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THIS PAPER EXPLORES THE ACTUAL AND POTENTIAL USEFULNESS OF OPINION POLLS FOR ANALYZING WHO GAINS AND WHO LOSES WHEN COLLECTIVE GOODS ARE PROVIDED. THE AUTHOR ARGUES THAT ANSWERS TO OPINION POLLS CAN REVEAL SOMETHING ABOUT THE PERCEIVED DISTRIBUTION OF GAINS AND LOSSES AMONG PEOPLE OF VARIOUS AGES, INCOMES, RACES AND EDUCATIONAL GROUPS.

Nicotine exerts its psychopharmacological effects by activating the nicotinic acetylcholine receptor (nAChR), composed of alpha and/or beta subunits, giving rise to a diverse population of receptors with a distinct pharmacology. β4-containing (β4*) nAChRs are located almost exclusively in the habenulo-interpeduncular pathway. We examined the role of β4* nAChRs in the medial habenula (MHb) and the interpeduncular nucleus (IPN) in nicotine reinforcement using behavioral, electrophysiological, and molecular techniques in transgenic mice. Nicotine intravenous self-administration (IVSA) was lower in constitutive β4 knockout (KO) mice at all doses tested (7.5, 15, 30, and 60 μg/kg/infusion) compared with wild-type (WT) mice. In vivo microdialysis showed that β4KO mice have higher extracellular dopamine (DA) levels in the nucleus accumbens than in WT mice, and exhibit a differential sensitivity to nicotine-induced DA outflow. Furthermore, electrophysiological recordings in the ventral tegmental area (VTA) demonstrated that DA neurons of β4KO mice are more sensitive to lower doses of nicotine than that of WT mice. Re-expression of β4* nAChRs in IPN neurons fully restored nicotine IVSA, and attenuated the increased sensitivity of VTA DA neurons to nicotine. These findings suggest that β4* nAChRs in the IPN have a role in maintaining nicotine IVSA ; This work was supported by the Spanish Instituto de Salud Carlos III (RD06/001/001 and PI10/01708; PI14/00210), FEDER funds, Ministerio de Ciencia e Innovación (#SAF2014-59648-P), the Catalan Government AGAUR (#2014-SGR-1547), Plan Nacional Sobre Drogas, Ministerio de Sanidad, Asuntos Sociales e Igualdad-MSASI (#PNSD- 2013-0068), FP7 ERANET program (NICO-GENE), the ICREA Foundation (ICREA Academia-2008), and a postdoctoral fellowship from CONACyT to AHS. The work in Paris was supported by the Institut Pasteur, Centre National de la Recherche Scientifique CNRS UMR 3571 (UM) and CNRS UMR 8246 (PF), the INSERM U1130 (PF), the Pierre et Marie Curie University (UM119), the Agence Nationale pour la Recherche (ANR Neuroscience), and FP7 ERANET program (NICO-GENE), Grant agreement n009 BLANC 20092009BLANC 20 NeuroCypres" project), Fondation EDF, the Fondation des Treilles, and the Foundation for Medical Research FMR (Equipe FRMDEQ20130326488 to PF). The groups of UM and PF are members of the Bio-Psy Labex. As such this work was supported by French state funds managed by the ANR within the Investissements d'Avenir programme under reference ANR-11-IDEX-0004-02. The teams of UM and PF are part of the École des Neurosciences de Paris Ile-de-France Network. We would like to thank Martine Soudant, Stephanie Pons, and Dulce Real for technical support, and Inés Ibañes-Tallon and Jessica/nAbles for providing the Tg(Chrnb4-cre)OL57Gsat/+ transgenic mice

