Oswaldo Cruz Institute FIOCRUZ

Rio de Janeiro, Brazil

Oswaldo Cruz Institute FIOCRUZ

Rio de Janeiro, Brazil

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Araujo J.M.G.,Federal University of Rio Grande do Norte | Bello G.,Instituto Oswaldo Cruz FIOCRUZ | Romero H.,University of the Republic of Uruguay | Nogueira R.M.R.,Oswaldo Cruz Institute FIOCRUZ
PLoS Neglected Tropical Diseases | Year: 2012

The incidence of dengue fever and dengue hemorrhagic fever in Brazil experienced a significant increase since the emergence of dengue virus type-3 (DENV-3) at the early 2000s. Despite the major public health concerns, there have been very few studies of the molecular epidemiology and time-scale of this DENV lineage in Brazil. In this study, we investigated the origin and dispersion dynamics of DENV-3 genotype III in Brazil by examining a large number (n = 107) of E gene sequences sampled between 2001 and 2009 from diverse Brazilian regions. These Brazilian sequences were combined with 457 DENV-3 genotype III E gene sequences from 29 countries around the world. Our phylogenetic analysis reveals that there have been at least four introductions of the DENV-3 genotype III in Brazil, as signified by the presence of four phylogenetically distinct lineages. Three lineages (BR-I, BR-II, and BR-III) were probably imported from the Lesser Antilles (Caribbean), while the fourth one (BR-IV) was probably introduced from Colombia or Venezuela. While lineages BR-I and BR-II succeeded in getting established and disseminated in Brazil and other countries from the Southern Cone, lineages BR-III and BR-IV were only detected in one single individual each from the North region. The phylogeographic analysis indicates that DENV-3 lineages BR-I and BR-II were most likely introduced into Brazil through the Southeast and North regions around 1999 (95% HPD: 1998-2000) and 2001 (95% HPD: 2000-2002), respectively. These findings show that importation of DENV-3 lineages from the Caribbean islands into Brazil seems to be relatively frequent. Our study further suggests that the North and Southeast Brazilian regions were the most important hubs of introduction and spread of DENV-3 lineages and deserve an intense epidemiological surveillance. © 2012 Araújo et al.

Matta Guedes P.M.,Federal University of Rio Grande do Norte | Gutierrez F.R.S.,Antonio Nariño University | Nascimento M.S.L.,University of Sao Paulo | Do-Valle-Matta M.A.,Oswaldo Cruz Institute FIOCRUZ | Silva J.S.,University of Sao Paulo
Tropical Medicine and International Health | Year: 2012

Chronic chagasic cardiomyopathy affects 20% of Chagas' disease patients. At present, Chagas' disease chemotherapy uses nitrofurans, benznidazole (Rochagan®, Rodanil®, Roche) or nifurtimox (Lampit®, Bayer). Treatment during acute and recent chronic phases in childhood effects 71.5% and 57.6%, respectively, of parasitological cure. However, in clinical trials during the late chronic phase, only 5.9% of parasitological cure were achieved. This review focuses on the benefit from aetiological treatment to avoid, stop or revert myocarditis. Divergent data gathered from clinical practice are not convincing to support prescription of aetiological treatment as routine for indeterminate and cardiac chronic patients. © 2012 Blackwell Publishing Ltd.

Spinasse L.B.,Oswaldo Cruz Institute Fiocruz | Santos A.R.,Oswaldo Cruz Institute Fiocruz | Suffys P.N.,Oswaldo Cruz Institute Fiocruz | Muxfeldt E.S.,Federal University of Rio de Janeiro | Salles G.F.,Federal University of Rio de Janeiro
Pharmacogenomics | Year: 2014

Aim: Hydralazine, a vasodilator used in resistant hypertension (RH) treatment is metabolized by an acetylation reaction mediated by N-acetyltransferase 2, the activity of which depends on NAT2 polymorphisms. Our aim was to evaluate whether different acetylation phenotypes influenced the antihypertensive effect of hydralazine in patients with RH. Patients & methods: DNA samples from 169 RH patients using hydralazine were genotyped by sequencing the NAT2 coding region, and acetylation phenotypes were defined. Results: Sixty-five patients (38.5%) were intermediate, 60 (35.5%) slow and 21 (12.4%) fast acetylators. Twenty-three (13.6%) patients were indeterminate. Upon association analysis, only slow acetylators had significant blood pressure reductions after hydralazine use, with mean 24-h systolic and diastolic blood pressure reductions of 9.2 and 5.5 mmHg. Four patients presented hydralazine adverse effects resulting in drug withdrawal, three of them were slow acetylators. Conclusion: The slow acetylation phenotype, determined by polymorphisms within NAT2, influenced both the antihypertensive and adverse effects of hydralazine in RH. Original submitted 31 May 2013; Revision submitted 7 October 201. © 2014 Future Medicine Ltd.

