Role of the hypocretin system in cocaine- and alcohol-related behaviors : evidence from hypocretin-deficient mice

RésuméL'addiction aux drogues est une maladie multifactorieile affectant toutes les strates de notre société. Cependant, la vulnérabilité à développer une addiction dépend de facteurs environnementaux, génétiques et psychosociaux. L'addiction aux drogues est décrite comme étant une maladie chronique avec un taux élevé de rechutes. Elle se caractérise par un besoin irrépressible de consommer une drogue et une augmentation progressive de la consommation en dépit des conséquences néfastes. Les mécanismes cérébraux responsables des dépendances aux drogues ne sont que partiellement élucidés, malgré une accumulation croissante d'évidences démontrant des adaptations au niveau moléculaire et cellulaire au sein des systèmes dopaminergique et glutamatergique. L'identification de nouveaux facteurs neurobiologiques responsables de la vulnérabilité aux substances d'abus est cruciale pour le développement de nouveaux traitements thérapeutiques capables d'atténuer et de soulager les symptômes liés à la dépendance aux drogues.Au cours des dernières années, de nombreuses études ont démontré qu'un nouveau circuit cérébral, le système hypocrétinergique, était impliqué dans plusieurs fonctions physiologiques, tel que l'éveil, le métabolisme énergétique, la motivation, le stress et les comportements liés aux phénomènes de récompense. Le système hypocrétinergique est composé d'environ 3000-4000 neurones issus de l'hypothalamus latéral projetant dans tout ie cerveau. Des souris transgéniques pour le gène des hypocrétines ont été générées et leur phénotype correspond à celui des animaux sauvages, excepté le fait qu'elles soient atteintes d'attaques de sommeil similaires à celles observées chez les patients narcoleptiques. H semblerait que les hypocrétines soient requises pour l'acquisition et l'expression de la dépendance aux drogues. Cependant, le mécanisme précis reste encore à être élucidé. Dans ce rapport, nous rendons compte des comportements liés aux phénomènes de récompense liés à l'alcool et à la cocaine chez les souris knock-out (KO), hétérozygotes (HET) et sauvages (WT).Nous avons, dans un premier temps, évalué l'impact d'injections répétées de cocaïne (15 mg/kg, ip) sur la sensibilisation locomotrice et sur le conditionnement place préférence. Nous avons pu observer que les souris WT, HET et KO exprimaient une sensibilisation locomotrice induite par une administration chronique de cocaïne, cependant les souris déficientes en hypocrétines démontraient une sensibilisation retardée et atténuée. Π est intéressant de mentionner que les mâles HET exprimaient une sensibilisation comportementale intermédiaire. Après normalisation des données, toutes les souris exprimaient une amplitude de sensibilisation similaire, excepté les souris mâles KO qui affichaient, le premier jour de traitement, une sensibilisation locomotrice réduite et retardée, reflétant un phénotype hypoactif plutôt qu'une altération de la réponse aux traitements chroniques de cocaïne. Contre toute attente, toutes les souris femelles exprimaient un pattern similaire de sensibilisation locomotrice à la cocaïne. Nous avons ensuite évalué l'effet d'un conditionnement comportemental à un environnement associé à des injections répétées de cocaine (15 mg / kg ip). Toutes les souris, quelque soit leur sexe ou leur génotype, ont manifesté une préférence marquée pour l'environnement apparié à la cocaïne. Après deux semaines d'abstinence à la cocaïne, les mâles et les femelles déficientes en hypocrétines n'exprimaient plus aucune préférence pour le compartiment précédemment associé à la cocaïne. Alors que les souris WT et HET maintenaient leur préférence pour le compartiment associé à la cocaïne. Pour finir, à l'aide d'un nouveau paradigme appelé IntelliCage®, nous avons pu évaluer la consommation de liquide chez les femelles WT, HET et KO. Lorsqu'il n'y avait que de l'eau disponible, nous avons observé que les femelles KO avaient tendance à moins explorer les quatre coins de la cage. Lorsque les souris étaient exposées à quatre types de solutions différentes (eau, ImM quinine ou 0.2% saccharine, alcool 8% et alcool 16%), les souris KO avaient tendance à moins consommer l'eau sucrée et les solutions alcoolisées. Cependant, après normalisation des données, aucune différence significative n'a pu être observée entre les différents génotypes, suggérant que la consommation réduite d'eau sucrée ou d'alcool peut être incombée à l'hypoactivité des souris KO.Ces résultats confirment que le comportement observé chez les souris KO serait dû à des compensations développementales, puisque la sensibilisation locomotrice et le conditionnement comportemental à la cocaïne étaient similaires aux souris HET et WT. En ce qui concerne la consommation de liquide, les souris KO avaient tendance à consommer moins d'eau sucrée et de solutions alcoolisées. Le phénotype hypoactif des souris déficientes en hypocrétine est probablement responsable de leur tendance à moins explorer leur environnement. Il reste encore à déterminer si l'expression de ce phénotype est la conséquence d'un état de vigilance amoindri ou d'une motivation diminuée à la recherche de récompense. Nos résultats suggèrent que les