Comparative in vitro effects of closantel and selected beta-ketoamide anthelmintics on a gastrointestinal nematode and vertebrate liver cells

PNU-87407 and PrNU-88509, beta-ketoamide anthelmintics that are structurally related to each other and to the salicylanilide anthelmintic closantel, exhibit different anthelmintic spectra and apparent toxicity in mammals, The basis for this differential pharmacology was examined in experiments that measured motility and adenosine triphosphate (ATP) levels in larval and adult stages of the gastrointestinal nematode, Haemonchus contortus, and in a vertebrate liver cell line and mitochondria, PNU-87407 and PNU-88509 both exhibited functional cross-resistance with closantel in larval migration assays using closantel-resistant and -sensitive isolates of H, contortus. Each compound reduced motility and,ATP levels in cultured adult H. contortus in a concentration- and time-dependent manner: however, motility was reduced more rapidly by PNU-88509, and ATP levels were reduced by lower concentrations of closantel than the beta-ketoamides. Tension recordings from segments of adult H, contortus showed that PNU-88509 induces spastic paralysis, while PNU-87407 and closantel induce flaccid paralysis of the somatic musculature. Marked differences in the actions of these compounds were also observed in the mammalian preparations. In Chang liver cells, ATP levels were reduced after 3 h exposures to greater than or equal to 0.25 mu M PNU-87407 1 mu M closantel or 10 mu M PNU-88509, Reductions in ATP caused by PNU-88509 were completely reversible, while the effects of closantel and PNU-87407; were irreversible. PNU-87407, closantel and PNU-88509 uncoupled oxidative phosphorylation in isolated rat liver mitochondria, inhibiting the respiratory control index (with glutamate or succinate as substrate) by 50% at concentrations of 0.14, 0.9 and 7.6 mu M respectively.

Haemonchus contortus: The uptake and metabolism of closantel

Closantel is an anthe lmintic which associates with plasma albumin and is useful for the control of sheep parasites, such as Haemonchus contortus, that ingest blood. However, the utility of closantel for parasite control has been threatened by the emergence of resistance. The mechanisms of resistance are unknown. A closantel-resistant and a closantel-susceptible isolate of H. contortus were compared with respect to the distribution and metabolism of closantel. Neither strain appeared to metabolise closantel in vitro or in vivo. Following treatment of infected sheep with radioactively labelled closantel, isotope levels in closantel-resistant adult H. contortus were significantly lower than in susceptible worms. This reduced accumulation of drug could contribute to closantel resistance by mechanisms such as reduced feeding, failure to dissociate the drug-albumin complex in the gut or increased efflux of closantel from resistant worms. (C) 1997 Australian Society for Parasitology.

Infectious diseases in paediatric pathology: experience from a developing country

Infectious and parasitic diseases have always challenged man. Although many of them are typically seen in some areas of the world and can be adequately managed by just improving socioeconomic status and sanitary conditions, they are still quite prevalent and may sometimes be seen outside their original geographical areas. Human migration due to different reasons, tourism, blood transfusion and solid organ transplantation has created new concerns for health professionals all over the world. If not for diagnostic purposes, at least these tropical and infectious diseases should be largely known because their epidemiology, pathogenesis, host/parasite interaction, inflammatory and reparative responses are quite interesting and teach us about human biology. Curiosity is inherent to pathology practice and so we are compelled to look for things other than tumours or degenerative diseases. This review focuses on infectious and parasitic diseases found in a developing country and brings up-to-date information on diseases caused by viruses (dengue, yellow fever), bacteria (typhoid fever, leprosy), parasites (Chagas` disease, cutaneous and visceral leishmaniasis, amoebiasis, Capillaria hepatica, schistosomiasis, cysticercosis) and caused by fungi (paracoccidioidomycosis, cryptococcosis, histoplasmosis) that may be useful for pathologists when facing somewhat strange cases from developing countries.