Kumar T.,Indian Institute of Technology Bombay | Verma D.,Indian Institute of Technology Bombay | Menna-Barreto R.F.S.,Oswaldo Cruz Institute FIOCRUZ | Valenca W.O.,Federal University of Minas Gerais | And 2 more authors.
Organic and Biomolecular Chemistry | Year: 2015

A one-pot, two step synthesis of highly substituted imidazoles has been carried out in good to excellent yields for the first time via a cascade intermolecular aza-SN2′-intramolecular aza-Michael addition involving a variety of Morita-Baylis-Hillman acetates of nitroalkenes and amidines in the presence of DABCO at room temperature. The synthetic and biological utility of the products has been demonstrated. In particular, some of the imidazoles exhibited potent activity against T. cruzi, the etiological agent of Chagas disease. This journal is © The Royal Society of Chemistry 2015.

De Almeida A.S.,Vanderbilt University | De Almeida A.S.,Oswaldo Cruz Institute FIOCRUZ | Fiske C.T.,Vanderbilt University | Sterling T.R.,Vanderbilt University | Kalams S.A.,Vanderbilt University
Clinical and Vaccine Immunology | Year: 2012

Extrapulmonary tuberculosis may be due to underlying immune compromise. Immunosuppressive regulatory T cells (Treg cells), and CD4 + T lymphocytes in general, are important in the host immune response to Mycobacterium tuberculosis. We evaluated T lymphocytes from patients after recovery from extrapulmonary tuberculosis, which may reflect conditions before M. tuberculosis infection. A case-control study was conducted among HIV-uninfected adults with previously treated extrapulmonary tuberculosis and 3 sets of controls: (i) subjects with previously treated pulmonary tuberculosis, (ii) close tuberculosis contacts with M. tuberculosis infection, and (iii) close tuberculosis contacts with no infection. Monocyte-depleted peripheral blood mononuclear cells (PBMC-M) were stained for CD4 + CD25 hi CD127 low FoxP3 + cell (Treg cell) and T lymphocyte activation. Both characteristics were compared as continuous variables between groups with the Kruskal-Wallis test. There were 7 extrapulmonary tuberculosis cases, 18 pulmonary tuberculosis controls, 17 controls with M. tuberculosis infection, and 18 controls without M. tuberculosis infection. The median Treg cell proportion was highest among persons with previous extrapulmonary tuberculosis (1.23%) compared to subjects with pulmonary tuberculosis (0.56%), latent M. tuberculosis infection (0.14%), or no M. tuberculosis infection (0.20%) (P = 0.001). The median proportion of CD4 + T lymphocytes that expressed the activation markers HLA-DR and CD38 was highest for CD4 + T lymphocytes from persons with previous extrapulmonary tuberculosis (0.79%) compared to subjects with pulmonary tuberculosis (0.44%), latent M. tuberculosis infection (0.14%), or no M. tuberculosis infection (0.32%) (P = 0.005). Compared with controls, persons with previously treated extrapulmonary tuberculosis had the highest Treg cell frequency, but also the highest levels of CD4 + T lymphocyte activation. Immune dysregulation may be a feature of individuals at risk for extrapulmonary tuberculosis. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

Cascabulho C.M.,Oswaldo Cruz Institute Fiocruz | Correa C.B.,Oswaldo Cruz Institute Fiocruz | Cotta-De-Almeida V.,Oswaldo Cruz Institute Fiocruz | Henriques-Pons A.,Oswaldo Cruz Institute Fiocruz
American Journal of Pathology | Year: 2012

