Caractérisation des fonctions immunomodulatrices de la Cardiotrophin-Like Cytokine

La Cardiotrophin-Like Cytokine (CLCF1) est une cytokine de la famille de l’IL-6 connue principalement pour ses fonctions neurotrophiques médiées par l’activation du récepteur au CNTF (CNTFR). Contrairement à son homologue le CNTF, CLCF1 est efficacement sécrété des cellules sous forme de cytokine composite avec le récepteur soluble CRLF1. Des mutations dans les gènes codants pour CLCF1 ou son partenaire de sécrétion le CRLF1 mènent au développement des syndromes CISS et Crisponi, deux syndromes sévères comprenant des phénotypes complexes similaires. L’étude des phénotypes des patients CISS et Crisponi a mené à l’hypothèse de l’existence d’importantes fonctions non redondantes de CLCF1 dans le développement et la régulation du système immunitaire. Afin de caractériser les activités immunomodulatrices de cette cytokine, nous avons initialement étudié les rôles de CLCF1 dans l’hématopoïèse. Nous avons observé que CLCF1 stimule la prolifération des cellules hématopoïétiques multipotentes et induit l’expansion de celles-ci en absence d’autres facteurs de croissance. In vivo, l’administration de la cytokine a fortement accéléré la reconstitution des cellules myéloïdes dans un modèle de transplantation congénique de moelle osseuse. Ces résultats suggèrent des rôles jusqu’alors non identifiés de CLCF1 dans la régulation de la myélopoïèse. Dans une étude subséquente, nous avons évalué la capacité de CLCF1 à moduler l’activation des cellules myéloïdes. Pour ce faire, nous avons étudié l’impact de CLCF1 sur la différenciation et la fonction des macrophages. Au cours de ce projet, nous avons déterminé que CLCF1 1) active les voies de signalisation JAK/STAT dans les macrophages dérivés de la moelle osseuse (BMDM), 2) induit l’augmentation de l’expression du récepteur éboueur SR-A1 et 3) favorise la formation des cellules spumeuses proathérogènes. Ensemble, ces résultats indiquent que CLCF1 pourrait être une nouvelle cible thérapeutique à étudier dans des modèles précliniques d’athérosclérose. Alors que CLCF1 a auparavant été présenté comme un facteur de stimulation des lymphocytes B, les résultats contenus dans les deux premiers articles de cette thèse suggèrent des fonctions biologiques dans la formation et la régulation des cellules myéloïdes. Parallèlement, nous avons défini de nouvelles interactions biochimiques entre CLCF1 et les lipoprotéines plasmatiques. Nous avons notamment démontré l’existence de complexes entre CLCF1 et l’apolipoprotéine E ainsi qu’avec les lipoprotéines de basse et de très basse densité. De manière intéressante, notre étude indique que les activités biologiques de CLCF1 sont modulées par des lipoprotéines de très basse densité. Ces résultats révèlent une interaction directe entre les lipoprotéines et les cytokines et suggèrent que certaines composantes métaboliques sont en mesure de moduler les fonctions immunes des cytokines. Les résultats présentés dans cette thèse ont ainsi mené à une meilleure compréhension des propriétés immunomodulatrices de la Cardiotrophin-Like cytokine et de son potentiel d’applications thérapeutiques.Cardiotrophin-Like Cytokine (CLCF1) is a cytokine of the IL-6 family recognized primarily for its neurotrophic functions mediated by CNTF receptor activation (CNTFR). In contrast to its counterpart CNTF, CLCF1 is efficiently secreted as a composite cytokine with the soluble receptor CRLF1. Mutations in the genes encoding for CLCF1 or its secretion partner CRLF1 lead to the development of CISS and Crisponi syndromes, two severe conditions associated with complex overlapping phenotypes. Studying patients’ phenotypes led us to hypothesize important, non-redundant CLCF1 functions in the development and regulation of the immune system. To characterize the immunomodulatory properties of this cytokine, we first studied the roles of CLCF1 in hematopoiesis. We observed that CLCF1 stimulates the proliferation of multipotent hematopoietic cells and induces their expansion in absence of other growth factors. In vivo, administration of the cytokine accelerated myeloid cell reconstitution in a model of congenic bone marrow transplantation. These results therefore suggest yet-unidentified roles for CLCF1 in myelopoiesis regulation. In a subsequent study, we assessed the ability of CLCF1 to modulate myeloid cell activation. Assessing the impact of CLCF1 on macrophages functions and differentiation, we determined that CLCF1 1) activates JAK/STAT signaling pathways in bone marrow-derived macrophages (BMDM), 2) induces the upregulation of scavenger receptor SR-A1 expression and 3) promotes the formation of pro-atherogenic foam cells. Altogether, these results indicate that CLCF1 may constitute a novel and attractive therapeutic target to be investigated in preclinical models of atherosclerosis. While CLCF1 has previously been recognized as a B-cell stimulating factor, the results presented in the first two articles of this thesis indicate biological functions for CLCF1 in the formation and regulation of myeloid cells. In parallel, we defined new biochemical interactions between CLCF1 and plasma lipoproteins. In particular, we have demonstrated the existence of complexes between CLCF1, apolipoprotein E, low- and very low-density lipoproteins. Furthermore, we observed that CLCF1 biological activities are modulated by very low-density lipoproteins. These results provide evidence of direct interactions between lipoproteins and cytokines and suggest that certain metabolic components modulate the immune functions of type I cytokines. In conclusion, the results summarized in this thesis have improved our understanding of CLCF1 immunomodulatory properties and of its potential therapeutic applications

