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Background Patients with bipolar disorder (BD) suffer from greater physical morbidity and mortality than the general population. The aim of the present study is to explore the prevalence and clinical correlates of General Medical Conditions (GMC) in a large consecutive sample of patients with BD. Method The study sample comprised of 347 patients who met DSM-IV-TR criteria for BD I (n=207, 59.7%), BD II or Cyclothymic Disorder (n=140, 40.3). Diagnostic information was collected by means of the Structured Clinical Interview for DSM-IV Axis I Disorders– Clinical Version (SCID-I), and information about personal and family history were collected by the Semi-Structured Interview for Mood Disorder-Revised (SIMD-R). Standardized procedure was used to assess the diagnosis of GMC, which was considered present only if a specific therapy to treat the condition was prescribed by a specialist or a general practitioner. In order to explore possible relationships between physical comorbidity and clinical features of BD, we compared patients with (MD) and without (No-MD) Metabolic Diseases (MD) and patients with (AAD) and without (No-AAD) Autoimmune-Allergic Diseases (AAD). Results The most commonly reported GMCs were: Headache, Hypercholesterolemia (>200 mg/dl), Chronic Constipation, Obesity, Arterial Hypertension (BP >140/90 mmHg), Hypothyroidism, Allergic Rhino-Conjunctivitis, Irritable Bowel Syndrome, Hypertriglyceridemia (>150 mg/dl), Metabolic Syndrome, Hiatus Hernia, Dysmenorrhea, Urticaria, Atopic Dermatitis, Psoriasis, Seborrheic Dermatitis, Diabetes Mellitus, Bronchial Asthma, Cardiac Arrhythmias, Biliary Lithiasis, and COPD. In our sample, MD (n=148, 42.7%) and AAD (n=167, 48.1%) were the most common categories of GMCs. Interestingly, the lifetime prevalence of cancer and neoplastic diseases was very low: 1 patient (.3%) reported Lung Adenocarcinoma and 2 (.6%) patients Bowel Cancer. In the group comparisons, length of pharmacological treatment (OR=1.054; 95% CI=1.030–1.078), age at onset of first major episode (OR=1.043; 95% CI=1.019–1.067), length of the current episode (OR=1.025; 95% CI=1.020–1.533) and absence of lifetime comorbid substance abuse (OR=.373; 95% CI=.141–.989) were statistically associated with the presence of comorbid MD; while only AD-induced hypomania (OR=1.62; 95% CI=1.011–2.597), and cyclothymic temperament (OR=1.051; 95% CI=1.016–1.087) were statistically associated with the presence of comorbid AAD. Limitations Possible referral and selection bias; retrospective, non-blind, cross-sectional evaluation. Conclusion MD and AAD were highly represented in our sample, while cancer and neoplastic diseases were uncommon. The clinical correlates of different sub-groups of GMC suggest different interpretations. The presence of MD seems to be correlated with the progression of BD and the chronic medication exposure, while comorbid AAD seems to correlate with a specific clinical subtype of BD, characterized by mood reactivity and temperamental mood instability. If the link with autoimmune-allergic diathesis will be confirmed, it could provide an interesting new paradigm for the study of the “systemic” nature of mood disorders and a promising target for future treatment options.

Objective To propose an easy predictive model for the risk of rehospitalization, built from hospital administrative data, in order to prevent repeated admissions and to improve transitional care. Design Retrospective cohort study. Setting Azienda Ospedaliero Universitaria Pisana (Pisa University Hospital). Participants Patients residing in the territory of the province of Pisa (Tuscany Region) with at least one unplanned hospital admission leading to a medical Diagnosis-Related Group (DRG) in the calendar year 2012. Intervention We compared two groups of patients: patients coded as 'RA30' (readmitted within 30 days after the previous discharge) and patients coded as 'NRA30' (either admitted only once or readmitted after 30 days since the latest discharge). Main Outcome Measures The effect of age, sex, length of stay, number of diagnoses, normalized number of admissions and presence of diseases on the probability of rehospitalization within 30 days after discharge was evaluated. Results The significant variables included in the predictive model were: age, odds ratio (OR) = 1.018, 95% confidence interval (CI) = 1.011-1.026; normalized number of admissions, OR = 1.257, CI = 1.225-1.290; number of diagnoses, OR = 1.306, CI = 1.174-1.452 and presence of cancer diagnosis, OR = 1.479, CI = 1.088-2.011. Conclusions The model can be easily applied when discharging patients who have been hospitalized after an access to the Emergency Department to predict the risk of rehospitalization within 30 days. The prediction can be used to activate focused hospital-primary care transitional interventions. The model has to be validated first in order to be implemented in clinical practice.

Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. Thus, MMP-13-selective inhibitors are promising candidates in osteoarthritis therapy. Recently, we designed an N-isopropoxy-arylsulfonamide-based hydroxamate inhibitor, which showed low nanomolar activity and high selectivity for MMP-13. In parallel to further studies aiming to assess the in vivo activity of our compound, we screened the Life Chemicals database through computational docking to seek for novel scaffolds as zinc-chelating non-hydroxamate inhibitors. Experimental evaluation of 20 selected candidate compounds verified five novel leads with IC 50 in the low μM range. These newly discovered inhibitors are structurally unrelated to the ones known so far and provide useful scaffolds to develop compounds with more desirable properties. Finally, a first round of structure-based optimization on lead 1 was accomplished and led to an increase in potency of more than 5 fold. © 2011 Elsevier Masson SAS. All rights reserved.

Matrix metalloproteinases (MMPs) are important factors in gliomas since these enzymes facilitate invasion into the surrounding brain and participate in neovascularization. In particular, the gelatinases (MMP-2 and MMP-9), and more recently MMP-25, have been shown to be highly expressed in gliomas and have been associated with disease progression. Thus, inhibition of these MMPs may represent a promising non-cytotoxic approach to glioma treatment. We report herein the synthesis and biological evaluation of a series of 4-butylphenyl(ethynylthiophene)sulfonamido-based hydroxamates. Among the new compounds tested, a promising derivative, 5a, was identified, which exhibits nanomolar inhibition of MMP-2, MMP-9, and MMP-25, but weak inhibitory activity towards other members of the MMP family. This compound also exhibited anti-invasive activity of U87MG glioblastoma cells at nanomolar concentrations, without affecting cell viability.

Overexpression of macrophage elastase (MMP-12), a member of the matrix metalloproteinases family, can be linked to tissue remodeling and degradation in some inflammatory processes, such as chronic obstructive pulmonary disease (COPD), emphysema, rheumatoid arthritis (RA), and atherosclerosis. On this basis, MMP-12 can be considered an attractive target for studying selective inhibitors that are useful in the development of new therapies for COPD and other inflammatory diseases. We report herein the design, synthesis, and in vitro evaluation of a new series of compounds, possessing an arylsulfonyl scaffold, for their potential as selective inhibitors of MMP-12. The best compound in the series showed an IC50 value of 0.2 nM, with good selectivity over MMP-1 and MMP-14. A docking study was carried out on this compound in order to investigate its binding interactions with MMP-12, and NMR studies on the complex with the MMP-12 catalytic domain were able to validate the proposed binding mode.

Despite the increase of community acquired cases of legionellosis in Italy over the last years, the Italian guidelines do not give indications for prevention and control of Legionella in the hot water networks (or centralized conditioning systems) of residential buildings. We performed a survey on eight medium sized apartment buildings in the Pisa district to assess the prevalence of Legionella spp. in the water network and the respondance to drinking water requisites at the point of use, according to the Italian norms.For each building two hot water and three cold water samples (located at water entrance from the aqueduct network into the building pipework, at the exit from pressure autoclave, and at a remote tap) were collected.Legionella was detected in 20% of residential buildings, mostly in those with a central hot water production system.The study highlights a condition of potential risk for susceptible population subgroups and supports the need for measures of risk assessment and control.

