ACUTE AND PROLONGED EFFECT OF NEW TREATMENTS (LEVOSIMENDAN AND SACUBITRIL/VALSARTAN) IN HEART FAILURE: AN HOLISTIC EVALUATION

Alveolar-capillary membrane evaluated by carbon monoxide diffusion (DLCO) plays an important role in heart failure (HF). Surfactant Proteins (SPs) have also been suggested as a worthwhile marker. In acute HF, Levosimendan improves pulmonary hemodynamics and reduces lung fluids but associated SPs and DLCO changes are unknown. Sixty-five acute HF patients underwent spirometry, cardiopulmonary exercise test (CPET) and SPs determination before and after Levosimendan. Levosimendan caused natriuretic peptide-B (BNP) reduction, peakVO2 increase and VE/VCO2 slope reduction. Spirometry improved but DLCO did not. SP-A, SP-D and immature SP-B reduced (73.7\u202f\ub1\u202f25.3 vs. 66.3\u202f\ub1\u202f22.7\u202fng/mL*, 247\u202f\ub1\u202f121 vs. 223\u202f\ub1\u202f110\u202fng/mL*, 39.4\u202f\ub1\u202f18.7 vs. 34.4\u202f\ub1\u202f17.9AU*, respectively); while mature SP-B increased (424\u202f\ub1\u202f218 vs. 461\u202f\ub1\u202f243\u202fng/mL, *\u202f=\u202fp\u202f<\u202f0.001). Spirometry, BNP and CPET changes suggest hemodynamic improvement and lung fluid reduction. SP-A, SP-D and immature SP-B reduction indicates a reduction of inflammatory stress; conversely mature SP-B increase suggests alveolar cell function restoration. In conclusion, acute lung fluid reduction is associated with SPs but not DLCO changes. SPs are fast responders to alveolar-capillary membrane condition changes. On the other hand, regarding chronic heart failure, Sacubitril/Valsartan represents a novel therapy in the treatment of chronic heart failure with reduced ejection fraction (HFrEF), has recently proved efficacy in improving exercise tolerance and cardiac performance. We enrolled a cohort of HFrEF outpatients eligible for sacubitril/valsartan and performed serial cardiopulmonary exercise tests (CPET), pulmonary function tests, laboratory and echocardiographic assessments before and during the gradual titration of this treatment, in order to evaluate its effects on cardiopulmonary function and left ventricular remodeling. In this interim analysis, we examined twenty-five patients treated with sacubitril/valsartan for at three months. At a mean follow-up of 169\ub174 days, 92% of patients reached the maximum dose, without important safety concerns. Ejection fraction increased (31.0\ub15.4 vs. 37.2\ub19.6 %; p=0.009), while left ventricular end-diastolic and end-systolic volumes decreased (respectively, 116.8\ub131.4 vs. 90.5\ub121.3 ml, p=0.011; 80.9\ub124.5 vs. 58.2\ub121.4 ml, p=0.004). Peak oxygen consumption (VO2) improved from 63.4\ub112.5 to 70.3\ub113.3 % of predicted (p=0.002), along with workload at maximal exercise (97.0\ub139.3 vs. 103.7\ub139.7 watt, p=0.001) and VO2 at the anaerobic threshold (881\ub1278 to 1056\ub1350 ml, p=0.012). Minute ventilation/carbon dioxide production relationship (VE/VCO2 slope) did not reach statistical significance in this sub-population. New York Heart Association functional class improved (p=0.004), together with a significant decrease of MECKI (Metabolic Exercise test data combined with Cardiac and Kidney Indexes) score from 3.0 (IQR 1.7-6.3) to 1.8 (0.8-3.6) %, with a positive impact on two-year HF prognosis (p=0.009).In conclusion medium-term treatment with sacubitril/valsartan demonstrated beneficial effects on exercise tolerance, left ventricular remodelling and functional status, confirming the results from previous clinical trials in real-life. The longer follow-up and larger population of the finished study will further contribute to the assessment of its positive effects on HF patients

Magnetic Reversal Time in Open Long Range Systems

Topological phase space disconnection has been recently found to be a general phenomenon in isolated anisotropic spin systems. It sets a general framework to understand the emergence of ferromagnetism in finite magnetic systems starting from microscopic models without phenomenological on-site barriers. Here we study its relevance for finite systems with long range interacting potential in contact with a thermal bath. We show that, even in this case, the induced magnetic reversal time is exponentially large in the number of spins, thus determining {\it stable} (to any experimental observation time) ferromagnetic behavior. Moreover, the explicit temperature dependence of the magnetic reversal time obtained from the microcanonical results, is found to be in good agreement with numerical simulations. Also, a simple and suggestive expression, indicating the Topological Energy Threshold at which the disconnection occurs, as a real energy barrier for many body systems, is obtained analytically for low temperature

