Regulatory T cells decrease C3-positive reactive astrocytes in Alzheimer-like pathology.

BACKGROUND: Increasing evidence supports a key role for peripheral immune processes in the pathophysiology of Alzheimer's disease (AD), highlighting an intricate interplay between brain resident glial cells and both innate and adaptive peripheral immune effectors. We previously showed that regulatory T cells (Tregs) have a beneficial impact on disease progression in AD-like pathology, notably by modulating the microglial response associated with Aß deposits in a mouse model of amyloid pathology. Besides microglia, reactive astrocytes also play a critical role in neuroinflammatory processes associated with AD. Different phenotypes of reactive astrocytes have previously been characterized, including A1-like neurotoxic and A2-like neuroprotective subtypes. However, the precise impact of Tregs on astrocyte reactivity and phenotypes in AD still remains poorly defined. METHODS: We assessed the impact of Treg immunomodulation on astrocyte reactivity in a mouse model of AD-like amyloid pathology. Using 3D imaging, we carried out extensive morphological analyses of astrocytes following either depletion or amplification of Tregs. We further assessed the expression of several A1- and A2-like markers by immunofluorescence and RT-qPCR. RESULTS: Modulation of Tregs did not significantly impact the magnitude of global astrocyte reactivity in the brain nor in the close vicinity of cortical amyloid deposits. We did not observe changes in the number, morphology, or branching complexity of astrocytes according to immunomodulation of Tregs. However, early transient depletion of Tregs modulated the balance of reactive astrocyte subtypes, resulting in increased C3-positive A1-like phenotypes associated with amyloid deposits. Conversely, early depletion of Tregs decreased markers of A2-like phenotypes of reactive astrocytes associated with larger amyloid deposits. Intriguingly, modulation of Tregs also impacted the cerebral expression of several markers of A1-like subsets in healthy mice. CONCLUSIONS: Our study suggests that Tregs contribute to modulate and fine-tune the balance of reactive astrocyte subtypes in AD-like amyloid pathology, by dampening C3-positive astrocytes in favor of A2-like phenotypes. This effect of Tregs may partly relate to their capacity at modulating steady state astrocyte reactivity and homeostasis. Our data further highlight the need for refined markers of astrocytes subsets and strategy of analysis for better deciphering the complexity of astrocyte reactivity in neurodegeneration.

Blocking interleukin-23 ameliorates neuromuscular and thymic defects in myasthenia gravis.

Acetylcholine receptor (AChR) myasthenia gravis (MG) is a chronic autoimmune disease characterized by muscle weakness. The AChR+ autoantibodies are produced by B-cells located in thymic ectopic germinal centers (eGC). No therapeutic approach is curative. The inflammatory IL-23/Th17 pathway is activated in the thymus as well as in the blood and the muscle, contributing to the MG pathogenic events. We aimed to study a potential new therapeutic approach that targets IL-23p19 (IL-23) in the two complementary preclinical MG models: the classical experimental MG mouse model (EAMG) based on active immunization and the humanized mouse model featuring human MG thymuses engrafted in NSG mice (NSG-MG). In both preclinical models, the anti-IL-23 treatment ameliorated MG clinical symptoms. In the EAMG, the treatment reduced IL-17 related inflammation, anti-AChR IgG2b antibody production, activated transduction pathway involved in muscle regeneration and ameliorated the signal transduction at the neuromuscular junction. In the NSG-MG model, the treatment reduced pathogenic Th17 cell population and expression of genes involved in eGC stabilization and B-cell development in human MG thymus biopsies. Altogether, these data suggest that a therapy targeting IL-23p19 may promote significant clinical ameliorations in AChR+ MG disease due to concomitant beneficial effects on the thymus and skeletal muscle defects.

Perifosine treatment in chronic lymphocytic leukemia: results of a phase II clinical trial and in vitro studies.

Abstract Because of the importance of the phosphoinositide 3-kinase (PI3K)/AKT pathway in chronic lymphocytic leukemia (CLL), we evaluated in vitro cytotoxicity induced by perifosine, an AKT inhibitor, in CLL lymphocytes and found that the mean 50% effective dose (ED50) was 313 nM. We then performed a phase II trial of perifosine in patients with relapsed/refractory CLL to assess response, outcomes, toxicity and ex vivo correlative measures. After 3 months of treatment, six of eight patients showed stable disease, one achieved a partial response and one had progressive disease. Median event-free survival and overall survival in all patients treated were 3.9 and 9.7 months. Adverse events included hematologic, infectious/fever, pain, gastrointestinal and constitutional toxicities. Unexpectedly, AKT phosphorylation in CLL lymphocytes from treated patients was not correlated with response. Additionally, perifosine did not inhibit AKT phosphorylation in cultured CLL lymphocytes. Perifosine is cytotoxic to CLL cells in vitro, and largely induces stabilized disease in vivo, with an AKT-independent mechanism.