souris déficientes en hypocrétine affichent une motivation certaine à la recherche de récompense lorsqu'elles sont exposées à des environnements où peu d'efforts sont à fournir afin d'obtenir une récompense.AbstractDrug addiction is a multifactorial disorder affecting human beings regardless their education level, their economic status, their origin or even their gender, but the vulnerability to develop addiction depends on environmental, genetic and psychosocial dispositions. Drug addiction is defined as a chronic relapsing disorder characterized by compulsive drug seeking, with loss of control over drug intake and persistent maladaptive decision making in spite of adverse consequences. The brain mechanisms responsible for drug abuse remain partially unknown despite accumulating evidence delineating molecular and cellular adaptations within the glutamatergic and the dopaminergic systems. However, these adaptations do not fully explain the complex brain disease of drug addiction. The identification of other neurobiological factors responsible for the vulnerability to substance abuse is crucial for the development of promising therapeutic treatments able to alleviate signs of drug dependence.For the past few years, growing evidence demonstrated that a recently discovered brain circuit, the hypocretinergic system, is implicated in many physiological functions, including arousal, energy metabolism, motivation, stress and reward-related behaviors. The hypocretin system is composed of a few thousands neurons arising from the lateral hypothalamus and projecting to the entire brain. Hypocretin- deficient mice have been generated, and unexpectedly, their phenotype resembles that of wild type mice excepting sleep attacks strikingly similar to those of human narcolepsy patients. Evidence suggesting that hypocretins are required for the acquisition and the expression of drug addiction has also been reported; however the precise mechanism by which hypocretins modulate drug seeking behaviors remains a matter of debate. Here, we report alcohol and cocaine reward-related behaviors in hypocretin-deficient mice (KO), as well as heterozygous (HET) and wild type (WT) littermates.We first evaluated the impact of repeated cocaine injections (15 mg/kg, ip) on locomotor sensitization and conditioned place preference. We observed that WT, HET and KO mice exhibited behavioral sensitization following repeated cocaine administrations, but hypocretin deficient males displayed a delayed and attenuated response to chronic cocaine administrations. Interestingly, HET males exhibited an intermediate pattern of behavioral sensitization. However, after standardization of the post-injection data versus the period of habituation prior to cocaine injections, all mice displayed similar amplitudes of behavioral sensitization, except a reduced response in KO males on the first day, suggesting that the delayed and reduced cocaine-induced locomotor sensitization may reflect a hypoactive phenotype and probably not an altered response to repeated cocaine administrations. Unexpectedly, all female mice exhibited similar patterns of cocaine-induced behavioral sensitization. We then assessed the behavioral conditioning for an environment repeatedly paired with cocaine injections (15 mg/kg ip). All mice, whatever their gender or genotype, exhibited a robust preference for the environment previously paired with cocaine administrations. Noteworthy, following two weeks of cocaine abstinence, hypocretin-deficient males and females no longer exhibited any preference for the compartment previously paired with cocaine rewards whereas both WT and HET mice continued manifesting a robust preference. We finally assessed drinking behaviors in WT, HET and KO female mice using a novel paradigm, the IntelliCages®. We report here that KO females tended to less explore the four cage comers where water was easily available. When exposed to four different kinds of liquid solutions (water, ImM quinine or saccharine 0.2%, alcohol 8% and alcohol 16%), KO mice tended to less consume the sweet and the alcoholic beverages. However, after data standardization, no significant differences were noticed between genotypes suggesting that the hypoactive phenotype is most likely accountable for the trend regarding the reduced sweet or alcohol intake in KO.Taken together, the present findings confirm that the behavior seen in Hcrt KO mice likely reflects developmental compensations since only a slightly altered cocaine-induced behavioral sensitization and a normal behavioral conditioning with cocaine were observed in these mice compared to HET and WT littermates. With regards to drinking behaviors, KO mice barely displayed any behavioral changes but a trend for reducing sweet and alcoholic beverages. Overall, the most striking observation is the constant hypoactive phenotype seen in the hypocretin-deficient mice that most likely is accountable for their reduced tendency to explore the environment. Whether this hypoactive phenotype is due to a reduced alertness or reduced motivation for reward seeking remains debatable, but our findings suggest that the hypocretin-deficient mice barely display any altered motivation for reward seeking in environments where low efforts are required to access to a reward.