Fluorinated, arylsulfone-based inhibitors of Matrix Metalloproteinases (MMP) have been used, in the [ 18 F]-radiolabelled version, as radiotracers targeted to MMP-2/9 for Positron Emission Tomography (PET). Although they showed acceptable tumour uptake, specificity was rather low. To get further insights into the reason of low specificity, the binding interaction of these compounds with Human Serum Albumin (HSA) has been investigated. 19 F NMR spectroscopy showed that all compounds considered partition between multiple HSA binding sites, being characterized by either slow-exchange kinetics (with K a in the order of 10 5 M −1 ) and fast-exchange kinetics (with K a in the order of 10 4 M -1 ). For 2-(2-(4′-(2-fluoroethoxy)biphenyl-4-ylsulfonyl)phenyl)acetic acid ( 1a ) and 2-(2-(4′-(2-fluoroacetamido)biphenyl-4-ylsulfonyl)phenyl)acetic acid ( 1c ), these slow and fast-exchanging binding sites could be mapped to Sudlow's site I and II, respectively. It is shown that high affinity albumin binding constitutes a theoretical limitation for the specificity achievable by MMP-inhibitors as MMP-targeted PET tracers in cancer imaging, because albumin accumulating aspecifically in tumours lowers the binding potential of radiotracers.

Activated leukocyte cell adhesion molecule (ALCAM) is expressed at the surface of epithelial ovarian cancer (EOC) cells and is released in a soluble form (sALCAM) by ADAM-17-mediated shedding. This process is relevant to EOC cell motility and invasiveness, which is reduced by inhibitors of ADAM-17. In addition, ADAM-17 plays a key role in EGFR signaling and thus may represent a useful target in anticancer therapy. Herein we report our hit optimization effort to identify potent and selective ADAM-17 inhibitors, starting with previously identified inhibitor 1. A new series of secondary sulfonamido-based hydroxamates was designed and synthesized. The biological activity of the newly synthesized compounds was tested in vitro on isolated enzymes and human EOC cell lines. The optimization process led to compound 21, which showed an IC50 of 1.9 nM on ADAM-17 with greatly increased selectivity. This compound maintained good inhibitory properties on sALCAM shedding in several in vitro assays.

Activated leukocyte cell adhesion molecule (ALCAM) plays a relevant role in tumor biology and progression. Our previous studies showed that ALCAM is expressed at the surface of epithelial ovarian cancer (EOC) cells and is released in a soluble form by ADAM-17-mediated shedding. This process is relevant to EOC cell motility and invasiveness, which is reduced by nonspecific inhibitors of ADAM-17. For this reason, ADAM-17 may represent a new useful target in anticancer therapy. Herein, we report the synthesis and biological evaluation of new ADAM-17 inhibitors containing an arylsulfonamidic scaffold. Among the new potential inhibitors, two very promising compounds 17 and 18 were discovered, with a nanomolar activity for ADAM-17 isolated enzyme. These compounds proved to be also the most potent in inhibiting soluble ALCAM release in cancer cells, showing a nanomolar activity on A2774 and SKOV3 cell lines.

Glioblastoma multiforme is the most commonly diagnosed malignant primary brain tumour in adults. Invasive behaviour is the pathological hallmark of malignant gliomas; consequently, its inhibition has been suggested as a therapeutic strategy. Tumour cell-derived gelatinases (matrix metalloproteinase-2, matrix metalloproteinase-9) can be considered prime factors in glioma invasiveness: their expression correlates with the progression and the degree of malignancy. Thus, broad spectrum matrix metalloproteinase inhibitors (MMP inhibitors) have been included in clinical trials. In the present study, the invasiveness, viability and progression of the human glioma cell line U87MG were investigated following treatment with N-O-isopropyl sulfonamido-based hydroxamates (compounds 1 and 2) as MMP-2 inhibitors used at nanomolar concentration. A standard broad spectrum MMP-inhibitor belonging to the classical tertiary sulfonamido-based hydroxamates family (CGS_27023A) was used too. The compounds 1 and 2 resulted in potent inhibition of cell invasiveness (P

Matrix metalloproteinase-13 (MMP-13) is a key enzyme implicated in the degradation of the extracellular matrix in osteoarthritis (OA). For this reason, MMP-13 synthetic inhibitors are being sought as potential therapeutic agents to prevent cartilage degradation and to halt the progression of OA. Herein, we report the synthesis and in vitro evaluation of a new series of selective MMP-13 inhibitors possessing an arylsulfonamidic scaffold. Among these potential inhibitors, a very promising compound was discovered exhibiting nanomolar activity for MMP-13 and was highly selective for this enzyme compared to MMP-1, -14, and TACE. This compound acted as a slow-binding inhibitor of MMP-13 and was demonstrated to be effective in an in vitro collagen assay and in a model of cartilage degradation. Furthermore, a docking study was conducted for this compound in order to investigate its binding interactions with MMP-13 and the reasons for its selectivity toward MMP-13 versus other MMPs.