Phase II study of cenersen, an antisense inhibitor of p53, in combination with fludarabine, cyclophosphamide and rituximab for high-risk chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) with deletion or mutation of TP53 have exceedingly poor clinical outcomes. Cenersen, an oligonucleotide targeting TP53, has been shown to abrogate the activity of TP53 gain-of-function mutants and to increase sensitivity of lymphoma cells to cytotoxic chemotherapy in vitro. We combined cenersen with fludarabine, cyclophosphamide and rituximab (FCR) as treatment for patients with high-risk CLL. The purpose of this phase II study was to determine the overall response rate, response duration and toxicity of cenersen administered in combination with FCR. Twenty patients with relapsed or high-risk CLL were evaluated. Nineteen patients were previously treated. The complete response rate was 18%; the overall response rate was 53%. Median progression-free and overall survival was 5.3 and 10.6 months, respectively. The most common serious adverse events were neutropenia and thrombocytopenia. In this single arm phase II study, cenersen combined with FCR yielded clinical responses with acceptable toxicity in patients with high-risk CLL.

Psicologia e educação a distância: uma revisão bibliográfica / Psychology And Distance Education: a literature review / Psicología Y Educación A Distancia: una revisión de la literatura artigo

O presente estudo investigou as contribuições da Psicologia para a educação a distância - EAD. Para isso, realizou-se revisão bibliográfica de publicações nacionais, entre 1999 e 2009, nas bases de dados SciELO, Lilacs, PsycINFO, BVS e Google Acadêmico. Foram selecionados 69 estudos, dos quais se excluíram 15, por não serem compatíveis com a pesquisa. Os resultados evidenciaram nove eixos temáticos: (1) tecnologia educacional a distância com fundamentos psicológicos, (2) afeição, (3) papel do tutor/professor, (4) teorias psicológicas, (5) interatividade, (6) evasão, (7) relatos de experiências, (8) avaliação de treinamento, desenvolvimento e educação a distância e (9) outros. Os temas tecnologia educacional a distância com fundamentos psicológicos e afeição obtiveram maior frequência nas publicações. Neste estudo, registrou-se, também, que, embora em ascensão desde 2006, os anos de maiores publicações da Psicologia na educação a distância foram 2008 e 2009. Sugere-se que estudos futuros ampliem esta pesquisa para incluir bases de dados internacionais.(AU)

This study investigated the contributions of Psychology to Distance Learning. A literature review of national publications between 1999 to 2009 was made in the electronic databases SciELO, LILACS, PsycINFO, BVS and Google Scholar. From the 69 studies selected, 15 were excluded because they were not compatible with the research. The results showed nine themes: (1) the distance learning technology with psychological grounding, (2) affection, (3)the role of the tutor/professor, (4) psychological theories, (5) interactivity, (6) dropout, (7) reports of experiences, (8) assessment of distance training, development and education and (9) others. The topics distance education technology with psychological grounding and affection had a larger frequency in the publications. Since 2006, there was an increasing number of publications in psychology distance education, but the years of major publications were from 2008 to 2009. It is suggested that future studies expand this research including international databases.(AU)

El presente estudio investigó las contribuciones de la Psicología para la Educación a Distancia - EAD. Para eso, fue realizada una revisión bibliográfica de publicaciones nacionales, entre 1999 y 2009 en las bases de datos SciELO, Lilacs, PsycINFO, BVS y Google Académico. Fueron seleccionados 69 estudios, de los cuales se excluyeron 15, por no ser compatibles con la pesquisa. Los resultados evidenciaron nueve ejes temáticos (1) tecnología educacional la distancia con fundamentos psicológicos; (2) afección; (3) papel del tutor/profesor; (4) teorías psicológicas; (5) interactividad; (6) evasión; (7) relatos de experiencias, (8) evaluación de entrenamiento, desarrollo y educación distancia y (9) otros. Los temas tecnología educacional a distancia con fundamentos psicológicos y afección obtuvieron mayor frecuencia en las publicaciones. En ese estudio se registró, también, que, aunque en ascensión desde 2006, los años de mayores publicaciones de la psicología en la educación a distancia, fueron 2008 y 2009. Se sugiere que estudios futuros amplíen esa pesquisa para incluir bases de datos internacionales.(AU)

