The effect of voltage distortion on ageing acceleration of insulation systems under partial discharge activity

The features of harmonic distortion which may affect significantly the reliability of typical ac-power network equipment, such as low-voltage self-healing capacitors used for reactive power and harmonic compensation are investigated. Moreover, the effect of high-frequency pulse-like voltage generated by adjustable speed drives (ASD) on electrical machine insulation is also investigated, resorting to life tests carried out on different insulating materials of the standard and "corona resistant" type, at electrical field levels able to incept partial discharges (PD)

Simultaneous Contralateral Vestibular Schwannoma and Middle Ear Paraganglioma Tumor

To the best of our knowledge, only 2 cases of a simultaneous contralateral vestibular schwannoma (VS) and middle ear paraganglioma (MEP) have previously been reported in literature. We report the third case observed in a 43-year-old male, who presented with an 11-year history of right-sided hearing loss and a 1-year history of left-sided pulsatile tinnitus. A magnetic resonance imaging (MRI) showed a VS on the right side and computer tomography (CT) identified a Fisch type A1 paraganglioma on the left side. The VS was treated using a translabyrinthine approach and the MEP was kept under radiological observation for 1 year. Due to the growth of the MEP (Fisch type A2), it was treated with excision via a retroauricular approach. Our case was very challenging because there was a different and important pathology on each side, both carrying a risk of deafness as a consequence of the disease and/or the treatments

Systemic diseases and biotherapies: Understanding, evaluating, and preventing the risk of hepatitis B reactivation

Hepatitis B virus (HBV) reactivation can occur in chronic carriers of the HBV surface antigen (HBsAg) and constitutes a well-known complication of immunosuppressive therapy. HBV reactivation has also been reported after contact with the HBV. The increasing use of biological agents (TNFα antagonists, rituximab, abatacept, and tocilizumab) to treat systemic diseases has resulted in numerous publications about the risk of HBV reactivation. The relevant scientific societies have issued recommendations designed to prevent HBV reactivation. The main measures consist of screening for markers indicating chronic HBV infection (HBsAg) or HBV infection in the distant past (antibodies to the HBV core antigen) before initiating biological therapies, vaccinating marker-negative patients, and considering close follow-up or antiviral treatment before immunosuppressive treatment initiation or in the event of HBV reactivation. Here, we discuss the pathophysiological mechanisms underlying HBV reactivation during biological treatments, most notably in patients with occult HBV infection or markers for remote HBV infection, whose hepatocyte nuclei may contain a resistance form of HBV DNA known as covalently closed circular DNA (cccDNA). Assessment of the risk of reactivation relies on the HBV status, drugs used, and data from the literature. Finally, we discuss the various recommendations and modalities for HBV vaccination, preemptive treatment, and patient management, according to the level of risk and to the circumstances in which reactivation occurs

Analysis on the impact of additives on space charge behavior of thermally aged XLPE plaques

This article investigates the space charge properties of XLPE-based materials characterized by different concentration and types of additives and fillers inside the polymeric compound. Materials were aged under three different temperatures (87 °C, 110 °C and 130 °C) for 24, 18 and 12 months, respectively. Space charge profiles of both unaged and aged materials were obtained through the Pulsed Electro Acoustic (PEA) method. Additives and fillers are proven to significantly impact the space charge behavior of the insulating material both in the unaged and aged states. The impact of antioxidants, together with their kinetics under thermal aging conditions, is analyzed and claims an effective containment of the degradation kinetics, keeping the accumulated space charge to low values

SPHINGOLIPID SIGNALING AS A TARGET IN PHOTORECEPTOR DEGENERATION: AN IN VITRO MODEL FOR THERAPEUTIC STRATEGIES IN RETINITIS PIGMENTOSA