Duchenne muscular dystrophy (DMD), an X-linked recessive disorder affecting 1 in 3500 males, is caused by mutations in the dystrophin gene. DMD leads to degeneration of skeletal and cardiac muscles and to chronic inflammation. The mdx/mdx mouse has been widely used to study DMD; this model mimics most characteristics of the disease, including low numbers of T cells in damaged muscles. In this study, we aimed to assess migration of T cells to the heart and to identify any alterations in adhesion molecules that could possibly modulate this process. In 6-week-old mdx/mdx mice, blood leukocytes, including T cells, were CD62L+, but by 12 weeks of age down-modulation was evident, with only approximately 40% of T cells retaining this molecule. Our in vitro and in vivo results point to a P2X7-dependent shedding of CD62L (with high levels in the serum), which in 12-week-old mdx/mdx mice reduces blood T cell competence to adhere to cardiac vessels in vitro and to reach cardiac tissue in vivo, even after Trypanosoma cruzi infection, a known inducer of lymphoid myocarditis. In mdx/mdx mice treated with Brilliant Blue G, a P2X7 blocker, these blood lymphocytes retained CD62L and were capable of migrating to the heart. These results provide new insights into the mechanisms of inflammatory infiltration and immune regulation in DMD. © 2012 American Society for Investigative Pathology.

Lima-Junior J.C.,Oswaldo Cruz Institute Fiocruz | Pratt-Riccio L.R.,Oswaldo Cruz Institute Fiocruz
Frontiers in Immunology | Year: 2016

The importance of host and parasite genetic factors in malaria resistance or susceptibility has been investigated since the middle of the last century. Nowadays, of all diseases that affect man, malaria still plays one of the highest levels of selective pressure on human genome. Susceptibility to malaria depends on exposure profile, epidemiological characteristics, and several components of the innate and adaptive immune system that influences the quality of the immune response generated during the Plasmodium lifecycle in the vertebrate host. But it is well known that the parasite's enormous capacity of genetic variation in conjunction with the host genetics polymorphism is also associated with a wide spectrum of susceptibility degrees to complicated or severe forms of the disease. In this scenario, variations in genes of the major histocompatibility complex (MHC) associated with host resistance or susceptibility to malaria have been identified and used as markers in host-pathogen interaction studies, mainly those evaluating the impact on the immune response, acquisition of resistance, or increased susceptibility to infection or vulnerability to disease. However, due to the intense selective pressure, number of cases, and mortality rates, the majority of the reported associations reported concerned Plasmodium falciparum malaria. Studies on the MHC polymorphism and its association with Plasmodium vivax, which is the most widespread Plasmodium and the most prevalent species outside the African continent, are less frequent but equally important. Despite punctual contributions, there are accumulated evidences of human genetic control in P. vivax infection and disease. Herein, we review the current knowledge in the field of MHC and derived molecules (HLA Class I, Class II, TNF-α, LTA, BAT1, and CTL4) regarding P. vivax malaria. We discuss particularly the results of P. vivax studies on HLA class I and II polymorphisms in relation to host susceptibility, naturally acquired immune response against specific antigens and the implication of this knowledge to overcome the parasite immune evasion. Finally, the potential impact of such polymorphisms on the development of vaccine candidate antigens against P. vivax will be studied. © 2016 Lima-Junior and Pratt-Riccio.

Jansen A.M.,Oswaldo Cruz Institute Fiocruz | Xavier S.C.C.,Oswaldo Cruz Institute Fiocruz | Roque A.L.R.,Oswaldo Cruz Institute Fiocruz
Acta Tropica | Year: 2015