An exploratory study on facial emotion recognition capacity in beginning Alzheimer's disease.

Objective: It was the aim of this study to investigate facial emotion recognition (FER) in the elderly with cognitive impairment. Method: Twelve patients with Alzheimer's disease (AD) and 12 healthy control subjects were asked to name dynamic or static pictures of basic facial emotions using the Multimodal Emotion Recognition Test and to assess the degree of their difficulty in the recognition task, while their electrodermal conductance was registered as an unconscious processing measure. Results: AD patients had lower objective recognition performances for disgust and fear, but only disgust was accompanied by decreased subjective FER in AD patients. The electrodermal response was similar in all groups. No significant effect of dynamic versus static emotion presentation on FER was found. Conclusion: Selective impairment in recognizing facial expressions of disgust and fear may indicate a nonlinear decline in FER capacity with increasing cognitive impairment and result from progressive though specific damage to neural structures engaged in emotional processing and facial emotion identification. Although our results suggest unchanged unconscious FER processing with increasing cognitive impairment, further investigations on unconscious FER and self-awareness of FER capacity in neurodegenerative disorders are required.

Impending status epilepticus and anxiety in a pregnant woman treated with levetiracetam.

Levetiracetam (LEV) has been considered to undergo no significant change in bioavailability during pregnancy; however, it was recently demonstrated to display modifications leading to a drop in its serum level. We describe a patient who displayed impending status epilepticus following a fall in her LEV level during the first trimester. The oral LEV dosage was increased, and phenytoin and benzodiazepines were transiently prescribed. She experienced severe anxiety and an unbearable fear over the deleterious consequences for her baby despite repeated, reassuring explanations. Her anxiety was so strong that she aborted electively shortly after leaving the hospital. This observation emphasizes the need for LEV level monitoring during pregnancy to prevent unexpected seizure relapses. The rapid increase in levetiracetam dosage in parallel with the loss of seizure control is suspected of facilitating the induction of significant psychiatric changes.

Änderung des Therapieziels am Lebensende: Effekte einer Klinik-Leitlinie [Changing the treatment goal at the end of life: effects of a guideline at a hospital].

BACKGROUND AND OBJECTIVE: Deciding about treatment goals at the end of life is a frequent and difficult challenge to medical staff. As more health care institutions issue ethico-legal guidelines to their staff the effects of such a guideline should be investigated in a pilot project.¦PARTICIPANTS AND METHODS: Prospective evaluation study using the pre-post method. Physicians and nurses working in ten intensive care units of a university medical center in Germany answered a specially designed questionnaire before and one year after issuance of the guideline.¦RESULTS: 197 analyzable answers were obtained from the first (pre-guideline) and 251 from the second (post-guideline) survey (54 % and 58 % response rate, respectively). Initially the clinicians expressed their need for guidelines, advice on ethical problems, and continuing education. One year after introduction of the guideline one third of the clinicians was familiar with the guideline's content and another third was aware of its existence. 90% of those who knew the document welcomed it. Explanation of the legal aspects was seen as its most useful element. The pre- and post-guideline comparison demonstrated that uncertainty in decision making and fear of legal consequences were reduced, while knowledge of legal aspects and the value given to advance directives increased. The residents had derived the greatest benefit.¦CONCLUSION: By promoting the knowledge of legal aspects and ethical considerations, guidelines given to medical staff can lead to more certainty when making in end of life decision.