Introduzione: gli Sfingolipidi sono una vasta famiglia di molecole con il duplice ruolo di componenti strutturali di membrane e mediatori intra ed extra cellulari. Sono implicati nel controllo di proliferazione, differenziazione e sopravvivenza cellulare ma anche di fenomeni legati alla morte, tra cui l\u2019apoptosi. Ceramide (Cer), alla base degli sfingolipidi complessi, pu\uf2 andare incontro a deacilazione generando sfingosina e sfingosina-1-fosfato (S1P). Quest\u2019ultimo \ue8 considerato un mediatore di sopravvivenza e proliferazione cellulare, in opposizione a Cer, che promuove arresto del ciclo ed apoptosi. La degenerazione retinica ed, in particolare la Retinite Pigmentosa (RP) sono associate all\u2019accumulo di Cer ed all\u2019induzione di morte cellulare. L\u2019inibizione della sintesi e dell\u2019accumulo di Cer, inattivando la serina palmitoiltransferasi (SPT) attraverso l\u2019utilizzo di Miriocina, \ue8 stata dimostrata essere coinvolta nel recupero morfologico e funzionale dei fotorecettori retinici, in particolare dei coni, in un modello murino di RP (mutante rd10). Scopo: Il nostro scopo \ue8 di intervenire sul metabolismo degli sfingolipidi per ridurre il danno di fotorecettori retinici, attarveso l\u2019utilizzo di una linea cellulare di fotorecettori coni. In particolare, promuovendo l\u2019aumento di S1P intracellulare, tramite l\u2019inibizione dell\u2019enzima S1P liasi, e la riduzione di Cer attraverso l\u2019inattivazione di SPT. Metodi: le cellule murine 661W, una linea di fotorecettori (coni), sono state trattate con 2-acetil-4(5)-(1(R),2(S),3(R),4-tetraidrobutil)-imidazolo (THI) 75\ub5M, un inibitore dell\u2019enzima S1Pliasi, per 2 ore; quindi, le cellule sono state sottoposte a deprivazione di siero e trattate con H2O2 1mM per differenti lassi di tempo. La curva di crescita di queste cellule \ue8 stata determinata attraverso il saggio MTT e la vitalit\ue0 con Typan blue. Il saggio TUNEL e il FRAP test sono stati impiegati per verificare, rispettivamente, il grado di apoptosi e il potere antiossidante intrinseco dei fotorecettori. I contenuti intracellulari di sfingolipidi sono stati misurati attraverso l\u2019analisi LC-MS. La tecnica del Western blotting, attraverso l\u2019impiego di anticorpi specifici, \ue8 stata utilizzata per valutare la fosforilazione di ERK1/2 e Akt/PKB, il rapporto tra Bcl-2/Bax e l\u2019espressione proteica di Nrf2. Attraverso Real time-PCR, le modulazioni nell\u2019espressione dei trascritti di HO-1 e dei recettori di S1P sono stati valutati in seguito a stress ossidativo e trattamento con THI. S1P esogeno (100nM) e Miriocina (10\ub5M) sono stati impiegati, rispettivamente 1 ora e 5 ore prima H2O2, per antagonizzare l\u2019effetto dello stimolo ossidativo sui fotorecettori. In fine, abbiamo esaminato 30 composti di nuova sintesi per determinare la loro capacit\ue0 inibitoria su SPT, attraverso un saggio di attivit\ue0 enzimatica. Risultati: i nostri risultati mostrano che l\u2019aumentata stabilit\ue0 di S1P, ottenuta tramite l\u2019utilizzo di THI, \ue8 in grado di ridurre l\u2019effetto inibitorio sulla proliferazione e la vitalit\ue0 cellulare, dato dalla deprivazione di siero e dal trattamento con H2O2. Il pretrattamento con THI, infatti, antagonizza la de-fosforilazione di ERK1/2 e la fosforilazione di Akt su Ser473, indotte dagli stimoli di morte utilizzati. Abbiamo, quindi, focalizzato la nostra ricerca sugli effetti dello stress ossidativo, evidenziando che THI si contrappone all\u2019induzione dell\u2019apopstosi tramite l\u2019aumento del rapporto Bcl-2/Bax e influenza il potere antiossidante intrinseco dei fotorecettori modulando la via di segnale di Nrf2 e HO-1. Inoltre, THI aumenta l\u2019espressione dei recettori di S1P, mostrando un effetto maggiore sui recettori S1P4 e S1P5. Inoltre, abbiamo osservato che basse concentrazioni di S1P migliorano la proliferazione, la vitalit\ue0 e la risposta antiossidante di cellule 661W, mentre alte concentrazioni portano alla saturazione dei recettori.Il pretrattamento con miriocina, sia da solo che in combinazione con THI, protegge i fororecettori dallo stress ossidativo e riduce drasticamente i livelli intracellulari di tutte le specie di Cer. Parallelamente, abbiamo selezionato tre composti con attivit\ue0 inbitoria su SPT, determinando i rispettivi valori di IC50 che sono risultati essere compresi tra 17,71\ub5M e 40,41\ub5M. Conclusioni: possiamo quindi concludere che la stabilizzazione di S1P e, pi\uf9 in generale, l\u2019azione sul metabolismo degli sfingolipidi \ue8 da considerarsi un target terapeutico per promuovere la sopravvivenza fotorecettoriale in differenti condizioni di stress, tra cui lo stress ossidativo.Background: Sphingolipids are a broad class of molecules with the double role of cell membranes components and intra/extra cellular signal mediators, controlling proliferation, differentiation, stress survival and apoptosis. Ceramide (Cer), the core of complex sphingolipids, can undergo deacylation giving rise to sphingosine and sphingosine-1-phosphate (S1P). This latter exerts a pro-survival and proliferative activity, as opposed to Cer, which promotes cell cycle arrest and apoptosis. Retinal degeneration and in particular Retinitis Pigmentosa (RP) are associated to Cer accumulation and cell death induction. In a murine model of RP (rd10 mutant mice), it has been demonstrated that inhibition of Cer synthesis and accumulation, blocking serine palmitoyltransferase (SPT) with Myriocin, rescues retinal photoreceptors, especially cones, from degeneration. Aim: Our aim is to target sphingolipid metabolism to reduce retinal photoreceptor damage, in a cone photoreceptors cell line. In particular, promoting S1P intracellular increase by S1Plyase inhibition and Cer depletion through SPT inactivation. Methods: Murine 661W cone-like cell line were treated with 75\ub5M 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI), an inhibitor of S1Plyase, for 2 hours; next, cells were starved and treated with 1mM H2O2 for different times. Cell growth curve was determined by MTT assay and viability with Trypan blue. TUNEL assay and FRAP test were employed to verify, respectively, apoptosis degree and antioxidant-intrinsic power. Sphingolipid intracellular amounts were measured through LC-MS analysis. ERK1/2 and Akt/PKB phosphorylation, Bcl-2/Bax ratio and Nrf2 expression was evaluated by Western blotting with specific antibodies. Real time-PCR was performed to establish HO-1 and S1P receptors transcript changes upon THI and oxidative stress treatments. Exogenous S1P (100nM) and Myriocin (10\ub5M) were also employed, respectively 1 hour and 5 hours before H2O2, to antagonize oxidative stress effect on photoreceptors. Lastly, we screened 30 new synthetic compounds to determine their ability in inhibiting SPT, through an enzymatic activity assay. Results: We show that enhanced stability of S1P, obtained through THI administration, reduces inhibitory starvation and H2O2 effect on cell proliferation and viability. In particular, through THI ability to reverse stresses-induced ERK1/2 dephosphorylation and Akt phosphorylation on Ser473. We focused our investigations on oxidative stress, finding that THI counteracts H2O2-induced apoptosis increasing Bcl-2/Bax ratio and antioxidant-intrinsic power modulating Nrf2/HO-1 pathway. Furthermore, THI differentially induces S1P receptors transcript expression, showing the major effect on S1P4 and S1P5. In addition, low exogenous S1P improves 661W proliferation, viability and antioxidant response, whereas higher concentration leads to S1P receptors saturation. Myriocin treatment, either alone or in combination with THI, rescues photoreceptors from H2O2-induced oxidative stress and drastically reduces all Cer pools. Simultaneously, we selected three compounds with inhibitory activity on SPT, showing an IC50 values ranging from 17.71\ub5M to 40.41\ub5M. Conclusions: We conclude that S1P stabilization and, in general, sphingolipid metabolism manipulation can be considered a therapeutic target in order to promote photoreceptors survival under different stress conditions, such as oxidative stress

