Dose and time-dependent selective neurotoxicity induced by mephedrone in mice.

Mephedrone is a drug of abuse marketed as 'bath salts'. There are discrepancies concerning its long-term effects. We have investigated the neurotoxicity of mephedrone in mice following different exposition schedules. Schedule 1: four doses of 50 mg/kg. Schedule 2: four doses of 25 mg/kg. Schedule 3: three daily doses of 25 mg/kg, for two consecutive days. All schedules induced, in some animals, an aggressive behavior and hyperthermia as well as a decrease in weight gain. Mephedrone (schedule 1) induced dopaminergic and serotoninergic neurotoxicity that persisted 7 days after exposition. At a lower dose (schedule 2) only a transient dopaminergic injury was found. In the weekend consumption pattern (schedule 3), mephedrone induced dopamine and serotonin transporter loss that was accompanied by a decrease in tyrosine hydroxylase and tryptophan hydroxylase 2 expression one week after exposition. Also, mephedrone induced a depressive-like behavior, as well as a reduction in striatal D2 density, suggesting higher susceptibility to addictive drugs. In cultured cortical neurons, mephedrone induced a concentration-dependent cytotoxic effect. Using repeated doses for 2 days in an elevated ambient temperature we evidenced a loss of frontal cortex dopaminergic and hippocampal serotoninergic neuronal markers that suggest injuries at nerve endings.

Optimization of KOH etching process to obtain textured substrates suitable for heterojunction solar cells fabricated by HWCVD

In this work, we have studied the texturization process of (100) c-Si wafers using a low concentration potassium hydroxide solution in order to obtain good quality textured wafers. The optimization of the etching conditions have led to random but uniform pyramidal structures with good optical properties. Then, symmetric heterojunctions were deposited by Hot-Wire CVD onto these substrates and the Quasi-Steady-State PhotoConductance technique was used to measure passivation quality. Little degradation in the effective lifetime and implicit open circuit voltage of these devices (< 20 mV) was observed in all cases. It is especially remarkable that for big uniform pyramids, the open-circuit voltage is comparable to the values obtained on flat substrates.

Design and optimization of selfnanoemulsifying drug delivery systems for enhanced dissolution of gemfibrozil

Self-nanoemulsifying drug delivery systems of gemfibrozil were developed under Quality by Design approach for improvement of dissolution and oral absorption. Preliminary screening was performed to select proper components combination. BoxBehnken experimental design was employed as statistical tool to optimize the formulation variables, X1 (Cremophor® EL), X2 (Capmul® MCM-C8), and X3 (lemon essential oil). Systems were assessed for visual characteristics (emulsification efficacy), turbidity, droplet size, polydispersity index and drug release. Different pH media were also assayed for optimization. Following optimization, the values of formulation components (X1, X2, and X3) were 32.43%, 29.73% and 21.62%, respectively (16.22% of gemfibrozil). Transmission electron microscopy demonstrated spherical droplet morphology. SNEEDS release study was compared to commercial tablets. Optimized SNEDDS formulation of gemfibrozil showed a significant increase in dissolution rate compared to conventional tablets. Both formulations followed Weibull mathematical model release with a significant difference in td parameter in favor of the SNEDDS. Equally amodelistic parameters were calculated being the dissolution efficiency significantly higher for SNEDDS, confirming that the developed SNEDDS formulation was superior to commercial formulation with respect to in vitro dissolution profile. This paper provides an overview of the SNEDDS of the gemfibrozil as a promising alternative to improve oral absorption.

Dose and time-dependent selective neurotoxicity induced by mephedrone in mice.

Mephedrone is a drug of abuse marketed as 'bath salts'. There are discrepancies concerning its long-term effects. We have investigated the neurotoxicity of mephedrone in mice following different exposition schedules. Schedule 1: four doses of 50 mg/kg. Schedule 2: four doses of 25 mg/kg. Schedule 3: three daily doses of 25 mg/kg, for two consecutive days. All schedules induced, in some animals, an aggressive behavior and hyperthermia as well as a decrease in weight gain. Mephedrone (schedule 1) induced dopaminergic and serotoninergic neurotoxicity that persisted 7 days after exposition. At a lower dose (schedule 2) only a transient dopaminergic injury was found. In the weekend consumption pattern (schedule 3), mephedrone induced dopamine and serotonin transporter loss that was accompanied by a decrease in tyrosine hydroxylase and tryptophan hydroxylase 2 expression one week after exposition. Also, mephedrone induced a depressive-like behavior, as well as a reduction in striatal D2 density, suggesting higher susceptibility to addictive drugs. In cultured cortical neurons, mephedrone induced a concentration-dependent cytotoxic effect. Using repeated doses for 2 days in an elevated ambient temperature we evidenced a loss of frontal cortex dopaminergic and hippocampal serotoninergic neuronal markers that suggest injuries at nerve endings.

Some optimization and decision problems in proportional reinsurance

Reinsurance is one of the tools that an insurer can use to mitigate the underwriting risk and then to control its solvency. In this paper, we focus on the proportional reinsurance arrangements and we examine several optimization and decision problems of the insurer with respect to the reinsurance strategy. To this end, we use as decision tools not only the probability of ruin but also the random variable deficit at ruin if ruin occurs. The discounted penalty function (Gerber & Shiu, 1998) is employed to calculate as particular cases the probability of ruin and the moments and the distribution function of the deficit at ruin if ruin occurs.