Does falls efficacy predict gait performance in high-functioning older people?

Introduction: Falls efficacy, defined as confidence in performing activities without falling, is a measure of fear of falling associated with gait impairment, falls and functional decline in frail older people. This relationship has not been well studied in high-functioning older people. Objective: To evaluate the relationship between falls efficacy and gait performance in a cohort of high-functioning older people. Methods: Subjects (N = 864) were a subsample of communitydwelling older people aged 65 to 70 years, enrolled in the "Lc65+" cohort, who completed gait assessment at baseline. Data were collected on demographics, functional, cognitive, affective, and health status. Falls efficacy was assessed using the Falls Efficacy Scale- International (FES-I) that measures confidence in performing 16 activities of daily life (ADL) without falling (score from 16 to 64, higher score indicates lower confidence). Gait parameters were measured over a 20 m walk at preferred gait speed using Physilog, an ambulatory gait monitoring system. Results: Participants (mean age 68.0 ± 1.4 years, 55.0% women) had excellent physical (92.2% independent in basic ADL, mean gait speed 1.13 ± 0.16 m/sec) and cognitive (98.0% with MMSE 024) performance. Nevertheless, 22.1% reported depressive symptoms and 16.1% one or more fall in the previous year. Mean FES-I score was 18.8 ± 4.1. Falls efficacy was associated with gait speed (Spearman rho -0.23, P <.001) and gait variability (Spearman rho 0.10, P = .006), measured by the coefficient of variation of stride velocity. These associations remained in multivariate analysis for both gait speed (adj [beta] coeff: -0.008, 95%CI -0.005 to -0.010, P <.001) and gait variability (adj [beta] coeff 0.024, 95%CI 0.003 to 0.045, P = .023) independent of gender, falls, functional, affective, cognitive, and frailty (Fried's criteria) status. On average, compared to subjects with poor confidence in performing one ADL without falling, those with full confidence had a 0.02 m/sec (2%) faster gait speed and a 2% decrease in gait variability. Conclusion: Even in high-functioning older people, poor falls efficacy is associated with reduced gait speed and stability, independent of health, functional, and frailty status. The direction of this relationship needs to be investigated prospectively to determine causality and design interventions to improve gait performance, reduce fall risk, and prevent functional decline.

The Outlaw Pirate Heroine, An Analysis of a Durgā Figure in a 1935 Prabhat Film

(Résumé de l'ouvrage) She kills and destroys. She causes illness and disaster. The wild goddess evokes fear and terror. People worship her with blood-sacrifices and alcohol in order to appease her rage, but also in order to participate in her power for she is at once a force of destruction and a force of regeneration, of life, and of sexuality. Her creative violence reflects the ambivalent power of nature. The idea of frightening goddesses is preserved in regionally different forms throughout South Asia. The Institute for the Science of Religions, University of Berne, and the Museum of Anthropology of the University of Zurich, coordinated a symposium on wild goddesses in India and Nepal. The papers and reports on ongoing research presented at this symposium are published in this volume.

