Rapid LC-MS/MS quantification of the major benzodiazepines and their metabolites on dried blood spots using a simple and cost-effective sample pretreatment.

BACKGROUND: Dried blood spots (DBS) sampling has gained popularity in the bioanalytical community as an alternative to conventional plasma sampling, as it provides numerous benefits in terms of sample collection and logistics. The aim of this work was to show that these advantages can be coupled with a simple and cost-effective sample pretreatment, with subsequent rapid LC-MS/MS analysis for quantitation of 15 benzodiazepines, six metabolites and three Z-drugs. For this purpose, a simplified offline procedure was developed that consisted of letting a 5-µl DBS infuse directly into 100 µl of MeOH, in a conventional LC vial. RESULTS: The parameters related to the DBS pretreatment, such as extraction time or internal standard addition, were investigated and optimized, demonstrating that passive infusion in a regular LC vial was sufficient to quantitatively extract the analytes of interest. The method was validated according to international criteria in the therapeutic concentration ranges of the selected compounds. CONCLUSION: The presented strategy proved to be efficient for the rapid analysis of the selected drugs. Indeed, the offline sample preparation was reduced to a minimum, using a small amount of organic solvent and consumables, without affecting the accuracy of the method. Thus, this approach enables simple and rapid DBS analysis, even when using a non-DBS-dedicated autosampler, while lowering the costs and environmental impact.

Plasticity in the sensorimotor cortex induced by Music-supported therapy in stroke patients: a TMS study.

Playing a musical instrument demands the engagement of different neural systems. Recent studies about the musician"s brain and musical training highlight that this activity requires the close interaction between motor and somatosensory systems. Moreover, neuroplastic changes have been reported in motor-related areas after short and long-term musical training. Because of its capacity to promote neuroplastic changes, music has been used in the context of stroke neurorehabilitation. The majority of patients suffering from a stroke have motor impairments, preventing them to live independently. Thus, there is an increasing demand for effective restorative interventions for neurological deficits. Music-supported Therapy (MST) has been recently developed to restore motor deficits. We report data of a selected sample of stroke patients who have been enrolled in a MST program (1 month intense music learning). Prior to and after the therapy, patients were evaluated with different behavioral motor tests. Transcranial Magnetic Stimulation (TMS) was applied to evaluate changes in the sensorimotor representations underlying the motor gains observed. Several parameters of excitability of the motor cortex were assessed as well as the cortical somatotopic representation of a muscle in the affected hand. Our results revealed that participants obtained significant motor improvements in the paretic hand and those changes were accompanied by changes in the excitability of the motor cortex. Thus, MST leads to neuroplastic changes in the motor cortex of stroke patients which may explain its efficacy.

Plasticity in the sensorimotor cortex induced by Music-supported therapy in stroke patients: a TMS study.

Playing a musical instrument demands the engagement of different neural systems. Recent studies about the musician"s brain and musical training highlight that this activity requires the close interaction between motor and somatosensory systems. Moreover, neuroplastic changes have been reported in motor-related areas after short and long-term musical training. Because of its capacity to promote neuroplastic changes, music has been used in the context of stroke neurorehabilitation. The majority of patients suffering from a stroke have motor impairments, preventing them to live independently. Thus, there is an increasing demand for effective restorative interventions for neurological deficits. Music-supported Therapy (MST) has been recently developed to restore motor deficits. We report data of a selected sample of stroke patients who have been enrolled in a MST program (1 month intense music learning). Prior to and after the therapy, patients were evaluated with different behavioral motor tests. Transcranial Magnetic Stimulation (TMS) was applied to evaluate changes in the sensorimotor representations underlying the motor gains observed. Several parameters of excitability of the motor cortex were assessed as well as the cortical somatotopic representation of a muscle in the affected hand. Our results revealed that participants obtained significant motor improvements in the paretic hand and those changes were accompanied by changes in the excitability of the motor cortex. Thus, MST leads to neuroplastic changes in the motor cortex of stroke patients which may explain its efficacy.

Plasticity in the sensorimotor cortex induced by Music-supported therapy in stroke patients: a TMS study.

