962 resultados para PD-1 (Programmed death-1)


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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

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Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

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O fracasso escolar é uma realidade nacional alarmante que torna indispensável o aprimoramento da tecnologia de ensino. O paradigma de equivalência tem contribuído para a compreensão de processos comportamentais relacionados à aquisição de repertórios lingüísticos e de habilidades cognitivas. As investigações acerca da aprendizagem de leitura por meio deste paradigma tem sido relevantes tanto para a identificação das variáveis de controle de respostas corretas e de respostas incorretas na leitura de palavras com função substantiva, quanto para a análise de quais procedimentos são eficazes no sentido de o responder ficar sob controle de propriedades relevantes dos estímulos impressos. Investigou-se, por meio de uma replicação sistemática, o ensino de leitura com compreensão de frases compostas por pronome demonstrativo, substantivo, adjetivo e verbo intransitivo. Participaram cinco alunos com dificuldades em leitura. Os estímulos foram de modalidade auditiva (sílabas, palavras e frases faladas), representada pela letra A; visual (grafia de sílabas, palavras, frases e figuras que representam palavras e frases), representada pela letra B para as figuras e pela letra C para os estímulos impressos e modalidade auditivo-visual. Foi realizado o treino das discriminações condicionais entre palavras/frases faladas e figuras (relações AB) e sílabas/palavras/frases faladas e estímulos impressos (relações ACs, ACp e ACf). Foram programadas conseqüências diferenciais (reforço social) para os acertos e aplicação de procedimentos de correção ou procedimentos especiais para respostas incorretas. Pretendeu-se investigar se após o ensino destas relações pré-requisitos ocorreriam relações equivalentes (palavras impressas e figuras e vice-versa), bem como se os participantes demonstrariam o desempenho de leitura generalizada. Não foram programadas conseqüências diferenciais durante a aplicação dos testes. Ao término de cada sessão, os participantes recebiam brindes variados. Foram programadas quatro fases experimentais. Na Fase I, os estímulos impressos eram palavras com função substantiva. Na Fase II, frases formadas por palavras com funções substantiva e adjetiva. Na Fase III, acrescentou-se o pronome demonstrativo às frases. Na Fase IV, acrescentaram-se verbos intransitivos às frases. Na Fase V, programou-se a retenção do desempenho aprendido durante o experimento. Todos os participantes, com exceção de um, aprenderam o desempenho de linha de base. Nos testes de equivalência e de leitura generalizada, houve maior variabilidade em relação aos estudos anteriores. Todos os participantes apresentaram a leitura com compreensão em pelo menos uma das fases envolvendo frases. Nas Etapas de leitura Generalizada, apenas uma participante obteve 100% de acertos nos testes da Fase II. Os demais participantes apresentaram leitura generalizada parcial ou ausência de leitura recombinativa, sendo necessária a aplicação de procedimento especial para promover escores mais elevados. Considerou-se o paradigma de equivalência promissor para proporcionar o ensino de leitura de frases com compreensão. Propôs-se mudanças no procedimento que tornem o controle experimental mais rígido. Sugeriu-se ainda a investigação da pertinência do paradigma de equivalência para o ensino de leitura de frases, com compreensão, envolvendo classes gramaticais como artigos, advérbios, verbos transitivos diretos e objetos diretos.

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A hanseníase, doença endêmica no Brasil, de caráter crônico, que afeta principalmente o tegumento cutâneo e os nervos periféricos. Também pode afetar a bucofaringe. Este trabalho objetivou realizar estudo sobre a Prevenção de Incapacidades (PI) em Hanseníase, na Primeira Região de Saúde de Rondônia, no Programa para Eliminação e Controle da Hanseníase com sede no município de Ji-Paraná, que envolve o atendimento sistemático aos portadores de Hanseníase de 16 municípios circunvizinhos. Utilizou-se como instrumento de coleta um levantamento de dados nos mapas de controle e relatórios da 1ª Região de Saúde de todos os indivíduos atendidos no programa no período de 2000 e 2001, considerando-se faixa etária, sexo, forma clínica e grau de incapacidade. Foram estudados 331 indivíduos, na faixa etária de 10 a 84 anos de ambos os sexos. Numa etapa posterior, foi analisado o cruzamento dos dados acima mencionados com outros estudos feitos a respeito do assunto. Baseado nos resultados encontrados e discutidos, ficou evidenciada a importância do diagnóstico precoce, do tratamento imediato pelo uso da poliquimioterapia e da prevenção de incapacidades como meio de estacionar ou regredir lesões advindas do acometimento dos nervos periféricos e pele, encontrados em algumas formas da hanseníase, principalmente, na Tuberculóide e Dimorfa, que são as de maior freqüência na área estudada.

