Access and adherence to isoniazid preventive therapy and occurrence of active TB in a cohort of people living with HIV: a retrospective cohort study in Sao Paulo, Brazil

Tuberculosis (TB) is still a leading cause of morbidity and mortality among people living with HIV (PLHIV). The diagnosis of latent TB is required for the implementation of prophylactic therapy with isoniazid (PTI). However, low access to diagnosis of latent TB and non-adherence to PTI may hinder potential benefits of this essential intervention. In this study, we addressed the access and adherence to PTI in a cohort of PLHIV with positive tuberculin skin test (TST) in a reference HIV clinic in Sao Paulo, Brazil. We have also analyzed the occurrence of active TB over a median of 131 months after a positive TST among study participants. Our findings revealed that 88.3% of the 238 TST-positive patients had access to PTI, and 196 (93.3%) of those with access adhered to PTI. Active tuberculosis was diagnosed in three of the 196 TST-positive patients who adhered to PTI (1.5%; 95% confidence interval [CI] 0.3-4.4%), whereas seven cases were detected among 42 patients without access or who did not adhere to PTI (16.6%; 95% CI 7.0-31.3%). The apparent beneficial effect of PTI in our cohort is consistent with previous studies including PLHIV, and highlights the importance of reliably delivering each of the steps between screening for latent TB and provision of PTI

Modificação do fenótipo linfocitário e aumento da sobrevida do enxerto de pele após a terapia com FTY720 + FK506

The development of new drugs to be associated with calcineurin inhibitors and promote additional immunosuppression with fewer side effects is the goal in transplantation. FTY720 is a new synthetic compound which presents immunomodulatory properties which are not fully understood. It has been reported that the main mechanism of action of FTY720 is to reduce the peripheral lymphocyte count by redirecting these cells toward secondary lymphoid organs. Skin allograft transplantation in a fully mismatched strain combination was used to investigate the potential of FTY720 alone or in combination with a calcineurin inhibitor - FK506 - in preventing rejection. The number and phenotype of immune system cells was also evaluated. FTY720 alone or in combination with FK506 provided significant skin allograft survival. FTY720+FK506 therapy was associated with decreases of total lymphocyte numbers in spleen and blood, and increases in apoptosis levels in splenocytes. In FTY720 isolated treatment, a significant decrease in the CD4 expression and significantly lower expressions of MHC II and ICAM-1 molecules were observed in spleen lymphocytes. Despite of allograft survival being the same in both FTY720 and FTY720+FK506 treated groups, the association of drugs was associated with the absence of macroscopic skin necrosis for a longer period than the other treatments (FTY720, FK506) and histology showed less cell infiltration. Our results suggest that a decrease of effector T cells due to elevated levels of apoptosis and impairment in the appearance of antigens were events associated with FTY720+FK506 administration.O objetivo na área dos transplantes é o desenvolvimento de novas drogas que possam ser associadas a inibidores da calcineurina para evitar o processo de rejeição e causar menos efeitos colaterais. FTY720 é um novo composto sintético que apresenta propriedades imunomoduladoras não completamente elucidadas. Foi relatado que o principal mecanismo de ação do FTY720 é a redução do número de linfócitos periféricos através do redirecionamento dessas células para órgãos linfóides secundários. O alotransplante de pele entre linhagens de camundongos completamente incompatíveis quanto ao MHC foi usado para investigar o potencial de FTY720 isolado ou em combinação com um inibidor da calcineurina - FK506 - na prevenção da rejeição. Também foram avaliados o número e fenótipo das células do sistema imune. A administração de FTY720 como monoterapia ou FTY720+FK506 associou-se a uma diminuição do número total de linfócitos no baço e no sangue e aumento dos níveis de apoptose nos esplenócitos. No grupo tratado somente com FTY720, foi observada uma diminuição mais importante da expressão de CD4 e expressão significativamente menor de moléculas de MHC II e ICAM-1. Apesar de a sobrevida do aloenxerto ter sido igual para os grupos tratados com FTY720 ou FTY720 +FK506, a associação das drogas promoveu ausência de necrose macroscópica da pele por um período maior do que os outros tratamentos (FTY720, FK506) e os achados histológicos mostraram menor infiltrado celular. Nossos resultados sugerem que uma diminuição do número de células T efetoras devido a elevados níveis de apoptose e o prejuízo da apresentação de antígenos foram os eventos associados à administração de FTY720+FK506.Faculdade de Medicina de São José do Rio PretoUniversidade Federal de São Paulo (UNIFESP)UNIFESPSciEL

