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.

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.

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.

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.

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.

A laser-plasma accelerator producing monoenergetic electron beams.

Particle accelerators are used in a wide variety of fields, ranging from medicine and biology to high-energy physics. The accelerating fields in conventional accelerators are limited to a few tens of MeV m(-1), owing to material breakdown at the walls of the structure. Thus, the production of energetic particle beams currently requires large-scale accelerators and expensive infrastructures. Laser-plasma accelerators have been proposed as a next generation of compact accelerators because of the huge electric fields they can sustain (>100 GeV m(-1)). However, it has been difficult to use them efficiently for applications because they have produced poor-quality particle beams with large energy spreads, owing to a randomization of electrons in phase space. Here we demonstrate that this randomization can be suppressed and that the quality of the electron beams can be dramatically enhanced. Within a length of 3 mm, the laser drives a plasma bubble that traps and accelerates plasma electrons. The resulting electron beam is extremely collimated and quasi-monoenergetic, with a high charge of 0.5 nC at 170 MeV.

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.

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.

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.

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.

[Interventricular management of patients over the age of 75 with acute coronary syndromes without persistent ST elevation]. / Stratégie interventionnelle de prise en charge des patients âgés de plus de 75 ans hospitalises pour syndrome coronaire aigu sans sus-décalage persistant du segment ST: resultats d'un registre prospectif multicentrique regional.

The aim ot tnis study was to assess the results of interventional strategy in patients over 75 years of age admitted to hospital with acute coronary syndromes (ACS) without persistent ST elevation. Over three months, patients over the age of 75 undergoing coronary angiography for ACS were included in a multicentre register and followed up for 6 months. A total of 126 patients with an average age of 79 were included: 70% had at least one poor prognostic factor. The treatment on admission included: Aspirin (84%), Clopidogrel (60%), anti GpIIb-IIIa (12%) and Heparin (81%, of which 3/4 of cases were low molecular weight heparins). Coronary angiography (average delay 80 hours) showed single, double and triple vessel disease in 21, 29 and 35% of cases respectively. Coronary angioplasty was proposed in 83 patients and carried out in 82. Eleven patients underwent coronary artery bypass grafting and 31 were treated medically. During the hospital phase, there were 3 major cardiovascular complications: 1 death during coronary angiography, 1 intra-stent thrombosis and 1 death in the group undergoing bypass grafting, with no major bleeding complications. At 6 months, there were 8 (6.5%) major cardiovascular adverse events with 6 in the "angioplasty" group; 5 deaths (3 cardiac deaths), 3 myocardial infarcts. Two thirds of patients were asymptomatic. The authors conclude that interventional strategy in ACS of elderly patients is associated with a low rate of major adverse events. The benefits of this strategy should be confirmed by randomised trial.

Prevalence of HIV-1 resistant to antiretroviral drugs in 81 individuals newly infected by sexual contact or injecting drug use. Investigators of the Quebec Primary Infection Study.

OBJECTIVE: Prolonged treatment with antiretroviral drugs results in the selection of HIV-1 variants with mutations conferring resistance to nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTI and NNRTI) or to protease inhibitors (PI). There is serious concern about transmission of resistant viruses to newly infected persons. This study monitored the prevalence of resistant viruses in individuals undergoing primary HIV infection. DESIGN: Resistance testing was performed on 81 individuals infected between 1997 and 1999 by injecting drug use (n =21), sexual (n = 56), or unknown (n = 4) transmission. METHODS: Automated sequencing was used to genotype the reverse transcriptase (RT) and protease regions of virus isolated from patients' plasma. The phenotypic susceptibility of stimulated peripheral blood mononuclear cells to antiretroviral drugs was assayed. Line probe assays detected quasispecies variations in wild-type and mutated RT codons. RESULTS: A high prevalence of PI and RT genotypic variants, associated with high-level resistance to antiretroviral drugs, was observed in individuals newly infected by injecting drug use (PI = 24%, RT = 24%) or sexual transmission (PI = 12%, RT = 22%). The PI mutations, L101, V82A, and L90M, were found in 10.5, 3 and 4% of cases, respectively; whereas for RT, primary mutations at positions T215Y (zidovudine), M184V (lamivudine), T69D/A (zalcitabine), and K103N (multi-NNRTI) were present in 8, 5, 4, and 4% of subjects, respectively. Resistance to NRTI was demonstrated by phenotypic, genotypic, and line probe analyses. Transmission of multidrug (NRTI/NNRTI/PI) resistance in eight subjects (9.9%) was confirmed by showing that source partners possessed viruses of similar genotype. CONCLUSIONS: The transmission of drug-resistant HIV is a serious problem that merits further attention by public health officials as well as virologists and clinicians.

Concentrations of riboflavin and related organic acids in children with protein-energy malnutrition.