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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

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Pós-graduação em Cirurgia Veterinária - FCAV

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Alveolar bone resorption results from the inflammatory response to periodontal pathogens. Systemic diseases that affect the host response, such as type 1 diabetes mellitus (DM1), can potentiate the severity of periodontal disease (PD) and accelerate bone resorption. However, the biological mechanisms by which DM1 modulates PD are not fully understood. The aim of this study was to determine the influence of DM1 on alveolar bone resorption and to evaluate the role of receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG) in osteoclastogenesis in rats. PD was induced by means of ligature in nondiabetic and in streptozotocyn-induced DM1 rats. Morphological and morphometric analyses, stereology and osteoclast counting were performed. RANKL and OPG mRNA levels, protein content, and location were determined. PD caused alveolar bone resorption, increased the number of osteoclasts in the alveolar bone crest and also promoted changes in RANKL/OPG mRNA expression. DM1 alone showed alveolar bone destruction and an increased number of osteoclasts at the periapical and furcal regions. DM1 exacerbated these characteristics, with a greater impact on bone structure, resulting in a low OPG content and a higher RANKL/OPG ratio, which correlated with prominent osteoclastogenesis. This work demonstrates that the effects of PD and DM1 enhance bone destruction, confirms the importance of the RANKL signaling pathway in bone destruction in DM1 in animal models and suggests the existence of alternative mechanisms potentiating bone degradation in PD.

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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

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Members of the subfamily Alphaherpesvirinae use the epithelium of the upper respiratory and/or genital tract as preferential sites for primary replication. However, bovine herpesvirus 5 (BoHV5) is neurotropic and neuroinvasive and responsible for meningoencephalitis in cattle and in animal models. A related virus, BoHV1 has also been occasionally implicated in natural cases of neurological infection and disease in cattle. The aim of the present study was to assess the in vitro effects of BoHV1 and BoHV5 replication in neuron-like cells. Overall, cytopathic effects, consisting of floating rounded cells, giant cells and monolayer lysis, induced by both viruses at 48 h postinfection (p.i.) resulted in a loss of cell viability and high virus titres (r = 0.978). The BoHV1 Cooper strain produced the lowest titres in neuron-like cells, although viral DNA was detected in infected cells during all experiments. Virus replication in infected cells was demonstrated by immunocytochemistry, flow cytometry and qPCR assays. BoHV antigens were better visualized at 48 h p.i. and flow cytometry analysis showed that SV56/90 and Los Angeles antigens were present at higher levels. In spite of the fact that BoHV titres dropped at 48 h p.i, viral DNA remained detectable until 120 h p.i. Sensitive TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) and annexin V assays were used to identify apoptosis. BoHV5 induced death in approximately 50 % of cells within 24 h p.i., similar to what has been observed for BoHV1 Los Angeles. Infection with the BoHV1 Cooper strain resulted in 26.37 % of cells being in the early stages of apoptosis; 63.69 % of infected cells were considered viable. Modulation of mitochondrial function, as measured by mitochondrial membrane depolarization, was synchronous with the virus replication cycle, cell viability and virus titres at 48 h p.i. Our results indicate that apoptosis plays an important role in preventing neuronal death and provides a bovine-derived in vitro system to study herpesvirus-neuron interactions.

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The State of Michigan is striving to eliminate bovine tuberculosis (Tb) infection among free-ranging white-tailed deer in the northeastern Lower Peninsula of the state. Aggressive reduction in the overall deer population abundance may help to further reduce TB prevalence, but this course of action is unacceptable to many hunters and landowners. Targeted culling of sick deer would likely be far more acceptable to these stakeholders, so in the winter of 2003 the Michigan Department of Natural Resources pilot-trialed a new strategy based on live-trapping and Tb-testing of wild deer. The field study was conducted in a township with relatively high TB prevalence within Deer Management Unit 452 in the northeastern Lower Peninsula. Over a 2-month trapping period, 119 individual deer were live-trapped, blood sampled, fitted with a radio-collar, and released. A total of 31 of these deer were subsequently classified as Tb-suspect by at least one of five blood tests employed (however there was a low level of agreement among tests). A delay in testing meant that only six of these suspect deer were culled by sharpshooters before pre-programmed release of their radio-collars, after which they could no longer be located. Mycobacterium bovis was cultured from one of these six suspect deer; the other five were negative on culture. All target deer were located to within shooting range with 1 – 2 days of effort, and all the radio-collars on the apparently-healthy deer dropped off after the intended 90-day interval, and were thereafter recovered for re-use. There was considerable support for this pilot project among hunters, farmers, state and federal agriculture agencies, the media and the general public, and so we recommend that further field trials be undertaken using this technique. The initial focus of these trials should be on improving the efficacy and reliability of the blood testing procedure.

