24 research outputs found

    Oxidative Stress: A Pathogenic Mechanism for Niemann-Pick Type C Disease

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    Niemann-Pick type C (NPC) disease is a neurovisceral atypical lipid storage disorder involving the accumulation of cholesterol and other lipids in the late endocytic pathway. The pathogenic mechanism that links the accumulation of intracellular cholesterol with cell death in NPC disease in both the CNS and the liver is currently unknown. Oxidative stress has been observed in the livers and brains of NPC mice and in different NPC cellular models. Moreover, there is evidence of an elevation of oxidative stress markers in the serumof NPC patients. Recent evidence strongly suggests that mitochondrial dysfunction plays an important role in NPC pathogenesis and that mitochondria could be a significant source of oxidative stress in this disease. In this context, the accumulation of vitamin E in the late endosomal/lysosomal compartments in NPC could lead to a potential decrease of its bioavailability and could be another possible cause of oxidative damage. Another possible source of reactive species in NPC is the diminished activity of different antioxidant enzymes. Moreover, because NPC is mainly caused by the accumulation of free cholesterol, oxidized cholesterol derivatives produced by oxidative stress may contribute to the pathogenesis of the disease

    Mycobacterium tuberculosis multi-drug-resistant strain M induces IL-17+ IFNγ- CD4+ T cell expansion through an IL-23 and TGF-β-dependent mechanism in patients with MDR-TB tuberculosis

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    We have previously reported that T cells from patients with multidrug-resistant tuberculosis (MDR-TB) express high levels of IL-17 in response to the MDR strain M(Haarlem family) of Mycobacterium tuberculosis (M.tuberculosis). Herein, we explore the pathways involved in the induction of h17 cells in MDR-TB patients and healthy tuberculin reactors (PPD+HD) by the M strain and the laboratory strain H37Rv. Our results show that IL-1β and IL-6 are crucial for the H37Rv and M-induced expansion of IL-17+IFNγ¯ and IL-17+IFNγ+ in CD4+ T cells from MDR-TB and PPD+HD. IL-23 plays an ambiguous role in Th1 and Th17 profiles: alone, IL-23 is responsible for M.tuberculosis induced IL-17 and IFNγ expression in CD4+ T cells from PPD+HD whereas, together with TGF-β, it promotes IL-17+IFNγ¯ expansion in MDR-TB. In fact, spontaneous and M.tuberculosis-induced TGF-β secretion is increased in cells from MDR-TB being theM strain the highest inducer. Interestingly, TLR-2 signaling mediates the expansion of IL-17+IFNγ¯ cells and the enhancement of latency-associated protein (LAP) expression in CD14+ and CD4+ T cells from MDR-TB, which suggests that M strain promotes IL-17+IFNγ¯ T cells through a strong TLR-2-dependent TGF-β production by antigenpresenting cells and CD4+ T cells. Finally, CD4+ T cells from MDR-TB patients infected with MDR Haarlem strains show higher IL-17+IFNγ¯ and lower IL-17+IFNγ+ levels than LAM-infected patients. The present findings deepen our understanding on the role of IL-17 in MDR-TB and highlight the influence of the genetic background of the infecting M.tuberculosis strain on the ex vivo Th17 response.Fil: Basile, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Kviatcovsky, Denise. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Romero, María Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Balboa, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Monteserin, Johana. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”; ArgentinaFil: Ritacco, Gloria Viviana. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”; ArgentinaFil: López, Beatriz. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”; ArgentinaFil: Sabio y García, Carmen Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: García, A.. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas “Dr. Francisco Javier Muñiz”; ArgentinaFil: Vescovo, M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas “Dr. Francisco Javier Muñiz”; ArgentinaFil: Gonzalez Montaner, Pablo. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas “Dr. Francisco Javier Muñiz”; ArgentinaFil: Palmero, Domingo. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas “Dr. Francisco Javier Muñiz”; ArgentinaFil: Sasiain, María del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: de la Barrera, Silvia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

    Clínicas del trabajo en Chile : tres experiencias de intervención en una sociedad dañada por la gestión ‘managerial’

