Hypoxia/hypoglycemia preconditioning prevents the loss of functional electrical activity in organotypic slice cultures.

In cerebral ischemic preconditioning (IPC), a first sublethal ischemia increases the resistance of neurons to a subsequent severe ischemia. Despite numerous studies, the mechanisms are not yet fully understood. Our goal is to develop an in vitro model of IPC on hippocampal organotypic slice cultures. Instead of anoxia, we chose to apply varying degrees of hypoxia that allows us various levels of insult graded from mild to severe. Cultures are exposed to combined oxygen and glucose deprivation (OGD) of varying intensities, ranging from mild to severe, assessing both the electrical activity and cell death. IPC was accomplished by exposure to the mildest ischemia condition (10% of O2 for 15 min) 24 h before the severe deprivation (5% of O2 for 30 min). Interestingly, IPC not only prevented delayed ischemic cell death 6 days after insult but also the transient loss of evoked potential response. The major interest and advantage of this system over both the acute slice preparation and primary cell cultures is the ability to simultaneously measure the delayed neuronal damage and neuronal function.

IL-2- and CD25-dependent immunoregulatory mechanisms in the homeostasis of T-cell subsets.

IL-2 plays a pivotal role in regulating the adaptive immune system by controlling the survival and proliferation of regulatory T (Treg) cells, which are required for the maintenance of immune tolerance. Moreover, IL-2 is implicated in the differentiation and homeostasis of effector T-cell subsets, including T(H)1, T(H)2, T(H)17, and memory CD8+ T cells. The IL-2 receptor is composed of 3 distinct subunits, namely the alpha (CD25), beta (CD122), and gamma (gammac) chains. Of crucial importance for the delivery of IL-2 signals to Treg cells is the expression of CD25, which, along with CD122 and gammac, confers high affinity binding to IL-2. Notably, recent findings suggest a novel role for CD25, whereby CD25 molecules on Treg cells and possibly other cells are capable of influencing T-cell homeostasis by means of IL-2 deprivation. This review explores these findings and integrates them into our current understanding of T-cell homeostasis.

Psychiatrie et violence : quel est le risque acceptable ?

L'évolution des connaissances et des compétences en matière d'évaluation et de gestion du risque de violence a permis une indiscutable avancée. Néanmoins les instruments utilisés restent encore source de controverses et prêtent le flanc à de nombreuses critiques. Dans ce contexte le climat sécuritaire actuel fait peser une lourde pression sur les équipes soignantes qui ont aussi à faire face à la violence des patients. Une réflexion sur les possibilités et les limites autant du soin que de la privation de liberté permet, peut-être d'envisager ce qu'est un risque acceptable. Evolution of knowledge and skills in violence risk management and assessment allowed an indisputable progress. Nevertheless instruments used such as HCR-20 still remain source of controversy and gives occurrence to numerous criticisms. In this context, the current high security climate puts added pressure on the medical teams which also have to deal with the violence of patients. A reflection on the possibilities and the limits of care as well as freedom deprivation may allow us to envision what is an acceptable risk.

Taxes de reincidència 2006 de justícia juvenil: actualització de la taxa de reincidència dels joves sotmesos a mesures de llibertat vigilada i internament en centre

L’estudi actualitza les taxes de reincidència dels menors sotmesos a una mesura d’internament o de llibertat vigilada que van ser publicades a la recerca “La reincidència en el delicte en la justícia de menors” l’any 2005. Si en aquell estudi es recollien per primer cop dades sobre la reincidència dels joves infractors que havien entrat en el circuit de la justícia de menors després de la posada en marxa de la Llei Orgànica 5/2000, de 12 de gener, reguladora de la responsabilitat penal dels menors (LORPM), en aquest s’actualitzen les dades pel col•lectiu de joves que van ser sotmesos a mesures de llibertat vigilada i internament i que les van finalitzar durant l’any 2003. Es fa un seguiment als joves fins a finals del 2006 per saber si han reincidit. També s’ha seguit als joves que hagin arribat a la majoria d’edat per saber si han entrat novament en el sistema d’execució penal, en aquest cas sentenciat al compliment d’una mesura penal alternativa, o a una mesura de privació de llibertat. L’estudi pretén iniciar una sèrie que permeti comparar els resultats anualment, de manera que puguem veure l’evolució de l’execució penal juvenil en algunes de les variables estudiades.