Leishmania amazonensis promastigotes in 3D Collagen I culture: an in vitro physiological environment for the study of extracellular matrix and host cell interactions

Leishmania amazonensis is the causative agent of American cutaneous leishmaniasis, an important neglected tropical disease. Once Leishmania amazonensis is inoculated into the human host, promastigotes are exposed to the extracellular matrix (ECM) of the dermis. However, little is known about the interaction between the ECM and Leishmania promastigotes. In this study we established L. amazonensis promastigote culture in a three-dimensional (3D) environment mainly composed of Collagen I (COL I). This 3D culture recreates in vitro some aspects of the human host infection site, enabling the study of the interaction mechanisms of L. amazonensis with the host ECM. Promastigotes exhibited “freeze and run” migration in the 3D COL I matrix, which is completely different from the conventional in vitro swimming mode of migration. Moreover, L. amazonensis promastigotes were able to invade, migrate inside, and remodel the 3D COL I matrix. Promastigote trans-matrix invasion and the freeze and run migration mode were also observed when macrophages were present in the matrix. At least two classes of proteases, metallo- and cysteine proteases, are involved in the 3D COL I matrix degradation caused by Leishmania. Treatment with a mixture of protease inhibitors significantly reduced promastigote invasion and migration through this matrix. Together our results demonstrate that L. amazonensis promastigotes release proteases and actively remodel their 3D environment, facilitating their migration. This raises the possibility that promastigotes actively interact with their 3D environment during the search for their cellular “home”—macrophages. Supporting this hypothesis, promastigotes migrated faster than macrophages in a novel 3D co-culture model

Uma Proposta de Ensino para trabalhar o Conteúdo de Mudanças do Estado Físico da Matéria

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Use of epidermic and granulocyte-colony stimulating growth factors in the prevention and treatment of necrotizing enterocolitis of the newborn

OBJETIVO: Revisar os conhecimentos existentes em relação ao uso de fatores de crescimento epidérmico e estimulador de colônias de granulócitos na prevenção e/ou no tratamento da enterocolite necrosante (ECN) durante o período neonatal. FONTES DE DADOS: Revisão da literatura, nas bases de dados Medline, Lilacs, SciELO e PubMed, utilizando os unitermos "recém-nascidos", "enterocolite" e "fatores de crescimento", no período de 2003 a 2007. Nesta busca, 49 artigos foram encontrados, sendo 17 pertinentes ao tema. Também foram utilizados outros artigos, independente do ano de publicação, relacionados a aspectos definidores da ECN no recém-nascido. SÍNTESE DOS DADOS: A ECN continua sendo responsável por uma elevada morbimortalidade neonatal. Os mecanismos fisiopatológicos vêm sendo elucidados e, a partir deles, são discutidas novas terapias, como o uso de fatores de crescimento, destacando-se o fator de crescimento epidérmico e o fator estimulador de colônias de granulócitos. CONCLUSÕES: O uso de fatores de crescimento no tratamento e prevenção da ECN neonatal parece promissor. É necessário maior número de ensaios clínicos para comprovar sua eficácia e segurança. Enquanto isso, a melhor prática médica continua sendo a prevenção da doença.OBJECTIVE: To review the literature regarding the use of hematopoietic and epidermic growth factors for prevention or treatment of neonatal necrotizing enterocolitis (NEC). DATA SOURCES: Literature review of Medline, Lilacs, SciELO and Pubmed databases, using the key-words "newborn", "enterocolitis" and "growth factors", from 2003 to 2007. Fourty-nine papers were retrieved, but only 17 related to the subject. Other studies that described some clinical aspects of enterocolitis were also included, regardless of the year of publication. DATA SYNTHESIS: Necrotizing and enterocolitis has been an important cause of morbidity and mortality in the neonatal period. As the knowledge about the pathophysiology of this disease improves, new therapies, such as the administration of epidermal growth factor and granulocyte colony-stimulating factor, are being discussed. CONCLUSIONS: The use of growth factors for treatment and prevention of NEC seems promising. However, further clinics assays are needed to evaluate the effectiveness and the safety of these growth factors. At this moment, the best clinical practice is the prevention of the disease