Essays in higher moment asset pricing and liquidity risk

This thesis focuses on theoretical asset pricing models and their empirical applications. I aim to investigate the following noteworthy problems: i) if the relationship between asset prices and investors' propensities to gamble and to fear disaster is time varying, ii) if the conflicting evidence for the firm and market level skewness can be explained by downside risk, Hi) if costly learning drives liquidity risk. Moreover, empirical tests support the above assumptions and provide novel findings in asset pricing, investment decisions, and firms' funding liquidity. The first chapter considers a partial equilibrium model where investors have heterogeneous propensities to gamble and fear disaster. Skewness preference represents the desire to gamble, while kurtosis aversion represents fear of extreme returns. Using US data from 1988 to 2012, my model demonstrates that in bad times, risk aversion is higher, more people fear disaster, and fewer people gamble, in contrast to good times. This leads to a new empirical finding: gambling preference has a greater impact on asset prices during market downturns than during booms. The second chapter consists of two essays. The first essay introduces a foramula based on conditional CAPM for decomposing the market skewness. We find that the major market upward and downward movements can be well preadicted by the asymmetric comovement of betas, which is characterized by an indicator called "Systematic Downside Risk" (SDR). We find that SDR can efafectively forecast future stock market movements and we obtain out-of-sample R-squares (compared with a strategy using historical mean) of more than 2.27% with monthly data. The second essay reconciles a well-known empirical fact: aggregating positively skewed firm returns leads to negatively skewed market return. We reconcile this fact through firms' greater response to negative maraket news than positive market news. We also propose several market return predictors, such as downside idiosyncratic skewness. The third chapter studies the funding liquidity risk based on a general equialibrium model which features two agents: one entrepreneur and one external investor. Only the investor needs to acquire information to estimate the unobservable fundamentals driving the economic outputs. The novelty is that information acquisition is more costly in bad times than in good times, i.e. counter-cyclical information cost, as supported by previous empirical evidence. Later we show that liquidity risks are principally driven by costly learning. Résumé Cette thèse présente des modèles théoriques dévaluation des actifs et leurs applications empiriques. Mon objectif est d'étudier les problèmes suivants: la relation entre l'évaluation des actifs et les tendances des investisseurs à parier et à crainadre le désastre varie selon le temps ; les indications contraires pour l'entreprise et l'asymétrie des niveaux de marché peuvent être expliquées par les risques de perte en cas de baisse; l'apprentissage coûteux augmente le risque de liquidité. En outre, des tests empiriques confirment les suppositions ci-dessus et fournissent de nouvelles découvertes en ce qui concerne l'évaluation des actifs, les décisions relatives aux investissements et la liquidité de financement des entreprises. Le premier chapitre examine un modèle d'équilibre où les investisseurs ont des tendances hétérogènes à parier et à craindre le désastre. La préférence asymétrique représente le désir de parier, alors que le kurtosis d'aversion représente la crainte du désastre. En utilisant les données des Etats-Unis de 1988 à 2012, mon modèle démontre que dans les mauvaises périodes, l'aversion du risque est plus grande, plus de gens craignent le désastre et moins de gens parient, conatrairement aux bonnes périodes. Ceci mène à une nouvelle découverte empirique: la préférence relative au pari a un plus grand impact sur les évaluations des actifs durant les ralentissements de marché que durant les booms économiques. Exploitant uniquement cette relation générera un revenu excédentaire annuel de 7,74% qui n'est pas expliqué par les modèles factoriels populaires. Le second chapitre comprend deux essais. Le premier essai introduit une foramule base sur le CAPM conditionnel pour décomposer l'asymétrie du marché. Nous avons découvert que les mouvements de hausses et de baisses majeures du marché peuvent être prédits par les mouvements communs des bêtas. Un inadicateur appelé Systematic Downside Risk, SDR (risque de ralentissement systématique) est créé pour caractériser cette asymétrie dans les mouvements communs des bêtas. Nous avons découvert que le risque de ralentissement systématique peut prévoir les prochains mouvements des marchés boursiers de manière efficace, et nous obtenons des carrés R hors échantillon (comparés avec une stratégie utilisant des moyens historiques) de plus de 2,272% avec des données mensuelles. Un investisseur qui évalue le marché en utilisant le risque de ralentissement systématique aurait obtenu une forte hausse du ratio de 0,206. Le second essai fait cadrer un fait empirique bien connu dans l'asymétrie des niveaux de march et d'entreprise, le total des revenus des entreprises positiveament asymétriques conduit à un revenu de marché négativement asymétrique. Nous décomposons l'asymétrie des revenus du marché au niveau de l'entreprise et faisons cadrer ce fait par une plus grande réaction des entreprises aux nouvelles négatives du marché qu'aux nouvelles positives du marché. Cette décomposition révélé plusieurs variables de revenus de marché efficaces tels que l'asymétrie caractéristique pondérée par la volatilité ainsi que l'asymétrie caractéristique de ralentissement. Le troisième chapitre fournit une nouvelle base théorique pour les problèmes de liquidité qui varient selon le temps au sein d'un environnement de marché incomplet. Nous proposons un modèle d'équilibre général avec deux agents: un entrepreneur et un investisseur externe. Seul l'investisseur a besoin de connaitre le véritable état de l'entreprise, par conséquent, les informations de paiement coutent de l'argent. La nouveauté est que l'acquisition de l'information coute plus cher durant les mauvaises périodes que durant les bonnes périodes, comme cela a été confirmé par de précédentes expériences. Lorsque la récession comamence, l'apprentissage coûteux fait augmenter les primes de liquidité causant un problème d'évaporation de liquidité, comme cela a été aussi confirmé par de précédentes expériences.

