Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

Rationale Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine. Objective The major aims were to investigate the pharmacokineticsa and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model. Methods Mephedrone was administered to male Sprague-Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180-240 min. Results Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (α=10.23 h−1, β=1.86 h−1). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10 % and the percentage of mephedrone protein binding was 21.59±3.67%. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85±0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic-pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect. Conclusions We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude,and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity.

Beyond the net generation debate: A comparison of digital learners in face-to-face and virtual universities

In the last decade, an important debate has arisen about the characteristics of today"s students due to their intensive experience as users of ICT. The main belief is that frequent use of technologies in everyday life implies that competent users are able to transfer their digital skills to learning activities. However, empirical studies developed in different countries reveal similar results suggesting that the"digital native" label does not provide evidence of a better use of technology to support learning. The debate has to go beyond the characteristics of the new generation and focus on the implications of being a learner in a digitalised world. This paper is based on the hypothesis that the use of technology to support learning is not related to whether a student belongs to the Net Generation, but that it is mainly influenced by the teaching model. The study compares behaviour and preferences towards ICT use in two groups of university students: face-to-face students and online students. A questionnaire was applied to a sample of students from five universities with different characteristics (one offers online education and four offer face-to-face education with LMS teaching support). Findings suggest that although access to and use of ICT is widespread, the influence of teaching methodology is very decisive. For academic purposes, students seem to respond to the requirements of their courses, programmes, and universities. There is a clear relationship between students" perception of usefulness regarding certain ICT resources and their teachers" suggested uses of technologies. The most highly rated technologies correspond with those proposed by teachers. The study shows that the educational model (face-to-face or online) has a stronger influence on students" perception of usefulness regarding ICT support for learning than the fact of being a digital native.

Transition aux soins adultes : une vue d'ensemble [Transition to adult care: an overview]

De nos jours, près de 90% des enfants atteints d'une maladie chronique survivent au-delà de l'âge de vingt ans et doivent passer de la pédiatrie aux soins adultes et de l'enfance à l'adolescence et à l'âge adulte. Selon la Society for Adolescent Medicine and Health (SAHM), les objectifs d'une transition organisée et coordonnée aux soins adultes pour les jeunes malades chroniques devraient permettre d'optimiser leur santé et de faciliter la réalisation de leur potentiel maximal.1 En conséquence, bien que le but principal de la transition soit la continuité des soins, elle n'est pas limitée au transfert (le passage de l'information et du patient de la pédiatrie aux soins adultes) mais est beaucoup plus large et inclut la préparation à la vie adulte. Ainsi donc, la transition devrait commencer tôt pendant l'adolescence, finir quand le patient devient un jeune adulte et englober trois parties : une phase de préparation en pédiatrie, une de transfert de la pédiatrie aux soins adultes et une dernière d'engagement aux soins adultes. Nowadays nearly 90% of children with a chronic condition survive to adulthood and must make the transition from pediatric to adult care. This transition must include not only the continuity of care but also the preparation for adult life so that these young people can develop their full potential. Divided into three phases (preparation, transfer and engagement), the transition process should be adapted to adolescents and ensure access to quality care.

Colorectal Cancer Screening in Switzerland: Cross-Sectional Trends (2007-2012) in Socioeconomic Disparities.

BACKGROUND: Despite universal health care coverage, disparities in colorectal cancer (CRC) screening by income in Switzerland have been reported. However, it is not known if these disparities have changed over time. This study examines the association between socioeconomic position and CRC screening in Switzerland between 2007 and 2012. METHODS: Data from the 2007 (n = 5,946) and 2012 (n = 7,224) population-based Swiss Health Interview Survey data (SHIS) were used to evaluate the association between monthly household income, education, and employment with CRC screening, defined as endoscopy in the past 10 years or fecal occult blood test (FOBT) in the past 2 years. Multivariable Poisson regression was used to estimate prevalence ratios (PR) and 95% Confidence Intervals (CI) adjusting for demographics, health status, and health utilization. RESULTS: CRC screening increased from 18.9% in 2007 to 22.2% in 2012 (padjusted: = 0.036). During the corresponding time period, endoscopy increased (8.2% vs. 15.0%, padjusted:<0.001) and FOBT decreased (13.0% vs. 9.8%, padjusted:0.002). CRC screening prevalence was greater in the highest income (>$6,000) vs. lowest income (≤$2,000) group in 2007 (24.5% vs. 10.5%, PR:1.37, 95%CI: 0.96-1.96) and in 2012 (28.6% vs. 16.0%, PR:1.45, 95%CI: 1.09-1.92); this disparity did not significantly change over time. CONCLUSIONS: While CRC screening prevalence in Switzerland increased from 2007 to 2012, CRC screening coverage remains low and disparities in CRC screening by income persisted over time. These findings highlight the need for increased access to CRC screening as well as enhanced awareness of the benefits of CRC screening in the Swiss population, particularly among low-income residents.