Psicologia e educação a distância: uma revisão bibliográfica / Psychology And Distance Education: a literature review / Psicología Y Educación A Distancia: una revisión de la literatura artigo

O presente estudo investigou as contribuições da Psicologia para a educação a distância - EAD. Para isso, realizou-se revisão bibliográfica de publicações nacionais, entre 1999 e 2009, nas bases de dados SciELO, Lilacs, PsycINFO, BVS e Google Acadêmico. Foram selecionados 69 estudos, dos quais se excluíram 15, por não serem compatíveis com a pesquisa. Os resultados evidenciaram nove eixos temáticos: (1) tecnologia educacional a distância com fundamentos psicológicos, (2) afeição, (3) papel do tutor/professor, (4) teorias psicológicas, (5) interatividade, (6) evasão, (7) relatos de experiências, (8) avaliação de treinamento, desenvolvimento e educação a distância e (9) outros. Os temas tecnologia educacional a distância com fundamentos psicológicos e afeição obtiveram maior frequência nas publicações. Neste estudo, registrou-se, também, que, embora em ascensão desde 2006, os anos de maiores publicações da Psicologia na educação a distância foram 2008 e 2009. Sugere-se que estudos futuros ampliem esta pesquisa para incluir bases de dados internacionais...

This study investigated the contributions of Psychology to Distance Learning. A literature review of national publications between 1999 to 2009 was made in the electronic databases SciELO, LILACS, PsycINFO, BVS and Google Scholar. From the 69 studies selected, 15 were excluded because they were not compatible with the research. The results showed nine themes: (1) the distance learning technology with psychological grounding, (2) affection, (3)the role of the tutor/professor, (4) psychological theories, (5) interactivity, (6) dropout, (7) reports of experiences, (8) assessment of distance training, development and education and (9) others. The topics distance education technology with psychological grounding and affection had a larger frequency in the publications. Since 2006, there was an increasing number of publications in psychology distance education, but the years of major publications were from 2008 to 2009. It is suggested that future studies expand this research including international databases...

El presente estudio investigó las contribuciones de la Psicología para la Educación a Distancia - EAD. Para eso, fue realizada una revisión bibliográfica de publicaciones nacionales, entre 1999 y 2009 en las bases de datos SciELO, Lilacs, PsycINFO, BVS y Google Académico. Fueron seleccionados 69 estudios, de los cuales se excluyeron 15, por no ser compatibles con la pesquisa. Los resultados evidenciaron nueve ejes temáticos (1) tecnología educacional la distancia con fundamentos psicológicos; (2) afección; (3) papel del tutor/profesor; (4) teorías psicológicas; (5) interactividad; (6) evasión; (7) relatos de experiencias, (8) evaluación de entrenamiento, desarrollo y educación distancia y (9) otros. Los temas tecnología educacional a distancia con fundamentos psicológicos y afección obtuvieron mayor frecuencia en las publicaciones. En ese estudio se registró, también, que, aunque en ascensión desde 2006, los años de mayores publicaciones de la psicología en la educación a distancia, fueron 2008 y 2009. Se sugiere que estudios futuros amplíen esa pesquisa para incluir bases de datos internacionales...

SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target.

B-cell chronic lymphocytic leukemia (CLL), an incurable leukemia, is characterized by defective apoptosis. We found that the SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A) tumor suppressor, is overexpressed in primary CLL cells and B-cell non-Hodgkin lymphoma (NHL) cell line cells. In CLL, increased levels of SET correlated significantly with disease severity (shorter time to treatment and overall survival). We developed SET antagonist peptides that bound SET, increased cellular PP2A activity, decreased Mcl-1 expression, and displayed selective cytotoxicity for CLL and NHL cells in vitro. In addition, shRNA for SET was cytotoxic for NHL cells in vitro. The SET antagonist peptide COG449 inhibited growth of NHL tumor xenografts in mice. These data demonstrate that SET is a new treatment target in B-cell malignancies and that SET antagonists represent novel agents for treatment of CLL and NHL.

