL L −1 ) for 24 h, and placement in tap water. β-Cyclodextrin-based nanosponges proved to enhance 1-MCP efficacy in all the tested species. According to the species, senescence symptoms were decreased or delayed. Anemone and poppy had a longer esthetic flower quality and vase life, and a reduced petal abscission. In ranunculus, β-CD-NS complex improved longevity. In sunflower, it also maintained longer chlorophyll leaf content and cut flower ornamental value. Peony opened more slowly and rose maintained its ornamental quality longer than 1-MCP treated flowers. This study opens possibilities for commercial use of the β-CD-NS complex in the floriculture industry.

Cyclodextrin-based nanosponges (NS) are solid nanoparticles, obtained from the cross-linking of cyclodextrins that have been proposed as delivery systems for many types of drugs. Various NS derivatives are currently under investigation in order that their properties might be tuned for different applications. In this work, new carboxylated cyclodextrin-based nanosponges (Carb-NS) carrying carboxylic groups within their structure were purposely designed as novel Acyclovir carriers. TEM measurements revealed their spherical shape and size of about 400 nm. The behaviour of Carb-NS, with respect to the incorporation and delivery of Acyclovir, was compared to that of NS, previously investigated as a drug carrier. DSC, XRPD and FTIR analyses were used to investigate the two NS formulations. The results confirm the incorporation of the drug into the NS structure and NS-Acyclovir interactions. The Acyclovir loading into Carb-NS was higher than that obtained using NS, reaching about 70% (w/w). In vitro release studies showed the release kinetics of Acyclovir from Carb-NS to be prolonged in comparison with those observed with NS, with no initial burst effect. The NS uptake into cells was evaluated using fluorescent Carb-NS and revealed the nanoparticle internalisation. Enhanced antiviral activity against a clinical isolate of HSV-1 was obtained using Acyclovir loaded in Carb-NS.

Camptothecin (CPT) is a potent DNA Topoisomerase I inhibitor with anti-tumor activity in hematological and solid tumors. However, it did not reach clinical use because of its poor solubility and high degrability. β-Cyclodextrin nanosponge (CN) have been demonstrated to be able to increase the solubility of lipophilic compounds and to protect them from degradation. In the present study, we evaluated whether β-Cyclodextrin nanosponge carriers can overcome CPT chemical disadvantages and improve the in vitro anti-tumor efficacy in the androgen refractory models of prostate cancer DU145 and PC-3 and the androgen sensitive model LNCaP. Camptothecin-loaded β-Cyclodextrin nanosponge (CN-CPT) showed sizes of about 400 nm, spherical shape and a drug loading of 38%. HPLC analysis, performed on the cell pellet after treatment with CN-CPT revealed that CPT concentration increased over time indicating a prolonged release of the drug. Moreover, CN-CPT inhibited Topoisomerase I activity, and induced DNA damage, and cell cycle arrest more effectively than CPT, indicating that the CN-CPT formulation does not affect activity of the drug. Moreover, Annexin V/Propidium Iodide staining showed an induction of cell death at low concentrations that were not effective for CTP. LNCaP cells were less sensitive to CPT than PC-3 and DU145 cells, but CN-CPT still exerted higher anti-proliferative activity and DNA damage ability than CPT. The experiments performed in LNCaP cells demonstrated that CN-CPT treatment inhibited expression of the androgen receptor at doses where CPT was ineffective. Our results demonstrated the higher anti-tumor effectiveness of CN-CPT compare to CPT in prostate cancer cells, supporting the relevance of future studies for the use of the β-Cyclodextrin nanosponge to deliver anticancer drugs in vivo.

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.

Three types of cyclodextrin nanosponges were synthetized cross-linking α, β or γ cyclodextrin with carbonyldiimidazole as cross-linker. Nanosponges are solid nanoparticles previously used as drug carriers. In this studies cyclodextrin nanosponges were developed as oxygen delivery system. For this purpose the three types of nanosponges suspended in water were saturated with oxygen and in vitro characterized. The nanosponge safety was tested on Vero cells. Their ability to release oxygen in the presence and in the absence of ultrasound (US) was determined over time. Oxygen permeation through a silicone membrane was obtained using a β-cyclodextrin nanosponge/hydrogel combination system. Nanosponge formulations might be potential gas delivery systems showing the ability to store and to release oxygen slowly over time.

