Social context increases ultrasonic vocalizations during restraint in adult mice.

Adult mice emit many ultrasonic vocalizations (USVs) during social interaction tasks, but only a few studies have yet reported USVs in stressed adult mice. Our aim was to study which experimental conditions favor USV emission during behaviors associated with different emotional states. As USVs likely mediate social communication, we hypothesized that temporary social isolation followed by exposure to a novel social congener would promote USV emission. USVs were recorded in three different behavioral paradigms: restraint, free moving in a new environment, and during a social interaction task. We compared USV emission, with or without the presence of a social congener, in animals socially isolated during different periods (0, 6 or 21 days). Social isolation decreased the number of USVs during free moving, whereas it increased during restraint. During the social interaction task, animals produced high-frequency USVs (median: 72.6 kHz, 25-75% range: 67.6-78.2 kHz), especially when the social partner was active and social motivation was high. During restraint, presence of a social congener increased the call rate of low-frequency USVs (median: 52.4 kHz, 25-75% range: 44.8-56.5 kHz). USV frequency followed two unimodal distributions that distinguished low-frequency USVs (≤ 60 kHz) mainly emitted during free-moving (90.9% of total USVs) and restraint (93.1%) conditions, from high-frequency USVs (> 60 kHz) mainly emitted during the social interaction task (85.1% of total USVs). The present study confirms that USV call rate and frequency depend on behavioral states, and provides evidence that the presence of a congener promotes ultrasonic vocalizations in restrained adult mice.

Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment.

Cenicriviroc, a dual CCR2/CCR5 antagonist, is being evaluated for treatment of nonalcoholic steatohepatitis and liver fibrosis (CENTAUR; NCT02217475). As it is metabolized by the liver, cenicriviroc was investigated in hepatic-impaired participants for pharmacokinetic changes. Participants with mild-to-moderate hepatic impairment (HI) (Child-Pugh class A (N  =  7) or B (N = 8)) and matched controls (N = 15) received cenicriviroc 150 mg once daily for 14 days. Serial blood samples were obtained on Days 1 and 14. Safety, tolerability, and effects on CCR2/CCR5 ligands, cytokines, and bacterial translocation biomarkers were evaluated. Cenicriviroc exposures were increased by moderate HI (AUC0-τ  55%, Cmax 29% higher) but were not with mild HI (AUC0-τ 38%, Cmax 40% lower). Cenicriviroc was well tolerated. Rapid and potent CCR2/CCR5 blockade was observed, not associated with increases in hepatic inflammation or bacterial translocation biomarkers. Study findings suggest that cenicriviroc 150 mg can be used in patients with mild-to-moderate HI.

Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial.

OBJECTIVE: This paper presents the final analysis of once-daily darunavir/ritonavir (DRV/r) vs. lopinavir/ritonavir (LPV/r) in treatment-naïve HIV-1-infected adults. METHODS: ARTEMIS (AntiRetroviral Therapy with TMC114 ExaMined In naïve Subjects; NCT00258557) was a randomized, open-label, phase-III, 192-week trial. Patients were stratified by baseline HIV-1 RNA and CD4 count, and randomized to once-daily DRV/r 800/100 mg or LPV/r 800/200 mg total daily dose (either once or twice daily) plus tenofovir/emtricitabine. RESULTS: Of 689 randomized patients receiving treatment (DRV/r: 343; LPV/r: 346), 85 and 114 patients in the DRV/r and LPV/r arms, respectively, had discontinued by week 192. Noninferiority was shown in the primary endpoint of virological response (HIV-1 RNA < 50 copies/mL) [DRV/r: 68.8%; LPV/r: 57.2%; P < 0.001; intent to treat (ITT)/time to loss of virological response; estimated difference in response 11.6% (95% confidence interval 4.4-18.8%)]. Statistical superiority in virological response of DRV/r over LPV/r was demonstrated for the primary endpoint (P = 0.002) and for the ITT non-virological-failure-censored analysis (87.4% vs. 80.8%, respectively; P = 0.040). No protease inhibitor (PI) primary mutations developed and only low levels of nucleoside reverse transcriptase inhibitor (NRTI) resistance developed in virological failures in both groups. Significantly fewer discontinuations because of adverse events were observed with DRV/r (4.7%) than with LPV/r (12.7%; P = 0.005). Grade 2-4 treatment-related diarrhoea was significantly less frequent with DRV/r than with LPV/r (5.0% vs. 11.3%, respectively; P = 0.003). DRV/r was associated with smaller median increases in total cholesterol and triglyceride levels than LPV/r. Changes in low- and high-density lipoprotein cholesterol were similar between groups. Similar increases in aspartate aminotransferase and alanine aminotransferase for DRV/r and LPV/r were observed. CONCLUSION: Over 192 weeks, once-daily DRV/r was noninferior and statistically superior in virological response to LPV/r, with a more favourable gastrointestinal profile, demonstrating its suitability for long-term use in treatment-naïve patients.

