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Blockade of the late Na+ current (INaL) protects from ischemia/reperfusion damage; nevertheless, information on changes in INaL during acute ischemia and their effect on intracellular milieu is missing. INaL, cytosolic Na+ and Ca2+ activities (Nacyt, Cacyt) were measured in isolated rat ventricular myocytes during 7 min of simulated ischemia (ISC); in all the conditions tested, effects consistently exerted by ranolazine (RAN) and tetrodotoxin (TTX) were interpreted as due to INaL blockade. The results indicate that INaL was enhanced during ISC in spite of changes in action potential (AP) contour; INaL significantly contributed to Nacyt rise, but only marginally to Cacyt rise. The impact of INaL on Cacyt was markedly enhanced by blockade of the sarcolemmal(s) Na+/Ca2+ exchanger (NCX) and was due to the presence of (Na+-sensitive) Ca2+ efflux through mitochondrial NCX (mNCX). sNCX blockade increased Cacyt and decreased Nacyt, thus indicating that, throughout ISC, sNCX operated in the forward mode, in spite of the substantial Nacyt increment. Thus, a robust Ca2+ source, other than sNCX and including mitochondria, contributed to Cacyt during ISC. Most, but not all, of RAN effects were shared by TTX. (1) The paradigm that attributes Cacyt accumulation during acute ischemia to decrease/reversal of sNCX transport may not be of general applicability; (2) INaL is enhanced during ISC, when the effect of Nacyt on mitochondrial Ca2+ transport may substantially contribute to INaL impact on Cacyt; (3) RAN may act mostly, but not exclusively, through INaL blockade during ISC.

Aims Pulmonary arterial hypertension (PAH) reflects abnormal pulmonary vascular resistance and causes right ventricular (RV) hypertrophy. Enhancement of the late sodium current (INaL) may result from hypertrophic remodelling. The study tests whether: (i) constitutive INaL enhancement may occur as part of PAH-induced myocardial remodelling; (ii) ranolazine (RAN), a clinically available INaL blocker, may prevent constitutive INaL enhancement and PAH-induced myocardial remodelling. Methods and results PAH was induced in rats by a single monocrotaline (MCT) injection [60 mg/kg intraperitoneally (i.p.)]; studies were performed 3 weeks later. RAN (30 mg/kg bid i.p.) was administered 48 h after MCT and washed-out 15 h before studies. MCT increased RV systolic pressure and caused RV hypertrophy and loss of left ventricular (LV) mass. In the RV, collagen was increased; myocytes were enlarged with T-tubule disarray and displayed myosin heavy chain isoform switch. INaL was markedly enhanced; diastolic Ca2+ was increased and Ca2+ release was facilitated. K+ currents were down-regulated and APD was prolonged. In the LV, INaL was enhanced to a lesser extent and cell Ca2+ content was strongly depressed. Electrical remodelling was less prominent than in the RV. RAN completely prevented INaL enhancement and limited most aspects of PAH-induced remodelling, but failed to affect in vivo contractile performance. RAN blunted the MCT-induced increase in RV pressure and medial thickening in pulmonary arterioles. Conclusion PAH induced remodelling with chamber-specific aspects. RAN prevented constitutive INaL enhancement and blunted myocardial remodelling. Partial mechanical unloading, resulting from an unexpected effect of RAN on pulmonary vasculature, might contribute to this effect.

The sustained component of the sodium current (INaL) has been recently found enhanced in several cardiac pathologies. INaL enhancement has been highlighted as a major cause of cellular dysfunction, caused by INaL-dependent electrical instability (arrythmias) and alterations in intracellular ions (Na and Ca) homeostasis. Recent evidence of beneficial effects of the INaL blocker ranolazine (RAN) in diabetes motivates interest in the role of the INaL in glucose-induced insulin secretion (GSIS). The aim of the present thesis is to characterize INaL, identified as steady-state current blocked by RAN (IRAN) or TTX (ITTX), and its function in rat INS-1E cells and human islet cells (HIc). Veratridine (VERA) was used as INaL enhancer. Baseline INaL was similar between INS-1E and HIc. In INS-1E cells, tolbutamide-triggered action potentials were suppressed by TTX, but not by RAN. VERA caused depolarization, countered by INaL blockade. ITTX and IRAN reversal potentials (EREV) were negative to Na+ equilibrium one, but they approached it when K+-channels were blocked. This revealed INaL coupling to Na+-activated K+ current (IKNa); expression of IKNa channels (Slo2.1/2.2) was confirmed by transcript analysis. Concomitant activation of IKNa might blunt the effects of INaL on membrane potential, but at the same time it might increase the impact of INaL on intracellular Ca2+. Consistently, INaL blockade (by TTX) blunted cytosolic Ca2+ response to depolarization, with the highest effect in the intermediate potentials. Long-term exposure to 33 mM glucose (CHG) enhanced INaL. Whereas acute INaL enhancement (VERA) increased GSIS, chronic one (CHG or VERA) depressed GSIS, which was partially restored by RAN. Conclusions: 1) INaL is expressed in insulin-secreting cells, is coupled to IKNa, affects Ca2+ signalling and, when enhanced acutely, increases GSIS 2) sustained hyperglycemic stress enhances INaL and this contributes to GSIS depression instead. Overall, INaL enhancement may represen

