Molecular basis, diagnosis and clinical management of mucopolysaccharidoses

Mucopolysaccharidoses (MPSs) are a group of hereditary, monogenic disorders caused by lysosomal storage of glycosaminoglycans. Their incidence as a group is between 1:25,000 and 1:45,000. At present 11 different enzyme deficiencies are know to be responsible of 7 similar but distinct diseases. The diagnosis is suspected clinically but must be confirmed through biochemical, enzymatic and molecular analysis. Prenatal diagnosis is feasible for each disease. The phenotype worsens with age, due to progressive storage, and mainly involves mucosal tissue, upper airways and lungs, bones and joints, central and peripheral nervous system, heart, liver, eye and ear. Any type of MPSs, is characterized by a wide variability of phenotype ranging from a severe fetal-neonatal disease to an attenuated form diagnosed in adult individuals. Recently new treatments, like hematopoietic stem cell transplantation and enzymatic replacement therapy, became available for many of these disorders entailing the urgency of early diagnosis to allow access to therapies. Thanks to therapies these patients have a longer life than in the past and this implies that also palliative treatments, of which the cardiological ones have a prominent part, must be undertaken diligently. The cardiologist may face, more frequently than expected, with the need to diagnose a patient with MPS who was not recognized by other specialists. The echocardiographic features of these patients are typical and may help in the clinical diagnosis. The future probably deserves to these disorders other new treatments or combination therapies, which might further improve prognosis of these diseases

Molecular basis and clinical management of Gaucher disease

Gaucher disease (GD) type I is an autosomal recessive disease caused by a genetic deficiency of lysosomal β-glucocerebrosidase that leads to accumulation of undergraded substrate glucocerebroside and other glycolipids, thus causing damage in different organs. GBA is the only gene in which mutations are known to cause GD. Nearly 300 mutations have been identified in GD patients, including frame-shift mutations, point mutations, deletions, insertions, splice site mutations and recombinants. The variety of phenotypes associated to GD shows imperfect correlation with mutations. GD encompasses a spectrum of clinical findings from a perinatal lethal form to an asymptomatic form. However the classification of GD by clinical subtype is still useful in describing the wide range of clinical findings and broad variability in presentation. Three major clinical types are delineated: type I (chronic nonneuropathic), type II (acute neuropathic), and type III (chronic neuropathic). Patients with type I GD present with visceromegaly, hematological complications, and bone disease. Cardiac and pulmonary complications are rare. Type I GD adult patients have elevated risk of malignancies, Parkinson’s disease or Parkinsonism. Neuropathic forms of GD are rare and clinically ranging from lethal perinatal form to very mild form limited to abnormalities of horizontal ocular saccades. Diagnosis of acid β-glucosylceramidase relies on enzyme activity in peripheral blood leukocytes or skin fibroblasts and/or identification of GBA mutations. Enzyme replacement therapy is an effective treatment for non-neuropathic GD. Substrate inhibitor is the alternative therapy for some patients with GD is miglustat, iminosugar inhibitor of glucocerebroside synthase

Voltage stability in unbalanced power systems: A new complementarity constraints-based approach

Voltage stability has become a fundamental issue in the new, liberalized markets due to the fact that the new power systems are approaching more and more the stability limits. Then, several approaches were proposed in the relevant literature to find the critical conditions and recently the problem was faced also with reference to unbalanced three phase power systems. The unbalances, in fact, can be responsible of more critical stability conditions than in balanced power systems. Continuation power flow and optimal power flows were applied to analyze such conditions. This paper deals with voltage stability analysis in unbalanced power systems and proposes a new optimization model to determine the critical point based on the use of complementarity constraints. Different formulations, with increasing complexity, of the optimization model are proposed and tested. In particular, the maximum stability margin is calculated by a single-stage or a multi-stage procedure that accounts for the relationship between the actual operating point and the maximum loading point. In addition, the multi-stage maximum stability margin problem is formulated also in a probabilistic framework to account for the uncertainties affecting the input data (e.g., load powers). An application is presented on a test system highlighting the feasibility and the goodness of the proposed technique. Both load and line unbalances are taken into account to capture the dependence of voltage stability on the level of unbalances

