Pharmacokinetic–pharmacodynamic modelling of the analgesic effects of lumiracoxib, a selective inhibitor of cyclooxygenase-2, in rats

Background and purpose: This study establishes a pharmacokinetic/pharmacodynamic (PK/PD) model to describe the time course and in vivo mechanisms of action of the antinociceptive effects of lumiracoxib, evaluated by the thermal hyperalgesia test in rats. Experimental approach: Female Wistar fasted rats were injected s.c. with saline or carrageenan in the right hind paw, followed by either 0, 1, 3, 10 or 30 mg·kg-1 of oral lumiracoxib at the time of carrageenan injection (experiment I), or 0, 10 or 30 mg·kg-1 oral lumiracoxib at 4 h after carrageenan injection (experiment II). Antihyperalgesic responses were measured as latency time (LT) to a thermal stimulus. PK/PD modelling of the antinociceptive response was performed using the population approach with NONMEM VI. Results: A two-compartment model described the plasma disposition. A first-order model, including lag time and decreased relative bioavailability as a function of the dose, described the absorption process. The response model was: LT = LT0/(1 + MED). LT0 is the baseline response, and MED represents the level of inflammatory mediators. The time course of MED was assumed to be equivalent to the predicted profile of COX-2 activity and was modelled according to an indirect response model with a time variant synthesis rate. Drug effects were described as a reversible inhibition of the COX-2 activity. The in vivo estimate of the dissociation equilibrium constant of the COX-2-lumiracoxib complex was 0.24 mg·mL-1. Conclusions: The model developed appropriately described the time course of pharmacological responses to lumiracoxib, in terms of its mechanism of action and pharmacokinetics

Effect of Build Parameters and Build Geometries on Residual Microstructures and Mechanical Properties of Ti-6Al-4V Components Built by Electron Beam Melting (EBM)

In this study, involving additive manufacturing (AM) using electron beam melting (EBM), we have examined build defects which result from beam tripping, porosities (including unmelted or unsintered zones) due to excursions from optimal build parameters (especially variations in melt scan beam current and scan speed), and gas bubbles trapped in atomized Ti-6Al-4V starting powder as well as recycled powder, and retained in the build. At optimized build conditions we have also examined microstructure-mechanical property (hardness, tensile strength, and elongation) variations for multiple rake building and multiple melt scans using optical metallography and scanning and transmission electron microscopy (SEM and TEM). These build variances cause cooling rate variances which promote α-phase growth and variations in dislocation density, as well as α-to-α' (martensite) phase changes, all of which produce some degree of mechanical property variations. These features (especially α-to-α' phase changes) are notable on comparing solid builds in comparison with a variety of mesh arrays where strut dimension and build-element complexities alter the cooling rates in a significant way. We illustrate these microstructure variations with corresponding variations in microindentation hardness measurements made directly on fine mesh (strut) structures. Finally, we have examined Ti-6Al-4V powder chemistries and solid build chemistries which for single-pass melt scans at optimized build conditions are shown to be relatively constant up to 40 cycles of powder reuse with the exception of Al content which was reduced by 10 to 15% in solid builds at optimized conditions. However, Al loss in solid builds approached 25% for multiple (2 and 3) melt scans, while no changes in Ar gas-bubble density were observed with changes in α-phase (grain) width which increased from 3 µm for a single melt scan to 4.5 and 6 µm for 2 and 3 melt scans, respectively. Corresponding Rockwell C-scale (HRC) hardness varied from 37, 36, and 35, respectively; with ultimate tensile strengths exceeding 1.2 GPa at elongations of 12% or higher for this melt scan sequence.Mechanical Engineerin

Supersymmetric null-surfaces

Single trace operators with the large R-charge in supersymmetric Yang-Mills theory correspond to the null-surfaces in $AdS_5\times S^5$. We argue that the moduli space of the null-surfaces is the space of contours in the super-Grassmanian parametrizing the complex $(2|2)$-dimensional subspaces of the complex $(4|4)$-dimensional space. The odd coordinates on this super-Grassmanian correspond to the fermionic degrees of freedom of the superstring.Comment: v4: added a reference to the earlier work; corrected the formula for the stabilizer of the BMN vacuum; added the discussion of the complex structure of the odd coordinates in Section 3.