BACKGROUND: Riboflavin, flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD) concentrations have been little studied in cases of malnutrition. OBJECTIVE: Our objective was to investigate the effects of malnutrition on riboflavin status and riboflavin's relation with thyroid hormones and concentrations of urinary organic acids. DESIGN: Malnourished children from the savannah in Benin (group S, n = 30) and the coast in Togo (group C, n = 30), as well as 24 control subjects from both regions, were studied. Blood riboflavin, FMN, and FAD were analyzed by HPLC; urinary organic acids were analyzed by gas chromatography-mass spectrometry. RESULTS: Children in group S were more severely malnourished than children in group C. Triiodothyronine concentrations were lower in group S than in group C or the control group (1.12 +/- 0.24 compared with 1.74 +/- 0.18 and 2.92 +/- 0.19 nmol/L, respectively; P < 0.0001). Plasma riboflavin concentrations in group S were higher than those in group C or the control group (66.90 +/- 12.75 compared with 28.09 +/- 9.12 and 20.08 +/- 3.03 nmol/L, respectively; P < 0.001). Plasma FAD concentrations in group S were lower than those in group C or the control group (31.57 +/- 10.19 compared with 59.02 +/- 5.60 and 65.35 +/- 5.23 nmol/L, respectively; P < 0.0001). Dicarboxylic aciduria was higher in group C than in group S or the control subjects. CONCLUSIONS: Children in group S had low triiodothyronine concentrations and low conversion of plasma riboflavin into its cofactors, leading to a plasma FAD deficiency. Plasma FAD was not correlated with urinary dicarboxylic acid concentrations.

Riboflavin and riboflavin-derived cofactors in adolescent girls with anorexia nervosa.

BACKGROUND: Thyroid hormones, riboflavin, riboflavin cofactors, and organic acids were assessed in girls with anorexia nervosa. OBJECTIVE: The objective was to examine the effect of malnutrition and low thyroid hormone concentrations on erythrocyte and plasma riboflavin metabolism and their relation with urinary organic acid excretion. DESIGN: Seventeen adolescent girls with anorexia nervosa [body mass index (BMI; in kg/m2): 14.8 +/- 2.2] and 17 age-matched, healthy girls (control subjects; BMI: 20.5 +/- 2.2) took part in the feeding study. Erythrocyte and plasma riboflavin as well as riboflavin cofactors (flavin mononucleotide and flavin adenine dinucleotide) were assessed by HPLC, whereas urinary organic acids were assessed by gas chromatography-mass spectrometry. RESULTS: Anorectic patients who began a feeding program had higher erythrocyte riboflavin (3.5 +/- 2.2 compared with <0.1 nmol/mol hemoglobin; P < 0.001), lower plasma flavin adenine dinucleotide (57.8 +/- 18.5 compared with 78.5 +/- 54.3 nmol/L; P < 0.05), and higher urinary ethylmalonic acid (7.12 +/- 4.39 compared with 1.3 +/- 2.8 micromol/mmol creatinine; P < 0.001) and isovalerylglycine (7.65 +/- 4.78 compared with 3.8 +/- 0.9 micromol/mmol creatinine; P < 0.05) concentrations than did control subjects. Triiodothyronine concentrations were low and negatively correlated with plasma riboflavin concentrations (r = -0.69, P < 0.01). Not all patients showed improvements in these biochemical indexes after 30 d of refeeding. CONCLUSIONS: The low triiodothyronine concentrations observed in anorexia nervosa could alter the extent of riboflavin conversion into cofactors, thus leading to high erythrocyte riboflavin concentrations, low plasma flavin adenine dinucleotide concentrations, and high rates of ethylmalonic acid and isovalerylglycine excretion.

Clinical and angiographic results of stenting for long coronary arterial atherosclerotic lesions.

A prospective registry of 187 patients who underwent percutaneous coronary angioplasty with attempted long NIR stent delivery was performed. A successful stent delivery was achieved in 93% of cases with a low rate of major cardiovascular events, and 6-month follow-up showed low rates of clinical events, new revascularization procedures, and angiographic restenosis.

Absolute pitch, early musical instruction, and spatial abilities.

The results of the study show that AP possessors performed better in the Hidden Figure Test than did NMs and musicians with RP and that age at which music instruction is initiated affects performance in specific spatial tasks. Individuals who begin extensive musical instruction at a very early age may have an advantage when completing selected spatial tests over those with no formal musical training. However, characteristics other than starting age of musical instruction are associated with AP and seem to affect musicians' performance in the Hidden Figure Test. The differences found between the performance of AP possessors and RP possessors in this nonmusical task suggest further research.

Intrapulmonary haematoma complicating mechanical ventilation in patients with chronic obstructive pulmonary disease.

Intrapulmonary haematomas occurred during mechanical ventilation of two patients with advanced chronic obstructive pulmonary disease and bullous dystrophy. In both cases, the haematomas were revealed by blood-stained aspirates, a fall in haemoglobin level, and the appearance of radiological opacities. Haematoma occurrence in the area of a bulla which recently has rapidly increased in size, suggests that the haematoma is due to the rupture of stretched vessels embedded in the wall of the bulla.