Drug-induced proarrhythmicity is a major concern for regulators and pharmaceutical companies. For novel drug candidates, the standard assessment involves the evaluation of the potassium hERG channels block and the in vivo prolongation of the QT interval. However, this method is known to be too restrictive and to stop the development of potentially valuable therapeutic drugs. The aim of this work is to create an in silico tool for early detection of drug-induced proarrhythmic risk. The system is based on simulations of how different compounds affect the action potential duration (APD) of isolated endocardial, midmyocardial, and epicardial cells as well as the QT prolongation in a virtual tissue. Multiple channel-drug interactions and state-of-the-art human ventricular action potential models ( O'Hara , T. , PLos Comput. Biol. 2011 , 7 , e1002061 ) were used in our simulations. Specifically, 206.766 cellular and 7072 tissue simulations were performed by blocking the slow and the fast components of the delayed rectifier current ( IKs and IKr, respectively) and the L-type calcium current ( ICaL) at different levels. The performance of our system was validated by classifying the proarrhythmic risk of 84 compounds, 40 of which present torsadogenic properties. On the basis of these results, we propose the use of a new index (Tx) for discriminating torsadogenic compounds, defined as the ratio of the drug concentrations producing 10% prolongation of the cellular endocardial, midmyocardial, and epicardial APDs and the QT interval, over the maximum effective free therapeutic plasma concentration (EFTPC). Our results show that the Tx index outperforms standard methods for early identification of torsadogenic compounds. Indeed, for the analyzed compounds, the Tx tests accuracy was in the range of 87-88% compared with a 73% accuracy of the hERG IC50 based test. ; L.R., J.C., J.G., B.T., J.S.: This work was partially supported by the Direccion General de Política Cientifíca de la Generalitat Valenciana (PROMETEU2016/088) as well as Ministerio de Economia y Competitividad and Fondo Europeo de Desarrollo Regional (FEDER) DPI2015-69125-R (MINECO/FEDER, UE). F.S, M.P.: received support from the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement no. 115002 (eTOX), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in-kind contributions

Operația multidomeniu, deși încă insuficient dezvoltată din punct de vedere teoretic și, mai ales, practic, poate rezuma schimbarea de paradigmă produsă la nivelul strategic, schimbare datorată evoluțiilor din mediul actual de securitate. Însă, deși acest tip de operație înglobează noile tipuri de tehnologii dezvoltate, în principal, ca nevoie pragmatică de către nivelul tactic și care își propune obținerea unor soluții coerente pentru contracararea amenințării de tip A2AD (anti acces și interdicție) la nivelul strategic, coordonarea aspectelor necesare desfășurării unei astfel de operații pare, în momentul de față, destul de dificil de realizat de către nivelul operativ, acesta având ca scop combinarea inovativă a tacticilor specifice categoriilor de forțe ale armatei pentru îndeplinirea obiectivelor de nivel operativ și strategic. Apreciem că ceea ce lipsește în momentul de față, ca instrument de planificare și ducere a acțiunilor militare, este modalitatea de obținere a unor efecte interdomenii. Astfel, în acest articol vom analiza măsura în care obținerea de efecte interdomenii în operația multidomeniu poate reprezenta liantul necesar implementării unei astfel de operații.

En 2018, el consumo de alcohol por los menores de edad sigue siendo un grave problema de salud pública en España. Por ello, volvemos a reflexionar sobre los cambios legislativos propuestos en la normativa estatal sobre la materia y su posible eficacia tanto en la protección de la infancia y la adolescencia como de la salud y prevención de las drogodependencias. También exponemos como esta problemática ha sido abordada, con diferentes perspectivas, por las normas de las Comunidades Autónomas.

Chronic exposure to specific carcinogens present in secondhand smoke has been associated with different types of cancers. Hair is an ideal matrix to develop a proper biomarker as it absorbs substances in circulation and allows measuring their average concentration over long periods of time. A method was developed for the simultaneous quantification of nicotine, cotinine, NNN, NNK and NNAL in 20 mg human hair samples. Concentrations were significantly different depending on the declared exposure. This study shows for the first time that NNK is present in hair samples from non-smokers in concentrations much higher than any other tobacco specific nitrosamine. NNN could also be detected in samples from the most exposed non-smokers while, as previously reported, NNAL was undetectable. NNK correlates well with nicotine and cotinine (rsp = 0.774 and rsp = 0.792 respectively, p < 0.001 in both cases). However, NNN concentrations did not correlate with any of the other analytes. Ratios between NNK and nicotine show variability with different concentrations of NNK present in samples with similar nicotine values. NNK has proven to be the best marker of tobacco specific nitrosamines in hair. Monitoring NNK may provide a good estimation of cancer risk associated with exposure to secondhand smoke. ; This study was funded by Instituto de Salud Carlos III, Subdirección General de Evaluación y Fomento de la Investigación, PN I + D + I 2008-2011, co-funded by the European Regional Development Fund (FEDER), Government of Spain (Grants PI081339, PI081436 and RTICC RD12/0036/0053).

BACKGROUND AND PURPOSE: Anatomical, biochemical and pharmacological evidence suggest the existence of a crosstalk between the orexinergic and endocannabinoid systems. While the orexin receptor 1 (OX1 receptor) modulates the reinforcing properties of cannabinoids, the participation of orexins in the acute pharmacological effects of Δ(9) -tetrahydrocannabinol (THC) remains unexplored. EXPERIMENTAL APPROACH: We assessed the possible role of orexins in THC-induced hypolocomotion, hypothermia, antinociception, anxiolytic- and anxiogenic-like effects and memory impairment. Selective OX1 and OX2 receptor antagonists and OX1 knockout (KO) mice as well as prepro-orexin (PPO) KO mice were used as pharmacological and genetic approaches. CB1 receptor levels in control and PPO KO mice were evaluated by immunoblot analysis. The expression of c-Fos after THC treatment was analysed in several brain areas in wild-type mice and in mice lacking the PPO gene. KEY RESULTS: The hypothermia, supraspinal antinociception and anxiolytic-like effects induced by THC were modulated by orexins through OX2 receptor signalling. OX1 receptors did not seem to be involved in these THC responses. No differences in CB1 receptor levels were found between wild-type and PPO KO mice. THC-induced increase in c-Fos expression was reduced in the central amygdala, medial preoptic area and lateral septum in these mutant mice. CONCLUSIONS AND IMPLICATIONS: Our results provide new findings to further clarify the interaction between orexins and cannabinoids. OX1 and OX2 receptors are differently implicated in the pharmacological effects of cannabinoids. ; This work was supported by the Instituto de Salud Carlos III grants [#PI13/00042 and #RD12/0028/0023 (RTA-RETICS)], by the Spanish Ministry of Science (#SAF2011-29864 and #SAF2014-59648-P), National Plan on Drugs (#2014I019) and the Catalan Government (SGR2014-1547)

Social stress in adulthood enhances cocaine self-administration, an effect that has been related with an increase in extracellular signal-regulated kinase and p38α mitogen-activated protein kinase phosphorylation. A detrimental effect of cocaine on blood-brain barrier (BBB) integrity has also been reported. This study evaluates the effects of repeated social defeat (RSD) during adolescence on the reinforcing and motivational effects of cocaine in adult mice and the changes induced by RSD on BBB permeability. Cocaine self-administration, conditioned place preference and quantitative analysis of claudin-5, laminin, collagen-IV and IgG immunoreactivity took place 3 weeks after RSD. Mice socially defeated during adolescence developed conditioned place preference and exhibited reinstated preference with a non-effective dose of cocaine (1 mg/kg). RSD mice needed significantly more sessions than control animals for the preference induced by 25 mg/kg of cocaine to be extinguished. However, acquisition of cocaine self-administration (0.5 mg/kg per injection) was delayed in the RSD group. Mice exposed to RSD displayed significant changes in BBB structure in adulthood, with a marked reduction in expression of the tight junction protein claudin-5 and an increase in basal laminin degradation (reflected by a decrease in laminin and collagen-IV expression) in the nucleus accumbens and hippocampus. The detrimental effect induced by cocaine (25 mg/kg) on collagen-IV expression in the hippocampus was more pronounced in RSD mice. In summary, our findings suggest that stress and cocaine can increase the long-term vulnerability of the brain to subsequent environmental insults as a consequence of a sustained disruption of the BBB. ; This work was supported by the Spanish Ministerio de Economía y Competitividad 'Instituto de Salud Carlos III', RETICS: RD12/0028/0005, RD12/0028/0023, RD12/0028/0002, PSI2011-24762, PSI2014-51847-R, SAF2011-29864 and SAF2013-40592-R. It is also supported by the Catalan Government (2014SGR1547) and the Valenciano Government (PROMETEOII/2014/063). The research leading to these results has also received funding from the European Community's Seventh Framework Programme (NEUROPAIN, HEALTH-F2-2013)