Clinical pharmacokinetics of tramadol and main metabolites in horses undergoing orchiectomy.

Tramadol is a synthetic codeine analogue used as an analgesic in human and veterinary medicine. It is not approved for use in horses, but could represent a valid tool for pain treatment in this species.The serum pharmacokinetic profile and urinary excretion of tramadol and its metabolites (O-desmethyltramadol [M1], N-desmethyltramadol [M2] and N,O-desmethyltramadol [M5]) was investigated in a multidrug anaesthetic and analgesic approach for orchiectomy in horses. The evaluation of the degree of cardiovascular stability, the intraoperative effect and postoperative analgesia obtained by the visual analogue scale are also reported. Animal and methods: Tramadol (4 mg/kg BW) was administered intravenously to eight male yearlings as a bolus over 60 seconds, 5 min after intubation and 15 min prior to surgery. Drug quantification was performed in serum and urine for tramadol, M1, M2 and M5 by high-performance liquid chromatography with fluorimetric detection.Mean tramadol concentration was 14.87 ± 11.14 μg/mL at 0.08 h, and 0.05 ± 0.06 μg/mL at 10 h. Serum concentrations of M1 and M2 metabolites were quite limited. For M1 and M2, median maximum concentration (Cmax) and time to achieve maximum concentration (Tmax) were 0.05 μg/mL and 0.75 h, and 0.08 μg/mL and 2 h, respectively; M5 was never detected. In urine, tramadol was the most recovered compound, followed by M1, M2 and M5.Showing no adverse events and based on the kinetic behaviour, pre-operative tramadol IV at a dose of 4 mg/kg BW might be useful and safe as analgesic in horses undergoing surgery

Kinetic analysis of gan-movpe via thickness profiles in the gas flow direction with systematically varied growth conditions

We carried out a kinetic analysis of metallorganic vapor phase epitaxy (MOVPE) of GaN to investigate the dependence of the growth rate on the process conditions as a function of residence time of the precursors in the reactor. The wafer was not rotated during growth, allowing us to analyze the thickness profile of the film in the direction of gas flow, and hence the dependence of the growth rate on the residence time. The growth rate is determined mainly by the concentration of the growth species and mass transfer of the growth species to the wafer surface. The growth rate peaked in the flow direction, and the position of this peak could, in most cases, be explained by considering a combination of the linear gas velocity and the time constant for vertical diffusion of trimethylgallium (TMGa) and/or growth species across the NH3 feed stream to the wafer surface. In some cases this was not possible, indicating that more complex effects were significant. This work is expected to contribute to understanDing of the reaction pathways for GaN-MOVPE, and the growth rate data reported here are expected to provide useful benchmarks for growth simulations that combine computational fluid dynamics and reaction models

A computational framework for testing hypotheses of the minimal mechanical requirements for cell aggregation using early annual killifish embryogenesis as a model

Introduction: Deciphering the biological and physical requirements for the outset of multicellularity is limited to few experimental models. The early embryonic development of annual killifish represents an almost unique opportunity to investigate de novo cellular aggregation in a vertebrate model. As an adaptation to seasonal drought, annual killifish employs a unique developmental pattern in which embryogenesis occurs only after undifferentiated embryonic cells have completed epiboly and dispersed in low density on the egg surface. Therefore, the first stage of embryogenesis requires the congregation of embryonic cells at one pole of the egg to form a single aggregate that later gives rise to the embryo proper. This unique process presents an opportunity to dissect the self-organizing principles involved in early organization of embryonic stem cells. Indeed, the physical and biological processes required to form the aggregate of embryonic cells are currently unknown.Methods: Here, we developed an in silico, agent-based biophysical model that allows testing how cell-specific and environmental properties could determine the aggregation dynamics of early Killifish embryogenesis. In a forward engineering approach, we then proceeded to test two hypotheses for cell aggregation (cell-autonomous and a simple taxis model) as a proof of concept of modeling feasibility. In a first approach (cell autonomous system), we considered how intrinsic biophysical properties of the cells such as motility, polarity, density, and the interplay between cell adhesion and contact inhibition of locomotion drive cell aggregation into self-organized clusters. Second, we included guidance of cell migration through a simple taxis mechanism to resemble the activity of an organizing center found in several developmental models.Results: Our numerical simulations showed that random migration combined with low cell-cell adhesion is sufficient to maintain cells in dispersion and that aggregation can indeed arise spontaneously under a limited set of conditions, but, without environmental guidance, the dynamics and resulting structures do not recapitulate in vivo observations.Discussion: Thus, an environmental guidance cue seems to be required for correct execution of early aggregation in early killifish development. However, the nature of this cue (e.g., chemical or mechanical) can only be determined experimentally. Our model provides a predictive tool that could be used to better characterize the process and, importantly, to design informed experimental strategies