Playing a musical instrument demands the engagement of different neural systems. Recent studies about the musician"s brain and musical training highlight that this activity requires the close interaction between motor and somatosensory systems. Moreover, neuroplastic changes have been reported in motor-related areas after short and long-term musical training. Because of its capacity to promote neuroplastic changes, music has been used in the context of stroke neurorehabilitation. The majority of patients suffering from a stroke have motor impairments, preventing them to live independently. Thus, there is an increasing demand for effective restorative interventions for neurological deficits. Music-supported Therapy (MST) has been recently developed to restore motor deficits. We report data of a selected sample of stroke patients who have been enrolled in a MST program (1 month intense music learning). Prior to and after the therapy, patients were evaluated with different behavioral motor tests. Transcranial Magnetic Stimulation (TMS) was applied to evaluate changes in the sensorimotor representations underlying the motor gains observed. Several parameters of excitability of the motor cortex were assessed as well as the cortical somatotopic representation of a muscle in the affected hand. Our results revealed that participants obtained significant motor improvements in the paretic hand and those changes were accompanied by changes in the excitability of the motor cortex. Thus, MST leads to neuroplastic changes in the motor cortex of stroke patients which may explain its efficacy.

Amlodipine and valsartan as components of a rational and effective fixed-dose combination.

Pharmacological treatment of hypertension is effective in preventing cardiovascular and renal complications. Calcium antagonists and blockers of the renin-angiotensin system are widely used today to initiate antihypertensive therapy but, when given as monotherapy, do not suffice in most patients to normalize blood pressure. Combining the two types of agents considerably increases the antihypertensive efficacy, but not at the expense of a deterioration of tolerability. This is exemplified by the experience accumulated with the recently developed fixed dose combination containing the AT(1)-receptor blocker valsartan (160 mg) and the dihydropyridine amlodipine (5 or 10 mg). In a randomized trial, an 8-week treatment normalized blood pressure (<140/90 mmHg) within 8 weeks in a large fraction of hypertensive patients (78.4% and 85.2% using the 5/160 [n = 371] and 10/160 mg [n = 377] dosage, respectively). Like all AT(1)-receptor blockers valsartan has a placebo-like tolerability. Valsartan prevents to a large extent the occurrence amlodipine-induced peripheral edema. Both amlodipine and valsartan have beneficial effects on cardiovascular morbidity and mortality, as well as protective effects on renal function. The co-administration of these two agents is therefore very attractive, as it enables a rapid and sustained blood pressure control in hypertensive patients. The availability of a fixed-dose combination based on amlodipine and valsartan is expected therefore to facilitate the management of hypertension, to improve long-term adherence with antihypertensive therapy and, ultimately, to have a positive impact on cardiovascular and renal outcomes.

Modeling and mitigation of supply-demand mismatches

In this thesis, I develop analytical models to price the value of supply chain investments under demand uncer¬tainty. This thesis includes three self-contained papers. In the first paper, we investigate the value of lead-time reduction under the risk of sudden and abnormal changes in demand forecasts. We first consider the risk of a complete and permanent loss of demand. We then provide a more general jump-diffusion model, where we add a compound Poisson process to a constant-volatility demand process to explore the impact of sudden changes in demand forecasts on the value of lead-time reduction. We use an Edgeworth series expansion to divide the lead-time cost into that arising from constant instantaneous volatility, and that arising from the risk of jumps. We show that the value of lead-time reduction increases substantially in the intensity and/or the magnitude of jumps. In the second paper, we analyze the value of quantity flexibility in the presence of supply-chain dis- intermediation problems. We use the multiplicative martingale model and the "contracts as reference points" theory to capture both positive and negative effects of quantity flexibility for the downstream level in a supply chain. We show that lead-time reduction reduces both supply-chain disintermediation problems and supply- demand mismatches. We furthermore analyze the impact of the supplier's cost structure on the profitability of quantity-flexibility contracts. When the supplier's initial investment cost is relatively low, supply-chain disin¬termediation risk becomes less important, and hence the contract becomes more profitable for the retailer. We also find that the supply-chain efficiency increases substantially with the supplier's ability to disintermediate the chain when the initial investment cost is relatively high. In the third paper, we investigate the value of dual sourcing for the products with heavy-tailed demand distributions. We apply extreme-value theory and analyze the effects of tail heaviness of demand distribution on the optimal dual-sourcing strategy. We find that the effects of tail heaviness depend on the characteristics of demand and profit parameters. When both the profit margin of the product and the cost differential between the suppliers are relatively high, it is optimal to buffer the mismatch risk by increasing both the inventory level and the responsive capacity as demand uncertainty increases. In that case, however, both the optimal inventory level and the optimal responsive capacity decrease as the tail of demand becomes heavier. When the profit margin of the product is relatively high, and the cost differential between the suppliers is relatively low, it is optimal to buffer the mismatch risk by increasing the responsive capacity and reducing the inventory level as the demand uncertainty increases. In that case, how¬ever, it is optimal to buffer with more inventory and less capacity as the tail of demand becomes heavier. We also show that the optimal responsive capacity is higher for the products with heavier tails when the fill rate is extremely high.

Case-based learning in VTLE: An effective strategy for improving learning design

This article presents preliminary research from an instructional design perspective on the design of the case method as an integral part of pedagogy and technology. Key features and benefitsusing this teaching and learning strategy in a Virtual Teaching and Learning Environment(VTLE) are identified, taking into account the requirements of the European Higher Education Area (EHEA) for a competence-based curricula design. The implications of these findings for alearning object approach exploring the possibilities of learning personalization, reusability and interoperability trough IMS LD, are also analyzed.

Secure Dynamic MANET On-demand (SEDYMO) Routing Protocol

This paper describes the state of the art of secure ad hoc routing protocols and presents SEDYMO, a mechanism to secure a dynamic multihop ad hoc routing protocol. The proposed solution defeats internal and external attacks usinga trustworthiness model based on a distributed certification authority. Digital signatures and hash chains are used to ensure the correctness of the protocol. The protocol is compared with other alternatives in terms of security strength, energy efficiency and time delay. Both computational and transmission costs are considered and it is shown that the secure protocol overhead is not a critical factor compared to the high network interface cost.

Population genomics of eusocial insects: the costs of a vertebrate-like effective population size

The evolution of reproductive division of labour and social life in social insects has lead to the emergence of several life-history traits and adaptations typical of larger organisms: social insect colonies can reach masses of several kilograms, they start reproducing only when they are several years old, and can live for decades. These features and the monopolization of reproduction by only one or few individuals in a colony should affect molecular evolution by reducing the effective population size. We tested this prediction by analysing genome-wide patterns of coding sequence polymorphism and divergence in eusocial vs. noneusocial insects based on newly generated RNA-seq data. We report very low amounts of genetic polymorphism and an elevated ratio of nonsynonymous to synonymous changes - a marker of the effective population size - in four distinct species of eusocial insects, which were more similar to vertebrates than to solitary insects regarding molecular evolutionary processes. Moreover, the ratio of nonsynonymous to synonymous substitutions was positively correlated with the level of social complexity across ant species. These results are fully consistent with the hypothesis of a reduced effective population size and an increased genetic load in eusocial insects, indicating that the evolution of social life has important consequences at both the genomic and population levels.

Cefuroxime prophylaxis is effective in noninstrumented spine surgery : a double-blind, placebo-controlled study

Rapport de synthèse : Plusieurs investigateurs ont démontré que l'utilisation d'une antibiothérapie prophylactique lors d'interventions neurochirurgicales en terrain non infecté (chirurgie propre) réduisait le taux d'infection. Toutefois, ces taux d'infections sont très variables en fonction des types de chirurgie et de la durée des interventions. Les craniotomies, la mise en place ou le remplacement de shunt ventriculo-cardiaque, l'extirpation de méningiomes intracrâniens et les interventions d'une durée de plus de quatre heures sont grevées d'un taux d'infections post-opératoires plus élevé. Si une prophylaxie antibiotique est maintenant reconnue et utilisée dans ce type de chirurgie, il n'a jamais été démontré que cette pratique amène un bénéfice dans les cas de chirurgie pour hernie discale. Des études ont montré que de nombreux organismes potentiellement pathogènes pouvaient être collectés et cultivés à proximité voire dans le champ opératoire. Malgré ces observations, le taux d'infections post-opératoires reste peu important (entre 1-4% selon les centres). Il n'est actuellement pas possible de distinguer le rôle respectif d'une antibiothérapie prophylactique et des pratiques d'asepsie habituelles (y compris l'usage de solutions de rinçage antiseptiques) dans la faible incidence des infections post-opératoires en ce qui concerne la chirurgie des hernies discales. Lorsque des opérations de chirurgie dite «propre » sont grevées d'un taux de complications aussi bas, une prophylaxie antibiotique n'est généralement pas recommandée, en raison d'un rapport coût-bénéfice défavorable. Le but de cette étude est d'évaluer la nécessité d'une antibiothérapie prophylactique par une céphalosporine de seconde génération (cefuroxime 1,5 g intraveineuse) dans la prévention des infections post-opératoires au cours d'une chirurgie pour hernie discale. Il s'agit d'un essai clinique prospectif, contrôlé contre placebo en insu réciproque, à répartition aléatoire. L'étude a été conduite dans les services de neurochirurgie de l'Hôpital Universitaire de Genève et du Centre Hospitalier Universitaire Vaudois de Lausanne. L'ensemble des patients admis dans ces deux services pour une opération de hernie discale et ayant donné leur consentement ont été inclus dans l'étude qui s'est déroulé sur une période de 6 ans. Mille trois cent soixante-neuf patients opérés pour une hernie discale ont été inclus dans cet essai et 132 patients ont été exclus de l'analyse pour diverses raisons. Au total 1'237 patients ont été analysés, respectivement 613 et 624 patients dans le groupe cefuroxime et le groupe placebo. Les patients des deux groupes présentaient des caractéristiques identiques. Nous n'avons objectivé aucun effet secondaire indésirable attribuable à la cefuroxime ou au placebo. Huit (1.3%) patients du groupe cefuroxime et 18 patients (2.8%) du groupe placebo ont développé une infection du site opératoire (P=0.073). Neuf des patients infectés dans le groupe placebo présentaient une infection profonde du site opératoire (spondylodiscite, abcès épidural) et aucun dans le groupe cefuroxime (P<0.01). Tous les patients avec infection profonde du site opératoire ont été traités par antibiothérapie par voie intraveineuse pour au moins 4 semaines et il a été procédé à une reprise chirurgicale chez deux patients. Ces résultats montrent qu'il faut traiter 69 patients avec une antibiothérapie prophylactique de cefuroxime pour prévenir une infection du site opératoire. En conclusion, l'administration d'une dose de cefuroxime 1.5 g intraveineuse comme prophylaxie lors d'opération de hernie discale, permet de réduire significativement le risque d'infection profonde du site opératoire.

Effective notch method assessment of misalignment for fatigue loaded welds

 The objective of this thesis work was to assess axial misalignment in fatigue loaded welds using the effective notch method. As a result, the fatigue behaviour of non-load carrying cruciform fillet welded joint under cyclic tensile loading has been studied. Various degrees of axial misalignment have been found in one series of non-load carrying cruciform fillet welded joints used in a laboratory investigation. As a result, it was important to carry out a comprehensive investigation since axial misalignment forms part of thequality of fatigue loaded structure and can reduce the fatigue strength. To extend the study, the correlation between fatigue strength and stress ratio, as well as stress concentration factor, were also studied. Moreover, a closer investigation of place of crack initiation and its dependence on weld sequence and imperfections of test specimen (angular distortion) was studied. For the fatigue class calculations, FEM (finite element method) and the effectivenotch approach are used. The addressed variable is the axial misalignment whichis introduce by modeling the entire joint. Fracture mechanics based calculations are also used and quantitatively compared with effective notch and experimental results.

Distributed Energy Production in the North-West Region of Russia

The energy system of Russia is the world's fourth largest measured by installed power. The largest are that of the the United States of America, China and Japan. After 1990, the electricity consumption decreased as a result of the Russian industry crisis. The vivid economic growth during the latest few years explains the new increase in the demand for energy resources within the State. In 2005 the consumption of electricity achieved the maximum level of 1990 and continues to growth. In the 1980's, the renewal of power facilities was already very slow and practically stopped in the 1990's. At present, the energy system can be very much characterized as outdated, inefficient and uneconomic because of the old equipment, non-effective structure and large losses in the transmission lines. The aim of Russia's energy reform, which was started in 2001, is to achieve a market based energy policy by 2011. This would thus remove the significantly state-controlled monopoly in Russia's energy policy. The reform will stimulateto decrease losses, improve the energy system and employ energy-saving technologies. The Russian energy system today is still based on the use of fossil fuels, and it almost totally ignores the efficient use of renewable sources such as wind, solar, small hydro and biomass, despite of their significant resources in Russia. The main target of this project is to consider opportunities to apply renewable energy production in the North-West Federal Region of Russia to partly solve the above mentioned problems in the energy system.