Prevalence of social phobia in a clinical sample of drug dependent patients.

INTRODUCTION: Social phobia is among the most frequent psychiatric disorders and can be classified into two subtypes, nongeneralized and generalized. Whereas it significantly worsens the morbidity of comorbid substance abuse disorders, and it often is associated with reduced treatment responses, there is still lacking data on its prevalence in clinical populations of drug abusing patients. METHODS: The study sample consisted of 75 inpatients and 75 outpatients meeting DSM-IV criteria for drug dependence. Symptoms of social phobia were assessed with the French-language version of the Liebowitz Social Anxiety Scale (LSAS). RESULTS: Prevalence rate were 20% for the generalized subtype and 42.6% for the nongeneralized subtype. Gender difference emerged in the severity of fear, women reporting significantly greater fear relating to performance situations than men. CONCLUSIONS: An important proportion of patients with substance dependence present a comorbid generalized or nongeneralized social phobia. Early recognition of social phobia and adequate interventions is warranted for these patients in order to improve their treatment response with regard to quality of life and relapse prevention.

Manual therapy followed by specific active exercises versus a placebo followed by specific active exercises on the improvement of functional disability in patients with chronic non specific low back pain: a randomized controlled trial.

BACKGROUND: Recent clinical recommendations still propose active exercises (AE) for CNSLBP. However, acceptance of exercises by patients may be limited by pain-related manifestations. Current evidences suggest that manual therapy (MT) induces an immediate analgesic effect through neurophysiologic mechanisms at peripheral, spinal and cortical levels. The aim of this pilot study was first, to assess whether MT has an immediate analgesic effect, and second, to compare the lasting effect on functional disability of MT plus AE to sham therapy (ST) plus AE. METHODS: Forty-two CNSLBP patients without co-morbidities, randomly distributed into 2 treatment groups, received either spinal manipulation/mobilization (first intervention) plus AE (MT group; n = 22), or detuned ultrasound (first intervention) plus AE (ST group; n = 20). Eight therapeutic sessions were delivered over 4 to 8 weeks. Immediate analgesic effect was obtained by measuring pain intensity (Visual Analogue Scale) before and immediately after the first intervention of each therapeutic session. Pain intensity, disability (Oswestry Disability Index), fear-avoidance beliefs (Fear-Avoidance Beliefs Questionnaire), erector spinae and abdominal muscles endurance (Sorensen and Shirado tests) were assessed before treatment, after the 8th therapeutic session, and at 3- and 6-month follow-ups. RESULTS: Thirty-seven subjects completed the study. MT intervention induced a better immediate analgesic effect that was independent from the therapeutic session (VAS mean difference between interventions: -0.8; 95% CI: -1.2 to -0.3). Independently from time after treatment, MT + AE induced lower disability (ODI mean group difference: -7.1; 95% CI: -12.8 to -1.5) and a trend to lower pain (VAS mean group difference: -1.2; 95% CI: -2.4 to -0.30). Six months after treatment, Shirado test was better for the ST group (Shirado mean group difference: -61.6; 95% CI: -117.5 to -5.7). Insufficient evidence for group differences was found in remaining outcomes. CONCLUSIONS: This study confirmed the immediate analgesic effect of MT over ST. Followed by specific active exercises, it reduces significantly functional disability and tends to induce a larger decrease in pain intensity, compared to a control group. These results confirm the clinical relevance of MT as an appropriate treatment for CNSLBP. Its neurophysiologic mechanisms at cortical level should be investigated more thoroughly. TRIAL REGISTRATION: Trial registration number: NCT01496144.