Spatial radial maze procedures and setups to dissociate local and distal relational spatial frameworks in humans.

BACKGROUND: Radial maze tasks have been used to assess optimal foraging and spatial abilities in rodents. The spatial performance was based on a capacity to rely on a configuration of local and distant cues. We adapted maze procedures assessing the relative weight of local cues and distant landmarks for arm choice in humans. NEW METHOD: The procedure allowed testing memory of places in four experimental setups: a fingertip texture-groove maze, a tactile screen maze, a virtual radial maze and a walking size maze. During training, the four reinforced positions remained fixed relative to local and distal cues. During subsequent conflict trials, these frameworks were made conflictive in the prediction of reward locations. RESULTS: Three experiments showed that the relative weight of local and distal relational cues is affected by different factors such as cues' nature, visual access to the environment, real vs. virtual environment, and gender. A fourth experiment illustrated how a walking maze can be used with people suffering intellectual disability. COMPARISON WITH EXISTING METHODS: In our procedure, long-term (reference) and short-term (working) memory can be assessed. It is the first radial task adapted to human that enables dissociating local and distal cues, to provides an indication as to their relative salience. Our mazes are moveable and easily used in limited spaces. Tasks are performed with realistic and spontaneous though controlled exploratory movements. CONCLUSION: Our tasks enabled highlighting the use of different strategies. In a clinical perspective, considering the use of compensatory strategies should orient towards adapted behavioural rehabilitation.

Availability, Cost or Culture ? : Obstacles to Childcare Services for Low-Income Families

Recent research has highlighted the existence of a social bias in the extent to which children have access to childcare. In general, children living in higher income households are more likely to be cared for in childcare centres. While the existence of a social bias in access to childcare services has been clearly demonstrated, we currently lack a clear explanation as to why this is the case. This paper uses a unique dataset based on survey data collected specifically to study patterns of childcare use in the Swiss canton of Vaud (N = 875). The paper exploits the variation in the way childcare is organised within the canton. Childcare is a municipal policy, as a result of which there are twenty-nine different systems in operation. Fees are progressive everywhere, but variation is substantial. Availability is also very different. This peculiar institutional setup provides an ideal situation to examine the determinants of childcare use by different income groups. Our findings suggest that differences in the fees charged to low-income households, as well as the degree of progressivity of the fee structure, are significant predictors of use, while availability seems to matter less.

From bird to sparrow: Learning-induced modulations in fine-grained semantic discrimination.

Recognition of environmental sounds is believed to proceed through discrimination steps from broad to more narrow categories. Very little is known about the neural processes that underlie fine-grained discrimination within narrow categories or about their plasticity in relation to newly acquired expertise. We investigated how the cortical representation of birdsongs is modulated by brief training to recognize individual species. During a 60-minute session, participants learned to recognize a set of birdsongs; they improved significantly their performance for trained (T) but not control species (C), which were counterbalanced across participants. Auditory evoked potentials (AEPs) were recorded during pre- and post-training sessions. Pre vs. post changes in AEPs were significantly different between T and C i) at 206-232ms post stimulus onset within a cluster on the anterior part of the left superior temporal gyrus; ii) at 246-291ms in the left middle frontal gyrus; and iii) 512-545ms in the left middle temporal gyrus as well as bilaterally in the cingulate cortex. All effects were driven by weaker activity for T than C species. Thus, expertise in discriminating T species modulated early stages of semantic processing, during and immediately after the time window that sustains the discrimination between human vs. animal vocalizations. Moreover, the training-induced plasticity is reflected by the sharpening of a left lateralized semantic network, including the anterior part of the temporal convexity and the frontal cortex. Training to identify birdsongs influenced, however, also the processing of C species, but at a much later stage. Correct discrimination of untrained sounds seems to require an additional step which results from lower-level features analysis such as apperception. We therefore suggest that the access to objects within an auditory semantic category is different and depends on subject's level of expertise. More specifically, correct intra-categorical auditory discrimination for untrained items follows the temporal hierarchy and transpires in a late stage of semantic processing. On the other hand, correct categorization of individually trained stimuli occurs earlier, during a period contemporaneous with human vs. animal vocalization discrimination, and involves a parallel semantic pathway requiring expertise.

A new multidisciplinary home care telemedicine system to monitor stable chronic human immunodeficiency virus-infected patients: a randomized study.

