The challenges with Glässer’s disease in technified pig production

The swine upper respiratory tract is early colonised by Haemophilus parasuis, a bacteria which causes Glässer´s disease under favorable conditions. Glässer’s disease is a septicemic infectious disease characterised by causing polyserositis. The prevention of Glässer disease still represents a big challenge for the production chain, since the mechanism of systemic infection in pigs and virulence factors that prevent phagocytosis are not yet well understood. Even in swine herds with high sanitary standard, itis the main cause of mortality that has led to productive and economic losses in the pig industry worldwide. Although the H. parasuis genome sequence has been completed already, diagnosis is still difficult due to the existence of non-virulent strains and the early colonisation of the upper respiratory tract of healthy swines. This review aims to provide up-to-date information about the etiology, epidemiology, pathogenesis, clinical signs, gross and microscopic lesions, diagnosis, treatment and control of Glässer’s disease.&nbsp

Nitroheterocyclic compounds are more efficacious than CYP51 inhibitors against Trypanosoma cruzi: implications for Chagas disease drug discovery and development

Advocacy for better drugs and access to treatment has boosted the interest in drug discovery and development for Chagas disease, a chronic infection caused by the genetically heterogeneous parasite, Trypanosoma cruzi. in this work new in vitro assays were used to gain a better understanding of the antitrypanosomal properties of the most advanced antichagasic lead and clinical compounds, the nitroheterocyclics benznidazole, nifurtimox and fexinidazole sulfone, the oxaborole AN4169, and four ergosterol biosynthesis inhibitors -posaconazole, ravuconazole, EPL-BS967 and EPL-BS1246. Two types of assays were developed: one for evaluation of potency and efficacy in dose-response against a panel of T. cruzi stocks representing all current discrete typing units (DTUs), and a time-kill assay. Although less potent, the nitroheterocyclics and the oxaborole showed broad efficacy against all T. cruzi tested and were rapidly trypanocidal, whilst ergosterol biosynthesis inhibitors showed variable activity that was both compoundand strain-specific, and were unable to eradicate intracellular infection even after 7 days of continuous compound exposure at most efficacious concentrations. These findings contest previous reports of variable responses to nitroderivatives among different T. cruzi strains and further challenge the introduction of ergosterol biosynthesis inhibitors as new single chemotherapeutic agents for the treatment of Chagas disease.DNDiInstitut Pasteur Korea (IPK)Reconstruction Credit Institution-Federal Ministry of Education and Research (KfW-BMBF)/GermanyMedecins Sans Frontieres (Doctors without Borders)/InternationalKorean government (MSIP), Gyeonggi-doKISTIInst Pasteur Korea, Ctr Neglected Dis Drug Discovery CND3, Songnam, South KoreaCtr Nacl Pesquisa Energia & Mat, Lab Nacl Biociencias LNBio, Campinas, SP, BrazilUniversidade Federal de São Paulo UNIFESP, Depto Microbiol Imunol & Parasitol, São Paulo, BrazilDrugs Neglected Dis Initiat DNDi, Geneva, SwitzerlandUniversidade Federal de São Paulo UNIFESP, Depto Microbiol Imunol & Parasitol, São Paulo, BrazilKorean government (MSIP), Gyeonggi-do: 2007-00559Web of Scienc

Cell therapy in pulmonary diseases: are there perspectives?

A terapia celular poderia ser conceituada de forma ampla e genérica como o emprego de células para tratamento de doenças. Apesar de um número não tão expressivo de relatos tendo o pulmão como objeto de estudo na terapia celular em pacientes humanos, há dados consistentes da literatura, tanto em humanos, quanto em modelos animais,que evidenciam a migração de células-tronco da medula óssea para o pulmão,em diferentes situações experimentais. Esses resultados forneceram o embasamento experimental para o emprego de células-tronco na regeneração do tecido pulmonar em modelos animais. Em nosso laboratório, vários projetos de pesquisa têm sido conduzidos com a finalidade de avaliar a resposta pulmonar (morfológica e funcional) ao tratamento com células-tronco adultas em camundongos com doença pulmonar obstrutiva crônica (DPOC) induzida experimentalmente. Os resultados obtidos, aliados àqueles de outros grupos de pesquisa, permitem aventar a possibilidade de aplicação, a curto prazo, da terapia celular em pacientes com DPOC. Em outra patologia pulmonar, fibrose cística (FC), cuja abordagem terapêutica com células-tronco apresenta aspectos particulares em relação às patologias pulmonares crônico-degenerativas, há avanços promissores e potencialmente interessantes; no entanto, os resultados podem ser considerados incipientes e deve-se assinalar, portanto, que a associação da terapia gênica e celular apresenta-se como uma alternativa possível, mas ainda muito distante quanto à sua consolidação e incorporação como opção terapêutica segura e eficaz em FC. Por outro lado, tendo por embasamento os resultados obtidos em modelos experimentais, é possível postular que a terapia celular com células-tronco hematopoéticas (ou de outras fontes) encerra perspectivas consistentes de aplicação em diversas outras patologias pulmonares humanas, especialmente em DPOC.Cell therapy can be briefly described as the use of cells in the treatment of diseases. Although the number of scientific reports involving lung and cell therapy in humans is not expressive, there are consistent data, both in humans and animal models. Experiments show the migration of bone marrow stem cells to the lung, in different situations. These results provide the experimental basis for the use of stem cells in the regeneration of the lung tissue in animal models. In our laboratory, several projects have been conducted aiming to evaluate the pulmonary response (morphological and functional) to treatment with adult stem cells in mice with experimentally induced chronic obstructive pulmonary disease. The results obtained, together with those from other research groups, allow us to consider the possibility of application, in the near future, of cell therapy in chronic obstructive pulmonary disease patients. For another disease, cystic fibrosis, cell therapy shows particular aspects in relation to other chronic degenerative pulmonary diseases. In this pathology, there are interesting and promising advances, however, the results are incipient and, thus, it must be said that the association between genetic and cell therapy appears to be a possibility, but still far from being consolidated and incorporated as a safe and effective therapeutic alternative in cystic fibrosis. On the other hand, based on the results obtained in experimental models, it is possible to postulate that cell therapy with hematopoietic stem cells (or from other sources) brings consistent application perspectives in several other human pulmonary diseases, especially in chronic obstructive pulmonary disease.CNPqFundunesp Fundação BiomaVal