Rheumatoid arthritis (RA), is the most common inflammatory musculoskeletal disease inducing diminished quality-of-life in the affected individuals and having major impact on society due to decrease work ability. Early diagnosis and immediate, effective therapy are crucial in order to prevent unfavorable outcome. Treatment of RA has progressed during the past two decades thanks to the advent of a large number of new agents targeting different specific molecules and pathways involved in the modulation of the inflammation. In this scenario an important role is covered by adenosine, a purine nucleoside released from a variety of cells in response to metabolic and inflammatory stress, which is considered to be a potent endogenous regulator acting through its interaction with 4 cell surface receptors named as A(1), A(2A), A(2B) and A(3). Adenosine receptor stimulation has complex effects on the release of pro-inflammatory cytokines depending on selective receptor engagement. Recent data show the involvement of adenosine pathways in RA and its potential therapeutic implications.

Camptothecin (CAM), a plant alkaloid and a potent antitumor agent, has a limited therapeutic utility because of its poor aqueous solubility, lactone ring instability and serious side effects. Cyclodextrin-based nanosponges (NS) are a novel class of cross-linked derivatives of cyclodextrins. They have been used to increase the solubility of poorly soluble actives, to protect the labile groups and control the release. This study aimed at formulating complexes of CAM with three types of beta-cyclodextrin NS obtained with different cross-linking ratio (viz. 1:2, 1:4 and 1:8 on molar basis with the cross-linker) to protect the lactone ring from hydrolysis and to prolong the release kinetics of CAM. Crystalline (F(1:2), F(1:4) and F(1:8)) and paracrystalline NS formulations were prepared. XRPD, DSC and FTIR studies confirmed the interactions of CAM with NS. XRPD showed that the crystallinity of CAM decreased after loading. CAM was loaded as much as 21%, 37% and 13% w/w in F(1:2), F(1:4) and F(1:8), respectively while the paracrystalline NS formulations gave a loading of about 10% w/w or lower. The particle sizes of the loaded NS formulations were between 450 and 600nm with low polydispersity indices. The zeta potentials were sufficiently high (-20 to -25mV) to obtain a stable colloidal nanosuspension. The in vitro studies indicated a slow and prolonged CAM release over a period of 24h. The NS formulations protected the lactone ring of CAM after their incubation in physiological conditions at 37 degrees C for 24h with a 80% w/w of intact lactone ring when compared to only around 20% w/w of plain CAM. The cytotoxicity studies on HT-29 cells showed that the CAM formulations were more cytotoxic than plain CAM after 24h of incubation.

Objectives To report 2 cases of sarcoidosis that developed during treatment with tumor necrosis factor α (TNFα) antagonists, infliximab and adalimumab, used for inflammatory rheumatic disease and to review previously reported cases. Methods We describe 2 patients, the first with psoriatic arthritis, the second with rheumatoid arthritis, who developed noncaseating granulomas of the lungs consistent with sarcoidosis while being treated with anti-TNFα drugs. A retrospective review of the literature was performed using the PubMed database. Results In our patients sarcoidosis developed after 2 years of continuous treatment with infliximab and adalimumab. Both patients presented with low-grade fever, chest pain, and dyspnea. The diagnosis of sarcoidosis was established by the typical well-formed noncaseating granulomas on transbronchial biopsy, after excluding all other granulomatous conditions. Following withdrawal of anti-TNFα agents and a brief course of steroids, the clinical picture resolved. Thirteen additional cases of sarcoidosis that developed after anti-TNFα treatment have been reported, and in 9 of these the causative agent was etanercept. Conclusions The development of sarcoidosis during treatment with TNFα antagonists represents a rare and paradoxical adverse event. The occurrence of sarcoidosis with all 3 available agents suggests a new “class effect” probably linked to a cytokine disequilibrium in patients receiving anti-TNFα treatment.