The mTOR kinase inhibitor rapamycin decreases iNOS mRNA stability in astrocytes

Abstract Background Reactive astrocytes are capable of producing a variety of pro-inflammatory mediators and potentially neurotoxic compounds, including nitric oxide (NO). High amounts of NO are synthesized following up-regulation of inducible NO synthase (iNOS). The expression of iNOS is tightly regulated by complex molecular mechanisms, involving both transcriptional and post-transcriptional processes. The mammalian target of rapamycin (mTOR) kinase modulates the activity of some proteins directly involved in post-transcriptional processes of mRNA degradation. mTOR is a serine-threonine kinase that plays an evolutionarily conserved role in the regulation of cell growth, proliferation, survival, and metabolism. It is also a key regulator of intracellular processes in glial cells. However, with respect to iNOS expression, both stimulatory and inhibitory actions involving the mTOR pathway have been described. In this study the effects of mTOR inhibition on iNOS regulation were evaluated in astrocytes. Methods Primary cultures of rat cortical astrocytes were activated with different proinflammatory stimuli, namely a mixture of cytokines (TNFα, IFNγ, and IL-1β) or by LPS plus IFNγ. Rapamycin was used at nM concentrations to block mTOR activity and under these conditions we measured its effects on the iNOS promoter, mRNA and protein levels. Functional experiments to evaluate iNOS activity were also included. Results In this experimental paradigm mTOR activation did not significantly affect astrocyte iNOS activity, but mTOR pathway was involved in the regulation of iNOS expression. Rapamycin did not display any significant effects under basal conditions, on either iNOS activity or its expression. However, the drug significantly increased iNOS mRNA levels after 4 h incubation in presence of pro-inflammatory stimuli. This stimulatory effect was transient, since no differences in either iNOS mRNA or protein levels were detected after 24 h. Interestingly, reduced levels of iNOS mRNA were detected after 48 hours, suggesting that rapamycin can modify iNOS mRNA stability. In this regard, we found that rapamycin significantly reduced the half-life of iNOS mRNA, from 4 h to 50 min when cells were co-incubated with cytokine mixture and 10 nM rapamycin. Similarly, rapamycin induced a significant up-regulation of tristetraprolin (TTP), a protein involved in the regulation of iNOS mRNA stability. Conclusion The present findings show that mTOR controls the rate of iNOS mRNA degradation in astrocytes. Together with the marked anti-inflammatory effects that we previously observed in microglial cells, these data suggest possible beneficial effects of mTOR inhibitors in the treatment of inflammatory-based CNS pathologies.</p

Fiber Bragg Grating sensors for deformation monitoring of GEM foils in HEP detectors

Fiber Bragg Grating (FBG) sensors have been so far mainly used in high energy physics (HEP) as high precision positioning and re-positioning sensors and as low cost, easy to mount, radiation hard and low space- consuming temperature and humidity devices. FBGs are also commonly used for very precise strain measurements. In this work we present a novel use of FBGs as flatness and mechanical tensioning sensors applied to the wide Gas Electron Multiplier (GEM) foils of the GE1/1 chambers of the Compact Muon Solenoid (CMS) experiment at Large Hadron Collider (LHC) of CERN. A network of FBG sensors has been used to determine the optimal mechanical tension applied and to characterize the mechanical stress applied to the foils. The preliminary results of the test performed on a full size GE1/1 final prototype and possible future developments will be discussed.Comment: Four pages, seven figures. Presented by Michele Caponero at IWASI 2015, Gallipoli (Italy

Cost-effectiveness of direct acting oral anticoagulants in the prevention of thromboembolic complications : limits and concerns of economic evaluations

Economic evaluations have a widespread application in many areas of clinical research and play a key role in the clinical decision-making process. However, economic analyses have been sometimes used to produce new 'evidence' that is not adequately tested in the target population. This is the case of data arising from a systematic review of clinical trials evaluating the use of direct acting oral anticoagulants for the prevention of stroke in patients with atrial fibrillation. Taking into account this example, here we discuss the concerns raised by the improper interpretation of the results. Our conclusions are three-fold. Data from economic analyses should not be shifted to a clinical recommendation. Simulation models should not be used to generate new 'evidence' that is not supported by experimental data and is misleading. Clinical judgment is therefore pivotal to interpret results emerging from economic analyses