Taxes de reincidència 2007 de justícia juvenil Actualització de la taxa de reincidència dels joves sotmesos a mesures de llibertat vigilada i internament en centre

L’estudi actualitza les taxes de reincidència dels menors sotmesos a una mesura d’internament o de llibertat vigilada que van ser publicades a la recerca “La reincidència en el delicte en la justícia de menors” finalitzada l’any 2005 i que van iniciar la sèrie. Aquesta recerca ja és la tercera del mateix tipus i en aquest cas estudia els joves que van finalitzar una mesura de llibertat vigilada i d’internament l’any 2004 i els segueix fins el 31 de desembre de 2007, per saber si han comès un nou delicte que hagi estat detectat per la Xarxa d’execució penal, tant de joves com d’adults. S’ha estudiat tota la població de joves desinternats de centres (N=169 subjectes l’any 2004). En el cas de llibertat vigilada, del total de joves que finalitzaren mesura l’any 2004 (N= 718), s’ha fet una mostra de 558 subjectes (interval de confiança:95,5%; marge d’error±2;p=q=50). Els resultats en llibertat vigilada apunten un descens significatiu en la taxa de reincidència, que ha passat del 31,9% al 2005 al 22,0% el 2007. En canvi en internament la fluctuació de la taxa no dona diferències significatives tot i que el 2005 era del 62,8%, va augmentar al 66,9% el 2006 i ha tornat a baixar al 56,2% l’any 2007. L’estudi permet comparar de forma seriada ja tres anys d’evolució de la taxa de reincidència juvenil després de la posada en marxa de la Llei Orgànica 5/2000, de 12 de gener, reguladora de la responsabilitat penal dels menors (LORPM).

Tasas de reincidencia 2007 de justicia juvenil: actualización de la tasa de reincidencia de los jóvenes sometidos a medidas de libertad vigilada y internamiento en centro

El estudio actualiza las tasas de reincidencia que se publicaron en 2005 en la investigación “La reincidencia en el delito en la justicia de menores”, relativas al colectivo de jóvenes que finalizaron medidas de libertad vigilada e internamiento durante el año 2004. Para ello se ha realizado un seguimiento de estos sujetos hasta finales de 2007. Este es ya el tercer estudio que se realiza de forma seriada sobre esta materia, y permite comparar los tres años de evolución de la tasa de reincidencia juvenil tras la puesta en marcha de la Ley Orgánica 5/2000, reguladora de la responsabilidad penal de los menores.

Alterations of Neuromuscular Function after the World's Most Challenging Mountain Ultra-Marathon.

We investigated the physiological consequences of the most challenging mountain ultra-marathon (MUM) in the world: a 330-km trail run with 24000 m of positive and negative elevation change. Neuromuscular fatigue (NMF) was assessed before (Pre-), during (Mid-) and after (Post-) the MUM in experienced ultra-marathon runners (n = 15; finish time  = 122.43 hours ±17.21 hours) and in Pre- and Post- in a control group with a similar level of sleep deprivation (n = 8). Blood markers of muscle inflammation and damage were analyzed at Pre- and Post-. Mean ± SD maximal voluntary contraction force declined significantly at Mid- (-13±17% and -10±16%, P<0.05 for knee extensor, KE, and plantar flexor muscles, PF, respectively), and further decreased at Post- (-24±13% and -26±19%, P<0.01) with alteration of the central activation ratio (-24±24% and -28±34% between Pre- and Post-, P<0.05) in runners whereas these parameters did not change in the control group. Peripheral NMF markers such as 100 Hz doublet (KE: -18±18% and PF: -20±15%, P<0.01) and peak twitch (KE: -33±12%, P<0.001 and PF: -19±14%, P<0.01) were also altered in runners but not in controls. Post-MUM blood concentrations of creatine kinase (3719±3045 Ul·(1)), lactate dehydrogenase (1145±511 UI·L(-1)), C-Reactive Protein (13.1±7.5 mg·L(-1)) and myoglobin (449.3±338.2 µg·L(-1)) were higher (P<0.001) than at Pre- in runners but not in controls. Our findings revealed less neuromuscular fatigue, muscle damage and inflammation than in shorter MUMs. In conclusion, paradoxically, such extreme exercise seems to induce a relative muscle preservation process due likely to a protective anticipatory pacing strategy during the first half of MUM and sleep deprivation in the second half.