Anticorrelation between ion acceleration and nonlinear coherent structures from laser-underdense plasma interaction.

In laser-plasma experiments, we observed that ion acceleration from the Coulomb explosion of the plasma channel bored by the laser is prevented when multiple plasma instabilities, such as filamentation and hosing, and nonlinear coherent structures (vortices or postsolitons) appear in the wake of an ultrashort laser pulse. The tailoring of the longitudinal plasma density ramp allows us to control the onset of these instabilities. We deduced that the laser pulse is depleted into these structures in our conditions, when a plasma at about 10% of the critical density exhibits a gradient on the order of 250 µm (Gaussian fit), thus hindering the acceleration. A promising experimental setup with a long pulse is demonstrated enabling the excitation of an isolated coherent structure for polarimetric measurements and, in further perspectives, parametric studies of ion plasma acceleration efficiency.

Focusing dynamics of high-energy density, laser-driven ion beams.

The dynamics of the focusing of laser-driven ion beams produced from concave solid targets was studied. Most of the ion beam energy is observed to converge at the center of the cylindrical targets with a spot diameter of 30 µm, which can be very beneficial for applications requiring high beam energy densities. Also, unbalanced laser irradiation does not compromise the focusability of the beam. However, significant filamentation occurs during the focusing, potentially limiting the localization of the energy deposition region by these beams at focus. These effects could impact the applicability of such high-energy density beams for applications, e.g., in proton-driven fast ignition.

Brunel-dominated proton acceleration with a few-cycle laser pulse.

Experimental measurements of backward accelerated protons are presented. The beam is produced when an ultrashort (5 fs) laser pulse, delivered by a kHz laser system, with a high temporal contrast (10(8)), interacts with a thick solid target. Under these conditions, proton cutoff energy dependence with laser parameters, such as pulse energy, polarization (from p to s), and pulse duration (from 5 to 500 fs), is studied. Theoretical model and two-dimensional particle-in-cell simulations, in good agreement with a large set of experimental results, indicate that proton acceleration is directly driven by Brunel electrons, in contrast to conventional target normal sheath acceleration that relies on electron thermal pressure.

Coulomb explosion of uniformly charged spheroids.

A simple, semianalytical model is proposed for nonrelativistic Coulomb explosion of a uniformly charged spheroid. This model allows us to derive the time-dependent particle energy distributions. Simple expressions are also given for the characteristic explosion time and maximum particle energies in the limits of extreme prolate and oblate spheroids as well as for the sphere. Results of particle simulations are found to be in remarkably good agreement with the model.

Two-dimensional s-polarized solitary waves in relativistic plasmas. I. The fluid plasma model.

The properties of two-dimensional linearly s-polarized solitary waves are investigated by fluid-Maxwell equations and particle-in-cell (PIC) simulations. These self-trapped electromagnetic waves appear during laser-plasma interactions, and they have a dominant electric field component E(z), normal to the plane of the wave, that oscillates at a frequency below the electron plasma frequency ω(pe). A set of equations that describe the waves are derived from the plasma fluid model in the case of cold or warm plasma and then solved numerically. The main features, including the maximum value of the vector potential amplitude, the total energy, the width, and the cavitation radius are presented as a function of the frequency. The amplitude of the vector potential increases monotonically as the frequency of the wave decreases, whereas the width reaches a minimum value at a frequency of the order of 0.82 ω(pe). The results are compared with a set of PIC simulations where the solitary waves are excited by a high-intensity laser pulse.