Stability improvement of the fatty acid binding protein Sm14 from S. mansoni by Cys replacement: Structural and functional characterization of a vaccine candidate

The Schistosoma mansoni fatty acid binding protein (FABP), SmA, is a vaccine candidate against, S. mansoni and F hepatica. Previously, we demonstrated the importance of a correct fold to achieve protection in immunized animals after cercariae challenge [[10]. C.R.R. Ramos, R.C.R. Figueredo, T.A. Pertinhez, M.M. Vilar, A.L.T.O. Nascimento, M. Tendler, I. Raw, A. Spisni, P.L. Ho, Gene structure and M20T polymorphism of the Schistosoma mansoni Sm14 fatty acid-binding protein: structural, functional and immunoprotection analysis. J. Biol. Chem. 278 (2003) 12745-12751]. Here we show that the reduction of vaccine efficacy over time is due to protein dimerization and subsequent aggregation. We produced the mutants Sm14-M20(C62S) and Sm14M20(C62V) that, as expected, did not dimerize in SDS-PAGE. Molecular dynamics calculations and unfolding experiments highlighted a higher structural stability of these mutants with respect to the wild-type. In addition, we found that the mutated proteins, after thermal denaturation, refolded to their active native molecular architecture as proved by the recovery of the fatty acid binding ability. Sm14-M20(C62V) turned out to be the more stable form over time, providing the basis to determine the first 3D solution structure of a Sm14 protein in its apo-form. Overall, Sm14-M20(C62V) possesses an improved structural stability over time, an essential feature to preserve its immunization capability and, in experimentally immunized animals, it exhibits a protection effect against S. mansoni cercariae infections comparable to the one obtained with the wild-type protein. These facts indicate this protein as a good lead molecule for large-scale production and for developing an effective Sm14 based anti-helminthes vaccine. (C) 2008 Elsevier B.V. All rights reserved.

Schistosoma japonicum cathepsin D aspartic protease cleaves human IgG and other serum components

Recombinant cathepsin D aspartic protease of Schistosoma japonicum cleaved human IgG in vitro in a time and dose-dependent manner. Optimal cleavage was seen at pH 3.6-4.5; modest cleavage remained at pH 5.0, and no cleavage was detected above pH 5.0. Amino terminal sequencing of the major cleavage fragments of human IgG identified a Fab fragment from the VH1 domain, and 2 cleavage sites in the CH2 domain below the hinge region. The P1 and P1' residues at the 2 CH2 cleavage sites were Phe254-Leu255 and Leu325-Thr326, indicating a preference by the schistosome protease for bulky hydrophobic residues flanking the scissile bond. No cleavage of the immunoglobulin light chain was detected. In addition, the recombinant schistosome protease indiscriminately degraded the human serum proteins complement C3 and serum albumin into numerous small fragments. These results demonstrate specific cleavage of human IgG by the recombinant schistosome aspartic protease, and highlight the broad range digestive specificity of the enzyme which may play a role in the degradation of host serum proteins ingested as part of the schistosome bloodmeal.

Vaccine efficacy of recombinant cathepsin D aspartic protease from Schistosoma japonicum

Mice were vaccinated with recombinant Schistosoma japonicum cathepsin D aspartic protease, expressed in both insect cells and bacteria, in order to evaluate the vaccine efficacy of the schistosome protease. Mean total worm burdens were significantly reduced in vaccinated mice by 21-38%, and significant reductions in female worm burdens were also recorded (22-40%). Vaccination did not reduce fecundity; rather, we recorded increased egg output per female worm in vaccinated animals, suggesting a crowding effect. Vaccinated mice developed high levels of antibodies (predominantly IgG1, IgG2a and IgG2b isotypes), but there was no correlation between antibody levels and protective efficacy. Immune sera from vaccinated mice did not inhibit the in vitro degradation of human haemoglobin by the recombinant protease, and passive transfer of serum or antibodies from vaccinated animals, before and after parasite challenge, did not significantly reduce worm or egg burdens in recipient animals. These results suggest that antibodies may not play a key role in the protective effect elicited, and that protection may be due to a combination of humoral and cell-mediated responses.