Estrategias de vacunación en Atención Primaria

Las actividades de inmunización no son exclusivas de la infancia, sino que deben proseguirse a lo largo de toda la vida, con un calendario vacunal que contemple las diferentes características de cada individuo (edad, condiciones laborales, viajes, enfermedades concomitantes, etc. ). La vacunación es, ante todo, una medida sanitaria de actuación sobre la comunidad que busca la protección o inmunidad colectiva o de grupo, a través de la cual, se ha conseguido una importante reducción de la incidencia y de la mortalidad asociadas a determinadas enfermedades inmunoprevenibles con relación a la era prevacunal. El efecto final (efectividad) de un programa de vacunaciones está condicionado tanto por la propia eficacia de la vacuna como por la cobertura vacunal (porcentaje de la población diana correctamente vacunada). La atención primaria constituye un contexto único para aplicar estrategias que favorezcan los objetivos del programa de vacunaciones. La progresiva informatización de los centros de salud permite utilizar metodología innovadora como los programas facilitados por los Centers of Disease Control de Atlanta (CDC) para el asesoramiento clínico de inmunización. http://www.cdc.gov/nip/casa/Default.htm que, acompañado de otras medidas, logran incrementar y mantener en el tiempo las coberturas vacunales. Los tres pilares de información sobre los que se sustentan los programas de vacunación son: La vigilancia epidemiológica de las enfermedades sujetas a control (enfermedades de declaración obligatoria, sistemas de información microbiológica, conjunto mínimo básico de datos de alta hospitalaria, etc.), Conocimiento de las coberturas vacunales, Estudios de seroprevalencia. Junto a estrategias generales de inmunización existen estrategias específicas dirigidas a grupos de riesgo. Estos suelen caracterizarse por bajas coberturas vacunales y donde suelen encontrarse los grupos a los que hay que dirigirse de forma específica, a veces relacionadas con falta de información sobre vacunaciones: viajeros, inmigrantes, poblaciones marginales, profesiones de riesgo, discapacitados, enfermos (inmunodeprimidos , enfermedades metabólicas, cardiópatas,...) y sujetos con condiciones de riesgo (drogadicción, promiscuidad sexual,...) En cualquier intervención en materia de vacunaciones, se hace imprescindible la coordinación entre los diferentes profesionales del equipo de Atención Primaria: médicos de familia, pediatras, enfermeros/as y trabajadores sociales.Una adecuada estructura del programa, junto a una correcta práctica profesional, son los apoyos básicos para la consecución de las metas de todo programa de vacunaciones: elevadas coberturas inmunitarias -merced a la consecución de altas coberturas vacunales- y reducción de la morbimortalidad por enfermedades inmunoprevenibles. En resumen, las líneas de avance inmediato han de aprovechar las oportunidades que ofrecen la gestión en atención primaria, las tecnologías de la información y la comunicación y la implicación de los ciudadanos en el diseño de futuros calendarios vacunales pediátricos y del adulto. Estas estrategias seguramente incrementarán las coberturas vacunales de la población que actualmente está menos inmunizada

Reflections on the Conception and Exercise of Law: Neoconstitucionalism and Hermeneutical Keys

La tesis principal de este artículo se puede formular de un modo sencillo. El estudio inicialmente se dirige a responder dos cuestiones muy concretas: ¿está cambiando la concepción del derecho en nuestros días?, ¿los cambios que se producen son suficientes para poder hablar de una nueva concepción del derecho? Como se ve, se trata esencialmente de contrastar y analizar la operatividad de las principales concepciones clásicas del derecho. Pero se trata también de ir perfilando, aunque sea sobre la marcha, posibles soluciones que comprendan y se adapten mejor al problema en cuestión. Es decir, en función de las transformaciones y cambios operados en la realidad jurídica contemporánea, el autor de este artículo también intentará ofrecer y valerse de una concepción más adecuada o que mejor se corresponda con dicha realidad.The main thesis of this article can be formulated in a simple way. The study initially aimed to answer two concrete questions: is it changing the conception of law nowadays?, are the changes that take place sufficient to be able to speak about a new conception of law? Since one sees, it is a question of confirming and analyze essentially the operability of the main classic conceptions of law. But it treats itself also of being outlining, though it is as you go along, possible solutions that they understand and adapt better to the problem in question. That is to say, depending on the transformations and changes produced in the juridical contemporary reality, the author of this article also will try to offer and to use of a conception more suitable or that better corresponds with the above mentioned reality