Vitimização secundária: O irmão testemunha o abuso sexual da irmã / Secondary victimization: The brother witnesses the sexual abuse of his sister

Este texto trata de um estudo de caso de um menino de 11 anos que observou a irmã de 10 anos ser abusada sexualmente pelo pai. O referencial teórico é o da Teoria Sistêmica, em seu escopo de intersubjetividade, contextualização e complexidade. Após o testemunho do abuso, o menino passou a ter problema "de nervoso" apresentando tremores nas pernas. Foram utilizadas observação do menino em situação de atividades numa instituição de serviço social e uma entrevista com sua mãe, como instrumentos. Os resultados centram o sofrimento do menino em seu conflito de lealdade: em seu sentimento e vínculo com o pai, ele o quer de volta; em seu sentimento e vínculo com a mãe, ele compreende que o pai colocou a irmã em perigo. Como resolver o impasse: amar a mãe e odiar o pai ou ser igual ao pai e ficar sem a família?(AU)

This text deals with a case study of an eleven years old boy who have witnessed the sexual abuse of his ten years old sister by their father. The theoretical referential is the Systemic Theory, in its intersubjectivity, contextualization and complexity scope. After having witnessed the abuse, the boy started to have nervous problems, presenting trembling legs. It was utilized, as instruments, the observation of the boy while in activity at a social service institution and an interview with his mother. The results focus on the suffering of the boy in his loyalty conflict: in his feeling and ties with his father he wants him back; in his feeling and ties with his mother, he understands that his father endangered his sister. How to solve this impasse? To love his mother and to hate his father or to be just like his father, losing his family?(AU)

Vitimização secundária: O irmão testemunha o abuso sexual da irmã / Secondary victimization: The brother witnesses the sexual abuse of his sister

Este texto trata de um estudo de caso de um menino de 11 anos que observou a irmã de 10 anos ser abusada sexualmente pelo pai. O referencial teórico é o da Teoria Sistêmica, em seu escopo de intersubjetividade, contextualização e complexidade. Após o testemunho do abuso, o menino passou a ter problema "de nervoso" apresentando tremores nas pernas. Foram utilizadas observação do menino em situação de atividades numa instituição de serviço social e uma entrevista com sua mãe, como instrumentos. Os resultados centram o sofrimento do menino em seu conflito de lealdade: em seu sentimento e vínculo com o pai, ele o quer de volta; em seu sentimento e vínculo com a mãe, ele compreende que o pai colocou a irmã em perigo. Como resolver o impasse: amar a mãe e odiar o pai ou ser igual ao pai e ficar sem a família?

This text deals with a case study of an eleven years old boy who have witnessed the sexual abuse of his ten years old sister by their father. The theoretical referential is the Systemic Theory, in its intersubjectivity, contextualization and complexity scope. After having witnessed the abuse, the boy started to have nervous problems, presenting trembling legs. It was utilized, as instruments, the observation of the boy while in activity at a social service institution and an interview with his mother. The results focus on the suffering of the boy in his loyalty conflict: in his feeling and ties with his father he wants him back; in his feeling and ties with his mother, he understands that his father endangered his sister. How to solve this impasse? To love his mother and to hate his father or to be just like his father, losing his family?

The BMP antagonist Noggin promotes cranial and spinal neurulation by distinct mechanisms.

Here we characterize the consequences of elevated bone morphogenetic protein (BMP) signaling on neural tube morphogenesis by analyzing mice lacking the BMP antagonist, Noggin. Noggin is expressed dorsally in the closing neural folds and ventrally in the notochord and somites. All Noggin-/- pups are born with lumbar spina bifida; depending on genetic background, they may also have exencephaly. The exencephaly is due to a primary failure of neurulation, resulting from a lack of mid/hindbrain dorsolateral hinge point (DLHP) formation. Thus, as previously shown for Shh signaling at spinal levels, BMP activity may inhibit cranial DLHP morphogenesis. However, the increased BMP signaling observed in the Noggin-/- dorsal neural tube is not sufficient to cause exencephaly; it appears to also depend on the action of a genetic modifier, which may act to increase dorsal Shh signaling. The spinal neural tube defect results from a different mechanism: increased BMP signaling in the mesoderm between the limb buds leads to abnormal somite differentiation and axial skeletal malformation. The resulting lack of mechanical support for the neural tube causes spina bifida. We show that this defect is due to elevated BMP4 signaling. Thus, Noggin is required for mammalian neurulation in two contexts, dependent on position along the rostrocaudal axis.