Implanta????o do pr??-atendimento na ag??ncia dos correios Adolfina de Pinheiros em S??o Paulo

A experi??ncia da Diretoria Regional de S??o Paulo Metropolitana dos Correios objetiva implementar melhoria em um dos seus principais processos: o atendimento nas ag??ncias. Dentro do contexto de gest??o pela qualidade total, destacamos o programa de ger??ncia da rotina e gerenciamento de melhorias (revis??o de processos), cujas ferramentas nortearam o nosso projeto. Nas ag??ncias, em decorr??ncia dos diversos produtos e servi??os que a ECT comercializa, faz-se necess??ria a gest??o das filas para que o tempo de espera excessivo n??o ocasione a insatisfa????o dos clientes. Com a implanta????o do pr??-atendimento em guich?? espec??fico, na ag??ncia Adolfina de Pinheiros, houve uma redu????o significativa do tempo de espera na fila, servindo como modelo para implanta????o em outras ag??ncias dos Correios. Al??m de atender ?? necessidade do cliente, estabelecida na matriz do QFD (Desdobramento da Fun????o Qualidade) do sistema de gest??o da qualidade da ECT, o projeto objetiva tornar a rotina de trabalho dos atendentes de guich?? mais f??cil, racional e produtiva

O sistema de avalia????o e monitoramento das pol??ticas e programas do MDS

A experi??ncia diz respeito ?? cria????o de um sistema de avalia????o e monitoramento dos programas e pol??ticas do Minist??rio de Desenvolvimento Social e Combate ?? Fome, MDS, formulado e implementado pela Secretaria de Avalia????o e Gest??o da Informa????o, SAGI. A cria????o e o conjunto de a????es dessa secretaria constituem uma inova????o na gest??o governamental brasileira, pois at?? ent??o n??o existia, em nenhum minist??rio, uma secretaria com essa finalidade exclusiva. O relato descreve, sucintamente, as a????es necess??rias para a implementa????o do sistema, apresentando-se um quadro dos recursos humanos e financeiros contratados, al??m dos resultados produzidos. Foram constru??dos e calculados 60 indicadores relativos aos programas, bem como duas ferramentas para o tratamento da informa????o: Dicion??rio de Vari??veis e Indicadores de Programas, DICI-VIP e a Matriz de Informa????es Sociais, MI Social. Na ??rea de avalia????o, existem, finalizadas, em andamento ou a contratar, 62 pesquisas, divulgadas por diferentes tipos de publica????o

Utiliza????o do QFD: Quality Function Deployment como ferramenta de planejamento

A utiliza????o da matriz do QFD (em portugu??s, Desdobramento da Fun????o Qualidade) como entrada para o planejamento estrat??gico regional solidificou o entendimento da Diretoria Regional sobre as expectativas dos clientes ante seus principais processos, avaliados por meio de pesquisa externa realizada bianualmente. Direcionou as a????es a serem tomadas por meio da prioriza????o, da tradu????o e do desdobramento dos requisitos mais importantes para os clientes em todos os n??veis dos processos, alinhando essas a????es com as estrat??gias, a pol??tica da qualidade e o or??amento. Da mesma forma, serviu para estabelecer metas globais de satisfa????o por segmento, de forma mais estruturada, sistematizando a avalia????o dos resultados e focando sempre a satisfa????o dos clientes cujos resultados j?? se comprovaram: ??ndice de 8,6 em 2000 para 9,2 em 2004

Sistema matricial de atividades

Tendo como objetivo a implementa????o de mecanismos voltados ao aperfei??oamento das decis??es do CADE e ?? garantia de maior efici??ncia no cumprimento das atribui????es legais previstas na Lei 8.884/94, introduziu-se na agenda de trabalho do CADE a cria????o do SISTEMA MATRICIAL DE ATIVIDADES. As premissas b??sicas que nortearam os trabalhos foram: garantir transpar??ncia das decis??es, seguran??a jur??dica, integra????o e racionaliza????o da estrutura, bem como incremento de produtividade. Nessas condi????es, com o intuito de organizar os trabalhos da Autarquia implantou-se um sistema matricial, com a forma????o de grupos de trabalhos interdisciplinares e por t??cnicos que atuam em diferentes ??reas do CADE, cuja preocupa????o central foi criar um mecanismo que possibilitasse alcan??ar maior efici??ncia na utiliza????o dos recursos humanos, materiais e financeiros dispon??veis. O pleno funcionamento do SISTEMA ?? avaliado em reuni??o operacional, realizada semanalmente, quando s??o repassadas as diversas tarefas, com a participa????o de todos os servidores t??cnicos e administrativos (alguns em sistema de rod??zio com outros colegas da mesma ??rea), em que s??o repassados os temas sobre acompanhamento das decis??es do CADE, agenda semana, previs??o de pauta para as pr??ximas sess??es e ata das sess??es anteriores, temas relevantes das sess??es de julgamento, relat??rio anual, matriz de atividades, procuradoria, informa????o e documenta????o, f??runs, p??gina na Internet e boletim estat??stico. Criado desde 1996, o SISTEMA tem permitido uma efic??cia e produtividade muito maiores nos trabalhos