Two-dimensional s-polarized solitary waves in plasmas. II. Stability, collisions, electromagnetic bursts, and post-soliton evolution.

The dynamics of two-dimensional s-polarized solitary waves is investigated with the aid of particle-in-cell (PIC) simulations. Instead of the usual excitation of the waves with a laser pulse, the PIC code was directly initialized with the numerical solutions from the fluid plasma model. This technique allows the analysis of different scenarios including the theoretical problems of the solitary wave stability and their collision as well as features already measured during laser-plasma experiments such as the emission of electromagnetic bursts when the waves reach the plasma-vacuum interface, or their expansion on the ion time scale, usually named post-soliton evolution. Waves with a single density depression are stable whereas multihump solutions decay to several waves. Contrary to solitons, two waves always interact through a force that depends on their relative phases, their amplitudes, and the distance between them. On the other hand, the radiation pattern at the plasma-vacuum interface was characterized, and the evolution of the diameter of different waves was computed and compared with the "snow plow" model.

Dependence on pulse duration and foil thickness in high-contrast-laser proton acceleration.

Experimental measurements of proton acceleration with high intensity and high-contrast short laser pulses have been carried out over an order of magnitude range in target thickness and laser pulse duration. The dependence of the maximum proton energy with these parameters is qualitatively supported by two-dimensional particle-in-cell simulations. They evidence that two regimes of proton acceleration can take place, depending on the ratio between the density gradient and the hot electron Debye length at the rear target surface. As this ratio can be affected by the target thickness, a complex interplay between pulse duration and target thickness is observed. Measurements and simulations support unexpected variations in the laser absorption and hot electron temperature with the pulse duration and laser intensity, for which density profile modification at the target front surface is the controlling parameter.

Enhanced isochoric heating from fast electrons produced by high-contrast, relativistic-intensity laser pulses.

Thin, mass-limited targets composed of V/Cu/Al layers with diameters ranging from 50 to 300 microm have been isochorically heated by a 300 fs laser pulse delivering up to 10 J at 2x10{19} W/cm{2} irradiance. Detailed spectral analysis of the Cu x-ray emission indicates that the highest temperatures, of the order of 100 eV, have been reached when irradiating the smallest targets with a high-contrast, frequency-doubled pulse despite a reduced laser energy. Collisional particle-in-cell simulations confirm the detrimental influence of the preformed plasma on the bulk target heating.

Cold optical injection producing monoenergetic, multi-GeV electron bunches.

A cold optical injection mechanism for a laser-plasma accelerator is described. It relies on a short, circularly polarized, low-energy laser pulse counterpropagating to and colliding with a circularly polarized main pulse in a low density plasma. Contrary to previously published optical injection schemes, injection is not caused here by electron heating. Instead, the collision between the pulses creates a spatially periodic and time-independent beat force. This force can block the longitudinal electron motion, leading to their entry and injection into the propagating wake. In a specific setup, we compute after acceleration over 0.6 mm, a 60 MeV, 50 pC electron bunch with 0.7 MeV rms energy spread, proving the interest of this scheme to inject electron bunches with a narrow absolute energy spread. Acceleration to 3 GeV with a rms spread smaller than 1% is computed after propagation over 3.8 cm in a plasma channel.

Effects of ritonavir-boosted darunavir vs. ritonavir-boosted atazanavir on lipid and glucose parameters in HIV-negative, healthy volunteers.