Effects of a cooling vest with sham condition on walking capacity in heat-sensitive people with Multiple Sclerosis

Purpose: Heat sensitivity is a common contraindication in people with Multiple Sclerosis (pwMS), and physical fatigue is one of the most frequently reported symptoms that can affect quality of life. Increases in body temperature may exacerbate fatigue and heat-related symptoms. Decreasing body temperature via cooling devices may mitigate disease symptoms and improve physical abilities and quality of life. This study evaluates the effects of a cooling vest with sham condition on walking capacity using a commercially-available cooling vest specifically designed for pwMS. Methods: A counter-balanced, cross-over design was used to assess the effects of a cooling vest (CryoVest Comfort, CryoInnov, France) (COLD) from a menthol-induced sham condition (CON) on ground walking time to exhaustion (Tex, s) and distance at exhaustion (Dex, m) in ambulatory pwMS. Secondary outcomes were heart rate (HR, bpm), thermal sensation (Tsens), skin chest (Tchest) and back (Tback) temperature. Results: Ten females with Multiple Sclerosis (59 \ub1 9\ua0years, EDSS 3.0\u20135.5) participated to the study. During COLD, pwMS walked significantly longer (1896 \ub1 602 vs. 1399 \ub1 404\ua0s, p < 0.001) and farther (1879 \ub1 539 vs. 1302 \ub1 318\ua0m, p < 0.001) than CON. Importantly, Tsens and HR at exhaustion were not significantly different between conditions, although Tchest ( 12\ua02.7 \ub1 1.8\ua0\ub0C, p < 0.01) and Tback ( 12\ua03.9 \ub1 1.8\ua0\ub0C, p < 0.001) were lower at volitional fatigue during COLD. Conclusion: The lightweight cooling vest improved total walking time and distance in heat-sensitive pwMS. These physiological improvements were likely due to feeling perceptually cooler in the COLD trial, compared to the corresponding point of fatigue in the CON condition

Attenuation of Acute Renal Injury After the Post-resuscitation Administration of Doxycycline in Surviving Newborn Piglets With Severe Hypoxia-Reoxygenation

Background: Asphyxiated neonates often have myocardial dysfunction and renal insufficiency. Previously we demonstrated that doxycycline improved cardio-renal function through matrix metalloproteinase (MMP)-2 inhibition in an acute swine model of neonatal hypoxia-reoxygenation. The prolonged cardio-renal protective effects of doxycycline in neonates still remained unknown. We therefore hypothesized that the protective effects of doxycycline persisted in surviving subjects.Methods: Newborn piglets were instrumented and subjected to 1 h of hypoxia followed by reoxygenation with 21–25% oxygen and observed for 4 days. Intravenous doxycycline (30 mg/kg) or normal saline (1 mL, saline-control group) was given at 5 min of reoxygenation (n = 8/group) in a randomized, blinded fashion. Sham-operated piglets (n = 5) received no hypoxia-reoxygenation. At 96 h after reoxygenation, the left ventricular function was assessed by Millar® catheter. Renal injury was investigated by measuring plasma creatinine, urinary N-acetyl-D-glucosaminidase activity, renal tissue lactate and MMP-2 activity.Results: Both hypoxia-reoxygenation groups had similar hypoxic stress with severe lactate acidosis, and hemodynamic recovery. Doxycycline-treated piglets had higher urine output with lower urine N-acetyl-D-glucosaminidase, plasma creatinine, and renal MMP-2 activity (vs. saline-controls; all p &lt; 0.05). These markers were all negatively correlated with urine output.Conclusions: In newborn piglets surviving hypoxia-reoxygenation, we observed a weak but significant and persistent attenuation of renal injury and improved recovery with the post-resuscitation administration of doxycycline

Elliptic and hyperelliptic magnetohydrodynamic equilibria

The present study is a continuation of a previous one on "hyperelliptic" axisymmetric equilibria started in [Tasso and Throumoulopoulos, Phys. Plasmas 5, 2378 (1998)]. Specifically, some equilibria with incompressible flow nonaligned with the magnetic field and restricted by appropriate side conditions like "isothermal" magnetic surfaces, "isodynamicity" or P + B^2/2 constant on magnetic surfaces are found to be reducible to elliptic integrals. The third class recovers recent equilibria found in [Schief, Phys. Plasmas 10, 2677 (2003)]. In contrast to field aligned flows, all solutions found here have nonzero toroidal magnetic field on and elliptic surfaces near the magnetic axis.Comment: 9 page