Reflex??es para Ibero-Am??rica: avalia????o de programas sociais

A ENAP Escola Nacional de Administra????o P??blica, com o apoio do Minist??rio do Planejamento, Or??amento e Gest??o, da Ag??ncia Brasileira de Coopera????o do Minist??rio das Rela????es Exteriores, do Centro Latino-americano de Administra????o para o Desenvolvimento (Clad) e da Caixa Econ??mica Federal, construiu uma s??rie de atividades de aprendizagem direcionadas a dirigentes e t??cnicos que atuam nas ??reas de planejamento estrat??gico e avalia????o de programas. Esses eventos de aprendizagem permitiram uma intensa troca de experi??ncias entre os 60 dirigentes e t??cnicos representantes de organismos governamentais de 16 pa??ses ibero-americanos ??? Argentina, Bol??via, Brasil, Chile, Col??mbia, Costa Rica, El Salvador, Guatemala, M??xico, Panam??, Paraguai, Peru, Portugal, Rep??blica Dominicana, Uruguai e Venezuela. A consolida????o desse per??odo de rica troca de experi??ncias est?? retratada nesta publica????o, que mostra o avan??o na constru????o de um conhecimento coletivo referente a desafios contempor??neos de nossos governos nas ??reas de planejamento e de avalia????o de programas sociais

Colet??nea planejamento e or??amento governamental: volume 1: o quadro l??gico - um m??todo para planejar e gerenciar mudan??as

O texto traz uma s??ntese do Enfoque do Quadro L??gico e constr??i um exemplo da matriz de planejamento do projeto, que ilustra para o leitor a estrutura do QL

Cat??logo de Cursos Enap - 1998

O documento apresenta o programa de cursos oferecidos pela Escola Nacional de Administra????o P??blica no segundo semestre de 1998

M??dulo 4 - fase de planejamento: curso elabora????o do Plano Diretor de Tecnologia da Informa????o (PDTI)

Esse documento trata de: T??cnica 5W2H; Atualizar crit??rios de prioriza????o; Matriz GUT; Priorizar as Necessidades Inventariadas; Definir Metas e A????es; Planejar a Execu????o das A????es; Planejar as A????es de Pessoal; Planejar Investimentos e Custeio; Consolidar a Proposta Or??ament??ria de TI; Aprovar os Planos Espec??ficos; Atualizar Crit??rios de Aceita????o de Riscos; Planejar o gerenciamento de riscos; Identificar Fatores Cr??ticos para a implanta????o do PDTI; Consolidar a Minuta do PDTI; Avaliar e Aprovar a minuta do PDTI; Publicar o PDTI

Prospectiva estrat??gica: instrumento para a constru????o do futuro e para a elabora????o de pol??ticas p??blicas

A prospectiva estrat??gica aparece como ferramenta que, apoiada nos instrumentos de an??lise econ??mica e social existentes e em t??cnicas espec??ficas, como o Delphi, a constru????o de cen??rios, a matriz de impactos cruzados e outras, possibilita ???vis??es de futuro???, que permitir??o a elabora????o de pol??ticas p??blicas que visem ?? constru????o de futuro desej??vel. Este trabalho pressup??e um Estado formulador de pol??ticas p??blicas e detentor de instrumentos de planejamento, o que nos remete a um vi??s ideol??gico: de que, no capitalismo contempor??neo, Estado e mercado coordenem os sistemas econ??micos, conforme explicitado no Plano Diretor da Reforma do Aparelho de Estado (Governo Federal, Brasil, 1995). S?? a aceita????o dessa hip??tese pode supor a exist??ncia e a necessidade de pol??ticas p??blicas, remetendo-nos o campo da ideologia e contrapondo-nos ao liberalismo.