Novel polymeric nanoparticles based on a beta-cyclodextrin-poly(4-acryloylmorpholine) mono-conjugate (beta-CD-PACM), a tadpole-shaped polymer in which the beta-CD ring is the hydrophilic head and the PACM chain the amphiphilic tail, were prepared by the solvent injection technique. Acyclovir-loaded nanoparticles were prepared from inclusion complexes of Acyclovir with beta-CD-PACM. Both unloaded and drug-loaded nanoparticles were characterized in terms of particle size distribution, morphology, zeta potential, drug loading and in vitro drug release rate. The antiviral activity of Acyclovir loaded into beta-CD-PACM nanoparticles against two clinical isolates of HSV-1 was evaluated and found to be remarkably superior compared with that of both the free drug and a soluble beta-CD-PACM complex reported in a previous paper. Fluorescent nanoparticles loaded with coumarin 6 were also prepared in order to investigate the nanoparticle cell uptake by confocal laser microscopy. It was found that the nanoparticles are internalized in cells and locate in the perinuclear compartment.

To verify whether myocardial impairment can be detected by tissue Doppler imaging (TDI) in patients with asymptomatic systemic sclerosis (SSc), 35 patients with SSc with normal left ventricular (LV) ejection fraction and 35 control subjects were studied.Myocardial longitudinal peak systolic velocity, strain, and strain rate (SR) were measured by TDI at a regional level, and for each parameter the average value was calculated using an LV 12-segment model. In addition, the mitral annulus diastolic velocities and the E/Ea ratio were obtained. Myocardial calibrated integrated backscatter (cIB) was used as an index of fibrosis.Compared with controls, patients with SSc showed lower peak strain (-19.5% +/- 2.3% vs -26.1% +/- 2.4%, P.001), peak SR (-1.34 +/- 0.14 s(-1) vs -1.59 +/- 0.14 s(-1), P.001), septal cIB (-19.5 +/- 3.1 dB vs -23.8 +/- 1.6 dB, P.001), and posterior wall cIB (-23.4 +/- 2.9 dB vs -28.6 +/- 2.5 dB, P = .001), and higher E/Ea (11.7 +/- 2.5 vs 9.8 +/- 1.1, P.001), whereas peak systolic velocities did not differ. Strain, SR, and E/Ea correlated better with cIB than systolic velocities.TDI-derived strain, SR, and E/Ea can detect impairment of LV myocardial function in asymptomatic patients with SSc with normal LV ejection fraction better than TDI systolic velocities.

Central Nervous System (CNS) involvement is a frequent SLE manifestation occurring in 15–75% of patients. However, diagnosis of CNS involvement is a difficult task and requires a careful clinical and laboratory assessment along with instrumental evaluation. In recent years major advances in neuroimaging techniques allowed a great improvement in our understanding of SLE pathogenesis. Anyway, since no single imaging technique covers all brain pathology and both inflammation and neurodegeneration contribute to SLE pathogenesis, it is very important to use a multimodality approach coupling a morphological with a functional imaging modality. In this setting, to date, conventional magnetic resonance imaging and single photon emission computed tomography are the most largely available and accessible techniques. Modern techniques such as perfusion weighted imaging, diffusion weighted imaging, magnetization transfer imaging and magnetic resonance spectroscopy provide useful information to assess brain tissue damage however, their clinical relevance in individual patients needs further evidence. In this review we would like to summarize what have we learned in the last few years about neuroimaging in NPSLE, what have been major advances in neuroimaging techniques and, finally, we would like to give some suggestions about what should be done in daily clinical practice to approach SLE patients with NP symptoms.