Background: Antiretroviral therapy has changed the natural history of human immunodeficiency virus (HIV) infection in developed countries, where it has become a chronic disease. This clinical scenario requires a new approach to simplify follow-up appointments and facilitate access to healthcare professionals. Methodology: We developed a new internet-based home care model covering the entire management of chronic HIV-infected patients. This was called Virtual Hospital. We report the results of a prospective randomised study performed over two years, comparing standard care received by HIV-infected patients with Virtual Hospital care. HIV-infected patients with access to a computer and broadband were randomised to be monitored either through Virtual Hospital (Arm I) or through standard care at the day hospital (Arm II). After one year of follow up, patients switched their care to the other arm. Virtual Hospital offered four main services: Virtual Consultations, Telepharmacy, Virtual Library and Virtual Community. A technical and clinical evaluation of Virtual Hospital was carried out. Findings: Of the 83 randomised patients, 42 were monitored during the first year through Virtual Hospital (Arm I) and 41 through standard care (Arm II). Baseline characteristics of patients were similar in the two arms. The level of technical satisfaction with the virtual system was high: 85% of patients considered that Virtual Hospital improved their access to clinical data and they felt comfortable with the videoconference system. Neither clinical parameters [level of CD4 + T lymphocytes, proportion of patients with an undetectable level of viral load (p = 0.21) and compliance levels 90% (p = 0.58)] nor the evaluation of quality of life or psychological questionnaires changed significantly between the two types of care. Conclusions: Virtual Hospital is a feasible and safe tool for the multidisciplinary home care of chronic HIV patients. Telemedicine should be considered as an appropriate support service for the management of chronic HIV infection.

Gold or green: the debate on Open Access policies

The movement for open access to science seeks to achieve unrestricted and free access to academic publications on the Internet. To this end, two mechanisms have been established: the gold road, in which scientific journals are openly accessible, and the green road, in which publications are self-archived in repositories. The publication of the Finch Report in 2012, advocating exclusively the adoption of the gold road, generated a debate as to whether either of the two options should be prioritized. The recommendations of the Finch Report stirred controversy among academicians specialized in open access issues, who felt that the role played by repositories was not adequately considered and because the green road places the burden of publishing costs basically on authors. The Finch Report"s conclusions are compatible with the characteristics of science communication in the UK and they could surely also be applied to the (few) countries with a powerful publishing industry and substantial research funding. In Spain, both the current national legislation and the existing rules at universities largely advocate the green road. This is directly related to the structure of scientific communication in Spain, where many journals have little commercial significance, the system of charging a fee to authors has not been adopted, and there is a good repository infrastructure. As for open access policies, the performance of the scientific communication system in each country should be carefully analyzed to determine the most suitable open access strategy. [Int Microbiol 2013; 16(3):199-203]

Finding an apprenticeship : hidden curriculum and social consequences

In Switzerland, the majority of students are oriented towards professional training after compulsory schooling. At this stage, one of the biggest challenges for them is to find an apprenticeship position. Matching supply and demand is a complex process that not only excludes some students from having direct access to professional training but also forces them to make early choices regarding their future sector of employment. So, how does one find an apprenticeship? And what do the students' descriptions of their search for apprenticeships reveal about the institutional determinants of social inequalities at play in the system? Based on 29 interviews conducted in 2014 with 23 apprentices and 6 recruiters in the Canton of Vaud, this article interrogates how the dimensions of educational and social trajectories combine to affect access to apprenticeships and are accentuated by recruiters using a "hidden curriculum" during the recruitment process. A hidden curriculum consists of knowledge and skills not taught by the educational institution but which appear decisive in obtaining an apprenticeship. By analysing the contrasting experiences of students in their search for an apprenticeship, we identify four types of trajectories that explain different types of school-to-apprenticeship transitions. We show how these determinants are reinforced by the "hidden curriculum" of recruitment based on the soft skills of feeling, autonomy, anticipation and reflexivity that are assessed in the context of recruitment interactions. The discussion section debates how the criteria that appear to be used to identify the "right apprentice" tend to (re)produce inequalities between students. This not only depends on their academic results but also on their social and cultural skills, their ability to anticipate their choices and, more widely, their ability to be a subject in their recruitment search. "The Subject is neither the individual, nor the self, but the work through which an individual transforms into an actor, meaning an agent able to transform his/her situation instead of reproducing it." (Touraine, 1992, p.476).

CBS: an open platform that integrates predictive methods and epigenetics information to characterize conserved regulatory features in multiple Drosophila genomes.