Renoncement aux soins: comment appréhender cette réalité en médecine de premier recours [Patients forgoing health care for economic reasons: how to identify this in a primary care setting?].

Although the performance of the Swiss health system is high, one out of ten patients in general practitioner's (GP) office declares having foregone care in the previous twelve months for economic reasons. Reasons for foregoing care are several and include a lack of knowledge of existing social aids in getting health insurance, unavailability of GPs and long waiting lists for various types of care. Although long term knowledge of patients or a psychosocial history of deprivation or poverty may help identify individuals at risk of foregoing care, many may remain undetected. We propose then a few instruments to help GPs to identify, in a simple and structured approach, patients at risk of forgoing care for economic reasons; these patients are frequently deprived and sometimes poor.

Uncovering a role for micro-RNAs in sleep homeostasis and energy metabolism

Micro-RNAs (miRNAs) are key, post-transcriptional regulators of gene expression and have been implicated in almost every cellular process investigated thus far. However, their role in sleep, in particular the homeostatic aspect of sleep control, has received little attention. We here assessed the effects of sleep deprivation on the brain miRNA transcriptome in the mouse. Sleep deprivation affected miRNA expression in a brain-region specific manner. The forebrain expression of the miRNA miR-709 was affected the most and in situ analyses confirmed its robust increase throughout the brain, especially in the cerebral cortex and the hippocampus. The hippocampus was a major target of the sleep deprivation affecting 37 miRNAs compared to 52 in the whole forebrain. Moreover, independent from the sleep deprivation condition, miRNA expression was highly region-specific with 45% of all expressed miRNAs showing higher expression in hippocampus and 55% in cortex. Next we demonstrated that down-regulation of miRNAs in Com/c2o-expressing neurons of adult mice, through a conditional and inducible Dicer knockout mice model (cKO), results in an altered homeostatic response after sleep deprivation eight weeks following the tamoxifen-induced recombination. Dicer cKO mice showed a larger increase in the electro-encephalographic (EEG) marker of sleep pressure, EEG delta power, and a reduced Rapid Eye Movement sleep rebound, compared to controls, highlighting a functional role of miRNAs in sleep homeostasis. Beside a sleep phenotype, Dicer cKO mice developed an unexpected, severe obesity phenotype associated with hyperphagia and altered metabolism. Even more surprisingly, after reaching maximum body weight 5 weeks after tamoxifen injection, obese cKO mice spontaneously started losing weight as rapidly as it was gained. Brain transcriptome analyses in obese mice identified several obesity-related pathways (e.g. leptin, somatostatin, and nemo-like kinase signaling), as well as genes involved in feeding and appetite (e.g. Pmch, Neurotensin). A gene cluster with anti-correlated expression in the cerebral cortex of post-obese compared to obese mice was enriched for synaptic plasticity pathways. While other studies have identified a role for miRNAs in obesity, we here present a unique model that allows for the study of processes involved in reversing obesity. Moreover, our study identified the cortex as a brain area important for body weight homeostasis. Together, these observations strongly suggest a role for miRNAs in the maintenance of homeostatic processes in the mouse, and support the hypothesis of a tight relationship between sleep and metabolism at a molecular - Les micro-ARNS (miARNs) sont des régulateurs post-transcriptionnels de l'expression des gènes, impliqués dans la quasi-totalité des processus cellulaires. Cependant, leur rôle dans la régulation du sommeil, et en particulier dans le maintien de l'homéostasie du sommeil, n'a reçu que très peu d'attention jusqu'à présent. Dans cette étude, nous avons étudié les conséquences d'une privation de sommeil sur l'expression cérébrale des miARNs chez la souris, et observé des changements dans l'expression de nombreux miARNs. Dans le cerveau antérieur, miR-709 est le miARN le plus affecté par la perte de sommeil, en particulier dans le cortex cérébral et l'hippocampe. L'hippocampe est la région la plus touchée avec 37 miARNs changés comparés à 52 dans le cerveau entier. Par ailleurs, indépendamment de la privation de sommeil, certains miARNs sont spécifiquement enrichis dans certaines aires cérébrales, 45% des miARNs étant surexprimés dans l'hippocampe contre 55% dans le cortex. Dans une seconde étude, nous avons observé que la délétion de DICER, enzyme essentielle à la biosynthèse des miARNs, et la perte subséquente des miARNs dans les neurones exprimant la protéine CAMK2a altère la réponse homéostatique à une privation de sommeil, 8 semaines après l'induction de la recombinaison génétique par le tamoxifen. Les souris sans Dicer (cKO) ont une plus large augmentation de l'EEG delta power, le principal marqueur électro-encéphalographique du besoin de sommeil, comparée aux contrôles, ainsi qu'un rebond en sommeil paradoxal plus petit. De façon surprenante, les souris Dicer cKO développent une obésité rapide, sévère et transitoire, associée à de l'hyperphagie et une altération de leur métabolisme énergétique. Après avoir atteint un pic maximal d'obésité, les souris cKO entrent spontanément dans une période de perte de poids rapide. L'analyse du transcriptome cérébral des souris obèses nous a permis d'identifier des voies associées à l'obésité (leptine, somatostatine et nemo-like kinase), et à la prise alimentaire (Pmch, Neurotensin), tandis que celui des souris post-obèses a révélé un groupe de gènes liés à la plasticité synaptique. Au-delà des nombreux modèles d'obésité existant chez la souris, notre étude présente un modèle unique permettant d'étudier les mécanismes sous-jacent la perte de poids. De plus, nous avons mis en évidence un rôle important du cortex cérébral dans le maintien de la balance énergétique. En conclusion, toutes ces observations soutiennent l'idée que les miARNs sont des régulateurs cruciaux dans le maintien des processus homéostatiques et confortent l'hypothèse d'une étroite relation moléculaire entre le sommeil et le métabolisme.