In this study, we report and discuss the results generated from over 20 years of studies of the Try-panosoma cruzi sylvatic transmission cycle. Our results have uncovered new aspects and reviewed old concepts on issues including reservoirs, true generalist species, association of mammalian species withdistinct discrete typing units - DTUs, distribution of T. cruzi genotypes in the wild, mixed infections, and T. cruzi transmission ecology. Using parasitological and serological tests, we examined T. cruzi infectionin 7,285 mammalian specimens from nine mammalian orders dispersed all over the Brazilian biomes.The obtained T. cruzi isolates were characterized by mini-exon gene sequence polymorphism and PCRRFLP to identify DTUs. Infection by T. cruzi was detected by serological methods in 20% of the examined animals and isolated from 41% of those infected, corresponding to 8% of all the examined mammals. Eachmammal taxon responded uniquely to T. cruzi infection. Didelphis spp. are able to maintain high and long-lasting parasitemias (positive hemocultures) caused by TcI but maintain and rapidly control parasitemiascaused by TcII to almost undetectable levels. In contrast, the tamarin species Leontopithecus rosalia and L. chrysomelas maintain long-lasting and high parasitemias caused by TcII similarly to Philander sp. Thecoati Nasua nasua maintains high parasitemias by both parental T. cruzi DTUs TcI or TcII and by TcII/TcIV(formerly Z3) at detectable levels. Wild and domestic canidae seem to display only a short period ofreservoir competence. T. cruzi infection was demonstrated in the wild canid species Cerdocyon thous and Chrysocyon brachyurus, and positive hemoculture was obtained in one hyper carnivore species (Leopar-dus pardalis), demonstrating that T. cruzi transmission is deeply immersed in the trophic net. T. cruzi DTU distribution in nature did not exhibit any association with a particular biome or habitat. TcI predomi-nates throughout (58% of the T. cruzi isolates); however, in spite of being significantly less frequent (17%),TcII is also widely distributed. Concomitant DTU infection occurred in 16% of infected mammals of allbiomes and included arboreal and terrestrial species, as well as bats. TcI/TcII concomitant infection was the most common and widely dispersed, with mixed TcI/TcII infections especially common in coatis andin Didelphimorphia. The second most common pattern of concomitant infection was TcI/TcIV, observedin Chiroptera, Didelphimorphia and Primates. Taken together, our results demonstrate the complexity ofT. cruzi reservoir system and its transmission strategies, indicating that there is considerably more to be learned regarding ecology of T. cruzi. © 2015 Elsevier B.V.

Lima M.D.R.Q.,Oswaldo Cruz Institute FIOCRUZ | Nogueira R.M.R.,Oswaldo Cruz Institute FIOCRUZ | De Filippis A.M.B.,Oswaldo Cruz Institute FIOCRUZ | Dos Santos F.B.,Oswaldo Cruz Institute FIOCRUZ
Clinical and Vaccine Immunology | Year: 2011

We compared two generations of Panbio (Brisbane, Australia) commercial kits for NS1 antigen capture for early diagnosis of dengue: the first-generation pan-E Dengue Early ELISA and the second-generation Dengue Early ELISA. The test improvement resulted in a highly sensitive and specific test suitable for use as a first-line test in the field. Copyright © 2011, American Society for Microbiology. All Rights Reserved.

Lima M.R.Q.,Oswaldo Cruz Institute FIOCRUZ | Nogueira R.M.R.,Oswaldo Cruz Institute FIOCRUZ | Schatzmayr H.G.,Oswaldo Cruz Institute FIOCRUZ | dos Santos F.B.,Oswaldo Cruz Institute FIOCRUZ
PLoS Neglected Tropical Diseases | Year: 2010

Background: Dengue is associated with explosive urban epidemics and has become a major public health problem in many tropical developing countries, including Brazil. The laboratory diagnosis of dengue can be carried out using several approaches, however sensitive and specific assays useful to diagnose in the early stage of fever are desirable. The flavivirus non-structural protein NS1, a highly conserved and secreted glycoprotein, is a candidate protein for rapid diagnosis of dengue in endemic countries. Methodology/Principal Findings: We aimed to evaluate the potential use of 3 commercial kits in a panel of 450 serum samples for early diagnosis of dengue in Brazil. The PanBio Early ELISA (PanBio Diagnostics) showed a sensitivity of 72.3% (159/220) and a specificity of 100%, while the sensitivity of the Platelia™ NS1 assay (Biorad Laboratories) was 83.6% (184/ 220). However, the highest sensitivity (89.6%; 197/220) was obtained by using the NS1 Ag Strip (Biorad Laboratories). A lower sensitivity was observed in DENV-3 cases by all 3 kits. Serum positive by virus isolation were more often positive than cases positive by RT-PCR by all three assays and a higher detection rate was observed during the first four days after the onset of the symptoms. The presence or absence of IgM showed no influence in the confirmation by the pan-E Early ELISA (P = 0,6159). However, a higher confirmation by both PlateliaTM NS1 (Biorad) and Dengue NS1 Ag Strip (Biorad) in the absence of IgM was statistically significant (P<0,0001 and P = 0,0008, respectively). Only the Platelia™ NS1 test showed a higher sensitivity in confirming primary infections than secondary ones. Conclusions/Significance: The results indicate that commercial kits of dengue NS1 antigen are useful for the laboratory diagnosis of acute primary and secondary dengue. It can be used in combination with the MAC-ELISA for case detection and as screening test to complement viral isolation. © 2010 Lima et al.

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