Background: Information about the composition of regulatory regions is of great value for designing experiments to functionally characterize gene expression. The multiplicity of available applications to predict transcription factor binding sites in a particular locus contrasts with the substantial computational expertise that is demanded to manipulate them, which may constitute a potential barrier for the experimental community. Results: CBS (Conserved regulatory Binding Sites, http://compfly.bio.ub.es/CBS) is a public platform of evolutionarily conserved binding sites and enhancers predicted in multiple Drosophila genomes that is furnished with published chromatin signatures associated to transcriptionally active regions and other experimental sources of information. The rapid access to this novel body of knowledge through a user-friendly web interface enables non-expert users to identify the binding sequences available for any particular gene, transcription factor, or genome region. Conclusions: The CBS platform is a powerful resource that provides tools for data mining individual sequences and groups of co-expressed genes with epigenomics information to conduct regulatory screenings in Drosophila.

Transnational private authority, regulatory space and workers' collective competences: Bringing local contexts and worker agency back in

The impact of transnational private regulation on labour standards remains in dispute. While studies have provided some limited evidence of positive effects on 'outcome standards' such as wages or occupational health and safety, the literature gives little reason to believe that there has been any significant effect on 'process rights' relating primarily to collective workers' voice and social dialogue. This paper probes this assumption by bringing local contexts and worker agency more fully into the picture. It outlines an analytical framework that emphasizes workers' potential to act collectively for change in the regulatory space surrounding the employment relationship. It argues that while transnational private regulation on labour standards may marginally improve workers access to regulatory spaces and their capacity to require the inclusion of enterprises in them, it does little to increase union leverage. The findings are based on empirical research work conducted in Sub-Saharan Africa.

Coev-web: a web platform designed to simulate and evaluate coevolving positions along a phylogenetic tree.

BACKGROUND: Available methods to simulate nucleotide or amino acid data typically use Markov models to simulate each position independently. These approaches are not appropriate to assess the performance of combinatorial and probabilistic methods that look for coevolving positions in nucleotide or amino acid sequences. RESULTS: We have developed a web-based platform that gives a user-friendly access to two phylogenetic-based methods implementing the Coev model: the evaluation of coevolving scores and the simulation of coevolving positions. We have also extended the capabilities of the Coev model to allow for the generalization of the alphabet used in the Markov model, which can now analyse both nucleotide and amino acid data sets. The simulation of coevolving positions is novel and builds upon the developments of the Coev model. It allows user to simulate pairs of dependent nucleotide or amino acid positions. CONCLUSIONS: The main focus of our paper is the new simulation method we present for coevolving positions. The implementation of this method is embedded within the web platform Coev-web that is freely accessible at http://coev.vital-it.ch/, and was tested in most modern web browsers.

Delivery of antigen to nasal-associated lymphoid tissue microfold cells through secretory IgA targeting local dendritic cells confers protective immunity.

BACKGROUND: Transmission of mucosal pathogens relies on their ability to bind to the surfaces of epithelial cells, to cross this thin barrier, and to gain access to target cells and tissues, leading to systemic infection. This implies that pathogen-specific immunity at mucosal sites is critical for the control of infectious agents using these routes to enter the body. Although mucosal delivery would ensure the best onset of protective immunity, most of the candidate vaccines are administered through the parenteral route. OBJECTIVE: The present study evaluates the feasibility of delivering the chemically bound p24gag (referred to as p24 in the text) HIV antigen through secretory IgA (SIgA) in nasal mucosae in mice. RESULTS: We show that SIgA interacts specifically with mucosal microfold cells present in the nasal-associated lymphoid tissue. p24-SIgA complexes are quickly taken up in the nasal cavity and selectively engulfed by mucosal dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin-positive dendritic cells. Nasal immunization with p24-SIgA elicits both a strong humoral and cellular immune response against p24 at the systemic and mucosal levels. This ensures effective protection against intranasal challenge with recombinant vaccinia virus encoding p24. CONCLUSION: This study represents the first example that underscores the remarkable potential of SIgA to serve as a carrier for a protein antigen in a mucosal vaccine approach targeting the nasal environment.

MetaNetX/MNXref - reconciliation of metabolites and biochemical reactions to bring together genome-scale metabolic networks.

MetaNetX is a repository of genome-scale metabolic networks (GSMNs) and biochemical pathways from a number of major resources imported into a common namespace of chemical compounds, reactions, cellular compartments-namely MNXref-and proteins. The MetaNetX.org website (http://www.metanetx.org/) provides access to these integrated data as well as a variety of tools that allow users to import their own GSMNs, map them to the MNXref reconciliation, and manipulate, compare, analyze, simulate (using flux balance analysis) and export the resulting GSMNs. MNXref and MetaNetX are regularly updated and freely available.