Bending modes, elastic constants and mechanical stability of graphitic systems

The thermodynamic and mechanical properties of graphitic systems are strongly dependent on the shear elastic constant C44. Using state-of-the-art density functional calculations, we provide the first complete determination of their elastic constants and exfoliation energies. We show that stacking misorientations lead to a severe lowering of C44 of at least one order of magnitude. The lower exfoliation energy and the lower C44 (more bending modes) suggest that flakes with random stacking should be easier to exfoliate than the ones with perfect or rhombohedral stacking. We also predict ultralow friction behaviour in turbostratic graphitic systems.Comment: 7 pages, 6 figure

High-Flow Oxygen with Capping or Suctioning for Tracheostomy Decannulation

9 p.BACKGROUND When patients with a tracheostomy tube reach a stage in their care at which decannulation appears to be possible, it is common practice to cap the tracheostomy tube for 24 hours to see whether they can breathe on their own. Whether this approach to establishing patient readiness for decannulation leads to better outcomes than one based on the frequency of airway suctioning is unclear. METHODS In five intensive care units (ICUs), we enrolled conscious, critically ill adults who had a tracheostomy tube; patients were eligible after weaning from mechanical ventilation. In this unblinded trial, patients were randomly assigned either to undergo a 24-hour capping trial plus intermittent high-flow oxygen therapy (control group) or to receive continuous high-flow oxygen therapy with frequency of suctioning being the indicator of readiness for decannulation (intervention group). The primary outcome was the time to decannulation, compared by means of the log-rank test. Secondary outcomes included decannulation failure, weaning failure, respiratory infections, sepsis, multiorgan failure, durations of stay in the ICU and hospital, and deaths in the ICU and hospital. RESULTS The trial included 330 patients; the mean (±SD) age of the patients was 58.3±15.1 years, and 68.2% of the patients were men. A total of 161 patients were assigned to the control group and 169 to the intervention group. The time to decannulation was shorter in the intervention group than in the control group (median, 6 days [interquartile range, 5 to 7] vs. 13 days [interquartile range, 11 to 14]; absolute difference, 7 days [95% confidence interval, 5 to 9]). The incidence of pneumonia and tracheobronchitis was lower, and the duration of stay in the hospital shorter, in the intervention group than in the control group. Other secondary outcomes were similar in the two groups. CONCLUSIONS Basing the decision to decannulate on suctioning frequency plus continuous highflow oxygen therapy rather than on 24-hour capping trials plus intermittent highflow oxygen therapy reduced the time to decannulation, with no evidence of a between-group difference in the incidence of decannulation failure. (REDECAP ClinicalTrials.gov number, NCT02512744.

Impairment of exogenous lactate clearance in experimental hyperdynamic septic shock is not related to total liver hypoperfusion

Introduction: Although the prognostic value of persistent hyperlactatemia in septic shock is unequivocal, its physiological determinants are controversial. Particularly, the role of impaired hepatic clearance has been underestimated and is only considered relevant in patients with liver ischemia or cirrhosis. Our objectives were to establish whether endotoxemia impairs whole body net lactate clearance, and to explore a potential role for total liver hypoperfusion during the early phase of septic shock. Methods: After anesthesia, 12 sheep were subjected to hemodynamic/perfusion monitoring including hepatic and portal catheterization, and a hepatic ultrasound flow probe. After stabilization (point A), sheep were alternatively assigned to lipopolysaccharide (LPS) (5 mcg/kg bolus followed by 4 mcg/kg/h) or sham for a three-hour study period. After 60 minutes of shock, animals were fluid resuscitated to normalize mean arterial pressure. Repeated series of measurements were performed immediately after fluid resuscitation (point B), and one (point C) and two hours later (point D). Monitoring included systemic and regional hemodynamics, blood gases and lactate measurements, and ex-vivo hepatic mitochondrial respiration at point D. Parallel exogenous lactate and sorbitol clearances were performed at points B and D. Both groups included an intravenous bolus followed by serial blood sampling to draw a curve using the least squares method. Results: Significant hyperlactatemia was already present in LPS as compared to sham animals at point B (4.7 (3.1 to 6.7) versus 1.8 (1.5 to 3.7) mmol/L), increasing to 10.2 (7.8 to 12.3) mmol/L at point D. A significant increase in portal and hepatic lactate levels in LPS animals was also observed. No within-group difference in hepatic DO2, VO2 or O2 extraction, total hepatic blood flow (point D: 915 (773 to 1,046) versus 655 (593 to 1,175) ml/min), mitochondrial respiration, liver enzymes or sorbitol clearance was found. However, there was a highly significant decrease in lactate clearance in LPS animals (point B: 46 (30 to 180) versus 1,212 (743 to 2,116) ml/min, P <0.01; point D: 113 (65 to 322) versus 944 (363 to 1,235) ml/min, P <0.01). Conclusions: Endotoxemia induces an early and severe impairment in lactate clearance that is not related to total liver hypoperfusion

La extensión en la Facultad de Psicología de la UNC: una experiencia de articulación entre la docencia e investigación al servicio de la promoción de la ciudadanía