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    El artículo se propone problematizar el proceso de transformaciones del trabajo contemporáneo en Chile. Se describen tres experiencias desde las clínicas del trabajo (educacional, psicosocial y socioanálisis) en diferentes escenarios laborales. A su vez, se realiza una reflexión sobre la pertinencia de la clínica del trabajo como forma de intervención para contribuir a la comprensión de los procesos subjetivos de los trabajadores, en su dimensión individual, grupal y política.O artigo propõe-se problematizar o processo de transformações do trabalho contemporâneo no Chile. Três experiências são descritas a partir de estudos desenvolvidas na perspetiva das clínicas do trabalho (educacional, psicossocial e socioanálise) em diferentes cenários de trabalho. A seguir, faz-se uma reflexão sobre a relevância da abordagem da clínica do trabalho como forma de intervenção que contribui para a compreensão dos processos subjetivos dos trabalhadores, nas suas dimensões individual, grupal e política.L'article propose une problématisation du processus de transformation du travail contemporain au Chili. Trois expériences sont décrites au départ d’études menées selon la perspective des cliniques de travail (éducatives, psychosociales et socio-analytiques) dans différents scénarios de travail. Une réflexion est menée ensuite à propos de la pertinence de l’approche de la clinique du travail, définie en tant que mode d’intervention contribuant à la compréhension des processus subjectifs des travailleurs, dans leur dimension individuelle, de groupe et politique.The paper aims at problematizing the process of contemporary work transformations in Chile. Three experiences are described from a clinical point of view (pedagogical, psychosocial and socio-analytical) in different work scenarios. Then, it reflects on the relevance of the clinical approach as a form of intervention, which contributes to the understanding of the workers’ subjective processes, in their individual, group and political dimensions

    Outbreaks of mycobacterium tuberculosis MDR strains induce high IL-17 T-cell response in patients with MDR tuberculosis that is closely associated with high antigen load

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    Fil: Basile, Juan I. Academia Nacional de Medicina. Instituto de Investigaciones Hematológicas Mariano R. Castex; Argentina.Fil: Geffner, Laura J. Academia Nacional de Medicina. Instituto de Investigaciones Hematológicas Mariano R. Castex; Argentina.Fil: Romero, María M. Academia Nacional de Medicina. Instituto de Investigaciones Hematológicas Mariano R. Castex; Argentina.Fil: Balboa, Luciana. Academia Nacional de Medicina. Instituto de Investigaciones Hematológicas Mariano R. Castex; Argentina.Fil: Sabio y García, Carmen. Academia Nacional de Medicina. Instituto de Investigaciones Hematológicas Mariano R. Castex; Argentina.Fil: Ritacco, Viviana. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas; Argentina.Fil: García, Ana. Hospital Muñíz. Instituto de Tisioneumonologías; Argentina.Fil: Cuffré, Mónica. Hospital Muñíz. Instituto de Tisioneumonologías; Argentina.Fil: Abbate, Eduardo. Hospital Muñíz. Instituto de Tisioneumonologías; Argentina.Fil: López, Beatriz. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas; Argentina.Fil: Barrera, Lucía. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas; Argentina.Fil: Ambroggi, Marta. Hospital Muñíz. Instituto de Tisioneumonologías; Argentina.Fil: Alemán, Mercedes. Academia Nacional de Medicina. Instituto de Investigaciones Hematológicas Mariano R. Castex; Argentina.Fil: Sasiain, María C. Academia Nacional de Medicina. Instituto de Investigaciones Hematológicas Mariano R. Castex; Argentina.Fil: de la Barrera, Silvia S. Academia Nacional de Medicina. Instituto de Investigaciones Hematológicas Mariano R. Castex; Argentina.Background. The proinflammatory cytokine interleukin 17 (IL-17) plays an important role in immune responses but it is also associated with tissue-damaging inflammation. So, we evaluated the ability of Mycobacterium tuberculosis clinical isolates to induce IL-17 in tuberculosis (TB) patients and in healthy human tuberculin reactors (PPD1HD). Methods. IL-17, interferon c (IFN-c), and interleukin 23 (IL-23) receptor expression were evaluated ex vivo and cultured peripheral blood mononuclear cells from TB and PPD1HD stimulated with irradiated clinical isolates from multidrug resistant (MDR) outbreaks M (Haarlem family) and Ra (Latin American–Mediterranean family), as well as drug-susceptible isolates belonging to the same families and laboratory strain H37Rv for 48 hours in T-cell subsets by flow cytometry. Results. We observed that: (1) MDR strains M and Ra are stronger IL-17 inducers than drug-susceptible Mtb strains of the Haarlem and Latin American–Mediterranean families, (2) MDR-TB patients show the highest IL-17 expression that is independent on the strain, (3) IL-17 expression is dependent on CD41 and CD81 T cells associates with persistently high antigen load. Conclusions. IL-17–producing T cells could play an immunopathological role in MDR-TB promoting severe tissue damage, which may be associated with the low effectiveness of the second-line drugs employed in the treatment

    Diseño para el desarrollo sustentable y la habitabilidad segura e incluyente

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    Este libro se divide en dos partes que permiten permear en el campo de la enseñanza del diseño; la primera se enfoca en temáticas que se desprenden del diseño en la educación para la sustentabilidad; en la segunda, se identifican las tendencias del diseño como un modo de verlo y sentirlo: va desde el diseño emocional hacia uno de conservación, reúso y reparación de objetos para reducir el consumo de recursos materiales

    Une cachette redécouverte : les objets métalliques antiques de Noyal-Châtillon-sur-Seiche (Ille-et-Vilaine, Bretagne).