Cannabis use in a Swiss male prison: qualitative study exploring detainees' and staffs' perspectives.

BACKGROUND: Several studies suggest a high prevalence of cannabis use before and during imprisonment, but subjective perspectives of detainees and staff towards its use in prison are lacking. This issue was explored in the framework of an observational study addressing tobacco use in three Swiss prisons in 2009 and 2010 that involved multiple strands (quantitative and qualitative components). This article presents qualitative data on cannabis use collected in one of the settings. METHODS: We used in-depth semi-structured interviews with both detainees and staff to explore their attitudes towards cannabis in one post-trial male Swiss prison. We performed specific coding and thematic analysis for cannabis with the support of ATLAS.ti, compared detainees' and staff's opinions, and considered the results with regard to drug policy in prison in general. RESULTS: 58 participants (31 male offenders, mean age 35 years, and 27 prison staff, mean age 46 years, 33% female) were interviewed. Detainees estimated the current use of cannabis use to be as high as 80%, and staff 50%. Participants showed similar opinions on effects of cannabis use that were described both at individual and institutional levels: analgesic, calming, self-help to go through the prison experience, relieve stress, facilitate sleep, prevent violence, and social pacifier. They also mentioned negative consequences of cannabis use (sleepiness, decreased perception of danger and social isolation), and dissatisfaction regarding the ongoing ambiguous situation where cannabis is forbidden but detection in the urine was not sanctioned. However, the introduction of a more restrictive regulation induced fear of violence, increased trafficking and a shift to other drug use. CONCLUSION: Although illegal, cannabis use is clearly involved in daily life in prison. A clearer and comprehensive policy addressing cannabis is needed, including appropriate measures tailored to individual users. To sustain a calm and safe environment in prison, means other than substance or medication use are required.

Treg-therapy allows mixed chimerism and transplantation tolerance without cytoreductive conditioning.

Establishment of mixed chimerism through transplantation of allogeneic donor bone marrow (BM) into sufficiently conditioned recipients is an effective experimental approach for the induction of transplantation tolerance. Clinical translation, however, is impeded by the lack of feasible protocols devoid of cytoreductive conditioning (i.e. irradiation and cytotoxic drugs/mAbs). The therapeutic application of regulatory T cells (Tregs) prolongs allograft survival in experimental models, but appears insufficient to induce robust tolerance on its own. We thus investigated whether mixed chimerism and tolerance could be realized without the need for cytoreductive treatment by combining Treg therapy with BM transplantation (BMT). Polyclonal recipient Tregs were cotransplanted with a moderate dose of fully mismatched allogeneic donor BM into recipients conditioned solely with short-course costimulation blockade and rapamycin. This combination treatment led to long-term multilineage chimerism and donor-specific skin graft tolerance. Chimeras also developed humoral and in vitro tolerance. Both deletional and nondeletional mechanisms contributed to maintenance of tolerance. All tested populations of polyclonal Tregs (FoxP3-transduced Tregs, natural Tregs and TGF-beta induced Tregs) were effective in this setting. Thus, Treg therapy achieves mixed chimerism and tolerance without cytoreductive recipient treatment, thereby eliminating a major toxic element impeding clinical translation of this approach.

The tobacco industry's past role in weight control related to smoking.

BACKGROUND: Smoking is thought to produce an appetite-suppressing effect by many smokers. Thus, the fear of body weight gain often outweighs the perception of health benefits associated with smoking cessation, particularly in adolescents. We examined whether the tobacco industry played a role in appetite and body weight control related to smoking and smoking cessation. METHODS: We performed a systematic search within the archives of six major US and UK tobacco companies (American Tobacco, Philip Morris, RJ Reynolds, Lorillard, Brown & Williamson and British American Tobacco) that were Defendants in tobacco litigation settled in 1998. Findings are dated from 1949 to 1999. RESULTS: The documents revealed the strategies planned and used by the industry to enhance effects of smoking on weight and appetite, mostly by chemical modifications of cigarettes contents. Appetite-suppressant molecules, such as tartaric acid and 2-acetylpyridine were added to some cigarettes. CONCLUSION: These tobacco companies played an active and not disclaimed role in the anti-appetite effects of smoking, at least in the past, by adding appetite-suppressant molecules into their cigarettes.