The Pricing Behaviour of Firms in the Euro Area: New Survey Evidence

This study investigates the pricing behaviour of firms in the euro area on the basis of surveys conducted by nine Eurosystem national central banks. Overall, more than 11,000 firms participated in the survey. The results are very robust across countries. Firms operate in monopolistically competitive markets, where prices are mostly set following mark-up rules and where price discrimination is a common practice. Our evidence suggests that both time- and state-dependent pricing strategies are applied by firms in the euro area: around one-third of the companies follow mainly time-dependent pricing rules while two-thirds use pricing rules with some element of state-dependence. Although the majority of firms take into account a wide range of information, including past and expected economic developments, about one-third adopts a purely backward-looking behaviour. The pattern of results lends support to the recent wave of estimations of hybrid versions of the New Keynesian Phillips Curve. Price stickiness arises both at the stage when firms review their prices and again when they actually change prices. The most relevant factors underlying price rigidity are customer relationships – as expressed in the theories about explicit and implicit contracts – and thus, are mainly found at the price changing (second) stage of the price adjustment process. Finally, we provide evidence that firms adjust prices asymmetrically in response to shocks, depending on the direction of the adjustment and the source of the shock: while cost shocks have a greater impact when prices have to be raised than when they have to be reduced, reductions in demand are more likely to induce a price change than increases in demand.