Structure and Mechanism of Copper- and Nickel-Substituted Analogues of Metallo-β-lactamase L1

In an effort to further probe metal binding to metallo-β-lactamase L1 (mβl L1), Cu- (Cu-L1) and Ni-substituted (Ni-L1) L1 were prepared and characterized by kinetic and spectroscopic studies. Cu-L1 bound 1.7 equiv of Cu and small amounts of Zn(II) and Fe. The EPR spectrum of Cu-L1 exhibited two overlapping, axial signals, indicative of type 2 sites with distinct affinities for Cu(II). Both signals indicated multiple nitrogen ligands. Despite the expected proximity of the Cu(II) ions, however, only indirect evidence was found for spin−spin coupling. Cu-L1 exhibited higher kcat (96 s−1) and Km (224 μM) values, as compared to the values of dinuclear Zn(II)-containing L1, when nitrocefin was used as substrate. The Ni-L1 bound 1 equiv of Ni and 0.3 equiv of Zn(II). Ni-L1 was EPR-silent, suggesting that the oxidation state of nickel was +2; this suggestion was confirmed by 1H NMR spectra, which showed relatively sharp proton resonances. Stopped-flow kinetic studies showed that ZnNi-L1 stabilized significant amounts of the nitrocefin-derived intermediate and that the decay of intermediate is rate-limiting. 1H NMR spectra demonstrate that Ni(II) binds in the Zn2 site and that the ring-opened product coordinates Ni(II). Both Cu-L1 and ZnNi-L1 hydrolyze cephalosporins and carbapenems, but not penicillins, suggesting that the Zn2 site modulates substrate preference in mβl L1. These studies demonstrate that the Zn2 site in L1 is very flexible and can accommodate a number of different transition metal ions; this flexibility could possibly offer an organism that produces L1 an evolutionary advantage when challenged with β-lactam-containing antibiotics

Effects of β2-receptor stimulation by indacaterol in chronic heart failure treated with selective or non-selective β-blockers: a randomized trial

Alveolar \u3b22-receptor blockade worsens lung diffusion in heart failure (HF). This effect could be mitigated by stimulating alveolar \u3b22-receptors. We investigated the safety and the effects of indacaterol on lung diffusion, lung mechanics, sleep respiratory behavior, cardiac rhythm, welfare, and exercise performance in HF patients treated with a selective (bisoprolol) or a non-selective (carvedilol) \u3b2-blocker. Study procedures were performed before and after indacaterol and placebo treatments according to a cross-over, randomized, double-blind protocol in forty-four patients (27 on bisoprolol and 17 on carvedilol). No differences between indacaterol and placebo were observed in the whole population except for a significantly higher VE/VCO2 slope and lower maximal PETCO2 during exercise with indacaterol, entirely due to the difference in the bisoprolol group (VE/VCO2 31.8\u2009\ub1\u20095.9 vs. 28.5\u2009\ub1\u20095.6, p\u2009<\u20090.0001 and maximal PETCO2 36.7\u2009\ub1\u20095.5 vs. 37.7\u2009\ub1\u20095.8\u2009mmHg, p\u2009<\u20090.02 with indacaterol and placebo, respectively). In carvedilol, indacaterol was associated with a higher peak heart rate (119\u2009\ub1\u200934 vs. 113\u2009\ub1\u200930 bpm, with indacaterol and placebo) and a lower prevalence of hypopnea during sleep (3.8 [0.0;6.3] vs. 5.8 [2.9;10.5] events/hour, with indacaterol and placebo). Inhaled indacaterol is well tolerated in HF patients, it does not influence lung diffusion, and, in bisoprolol, it increases ventilation response to exercise

The Type Ia supernovae rate with Subaru/XMM-Newton Deep Survey

We present measurements of the rates of high-redshift Type Ia supernovae derived from the Subaru/XMM-Newton Deep Survey (SXDS). We carried out repeat deep imaging observations with Suprime-Cam on the Subaru Telescope, and detected 1040 variable objects over 0.918 deg$^2$ in the Subaru/XMM-Newton Deep Field. From the imaging observations, light curves in the observed $i'$-band are constructed for all objects, and we fit the observed light curves with template light curves. Out of the 1040 variable objects detected by the SXDS, 39 objects over the redshift range $0.2 < z < 1.4$ are classified as Type Ia supernovae using the light curves. These are among the most distant SN Ia rate measurements to date. We find that the Type Ia supernova rate increase up to $z \sim 0.8$ and may then flatten at higher redshift. The rates can be fitted by a simple power law, $r_V(z)=r_0(1+z)^\alpha$ with $r_0=0.20^{+0.52}_{-0.16}$(stat.)$^{+0.26}_{-0.07}$(syst.)$\times 10^{-4} {\rm yr}^{-1}{\rm Mpc}^{-3}$, and $\alpha=2.04^{+1.84}_{-1.96}$(stat.)$^{+2.11}_{-0.86}$(syst.).Comment: 21 pages, 16 figures, accepted to PAS