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Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T cell-mediated destruction of pancreatic beta cells, resulting in insulin deficiency and hyperglycaemia. Recent studies have described that apoptosis impairment during central and peripheral tolerance is involved in T1D pathogenesis. In this study, the apoptosis-related gene expression in T1D patients was evaluated before and after treatment with high-dose immunosuppression followed by autologous haematopoietic stem cell transplantation (HDI-AHSCT). We also correlated gene expression results with clinical response to HDI-AHSCT. We observed a decreased expression of bad, bax and fasL pro-apoptotic genes and an increased expression of a1, bcl-xL and cIAP-2 anti-apoptotic genes in patients' peripheral blood mononuclear cells (PBMCs) compared to controls. After HDI-AHSCT, we found an up-regulation of fas and fasL and a down-regulation of anti-apoptotic bcl-xL genes expression in post-HDI-AHSCT periods compared to pre-transplantation. Additionally, the levels of bad, bax, bok, fasL, bcl-xL and cIAP-1 genes expression were found similar to controls 2 years after HDI-AHSCT. Furthermore, over-expression of pro-apoptotic noxa at 540 days post-HDI-AHSCT correlated positively with insulin-free patients and conversely with glutamic acid decarboxylase autoantibodies (GAD65) autoantibody levels. Taken together, the results suggest that apoptosis-related genes deregulation in patients' PBMCs might be involved in breakdown of immune tolerance and consequently contribute to T1D pathogenesis. Furthermore, HDI-AHSCT modulated the expression of some apoptotic genes towards the levels similar to controls. Possibly, the expression of these apoptotic molecules could be applied as biomarkers of clinical remission of T1D patients treated with HDI-AHSCT therapy.

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Background: Albuminuria has been considered a sine qua non condition for the diagnosis of diabetic nephropathy (DN) and has been widely used as a surrogate outcome of chronic kidney disease (CKD). However, recent data suggest that albuminuria may fail as a biomarker in a subset of patients, and the search for novel markers is intense. Methods: We analyzed the role of urinary RBP and of serum and urinary cytokines (TGF-beta, MCP-1 and VEGF) as predictors of the risk of dialysis. doubling of serum creatinine or death (primary outcome. PO) in 56 type 2 diabetic patients with macroalbuminuric DN. Results: Mean follow-up time was 30.7 +/- 10 months. Urinary RBP and MCP-1 were significantly higher in patients presenting the PO, whereas no difference was shown for TGF-beta or VEGF. In the Cox regression, urinary RBP. MCP-1 and VEGF were positively associated and serum VEGF was inversely related to the risk of the PO. However, after adjustments for creatinine clearance, proteinuria, and blood pressure only urinary RBP (OR 11.6; 95% CI 2.7-49.2, p = 0.001 for log RBP) and urinary MCP-1 (OR 11.0; 95% CI 1.6-76.4, p = 0.02 for log MCP-1) remained as significant independent predictors of the PO. Conclusion: Urinary RBP and MCP-1 are independently related to the risk of CKD progression in patients with macroalbuminuric DN. Whether these biomarkers have a role in the setting of normoalbuminuria and microalbuminuria in DN should be further investigated. (C) 2012 Elsevier Inc. All rights reserved.

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One of the greatest challenges in urological oncology is renal cell carcinoma (RCC), which is the third leading cause of death in genitourinary cancers. RCCs are highly vascularized and respond positively to antiangiogenic therapy. Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. In this study, we examined the potential of ES-based antiangiogenic therapy to activate tumor-associated endothelial cells in metastatic RCC (mRCC). Balb/c-bearing Renca cells were treated with NIH/3T3-LendSN or, as a control, with NIH/3T3-LXSN cells. The T-cell subsets and lymphocyte populations of tumors, mediastinal lymph nodes and the spleen were assessed by flow cytometry. The expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was assessed by real-time PCR, flow cytometry and immunohistochemistry analysis. ES gene therapy led to an increase in the percentage of infiltrating CD4-interferon (IFN)-gamma cells (P<0.05), CD8-IFN-gamma cells (P<0.01) and CD49b-tumor necrosis factor-alpha cells (P<0.01). In addition, ES therapy caused an increase at the mRNA level of ICAM-1 (1.4-fold; P<0.01) and VCAM-1 (1.5-fold) (control vs treated group; P<0.001). Through flow cytometry, we found a significant increase in the CD34/ICAM-1 cells (8.1-fold; P<0.001) and CD34/VCAM-1 cells (1.6-fold; P<0.05). ES gene therapy induced a significant increase in both T CD4 and CD8 cells in the lymph nodes and the spleen, suggesting that ES therapy may facilitate cell survival or clonal expansion. CD49b cells were also present in increased quantities in all of these organs. In this study, we demonstrate an antitumor inflammatory effect of ES in an mRCC model, and this effect is mediated by an increase in ICAM-1 and VCAM-1 expression in tumor-associated endothelial cells.