Objective. The values of microbial growth in the air exiting from the Heating, Ventilation and Air Conditioning (HVAC) ducts treated with silver/zeolite have been shown to be lower than those in the air coming out the traditional metal ones.This study aims to verify how long this antimicrobial activity lasts. Methods. All the tests were performed according to US ASTM E2180-01 and ISO-JIZ 22196 standards. Samples of aluminum cladding panels of different thickness and incorporating silver- zeolite were tested in order to verify their thickness depending antibacterial activity. The same kind of linings samples were analyzed after a simulated and accelerated ageing process. Ag- zeolite incorporating HVAC duct panels linings were tested after years from their installation, in order to verify the maintenance of their bactericidal power during time. Results and conclusions. For laminates containing different amounts of silver+Zeolite it was shown that also in panels with minimum thickness tested, the lowest germicidal effect (GE) found was still very good (GE of 5,76 ULog10). After their wearing and tearing the antimicrobial activity tended to increase passing from 7.2081 to 8.29922 LogUnits in panels 80microns thick. For still hos- pital working aluminium foils incorporatig Silver/Zeolite on panels installed through 2006 and 2008, the antimicrobial action of zeolite was still firmly present even after two years and three years.The germicidal effect standards were maintained even during time on constant values between 7.477 and 7.086 LogUnits. The persistence of bactericidal efficacy of Ag+zeolite treatment in all the materials used for the construction of HVAC ductworks can be confirmed.

Aims The Na channel mutation (p.S216L), previously associated with type 3 long-QT syndrome (LQT3) phenotype, and a common polymorphism (p.H558R) were detected in a patient with an intermittent Brugada syndrome (BS) ECG pattern. The study was aimed to assess the p.S216L electrical phenotype, its modulation by p.H558R, and to identify abnormalities compatible with a mixed BS-LQT3 phenotype. Methods and resultsThe mutation was expressed alone (S216L channels), or in combination with the polymorphism (S216LH558R channels), in a mammalian cell line (TSA201). Functional analysis included standard voltage clamp and dynamic clamp with endo-and epicardial action potential waveforms. Expression of S216L channels was associated with a 60 reduction in maximum Na current (INa) density, attributable to protein misfolding (rescued by mexiletine pretreatment) and moderate slowing of inactivation. INa density partially recovered in S216LH558R channels, but INa inactivation and its recovery were further delayed. The persistent component of INa (INaL) was unchanged. Under dynamic clamp conditions, INa decreased in S216L channels and displayed a 'resurgent component during late repolarization. In S216LH558R channels, INa density partially recovered and did not display a resurgent component. INa changes during dynamic clamp were interpreted by numerical modelling. ConclusionThe BS pattern of p.S216L might result from a decrease in INa density, which masked gating abnormalities that might otherwise result in a LQT phenotype. The p.H558R polymorphism decreased p.S216L expressivity, partly by lessening p.S216L effects and partly through the induction of further gating abnormalities suitable to blunt p.S216L effects during repolarization.

The air in hospital wards with patients at high risk (Surgeries, Intensive Care Units and Bone Marrow Transplant Centers) has been surveyed less than the one in Operating Rooms. Therefore in this study we considered useful to verify the microbic contamination of the air of those wards evaluating the consistency of ventilation systems in relation also to the presence and location of HEPA absolute filters. Seven departments of Genoese San Martino Hospital at high risk of infection were taken into account. In there, environmental investigations have been performed by air samplings and by analyzing bacterial and fungal growth on plates after an incubation period. Almost 60% of all samples taken in wards yielded a positive result and the average values of bacterial and aspergillar charges measured at air flow emission openings decisively exceed the ones considered standard in operating rooms. Still, the average values of airborne bacterial charges were significantly higher in those wards equipped with central filters (p inf. 0.001), while as far as the aspergillar charge is concerned, no statistically relevant differences were noticed. In wards with ventilation system, the bacterial charge value raises from the emission grids to the middle of the room and to the aspiration grids, while the ward not equipped with a ventilation system presents in the middle of the room an average bacterial charge 2 to 10 times higher than the one in other wards. The average values regarding bacterial and aspergillar charges resulted quite high in all the departments surveyed. Nevertheless, if we take into account ventilation systems equipped with absolute filters HEPA located centrally or peripherally, it can be outlined that the air quality from the point of view of both microbic and aspergillar contamination turns out to be decisively better in systems with peripheral filters. Moreover, a compared analysis of the three Hematology wards allows us to infer that the presence of artificial v