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    Labaune-Jean Françoise, Baratte François, Balboa-Garcia Alejandra, Biron Marina, Jean Stéphane. Une cachette redécouverte : les objets métalliques antiques de Noyal-Châtillon-sur-Seiche (Ille-et-Vilaine, Bretagne).. In: Aremorica. Études sur l'ouest de la Gaule romaine, n°6, 2014. pp. 89-113

    C5aR contributes to the weak Th1 profile induced by an outbreak strain of Mycobacterium tuberculosis

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    Fil: Sabio Y García, Carmen Alejandra. Academia Nacional de Medicina. Instituto de Medicina Experimental; Argentina.Fil: Yokobori, Noemí. Academia Nacional de Medicina. Instituto de Medicina Experimental; Argentina.Fil: Basile, Juan Ignacio. Academia Nacional de Medicina. Instituto de Medicina Experimental; Argentina.Fil: Balboa, Luciana. Academia Nacional de Medicina. Instituto de Medicina Experimental; Argentina.Fil: González, Alejandra. Hospital Nacional A. Posadas. Servicio de Neumonología; Argentina.Fil: López, Beatriz. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas; Argentina.Fil: Ritacco, Viviana. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas; Argentina.Fil: Barrera, Silvia de la. Academia Nacional de Medicina. Instituto de Medicina Experimental; Argentina.Fil: Sasiain, María Del Carmen. Academia Nacional de Medicina. Instituto de Medicina Experimental; Argentina.C5a anaphylatoxin is a component of the complement system involved in the modulation of T-cell polarization. Herein we investigated whether C5a receptors, C5aR and C5L2, modulate the cytokine profiles induced by Mycobacterium tuberculosis (Mtb). We analyzed the impact of both receptors on T helper cell polarization induced by the multidrug resistant outbreak strain named M, which is a poor IFN-γ inducer compared with the laboratory strain H37Rv. To this aim, we first blocked C5aR or C5L2 of peripheral blood monocytes (Mo) from patients with tuberculosis and healthy donors, then we stimulated the Mo either with H37Rv or the M strain, and finally we analyzed cytokine profiles of Mo/macrophages (MΦ) and CD4+ T-cells. We found that: (i) Mtb modulated the expression of both C5a receptors, (ii) C5aR inhibited the expansion of CD4+IFN-γ+ lymphocytes stimulated by the M strain but not by H37Rv, (iii) both receptors modulated the Mo/MΦ cytokine expression induced by Mtb. We conclude that C5aR, but not C5L2, plays a role in T helper cell polarization induced by Mtb and that this effect is strain- and donor-dependent. We speculate that the epidemiologically successful M strain takes advantage of this C5aR-mediated inhibition of Th1 polarization to survive within the host

    Vitamin E Dietary Supplementation Improves Neurological Symptoms and Decreases c-Abl/p73 Activation in Niemann-Pick C Mice

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    Niemann-Pick C (NPC) disease is a fatal neurodegenerative disorder characterized by the accumulation of free cholesterol in lysosomes. We have previously reported that oxidative stress is the main upstream stimulus activating the proapoptotic c-Abl/p73 pathway in NPC neurons. We have also observed accumulation of vitamin E in NPC lysosomes, which could lead to a potential decrease of its bioavailability. Our aim was to determine if dietary vitamin E supplementation could improve NPC disease in mice. NPC mice received an alpha-tocopherol (α-TOH) supplemented diet and neurological symptoms, survival, Purkinje cell loss, α-TOH and nitrotyrosine levels, astrogliosis, and the c-Abl/p73 pathway functions were evaluated. In addition, the effect of α-TOH on the c-Abl/p73 pathway was evaluated in an in vitro NPC neuron model. The α-TOH rich diet delayed loss of weight, improved coordination and locomotor function and increased the survival of NPC mice. We found increased Purkinje neurons and α-TOH levels and reduced astrogliosis, nitrotyrosine and phosphorylated p73 in cerebellum. A decrease of c-Abl/p73 activation was also observed in the in vitro NPC neurons treated with α-TOH. In conclusion, our results show that vitamin E can delay neurodegeneration in NPC mice and suggest that its supplementation in the diet could be useful for the treatment of NPC patients
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