In the present work multi-wall carbon nanotubes (MWNTs), which were synthesized on uncoated silicon by an easily scaled-up catalytical chemical vapor deposition (CVD), were subjected to three different functionalization treatments. Both acid treatment, by means of a HNO 3 –H 2 SO 4 1:3 mixture or chlorosulfuric acid (HSO 3 Cl) solution, and high temperature basic digestion with sodium hydroxide (NaOH) were involved. The efficiency of these methods were investigated by thermo-gravimetric analyses (TGA), Raman spectroscopy, Brunauer–Emmett–Teller (BET) analysis, X-ray photoelectron spectroscopy (XPS), energy dispersive X-ray (EDX) and electron microscopy (SEM, TEM) techniques, and the results were compared. Among the various treatments that have been tested, the 1:3 solution of nitric and sulphuric acid was the most effective in modifying the CNT surface, inducing the formation of functional groups that may be used in biological applications.

Sulfonated poly(etheretherketone) with a cardo group (SPEEK-WC) exhibiting a wide range of degree of sulfonation (DS) was used to prepare polymeric membranes and composite membranes obtained by incorporation of an amorphous zirconium phosphate sulfophenylenphosphonate (Zr(HPO 4 )(O 3 PC 6 H 4 SO 3 H), hereafter Zr(SPP)) in a SPEEK-WC matrix. The nominal composition of the composite membranes was fixed at 20 wt% of Zr(SPP). Both types of membrane were characterized for their proton conductivity, methanol permeability, water and/or methanol uptake, morphology by SEM and mechanical properties. For comparison, a commercial Nafion 117 membrane was characterized under the same operative conditions. The composite membranes exhibited a reduced water uptake in comparison with the polymeric membranes especially at high DS values and temperature higher than 50 °C. As a result, the water uptake into composite membranes remained about constant in the range 20–70 °C. The methanol permeability ( P ) of both polymeric and composite membranes was always lower than that of a commercial Nafion 117 membrane. At 22 °C and 100% relative humidity (RH), the proton conductivities ( σ ) of the polymeric membranes increased from 6 × 10 −4 to 1 × 10 −2 S cm −1 with the increase of DS from 0.1 to 1.04. The higher conductivity value was comparable with that of Nafion 117 membrane (3 × 10 −2 S cm −1 ) measured under the same operative conditions. The conductivities of the composite membranes are close to that of the corresponding polymeric membranes, but they are affected to a lesser extent by the polymer DS. The maximum value of the σ / P ratio (about 7 × 10 4 at 25 °C) was found for the composite membrane with DS = 0.2 and was 2.5 times higher than the corresponding value of the Nafion membrane.

Sulfonated polyetheretherketones are polymers of some interest for preparing membranes as alternative to the expensive perfluorinated membranes (e.g. Nafion) presently used for fuel cell applications. Sulfonated poly(oxa- p -phenylene-3,3-phtalido- p -phenylene-oxa- p -phenilene-oxy-phenylene) (PEEK-WC) with various degrees of substitution (DS) was prepared and then characterized by FT-IR analyses. Sulfonated PEEK-WC dense membranes were tested for their permeability to various gases and vapors. At 60 °C, the permeability coefficient of methanol in a sulfonated PEEK-WC membrane with 70% DS was about two orders of magnitude lower in comparison with that in a Nafion 117 membrane. Conductivity measurements were carried out by the impedance technique as a function of relative humidity (RH), at 100 °C, and as a function of temperature, in the range 50–115 °C, at 100% RH. The proton conductivity strongly increases with temperature and DS and reaches 2.5×10 −2 S cm −1 at 115 °C and 100% RH for DS=0.82. The hydration of the sulfonated polymer was also determined under the same conditions used for conductivity measurements.

Botrytis cinerea is one of the pathogens resulting in the heaviest commercial losses in ornamental cut flowers, and the severity of grey mould disease partly depends on the presence of ethylene in the storage environment. The efficacy of a β-cyclodextrin-based nanosponge 1:8 (CD-NS) – 1-methylcyclopropene (1-MCP) complex was evaluated as a novel control agent in protecting carnation (Dianthus caryophyllus L. ‘Idra di Muraglia’) cut flowers against B. cinerea infection. Two concentrations of this non-volatile 1-MCP formulation (CD-NS complex, 0.25 and 0.5 μL L−1, a.i.) were compared with commercial gaseous 1-MCP (0.25 μL L−1, a.i.), and an inoculated control. A non-inoculated control was also used to assess the natural infection level. Eleven days after inoculation, the development of grey mould on carnation was significantly reduced (59.9% of flower surface) in cut stems treated with the CD-NS complex at low dosage, compared to the high dosage of the CD-NS complex (91.5%), the commercial gaseous 1-MCP formulation (76.2%) and the inoculated control (100.0%). Endogenous ethylene production was associated with symptom development. Results showed a reduced ethylene production in 1-MCP treated flowers (0.25 μL L−1, a.i., both suspended and gaseous formulation). The CD-NS complex could therefore be an effective alternative to conventional chemicals to protect ornamental cut flowers.