Analyse des mutations des domaines ISDR et V3 de la protéine NS5A du virus de l'hépatite C avant le traitement par l'interféron avec ou sans ribavirine

Aim of the study. – The hepatitis C virus (HCV) non-structural NS5A protein has been controversially implicated in the resistance of HCV to interferon therapy in clinical studies. In Japan, mutations in the interferon sensitivity-determining region (ISDR) in the NS5A gene were associated with response to interferon therapy in patients infected with genotype 1b. In contrast, studies from Europe did not confirm such association. More recently, it has been suggested that the V3 domain outside the putative ISDR might also have amino acids changes that may be involved in the resistance to IFN. In this study, the relationship between NS5A mutations in ISDR and V3 domains and virological response to therapy were investigated. Materials and methods. – The NS5A gene was sequenced from 35 HCV genotype 1b infected patients at D0 of a prospective clinical trial of interferon therapy and interferon plus Ribavirin combination therapy. Results. – In the ISDR domain, we did not observe any significant differences in amino acids changes between responders (1.7 ± 1.8, n = 19, range 0–6) and non-responders (1.1 ± 0.8, n = 14, range: 0–3), (P = 0.483), to therapy before the beginning of treatment. In the V3 domain, we found more mutations in responders (6.5 ± 1.9, range: 2–11) than in non-responders (4.7 ± 1.2, range: 3–8) (P = 0.0013), before the beginning of treatment. Conclusion. – Our results confirm that, in Europe, the ISDR domain is not predictive for treatment success but suggest that the V3 domain have greater variability in responders than non-responders

The pricing behaviour of firms in the euro area : new survey evidence

This study investigates the pricing behaviour of firms in the euro area on the basis of surveys conducted by nine Eurosystem national central banks. Overall, more than 11,000 firms participated in the survey. The results are very robust across countries. Firms operate in monopolistically competitive markets, where prices are mostly set following mark-up rules and where price discrimination is a common practice. Our evidence suggests that both time- and state-dependent pricing strategies are applied by firms in the euro area: around one-third of the companies follow mainly time-dependent pricing rules while two-thirds use pricing rules with some element of state-dependence. Although the majority of firms take into account a wide range of information, including past and expected economic developments, about one-third adopts a purely backward-looking behaviour. The pattern of results lends support to the recent wave of estimations of hybrid versions of the New Keynesian Phillips Curve. Price stickiness arises both at the stage when firms review their prices and again when they actually change prices. The most relevant factors underlying price rigidity are customer relationships - as expressed in the theories about explicit and implicit contracts - and thus, are mainly found at the price changing (second) stage of the price adjustment process. Finally, we provide evidence that firms adjust prices asymmetrically in response to shocks, depending on the direction of the adjustment and the source of the shock: while cost shocks have a greater impact when prices have to be raised than when they have to be reduced, reductions in demand are more likely to induce a price change than increases in demand.price setting, nominal rigidity, real rigidity, inflation persistence, survey data.

Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

AIM: To evaluate the implication of substitutions in the hepatitis C virus (HCV) non-structural 5A (NS5A) protein in the resistance of HCV during mono-interferon (IFN) or combined IFN-ribavirin (IFN-R) therapy. Although NS5A has been reported to interact with the HCV RNA-dependent RNA polymerase, NS5B, as well as with many cellular proteins, the function of NS5A in the life cycle of HCV remains unclear. METHODS: HCV quasispecies were studied by cloning and sequencing of sequential isolates from patients infected by HCV genotype 1b. Patients were treated by IFN-alpha2b for 3 mo followed by IFN-alpha2b alone or combined IFN-R therapy for 9 additional months. Patients were categorized into two groups based on their response to the treatments: 7 with sustained virological response (SVR) (quasispecies = 150) and 3 non-responders (NR) to IFN-R (quasispecies = 106). RESULTS: Prior to treatment, SVR patients displayed a lower complexity of quasispecies than NR patients. Most patients had a decrease in the complexity of quasispecies during therapy. Analysis of amino acids substitutions showed that the degree of the complexity of the interferon sensitivity-determining region (ISDR) and the V3 domain of NS5A protein was able to discriminate the two groups of patients. Moreover, SVR patients displayed more variability in the NS5A region than NR patients. CONCLUSION: These results suggest that detailed molecular analysis of the NS5A region may be important for understanding its function in IFN response during HCV 1b infection

Assessment of human influenza pandemic scenarios in Europe

The response to the emergence of the 2009 influenza A(H1N1) pandemic was the result of a decade of pandemic planning, largely centred on the threat of an avian influenza A(H5N1) pandemic. Based on a literature review, this study aims to define a set of new pandemic scenarios that could be used in case of a future influenza pandemic. A total of 338 documents were identified using a searching strategy based on seven combinations of keywords. Eighty-three of these documents provided useful information on the 13 virus-related and health-system-related parameters initially considered for describing scenarios. Among these, four parameters were finally selected (clinical attack rate, case fatality rate, hospital admission rate, and intensive care admission rate) and four different levels of severity for each of them were set. The definition of six most likely scenarios results from the combination of four different levels of severity of the four final parameters (256 possible scenarios). Although it has some limitations, this approach allows for more flexible scenarios and hence it is far from the classic scenarios structure used for pandemic plans until 2009