Homer1a is a core brain molecular correlate of sleep loss.

Sleep is regulated by a homeostatic process that determines its need and by a circadian process that determines its timing. By using sleep deprivation and transcriptome profiling in inbred mouse strains, we show that genetic background affects susceptibility to sleep loss at the transcriptional level in a tissue-dependent manner. In the brain, Homer1a expression best reflects the response to sleep loss. Time-course gene expression analysis suggests that 2,032 brain transcripts are under circadian control. However, only 391 remain rhythmic when mice are sleep-deprived at four time points around the clock, suggesting that most diurnal changes in gene transcription are, in fact, sleep-wake-dependent. By generating a transgenic mouse line, we show that in Homer1-expressing cells specifically, apart from Homer1a, three other activity-induced genes (Ptgs2, Jph3, and Nptx2) are overexpressed after sleep loss. All four genes play a role in recovery from glutamate-induced neuronal hyperactivity. The consistent activation of Homer1a suggests a role for sleep in intracellular calcium homeostasis for protecting and recovering from the neuronal activation imposed by wakefulness.

La llibertat vigilada: pena accessòria o mesura de seguretat contra els condemnats per delictes sexuals i delictes de terrorisme

La llibertat vigilada s'incorpora al Codi penal com una mesura de seguretat a imposar a subjectes plenament responsables que hagin estat condemnats per delictes contra la llibertat i indemnitat sexual i per terrorisme, el compliment de la mateixa tindrà lloc una vegada que hagin complert la pena privativa de llibertat

IPH response to DSD Urban Regeneration and Community Development Policy Framework Consultation