The Lay Preacher

Il volume si propone di indagare la figura politica di Tony Blair, cercando di individuare gli elementi di continuit\ue0 e di rottura tra la politica blairiana, la cultura e la storia del Labour Party e l’eredit\ue0 politica di Margaret Thatcher. Sono presi in esame diversi aspetti del premier britannico: la biografia, l’ascesa nel partito, le idee politiche, lo stile comunicativo e le scelte compiute una volta al potere, sia in politica interna sia in politica estera, soprattutto nel rapporto con gli Stati Uniti e l’Unione Europea. In particolare, il volume si concentra sui primi sei anni dei Governi New Labour: dalla landslide victory del 1997 alla dichiarazione di guerra all’Iraq nel 2003, spartiacque decisivo nella carriera e nella legacy di Blair

Costs of adverse events associated with afatinib, erlotinib, and gefitinib first-line therapies in advanced non-small-cell lung cancer harboring EGFR-activating mutations

Costs of adverse events associated with afatinib, erlotinib, and gefitinib first-line therapies in advanced non-small-cell lung cancer harboring EGFR-activating mutationsIntroductionEpidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) afatinib, erlotinib, and gefitinib are an established treatment for advanced non-small cell lung cancer (NSCLC) with EGFR mutation.ObjectivesConsistent with published meta-analyses, this study compares the cost of management of the adverse events (AEs) associated with these three drugs from the perspective of the Italian National Health System (NHS).MethodsThe frequency of AEs was established based on a recently published meta-analysis. Only the costs of management of the AEs were considered. Resource utilization in the management of the AEs was estimated by a panel of Italian oncologists and based on previously published studies.ResultsThe mean cost per patient treated with afatinib, erlotinib, and gefitinib was €141.03, €90.74 and 121.87, respectively. With afatinib, the cost per patient and per AE of grades ≤2 and ≥3 was €36.70 and €104.33. With erlotinib, the cost per patient and per AE of grades ≤2 and ≥3 was €46.99 and €40.75, whereas the cost with gefitinib was €34.76 and €87.11, respectively.ConclusionIn advanced EGFR mutation-positive NSCLC patients, first-line treatment with erlotinib could reduce the cost of management of the AEs for the NHS

A novel homozygous mutation in GAD1 gene described in a schizophrenic patient impairs activity and dimerization of GAD67 enzyme

Recently, by whole exome sequencing of schizophrenia (SCZ) patients, we identified a subject that was homozygous for a novel missense substitution (c.391 A > G) in the glutamate acid decarboxylase 1 (GAD1) gene. GAD1 encodes for GAD67 enzyme, catalyzing the production of gamma-aminobutyric acid (GABA) from L-glutamic acid. Here, we studied the impact of this mutation on GAD67 activity, dimerization and subcellular localization. Biochemical assay revealed that c.391 A > G reduces GAD67 enzymatic activity by ~30%, probably due to the impaired homodimerization of homozygous mutants as highlighted by proximity ligation assays. The mutational screening of 120 genes of the "GABAergic system" in a cohort of 4,225 SCZ cases and 5,834 controls (dbGaP: phs000473.v1.p2), did not identify other cases that were homozygous for ultra-rare variants in GAD1, but highlighted an increased frequency of cases that were homozygous for rare variants in genes of the GABA system (SCZ: 0.14% vs. Controls: 0.00%; p-value = 0.0055). In conclusion, this study demonstrates the functional impact of c.391 A > G variant and its biological effect makes it a good candidate as risk variant for SCZ. This study also supports an involvement of ultra-rare variants in GABAergic genes in the etiopathogenesis of SCZ