BACKGROUND: Darunavir (TMC114) is a new HIV protease inhibitor (PI). DESIGN: This Phase I, randomized, open-label trial compared the effects of darunavir plus low-dose ritonavir (RTV) (darunavir/RTV) with those of atazanavir/RTV on lipid and glucose parameters. METHODS: Forty-nine HIV-negative, healthy male volunteers received RTV 100 mg once a day (qd) for 7 days, followed by either darunavir/RTV 800/100 mg qd (n=25) or atazanavir/RTV 300/100 mg qd (n=24) for 21 days. Mean changes in fasting lipid and glucose parameters at day 28 were calculated using post-RTV alone (day 7) and baseline (day -1) values as references. Short-term safety, tolerability and RTV pharmacokinetic parameters were evaluated. RESULTS: After 7 days of RTV treatment, the mean triglyceride concentration increased by approximately 30 mg/dL in both groups, changes in other lipid and glucose parameters were relatively small. Mean concentrations of lipids and glucose over the treatment period were mostly similar between the treatment groups. Mean changes from day 7 to day 28 for the darunavir/RTV and atazanavir/RTV groups, respectively, were -3.6 and -0.5 mg/dL for high-density lipoprotein cholesterol; 5.0 and 5.3 mg/dL for low-density lipoprotein cholesterol; 4.9 and 1.2 mg/dL for total cholesterol; 6.4 and 14.0 mg/dL for triglycerides; -1.7 and -2.4 mg/dL for glucose; and -1.4 and 0.3 mg/dL for insulin. No grade 3 or 4 lipid or glucose laboratory abnormalities were reported. Treatment-emergent hyperbilirubinaemia was reported for all volunteers (including five grade 4 cases) during atazanavir/RTV treatment. CONCLUSIONS: Co-administration of darunavir or atazanavir with low-dose RTV resulted in minor and similar changes in lipid and glucose parameters in HIV-negative healthy volunteers.

Observation of beam loading in a laser-plasma accelerator.

Beam loading is the phenomenon which limits the charge and the beam quality in plasma based accelerators. An experimental study conducted with a laser-plasma accelerator is presented. Beam loading manifests itself through the decrease of the beam energy, the reduction of dark current, and the increase of the energy spread for large beam charge. 3D PIC simulations are compared to the experimental results and confirm the effects of beam loading. It is found that, in our experimental conditions, the trapped electron beams generate decelerating fields on the order of 1 (GV/m)/pC and that beam loading effects are optimized for trapped charges of about 20 pC.

Intense gamma-ray source in the giant-dipole-resonance range driven by 10-TW laser pulses.

A gamma-ray source with an intense component around the giant dipole resonance for photonuclear absorption has been obtained via bremsstrahlung of electron bunches driven by a 10-TW tabletop laser. 3D particle-in-cell simulation proves the achievement of a nonlinear regime leading to efficient acceleration of several sequential electron bunches per each laser pulse. The rate of the gamma-ray yield in the giant dipole resonance region (8

Effect of repeated doses of darunavir plus low-dose ritonavir on the pharmacokinetics of sildenafil in healthy male subjects: phase I randomized, open-label, two-way crossover study.