In the last years many research studies have been focused on the features of MILD combustion that is a stable form of combustion, obtained with high temperature reactants and high exhaust gas recirculation and characterized by low flame temperature and, consequently, low Nox emissions. This form of combustion is also characterized by low light emissions (for this reason it is also called “flameless” combustion) and a large range of stable operation. MILD combustion has been already applied in industrial furnaces where ceramic regenerators provide to raise the temperature of the entering diluted air, the main advantages being high efficiency and low emissions. The introduction of MILD combustion in power plants would allow for increasing the temperature of the entering reactants beyond the self-ignition temperature without increasing the NOx emission. The main goals of this technique are low combustion exergy losses, large range of stable combustion, and low NOx emissions. Some experiments have shown that the flameless conditions can be obtained using diluted reactants, even using heavy fuel oil. Good results in terms of NOx emissions and soot formation have been obtained for heavy oil combustion in a 10% oxygen concentration of reactants and combustion chamber inlet temperature of about 900K. In order to meet these conditions, a semiclosed CCGT cycle with high recirculation ratio, suitable for the use of heavy fuel oil, is proposed here, assuming state-of-the-art technologies for gas turbine and steam plant and steam cooling of the turbine blades. The thermodynamic analysis shows that the overall plant efficiency of the new scheme is close to 60% that is about the efficiency that can be obtained in modern CCGT power plant fuelling natural gas.Copyright © 2004 by ASME

A novel Combined Cycle Gas Turbine layout is proposed for using heavy fuel oil in a combustion mode called “Mild Combustion”, characterized by a very low adiabatic flame temperature and flat temperature field in the combustion chamber and low pollutant emissions. “Mild Combustion” is obtained by means of the dilution of reactants with inert gas like combustion product resulting in a very low oxygen concentration of the mixture at the ignition. To stabilize the combustion process in such a condition the reactants temperature has to be raised above the self ignition value. In industrial application this particular preconditioning of the reactants can be reached partially before the combustion chamber and finally in process by means of a performed aerodynamic that further dilute and heat-up the mixture. An experimental analysis of the oil combustion behaviour inside the gas turbine exhaust flow has been arranged at Centro Combustione of Ansaldo Caldaie in Gioia del Colle (Italy). The turbine exhaust gases are simulated by mixing those produced in a gas burner with external air preheated at different temperatures in order to have different final oxygen concentrations and temperature levels. The influence of the main combustion parameters regarding the process feasibility and environmental impact are presented and analysed. Good results in terms of NOx emissions and soot formation have been obtained for heavy oil combustion in a 10% oxygen oxidizer concentration requiring a combustion chamber inlet temperature of about 900K. In order to meet these conditions, a novel CCGT cycle in which about 64% of combustion products are re-circulated before entering the combustion chamber, is proposed. The thermodynamic analysis shows that the efficiency that could be achieved by the proposed cycle is a few percent lower than the efficiency of a combined cycle power plant fuelling natural gas, with the same turbine inlet temperature and similar turbine blade cooling technology.Copyright © 2003 by ASME

An experimental investigation of the flowfield inside a high hub-to-tip ratio, single-stage compressor is described. Fast-response instrumentation was used for the measurements in the absolute and relative frames of reference. The information was digitized for further analysis of the instantaneous and averaged flow parameters. The calculation of power spectra and the autocorrelation function, and the phase-locked averaging technique are used in this study. This technique consists of dividing the long sample in time intervals equal to the period as obtained by fast Fourier transforms and ensemble averaging these intervals. This procedure has been adopted because it can handle singleand multicell patterns. Two types of perturbation are distinguished: the small eight-cell stall and the singleor double-cell pattern with deep stall. The overall flow behavior, as well as the detailed flowfield structure, are presented for the two cases as measured with stationary probes. On-blade flow measurements suggest the existence of important radial velocities near the rotor blade surface when deep stall occurs.