Managing Organizational Learning with Focus on The Theory U

The learning of the organization's employees and their perception can instruct the managerial adaptations in search of innovation of the processes. This study focuses on the Theory U, with the objective of studying the perception of stakeholders in the face of learning in the corporation. Its specific objectives are: (1) To raise stakeholders' perceptions regarding the learning tools and practices in the organization; (2) To characterize the possibility of organizational learning in the application of the Theory U; (3) Propose measures to modernize organizational learning tools and practices. The scenario is a military corporation in the Capital of Rondônia, Brazilian Amazon. The study of case method is applied, with procedures in search of qualitative and quantitative results. The collection of the stakeholders' perception was done through ethical protocol; interviews and in loco observation. A report was generated that points out the existence of a confrontation between corporate interests, indicating that managers do not promote the means to bring knowledge to their employees in the institution, while they become sceptical about their reality due to the emergence of a confrontation between theory and practice. The result suggests modernizing the organizational environment to support learning demands. It points that the tools and practices should be reoriented with the purpose of innovating the environment with organizational learning resizing, from now on to be integrative with new technologies, with collaborative focus, through redesigns of processes and procedures following advanced technological standards. This research is a contribution of the academy to managers who potentialize their stakeholders through organizational learning with innovative practices

Trypsin-like serine peptidase profiles in the egg, larval, and pupal stages of Aedes albopictus

BACKGROUND: Aedes albopictus, a ubiquitous mosquito, is one of the main vectors of dengue and yellow fever, representing an important threat to public health worldwide. Peptidases play key roles in processes such as digestion, oogenesis, and metamorphosis of insects. However, most of the information on the proteolytic enzymes of mosquitoes is derived from insects in the adult stages and is often directed towards the understanding of blood digestion. The aim of this study was to investigate the expression of active peptidases from the preimaginal stages of Ae. albopictus. METHODS: Ae. albopictus eggs, larvae, and pupae were analyzed using zymography with susbtrate-SDS-PAGE. The pH, temperature and peptidase inhibitor sensitivity was evaluated. In addition, the proteolytic activities of larval instars were assayed using the fluorogenic substrate Z-Phe-Arg-AMC. RESULTS: The proteolytic profile of the larval stage was composed of 8 bands ranging from 17 to 130 kDa. These enzymes displayed activity in a broad range of pH values, from 5.5 to 10.0. The enzymatic profile of the eggs was similar to that of the larvae, although the proteolytic bands of the eggs showed lower intensities. The pupal stage showed a complex proteolytic pattern, with at least 6 bands with apparent molecular masses ranging from 30 to 150 kDa and optimal activity at pH 7.5. Peptidases from larval instars were active from 10°C to 60°C, with optimal activity at temperatures between 37°C and 50°C. The proteolytic profile of both the larval and pupal stages was inhibited by phenyl-methyl sulfonyl-fluoride (PMSF) and Nα-Tosyl L-lysine chloromethyl ketone hydrochloride (TLCK), indicating that the main peptidases expressed during these developmental stages are trypsin-like serine peptidases. CONCLUSION: The preimaginal stages of Ae. albopictus exhibited a complex profile of trypsin-like serine peptidase activities. A comparative analysis of the active peptidase profiles revealed differential expression of trypsin-like isoforms among the preimaginal stages, suggesting that some of these enzymes are stage specific. Additionally, a comparison of the peptidase expression between larvae from eggs collected in the natural environment and larvae obtained from the eggs of female mosquitoes maintained in colonies for a long period of time demonstrated that the proteolytic profile is invariable under such conditions