Radial dose function of a 90Sr 90Y seed in water and A150: Comment on Calibration and characterization of beta-particle sources for intravascular brachytherapy

Intravascular brachytherapy with beta sources has become a useful technique to prevent restenosis after cardiovascular intervention. In particular, the Beta-Cath high-dose-rate system, manufactured by Novoste Corporation, is a commercially available 90Sr 90Y source for intravascular brachytherapy that is achieving widespread use. Its dosimetric characterization has attracted considerable attention in recent years. Unfortunately, the short ranges of the emitted beta particles and the associated large dose gradients make experimental measurements particularly difficult. This circumstance has motivated the appearance of a number of papers addressing the characterization of this source by means of Monte Carlo simulation techniques.

Spectroscopic characterization of phases formed by high-dose carbon ion implantation in silicon

High-dose carbon-ion-implanted Si samples have been analyzed by infrared spectroscopy, Raman scattering, and x-ray photoelectron spectroscopy (XPS) correlated with transmission electron microscopy. Samples were implanted at room temperature and 500°C with doses between 1017 and 1018 C+/cm2. Some of the samples were implanted at room temperature with the surface covered by a capping oxide layer. Implanting at room temperature leads to the formation of a surface carbon-rich amorphous layer, in addition to the buried implanted layer. The dependence of this layer on the capping oxide suggests this layer to be determined by carbon migration toward the surface, rather than surface contamination. Implanting at 500°C, no carbon-rich surface layer is observed and the SiC buried layer is formed by crystalline ßSiC precipitates aligned with the Si matrix. The concentration of SiC in this region as measured by XPS is higher than for the room-temperature implantation.

Orthologous and heterologous expression of a protein from Saccharomyces cerevisiae: Optimization for a biotechnological application

In this thesis (TFG) the results of the comparison between different methods to obtain a recombinant protein, by orthologous and heterologous expression, are exposed. This study will help us to identify the best way to express and purify a recombinant protein that will be used for biotechnology applications. In the first part of the project the goal was to find the best expression and purification system to obtain the recombinant protein of interest. To achieve this objective, a system expression in bacteria and in yeast was designed. The DNA was cloned into two different expression vectors to create a fusion protein with two different tags, and the expression of the protein was induced by IPTG or glucose. Additionally, in yeast, two promoters where used to express the protein, the one corresponding to the same protein (orthologous expression), and the ENO2 promoter (heterologous expression). The protein of interest is a NAD-dependent enzyme so, in a second time, its specific activity was evaluated by coenzyme conversion. The results of the TFG suggest that, comparing the model organisms, bacteria are more efficient than yeast because the quantity of protein obtained is higher and better purified. Regarding yeast, comparing the two expression mechanisms that were designed, heterologous expression works much better than the orthologous expression, so in case that we want to use yeast as expression model for the protein of interest, ENO2 will be the best option. Finally, the enzymatic assays, done to compare the effectiveness of the different expression mechanisms respect to the protein activity, revealed that the protein purified in yeast had more activity in converting the NAD coenzyme.

Contribution of cytochrome P450 and ABCB1 genetic variability on methadone pharmacokinetics, dose requirements, and response

Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4th Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R,S)-, (R) and (S)- methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements.

Swarm Intelligent Selection and Optimization of Machining System Parameters for Microchannel Fabrication in Medical Devices

Current technology trends in medical device industry calls for fabrication of massive arrays of microfeatures such as microchannels on to nonsilicon material substrates with high accuracy, superior precision, and high throughput. Microchannels are typical features used in medical devices for medication dosing into the human body, analyzing DNA arrays or cell cultures. In this study, the capabilities of machining systems for micro-end milling have been evaluated by conducting experiments, regression modeling, and response surface methodology. In machining experiments by using micromilling, arrays of microchannels are fabricated on aluminium and titanium plates, and the feature size and accuracy (width and depth) and surface roughness are measured. Multicriteria decision making for material and process parameters selection for desired accuracy is investigated by using particle swarm optimization (PSO) method, which is an evolutionary computation method inspired by genetic algorithms (GA). Appropriate regression models are utilized within the PSO and optimum selection of micromilling parameters; microchannel feature accuracy and surface roughness are performed. An analysis for optimal micromachining parameters in decision variable space is also conducted. This study demonstrates the advantages of evolutionary computing algorithms in micromilling decision making and process optimization investigations and can be expanded to other applications

Experimental analysis of optimization techniques on the road passenger transportation problem

Analyzing the state of the art in a given field in order to tackle a new problem is always a mandatory task. Literature provides surveys based on summaries of previous studies, which are often based on theoretical descriptions of the methods. An engineer, however, requires some evidence from experimental evaluations in order to make the appropriate decision when selecting a technique for a problem. This is what we have done in this paper: experimentally analyzed a set of representative state-of-the-art techniques in the problem we are dealing with, namely, the road passenger transportation problem. This is an optimization problem in which drivers should be assigned to transport services, fulfilling some constraints and minimizing some function cost. The experimental results have provided us with good knowledge of the properties of several methods, such as modeling expressiveness, anytime behavior, computational time, memory requirements, parameters, and free downloadable tools. Based on our experience, we are able to choose a technique to solve our problem. We hope that this analysis is also helpful for other engineers facing a similar problem