Adiabaticity Conditions for Volatility Smile in Black-Scholes Pricing Model

Our derivation of the distribution function for future returns is based on the risk neutral approach which gives a functional dependence for the European call (put) option price, C(K), given the strike price, K, and the distribution function of the returns. We derive this distribution function using for C(K) a Black-Scholes (BS) expression with volatility in the form of a volatility smile. We show that this approach based on a volatility smile leads to relative minima for the distribution function ("bad" probabilities) never observed in real data and, in the worst cases, negative probabilities. We show that these undesirable effects can be eliminated by requiring "adiabatic" conditions on the volatility smile

Acclimation to different depths by the marine angiosperm Posidonia oceanica: transcriptomic and proteomic profiles

For seagrasses, seasonal and daily variations in light and temperature represent the mains factors driving their distribution along the bathymetric cline. Changes in these environmental factors, due to climatic and anthropogenic effects, can compromise their survival. In a framework of conservation and restoration, it becomes crucial to improve our knowledge about the physiological plasticity of seagrass species along environmental gradients. Here, we aimed to identify differences in transcriptomic and proteomic profiles, involved in the acclimation along the depth gradient in the seagrass Posidonia oceanica, and to improve the available molecular resources in this species, which is an important requisite for the application of eco-genomic approaches. To do that, from plant growing in shallow (−5 m) and deep (−25 m) portions of a single meadow, (i) we generated two reciprocal Expressed Sequences Tags (EST) libraries using a Suppressive Subtractive Hybridization (SSH) approach, to obtain depth/specific transcriptional profiles, and (ii) we identified proteins differentially expressed, using the highly innovative USIS mass spectrometry methodology, coupled with 1D-SDS electrophoresis and labeling free approach. Mass spectra were searched in the open source Global Proteome Machine (GPM) engine against plant databases and with the X!Tandem algorithm against a local database. Transcriptional analysis showed both quantitative and qualitative differences between depths. EST libraries had only the 3% of transcripts in common. A total of 315 peptides belonging to 64 proteins were identified by mass spectrometry. ATP synthase subunits were among the most abundant proteins in both conditions. Both approaches identified genes and proteins in pathways related to energy metabolism, transport and genetic information processing, that appear to be the most involved in depth acclimation in P. oceanica. Their putative rules in acclimation to depth were discussed

Do rebreathing manoeuvres for non-invasive measurement of cardiac output during maximum exercise test alter the main cardiopulmonary parameters?

Background: Inert gas rebreathing has been recently described as an emergent reliable non-invasive method for cardiac output determination during exercise, allowing a relevant improvement of cardiopulmonary exercise test clinical relevance. For cardiac output measurements by inert gas rebreathing, specific respiratory manoeuvres are needed which might affect pivotal cardiopulmonary exercise test parameters, such as exercise tolerance, oxygen uptake and ventilation vs carbon dioxide output (VE/VCO2) relationship slope. Method: We retrospectively analysed cardiopulmonary exercise testing of 181 heart failure patients who underwent both cardiopulmonary exercise testing and cardiopulmonary exercise test+cardiac output within two months (average 16 \ub1 15 days). All patients were in stable clinical conditions (New York Heart Association I\u2013III) and on optimal medical therapy. Results: The majority of patients were in New York Heart Association Class I and II (78.8%), with a mean left ventricular ejection fraction of 31 \ub1 10%. No difference was found between the two tests in oxygen uptake at peak exercise (1101 (interquartile range 870\u20131418) ml/min at cardiopulmonary exercise test vs 1103 (844\u20131389) at cardiopulmonary exercise test-cardiac output) and at anaerobic threshold. However, anaerobic threshold and peak heart rate, peak workload (75 (58\u2013101) watts and 64 (42\u201390), p < 0.01) and carbon dioxide output were significantly higher at cardiopulmonary exercise testing than at cardiopulmonary exercise test+cardiac output, whereas VE/VCO2 slope was higher at cardiopulmonary exercise test+cardiac output (30 (27\u201335) vs 33 (28\u201337), p < 0.01). Conclusion: The similar anaerobic threshold and peak oxygen uptake in the two tests with a lower peak workload and higher VE/VCO2 slope at cardiopulmonary exercise test+cardiac output suggest a higher respiratory work and consequent demand for respiratory muscle blood flow secondary to the ventilatory manoeuvres. Accordingly, VE/VCO2 slope and peak workload must be evaluated with caution during cardiopulmonary exercise test+cardiac output