Nitrated and sulfonated PEEK-WC with various degrees of substitution were obtained. The modified PEEK and its derivatives are able to form asymmetric membranes. The sulfonation was carried out to increase hydrophilicity and permeability. The insertion of the nitro group allow us to obtain a new material with possible positive properties and also to have a reactive group suitable for further modifications through previous reduction to the amino group. Symmetric and asymmetric membranes made from these polymers were prepared and characterized. The influence of evaporation time, and of the functional groups on membrane morphology and performances were analyzed. Membrane morphology was investigated by using Atomic Force Microscopy.

Membranes of poly(oxa-p-phenylene-3,3-phtalido-p-phenylenxoxa-p-phenylenenexoxi-p-phenylene) (PEEK-WC) containing β-cyclodextrin (β-CD) derivatives (O-octyloxycarbonyl β-CD and monotosyl β-CD) have been prepared to investigate their catalytic behaviour towards the p-nitrophenyldiphenylphosphate (PNPDPP) hydrolysis. Membranes containing CD lead to very high reaction rate during the hydrolysis of PNPDPP. Best results were obtained using monotosyl β-CD 2.5 wt.% containing membrane at pH 8.

Background: T-cells in acute coronary syndromes (ACS) show reduced expression and activity of the immunomodulatory molecule CD31 compared to patients with stable angina (SA). In T-cells, the shedding of the CD31 functional domains 1 to 5 leads to uncontrolled lymphocyte activation. A recent

Background: A recent experimental model of plaque instability suggests that endothelial activation and the exposure of the extracellular matrix are involved in the inflammatory process of plaque erosion. These data, together with the notion of an intense immunostaining on eroded autoptic coronary

A cortisol-binding polymer was prepared by utilising a non-covalent molecular imprinting polymerisation technique. The obtained polymer was packed in a high-performance liquid chromatography (HPLC) column; the selectivity was studied by liquid chromatography, eluting cortisol, cortisone, corticosterone, progesterone, 11-ketoprogesterone, 11alpha-hydroxyprogesterone, 17alpha-hydroxyprogesterone, cortisol 21-hemisuccinate, and cortisol 21-acetate with chloroform, containing 0.5% (v/v) acetic acid, as mobile phase. The mechanism of molecular imprinting was confirmed and a good selectivity for cortisol, with limited recognition for cortisone and 11alpha-hydroxyprogesterone, was found.

It is not infrequent to hear ethical appeals in order to shorten the validation process of a new health technology, but ethical considerations are difficult to reconcile with studies that have essentially a commercial aim. Pharmaceutical companies seek to maximise the profit of their product while users/buyers look for drugs that maximise health at an ‘affordable’ cost. It is hoped that drugs are rapidly released for patients who need them but the willingness to help patients should not be at the expense of adequate knowledge about the benefit of drugs. Opinions on an earlier-than-ideal endpoint in the drug approval path vary from those who view it as an important step in improving public health by ensuring that beneficial drugs are made available as quickly as possible to those who see it as a dangerous shortcut that might jeopardise consumer health due to unsafe and ineffective drugs being marketed and prescribed. Research and development for a new drug is a long and complex process that has at least three critical steps: the passage from pre-clinical to clinical phases when first-time-to-men studies are to be done, the evaluation of its clinical risk-benefit ratio at the end of the clinical phase before granting market approval, and the evaluation of its cost-effectiveness before deciding its market access and price. Decision-makers such as governmental regulatory agencies, purchasers of pharmaceuticals, physicians and