Farmacoeconomia dei COXIB nella patologia osteoarticolare: revisione della letteratura

A new class of anti-inflammatory agents, the selective inhibitors of cyclooxygenase-2 (COXIBs), has been recently introduced into the market for the treatment of osteoarthritis and reumatoid arthritis. Randomized and controlled clinical trials showed a similar efficacy and a better tolerability profile of COXIBs compared with conventional non-steroidal anti-inflammatory drugs (NSAIDs). The aim of this study was to perform a scientific literature review relating to the economic impact produced by COXIBs' introduction. The research of references included the following databases: MEDLINE, EMBASE and the NHS (Economic Evaluation Database) of the York University. A total of 67 in extenso pubblications have been extracted. Of these 13 papers having the specific objective to evaluate the economic implications of COXIBs in comparison to conventional NSAIDs was analysed. In ten cases (77%), cost-effectiveness analyses were performed. The European context was considered in eight cases (62%), while that of North America and Asia were investigated in four and one case, respectively. The analysis of costs took always into account direct costs of the management of arthritis exclusively (drugs, and resources associated with the treatment of gastrointestinal side effects). Indirect and intangible costs were never considered. The results of this review highlight that the higher tollerability profile of COXIBs may generate a cost-saving. This cost-saving seems to be basically due to the reduced frequency of gastroprotective agents coprescription and also to a lesser appearance of severe gastrointestinal side effects compared with conventional NSAIDs. Besides the disease management improving, the cost-saving associated with COXIBs can completely or partially offset the net increase of expense induced by their higher price of purchase

Eco-friendly gas mixtures for Resistive Plate Chambers based on Tetrafluoropropene and Helium

Due to the recent restrictions deriving from the application of the Kyoto protocol, the main components of the gas mixtures presently used in the Resistive Plate Chambers systems of the LHC experiments will be most probably phased out of production in the coming years. Identifying possible replacements with the adequate characteristics requires an intense R&D, which was recently started, also in collaborations across the various experiments. Possible candidates have been proposed and are thoroughly investigated. Some tests on one of the most promising candidate - HFO-1234ze, an allotropic form of tetrafluoropropane- have already been reported. Here an innovative approach, based on the use of Helium, to solve the problems related to the too elevate operating voltage of HFO-1234ze based gas mixtures, is discussed and the relative first results are shown.Comment: 9 pages, 6 figures, 1 tabl

Analisi Costo Minimizzazione delle preparazioni di Interferon Beta per il trattamento della Sclerosi Multipla

The multiple sclerosis (MS) is a neurologic disease that is characterized by a progressive demielinization of the white matter of the central nervous system. In the lasts decades, several therapies have been introduced after randomized, double-blind, placebo controlled trials. These trials supported the efficacy of Interferon-beta (INF- b) in reducing relapsing frequency and slowing the progressive disability, mainly in cases affected by relapsing- remitting MS course. In Italy four different preparations of INF-b are available for MS treatment having different INF-b types (i.e., INF-b1a e INF-b1b), different administration schemes, different INF-b doses and ways of administration. Recently, the biological activity of these preparations have been compared using the same assay system against the same INF-b standard. The aim of this study was to carry out a cost-minimization analysis, on the MS treatments in Italy comparing of the available preparations in terms of cost per microgram standardized by the level of biological activity. The economic evaluation has been conducted adopting the hospital perspective. Health resources have been valued considering euro currency during 2004. According to registered treatment protocol, the results showed that the micrograms per week of INF-b standardized by the level of biological activity ranged from 30mg of Avonex® to 132mg of Rebif44®. Under the same levels of biological activity, Rebif44® resulted the INF-b preparation with the lower cost per micrograms (1.95 euro), followed by Rebif®22 and Betaferon® that had a similar cost (2.90 e 2.97 respectively). Avonex® resulted the INF-b preparation with the highest cost per micrograms (6,37 euro), about three times higher than that of the preparation with the lowest cost

Measurement of the absolute gas gain and gain variations study in straw-tube detectors

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