La experiencia del Servicio de Promoción y Protección de la Salud en el Adolescente de la Facultad de Psicología (UNC), nos permitió a un conjunto de docentes, concebir la extensión como una práctica educativa inserta en la dinámica pedagógica de la universidad que involucra las tres funciones sustantivas de la educación superior -docencia, investigación y extensión. Nos propusimos  capacitar - a los alumnos de la materia Diagnóstico  y Prevención de las Problemáticas en los Adolescentes, de prácticas de investigación, ayudantes alumnos y adscriptos de la materia Psicología Evolutiva de la Adolescencia -  en actividades conducentes a identificar demandas de la sociedad en temáticas de promoción de salud en los jóvenes, a través de proyectos basados en la participación juvenil, impulsando la idea del adolescente como  actor estratégico de cambio social  y el fortalecimiento de la ciudadanía. Para ello realizamos desde el año 2005 a la actualidad diversas experiencias en escuelas públicas y privadas del nivel medio, derivadas de la firma de convenios con organismos gubernamentales y no gubernamentales a nivel provincial y municipal de Córdoba, entre ellas: la capacitación con docentes, directivos y preceptores a fin de incorporar en la currícula temáticas como la educación en habilidades para la vida;  talleres de capacitación con los alumnos en proyectos de formación de líderes promotores de salud para abordar diversas problemáticas; conferencias para padres y público en general. Las acciones arrojan como resultado un alto impacto en los beneficiarios directos - los adolescentes escolarizados, los actores de la comunidad educativa - e indirectos las comunidades en las cuales se desarrollaron las acciones. A nivel del equipo docente se destacan como resultados: la formación de recursos humanos (becarios,  tesistas de grado y posgrado); diversas publicaciones en revistas con referato, libros, capítulos de libros, manual de capacitación para docentes, presentaciones en congresos a nivel nacional e internacional; la obtención de premios a nivel nacional y una mención especial en el premio Presidencia de la Nación “Prácticas Solidarias en la Educación Superior 2006”. Así, procuramos contribuir a la necesidad de consolidar los lazos entre la extensión, investigación y docencia “ofreciendo  la oportunidad de hacer experiencias de iniciación a la extensión universitaria, planificadas en forma integrada con los contenidos de aprendizajes formales. Y, a la vez, contribuir a la formación de profesionales conocedores de las necesidades de la comunidad al promover el compromiso social como principio rector de la universidad pública argentina” (REXUNI Plan Estratégico 2012-2015)

Application of capillary electrophoresis to the simultaneous determination and stability study of four extensively used penicillin derivatives

The applicability of capillary electrophoresis for the analysis of four extensively used penicillin derivatives (benzylpenicillin, ampicillin, amoxicillin, oxacilllin) has been studied. Because of structural similarities, the electrophoretic behavior of these derivatives is very similar; consequently an efficient separation using the conventional capillary zone electrophoresis is hard to be achieved. Their simultaneous separation was solved by using micellar electrokinetic capillary chromatography, the separation being based on the differential partition of the analytes between the micellar and aqueous phase. Using a buffer solution containing 25 mM sodium tetraborate and 100 mM sodium dodecyl sulfate as surfactant, at a pH of 9.3, applying a voltage of + 25 kV at a temperature of 25 °C, we achieved the simultaneous separation of the studied penicillin derivatives in less then 5 minutes. The separation conditions were optimized and the analytical performance of the method was evaluated in terms of precision, linearity, limit of detection, and quantification. Also, a simple capillary zone electrophoresis method was applied to study the stability of the studied penicillin derivatives in water at different temperatures, using ciprofloxacin hydrochloride as internal standard. It was observed that the extent of the hydrolysis of penicillins in water is highly dependent on the time and also temperature

Performance of ALICE AD modules in the CERN PS test beam

Two modules of the AD detector have been studied with the test beam at the T10 facility at CERN. The AD detector is made of scintillator pads read out by wave-length shifters (WLS) coupled to clean fibres that carry the produced light to photo-multiplier tubes (PMTs). In ALICE the AD is used to trigger and study the physics of diffractive and ultra-peripheral collisions as well as for a variety of technical tasks like beam-gas background monitoring or as a luminometer. The position dependence of the modules' efficiency has been measured and the effect of hits on the WLS or PMTs has been evaluated. The charge deposited by pions and protons has been measured at different momenta of the test beam. The time resolution is determined as a function of the deposited charge. These results are important ingredients to better understand the AD detector, to benchmark the corresponding simulations, and very importantly they served as a baseline for a similar device, the Forward Diffractive Detector (FDD), being currently built and that will be in operation in ALICE during the LHC Runs 3 and 4.Peer reviewe