The Urban Regeneration and Community Development Policy Framework for Northern Ireland sets out for DSD and its partners, clear priorities for urban regeneration and community development programmes, both before and after the operational responsibility for these is transferred to councils under the reform of local government. Four policy objectives have been developed, which will focus on the underlying structural problems in urban areas and also help strengthen community development throughout Northern Ireland. The policy objectives are as follows: Policy Objective 1 – To tackle area-based deprivation: Policy Objective 2 – To strengthen the competitiveness of our towns and cities: Policy Objective 3 – To improve linkages between areas of need and areas of opportunity: and Policy Objective 4 –To develop more cohesive and engaged communities. Key points from IPH response Urban regeneration and community development provide a basis for addressing the social determinants of health and reducing inequalities in health. This policy framework presents an opportunity for coherence and complementarity with ‘Fit and Well - Changing Lives’ as part of government’s overall approach to tackling health inequalities. It is now well established that a focus on early years’ interventions and family support services yields significant returns, so prioritising action in these areas is essential. Defined action plans on child poverty are essential if this policy framework is to make a real and lasting difference in deprived urban areas. Development of the environmental infrastructure to improve health in deprived areas should be supported by well-planned monitoring and evaluation. Linking the policy framework to economic development and local community plans will enhance effectiveness in the areas of education, job creation, commercial investment and access to services, which in turn are critical for the economic growth and stability of urban communities. Community profile data and health intelligence (as available through IPH Health Well) could usefully inform central and local government in terms of resource allocation and targeted service delivery.

IPH Response to draft Northern Ireland Programme for Government 2011-15

On 17 November 2011, the First Minister and deputy First Minister published the draft Programme for Government 2011-2015 for consultation. IPH recognise that health is influenced by a wide range of social determinants, including economic, biological, environmental and cultural factors such as housing, the environment, income, employment and access to education and health services . Improvements to health can be achieved through a well-designed PfG which addresses the economy, creates safer communities and delivers efficient public services.  IPH welcome this opportunity to submit our views to the Northern Ireland Executive on the Draft Programme for Government 2011-15. Key points from the IPH response include: • Northern Ireland has a poor population health status in key areas when compared to other regions in the United Kingdom and in the Republic of Ireland. IPH support and particularly welcome allocation of an increased proportion of the Northern Ireland budget to public health. • IPH endorses the perspective in the PfG that good population health makes a central contribution to economic and social development.   However we would welcome greater acknowledgement of the links between social deprivation and health outcomes.  • IPH welcomes the adoption of a social determinants of health approach to improving population health and tackling health inequalities which is in line with current health policy and recent policy developments across the United Kingdom and internationally (See report of the Commission on the Social Determinants of Health (CSDH))

IPH response to Social Investment Fund Consultation

The Social Investment Fund aims to reduce poverty, unemployment and physical deterioration in areas through area based interventions of significant scale which will be delivered in partnership with communities. The fund will encourage communities, statutory agencies, businesses and departments to work together in a coordinated way, reducing duplication, sharing best practice and enhancing provision for the benefits of those communities most in need. IPH calls for a consideration of health to be included in the Social Investment Fund.  Each of the four objectives of the programme will have the potential to positively impact on health by increasing education attainment and skill levels, tackling deprivation, increasing community support and enhancing the physical regeneration of communities.  IPH also call for greater clarification on the links with other area based partnerships.

Role of ENaC in skin wound healing and phenotypic analysis of GILZ-deficient mice