BACKGROUND AND OBJECTIVES: Darunavir (DRV, TMC114) is a novel protease inhibitor administered in combination with low-dose ritonavir (DRV/r) and is highly active against both wild-type and multidrug-resistant HIV-1 strains. Sildenafil is an oral therapy for erectile dysfunction. Concomitant administration of protease inhibitors and sildenafil increases sildenafil plasma concentrations. The potential for a pharmacokinetic drug interaction exists when sildenafil and DRV/r are co-administered, as these drugs are primarily metabolized by cytochrome P450 (CYP) 3A, and darunavir and ritonavir are CYP3A inhibitors. The primary objective of this open-label, crossover, phase I study was to assess the effect of multiple doses of DRV/r on the pharmacokinetics of sildenafil and its active metabolite N-desmethyl sildenafil. The secondary objective was to assess the short-term safety and tolerability of co-administration of sildenafil and DRV/r. METHODS: Sixteen HIV-negative healthy male subjects were randomized to one of two sequences. In two sessions each subject received treatments A and B. In treatment A, a single dose of sildenafil 100 mg was administered. In treatment B, the subjects received DRV/r 400/100 mg twice daily for 8 days and on day 7 a single dose of sildenafil 25 mg was co-administered. Full pharmacokinetic profiles of sildenafil, N-desmethyl sildenafil, darunavir and ritonavir were determined. Safety and tolerability were also assessed. RESULTS: Sildenafil exposure (area under the plasma concentration-time curve [AUC]) was comparable between the two treatments despite administration of a lower dose of sildenafil (25 mg) with DRV/r than when sildenafil (100 mg) was administered alone. When sildenafil 25 mg was co-administered with DRV/r, the sildenafil maximum plasma concentration (Cmax) was 38% lower compared with Cmax after administration of sildenafil alone at a dose of 100 mg. N-desmethyl sildenafil Cmax and AUC from the time of administration until the last time point with a measurable concentration after dosing (calculated by linear trapezoidal summation [AUClast]) values decreased by approximately 95% when sildenafil 25 mg was co-administered with DRV/r compared with sildenafil 100 mg alone. Combined treatment with DRV/r and sildenafil was generally safe and well tolerated. CONCLUSION: Sildenafil exposure is increased in the presence of DRV/r. In this setting, a dose adjustment for sildenafil is warranted; no more than 25 mg of sildenafil is recommended over a 48-hour period when co-administered with DRV/r.

Spectral features of laser-accelerated protons for radiotherapy applications.

Laser-induced particle accelerators have been recognized as a potential proton source for radiotherapeutic applications in recent years. However, there are still major difficulties--especially regarding the resulting proton spectra--to overcome for a successful application in the clinic. Here we elaborate on the physics of double-layer targets to propose a tentative 'optical gantry' setup. The spectral requirements for a quality dose deposition of the fast protons are estimated. Plasma simulations of the one-dimensional expansion of microstructured targets are performed according to various target dimensions, rear proton densities and substrate masses. Subsequently, the dependence of the resulting proton spectra on these parameters is evaluated and compared to previously published analytical considerations. Quasi-monoenergetic proton beams, which would be suitable for high-quality dose delivery, could be achieved from pure proton targets if one were able to select out the rear layer of those targets. However, much more realistic heavy substrate layered targets are not able to preserve this high spectral standard, partly due to a second Coulomb-expansion in the center-of-mass frame of the fast protons. This expansion can be mitigated by a reduction of the total positive charge in the rear layer, resulting in a comparable spectral quality as the previous target types. In conclusion, the promising spectral results as well as an estimation of the total number of fast protons which can be expected from such a setup, suggest that the introduction of laser-based proton accelerators into the clinic might be possible in the future.

Exact relativistic kinetic theory of an electron-beam-plasma system: hierarchy of the competing modes in the system-parameter space.

The stability analysis of an electron-beam-plasma system is of critical relevance in many areas of physics. Surprisingly, decades of extensive investigation have not yet resulted in a realistic unified picture of the multidimensional unstable spectrum within a fully relativistic and kinetic framework. All attempts made so far in this direction were indeed restricted to simplistic distribution functions and/or did not aim at a complete mapping of the beam-plasma parameter space. The present Letter comprehensively tackles this problem by implementing an exact linear model. Three kinds of modes compete in the linear phase, which can be classified according to the direction of their wave number with respect to the beam. We determine their respective domain of preponderance in a three-dimensional parameter space and support our results with multidimensional particle-in-cell simulations.

Proton acceleration with high-intensity ultrahigh-contrast laser pulses.

We report on simultaneous measurements of backward- and forward-accelerated protons spectra when an ultrahigh intensity (approximately 5 x 10(18) W/cm(20), ultrahigh contrast (>10(10)) laser pulse interacts with foils of thickness ranging from 0.08 to 105 microm. Under such conditions, free of preplasma originating from ionization of the laser-irradiated surface, we show that the maximum proton energies are proportional to the p component of the laser electric field only and not to the ponderomotive force and that the characteristics of the proton beams originating from both target sides are almost identical. All these points have been corroborated by extensive 1D and 2D particle-in-cell simulations showing a very good agreement with the experimental data.