The philosophical foundations of classical "rDzogs chen" in Tibet : investigating the distinction between dualistic mind (sems) and primordial knowing (ye shes)

While the syncretistic Tibetan tradition known as rDzogs chen ("Great Perfection") has attracted considerable attention over the past few decades, its philosophical foundations remain largely unknown to those unacquainted with its primary sources. This thesis looks at the essentials of rDzogs chen philosophy through the lens of two principal distinctions that the tradition has considered indispensable for understanding its distinctive views and practices: dualistic mind (sems) versus primordial knowing (ye shes) and dharmakâya versus the 'ground of all' (kun gzhi) conditioned experience. Arguing that the distinctions provided classical rDzogs chen scholars with a crucial framework for (a) articulating the necessary conditions of nondual primordial knowing, the conditio sine qua non of rNying ma soteriology, and (b) schematizing the relationship between the exoteric and esoteric vehicles of Indian Buddhism within a unifying conception of the Buddhist path as the progressive disclosure of primordial knowing, the thesis shows how the rDzogs chen philosophy of mind has been integral to the tradition's complex soteriology. The thesis consists of two parts: (1) a detailed philosophical investigation of the distinctions and (2) an anthology of previously untranslated Tibetan materials on the distinctions accompanied by critical editions and introductions. The first part systematically invesigates the nature and scope of the distinctions and traces their evolution and complex relationships with Indian Buddhist Cittamâtra, Madhyamaka, Pramàriavàda, and Vajrayâna views. It concludes with an exploration of some soteriological implications of the mind/primordial knowing distinction that became central to rDzogs chen path hermeneutics in the classical period as authors of rDzogs chen path summaries used this distinction to reconcile progressivist sutric and non-progressivist tantric models of the Buddhist path. The translations and texts included in part two of the thesis consist of (a) a short treatise from Klong chen pa's Miscellaneous Writings entitled Sems dang ye shes kyi dris lan (Reply to Questions Concerning Mind and Primordial Knowing), (b) selected passages on the distinctions from this author's monumental summary of the rDzogs chen snying thig system, the Theg mchog mdzod (Treasury of the Supreme Vehicle), and (c) an excerpt on rDzogs chen distinctions taken from 'Jigs med gling pa's (1729-1798) 18th century Klong chen sNying thig path summary entitled Treasury of Qualities (Yon tan mdzod) along with a word-by- word commentary by Yon tan rgya mtsho (b. 19th c.).

Contrasted influences of moon phases on the reproduction and movement patterns of four amphibian species inhabiting different habitats in central Italy

Many studies have provided evidence that prey adjust their behaviour to adaptively balance the fitness effects of reproduction and predation risk. Nocturnal terrestrial animals should deal with a range of environmental conditions during the reproductive season at the breeding sites, including a variable amount of natural ambient light. High degrees of illumination are expected to minimize those behaviours that might increase the animal detection by predators. Therefore, under habitat variable brightness conditions and in different ecosystems, the above mentioned behaviours are expected to depend on the variation in predation risk. Although moon effects on amphibian biology have been recognized, the direction of this influence is rather controversial with evidences of both increased and depressed activity under full moon. We tested in four nocturnal amphibian species (Hyla intermedia, Rana dalmatina, Rana italica, Salamandrina perspicillata) the effects of different (i) light conditions and (ii) habitats (open land vs. dense forest) on the reproductive phenology. Our results showed that the effects of the lunar cycle on the study species are associated with the change in luminosity, and there is no evidence of an endogenous rhythm controlled by biological clocks. The habitat type conditioned the amphibian reproductive strategy in relation to moon phases. Open habitat breeders (e. g., ponds with no canopy cover) strongly avoided conditions with high brightness, whereas forest habitat breeders were apparently unaffected by the different moon phases. Indeed, for all the studied species no effects of the moon phase itself on the considered metrics were found. Rather, the considered amphibian species seem to be conditioned mainly by moonlight irrespective of the moon phase. The two anurans spawning in open habitat apparently adjust their oviposition timing by balancing the fitness effects of the risk to be detected by predators and the reproduction.