In my first project, I analyzed the role of the amiloride-sensitive epithelial sodium channel ENaC) in the skin during wound healing. ENaC is present in the skin and a function in keratinocyte differentiation and barrier formation has been demonstrated. Previous findings suggested, that ENaC might be implicated in keratinocyte migration, although its role in wound healing was not analyzed yet. Using skin-specific (K14-Cre) conditional ENaC knockout and overexpressing mice, I determined the wound closure kinetic and performed morphometric measurements. The time course of wound repair was not significantly different in knockouts or transgenics when compared to control mice and the morphology of the closing wound was not altered. In my second project, I studied the glucocorticoid-induced leucine zipper (GILZ, Tsc22d3). GILZ is widely expressed and an important role has been predicted in immunity, adipogenesis and renal sodium handling. Mice were generated that constitutively lack all the functional domains of the Gilz gene. In these mice, the expression of GILZ mRNA transcripts and protein were completely abolished in all tissues tested. Surprisingly, knockout mice survived. To test whether GILZ mimicks glucocorticoid action, we studied its implication in T- and B- cell development and in a model of sepsis. We measured cytokine secretion in different inflammatory models, like in peritoneal and bone marrow-derived macrophages, in splenocytes and a model of sepsis. In all our experiments, cytokine secretion from GILZ- deficient cells was not different from controls. From 6 months onwards, knockout mice contained significantly less body fat and were lighter. Following sodium and water deprivation experiments, water and salt homeostasis was preserved. Sterility of knockout males was associated with a severe testis dysplasia, smaller seminiferous tubules, the number of Sertoli and germ cell was reduced while increased apoptosis, but not cell proliferation, was evidenced. The interstitial Leydig cell population was augmented, and higher plasma FSH and testosterone levels were found. Interestingly, the expression of the target gene Ppar2 was diminished in the testis and in the liver, but not in the skin, kidney or fat. Tsc22d1 mRNA transcript level was found to be upregulated in testis, but not in the kidney or fat tissue. In most tissue, excepted the testis, GILZ-deficient mice reveal functional redundancy amongst members of the Tsc22d family or genes involved in the same regulatory pathways. In summary, contrarily to the published in vitro data, GILZ does not play a crucial role attributed in immunology or inflammation, but we identified a novel function in spermatogenesis. -- Dans mon premier projet, j'ai analysé le rôle du canal épithélial sodique sensible à l'amiloride (ENaC) dans la cicatrisation de la peau. ENaC est présent dans la peau et il a une fonction dans la différenciation des kératinocytes et dans la formation de la barrière. Des études suggèrent qu'ENaC pourrait être impliqué dans la migration des kératinocytes, cependant, son rôle dans la cicatrisation n'a pas encore été étudié. A l'aide de souris qui surexpriment ou qui sont knockout pour ENaC, spécifiquement dans la peau (K14-Cre), j'ai analysé le temps de clôture de la cicatrice et j'ai aussi étudié la morphologie de la plaie guérissant. Chez les souris qui surexpriment ou chez les knockouts, la vitesse de fermeture et la morphologie de la cicatrice étaient identiques aux souris contrôles. Dans mon second projet, j'ai étudié le glucocorticoid-induced leucine zipper (GILZ, Tsc22d3). GILZ est largement exprimé et un rôle important a été prédit dans l'immunité, l'adipogénèse et le transport sodique rénal. Des souris ont été générées dont les domaines fonctionnels du gène Gilz sont éliminés. L'expression de GILZ en ARNm et protéine a été complètement abolie dans tous les tissus testés. Étonnamment, ces souris knockout survivent. Afin de tester si GILZ imite les effets des glucocorticoïdes, nous avons étudié son implication dans le développement des cellules T et B ainsi qu'un modèle de septicémie. Nous avons mesuré la sécrétion de cytokines à partir de différents modèles d'inflammation tels que des macrophages péritonéaux ou de moelle, de splénocytes ou encore d'un modèle de septicémie. Dans toutes nos expériences, la sécrétion de cytokines de cellules GILZ-déficientes était semblable. Dès 6 mois, les knockouts contenaient significativement moins de graisses et étaient plus légères. Suite à une privation sodique et aqueuse, l'homéostasie du sel et de l'eau était préservée. Les mâles knockouts présentaient une stérilité accompagnée d'une dysplasie testiculaire sévère, de tubules séminifères étaient plus petits et contenaient un nombre réduit de cellules de Sertoli et de cellules germinales. L'apoptose était augmentée dans ces cellules mais pas la prolifération cellulaire. Le nombre de cellules de Leydig était aussi plus élevé, ainsi que la FSH et la testostérone. L'expression du gène cible Pparγ2 était diminuée dans le testicule et le foie, mais pas dans la peau, le rein ou le tissu adipeux. L'ARNm de Tsc22d1 était plus exprimé dans le testicule, mais pas dans le rein ou le tissu adipeux. Dans la plupart des tissus, sauf le testicule, les souris knockouts révélaient une redondance fonctionnelle des autres membres de la famille Tsc22d ou de gènes impliqués dans les mêmes voies de régulation. En résumé, contrairement aux données in vitro, GILZ ne joue pas un rôle essentiel en immunologie, mais nous avons identifié une nouvelle fonction dans la spermatogénèse.