Cell therapy in diabetes mellitus

Nesta revisão são discutidas várias alternativas de regeneração do conjunto de células produtoras de insulina do pâncreas, usando células-tronco embrionárias do cordão umbilical e adultas, e o trabalho que está sendo realizado em nosso grupo de pesquisas utilizando imunossupressão em altas doses combinada com a infusão de células-tronco hematopoéticas autólogas em diabete do tipo 1 recém-diagnosticado.In this review, we discuss several alternatives for the regeneration of the pool of insulin-producing cells by the pancreas using embryonic, cord blood or adult stem cells and the work being carried out by our research group using high dose immunosuppression with autologous hematopoietic stem cells in newly diagnosed type 1 diabetes mellitus

O papel do transplante de célula-tronco hematopoética no diabetes mellitus tipo1

In this review, we present 1) scientific basis for the use of high dose immunosuppression followed by autologous peripheral blood hematopoietic stem cell transplantation for newly diagnosed type 1 diabetes mellitus, 2) an update of clinical and laboratory outcomes in 21 patients transplanted at the University Hospital of the Ribeirão Preto Medical School, University of São Paulo, Brazil, including 6 relapses in patients without previous ketoacidosis and 3) a discussion of future prospectives of cellular therapy for type 1 diabetes mellitus.Nesta revisão, são apresentadas: 1) as bases científicas para o uso de imunossupressão em alta dose seguida de transplante autólogo de células-tronco hematopoéticas do sangue periférico no diabete melito do tipo 1 recém-diagnosticado; 2) uma atualização da evolução clínica e laboratorial de 21 pacientes transplantados no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, da Universidade de São Paulo, Brasil, incluindo recaídas em seis pacientes transplantados sem cetoacidose prévia; e 3) uma discussão das perspectivas futuras de terapia celular no diabete melito do tipo 1

Current and future chemotherapy for Chagas disease

Luís Gaspar is thankful to FCT for funding (scholarship reference: SFRH/BD/81604/2011). The research leading to these results has received funding from the European Community’s Seventh Framework Programme under grant agreement No.602773 (Project KINDRED) and No. 603240 (Project NMTrypI).American trypanosomiasis, commonly called Chagas disease, is one of the most neglected illnesses in the world and remains one of the most prevalent chronic infectious diseases of Latin America with thousands of new cases every year. The only treatments available have been introduced five decades ago. They have serious, undesirable side effects and disputed benefits in the chronic stage of the disease – a characteristic and debilitating cardiomyopathy and/or megavisceras. Several laboratories have therefore focused their efforts in finding better drugs. Although recent years have brought new clinical trials, these are few and lack diversity in terms of drug mechanism of action, thus resulting in a weak drug discovery pipeline. This fragility has been recently exposed by the failure of two candidates, posaconazole and E1224, to sterilely cure patients in phase 2 clinical trials. Such setbacks highlight the need for continuous, novel and high quality drug discovery and development efforts to discover better and safer treatments. In this article we will review past and current findings on drug discovery for Trypanosoma cruzi made by academic research groups, industry and other research organizations over the last half century. We will also analyze the current research landscape that is now better placed than ever to deliver alternative treatments for Chagas disease in the near futurePostprintPeer reviewe

Drug discovery for Chagas disease should consider Trypanosoma cruzi strain diversity.

This opinion piece presents an approach to standardisation of an important aspect of Chagas disease drug discovery and development: selecting Trypanosoma cruzi strains for in vitro screening. We discuss the rationale for strain selection representing T. cruzi diversity and provide recommendations on the preferred parasite stage for drug discovery, T. cruzi discrete typing units to include in the panel of strains and the number of strains/clones for primary screens and lead compounds. We also consider experimental approaches for in vitro drug assays. The Figure illustrates the current Chagas disease drug-discovery and development landscape

Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity

Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues (1-3) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes (Trypanosoma brucei PTR1-TbPTR1 and Leishmania major-LmPTR1) and parasites (Trypanosoma brucei and Leishmania infantum). A crystal structure of TbPTR1 in complex with compound 1 and the first crystal structures of LmPTR1-flavanone complexes (compounds 1 and 3) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound 1 showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants