Showing papers by "Oswaldo Cruz Foundation published in 2018"

Minimal information for studies of extracellular vesicles 2018 (MISEV2018) : a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

DynaMut: predicting the impact of mutations on protein conformation, flexibility and stability

Abstract: Proteins are highly dynamic molecules, whose function is intrinsically linked to their molecular motions. Despite the pivotal role of protein dynamics, their computational simulation cost has led to most structure-based approaches for assessing the impact of mutations on protein structure and function relying upon static structures. Here we present DynaMut, a web server implementing two distinct, well established normal mode approaches, which can be used to analyze and visualize protein dynamics by sampling conformations and assess the impact of mutations on protein dynamics and stability resulting from vibrational entropy changes. DynaMut integrates our graph-based signatures along with normal mode dynamics to generate a consensus prediction of the impact of a mutation on protein stability. We demonstrate our approach outperforms alternative approaches to predict the effects of mutations on protein stability and flexibility (P-value < 0.001), achieving a correlation of up to 0.70 on blind tests. DynaMut also provides a comprehensive suite for protein motion and flexibility analysis and visualization via a freely available, user friendly web server at http://biosig.unimelb.edu.au/dynamut/.

Technical challenges of working with extracellular vesicles

Abstract: Extracellular Vesicles (EVs) are gaining interest as central players in liquid biopsies, with potential applications in diagnosis, prognosis and therapeutic guidance in most pathological conditions. These nanosized particles transmit signals determined by their protein, lipid, nucleic acid and sugar content, and the unique molecular pattern of EVs dictates the type of signal to be transmitted to recipient cells. However, their small sizes and the limited quantities that can usually be obtained from patient-derived samples pose a number of challenges to their isolation, study and characterization. These challenges and some possible options to overcome them are discussed in this review.

Ru(II) Compounds: Next-Generation Anticancer Metallotherapeutics?

Abstract: Metal based therapeutics are a precious class of drugs in oncology research that include examples of theranostic drugs, which are active in both diagnostic, specifically imaging, and therapeutics applications. Ruthenium compounds have shown selective bioactivity and the ability to overcome the resistance that platinum-based therapeutics face, making them effective oncotherapeutic competitors in rational drug invention approaches. The development of antineoplastic ruthenium therapeutics is of particular interest because ruthenium containing complexes NAMI-A, KP1019, and KP1339 entered clinical trials and DW1/2 is in preclinical levels. The very robust, conformationally rigid organometallic Ru(II) compound DW1/2 is a protein kinase inhibitor and presents new Ru(II) compound designs as anticancer agents. Over the recent years, numerous strategies have been used to encapsulate Ru(II) derived compounds in a nanomaterial system, improving their targeting and delivery into neoplastic cells. A new photodynamic th...

Genomic and epidemiological monitoring of yellow fever virus transmission potential

Abstract: The yellow fever virus (YFV) epidemic in Brazil is the largest in decades. The recent discovery of YFV in Brazilian Aedes species mosquitos highlights a need to monitor the risk of reestablishment of urban YFV transmission in the Americas. We use a suite of epidemiological, spatial, and genomic approaches to characterize YFV transmission. We show that the age and sex distribution of human cases is characteristic of sylvatic transmission. Analysis of YFV cases combined with genomes generated locally reveals an early phase of sylvatic YFV transmission and spatial expansion toward previously YFV-free areas, followed by a rise in viral spillover to humans in late 2016. Our results establish a framework for monitoring YFV transmission in real time that will contribute to a global strategy to eliminate future YFV epidemics.

Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis

Abstract: To characterize the genetic determinants of resistance to antituberculosis drugs, we performed a genome-wide association study (GWAS) of 6,465 Mycobacterium tuberculosis clinical isolates from more than 30 countries. A GWAS approach within a mixed-regression framework was followed by a phylogenetics-based test for independent mutations. In addition to mutations in established and recently described resistance-associated genes, novel mutations were discovered for resistance to cycloserine, ethionamide and para-aminosalicylic acid. The capacity to detect mutations associated with resistance to ethionamide, pyrazinamide, capreomycin, cycloserine and para-aminosalicylic acid was enhanced by inclusion of insertions and deletions. Odds ratios for mutations within candidate genes were found to reflect levels of resistance. New epistatic relationships between candidate drug-resistance-associated genes were identified. Findings also suggest the involvement of efflux pumps (drrA and Rv2688c) in the emergence of resistance. This study will inform the design of new diagnostic tests and expedite the investigation of resistance and compensatory epistatic mechanisms.

The Zika Virus Epidemic in Brazil: From Discovery to Future Implications.

Abstract: The first confirmed case of Zika virus infection in the Americas was reported in Northeast Brazil in May 2015, although phylogenetic studies indicate virus introduction as early as 2013. Zika rapidly spread across Brazil and to more than 50 other countries and territories on the American continent. The Aedesaegypti mosquito is thought to be the principal vector responsible for the widespread transmission of the virus. However, sexual transmission has also been reported. The explosively emerging epidemic has had diverse impacts on population health, coinciding with cases of Guillain-Barre Syndrome and an unexpected epidemic of newborns with microcephaly and other neurological impairments. This led to Brazil declaring a national public health emergency in November 2015, followed by a similar decision by the World Health Organization three months later. While dengue virus serotypes took several decades to spread across Brazil, the Zika virus epidemic diffused within months, extending beyond the area of permanent dengue transmission, which is bound by a climatic barrier in the south and low population density areas in the north. This rapid spread was probably due to a combination of factors, including a massive susceptible population, climatic conditions conducive for the mosquito vector, alternative non-vector transmission, and a highly mobile population. The epidemic has since subsided, but many unanswered questions remain. In this article, we provide an overview of the discovery of Zika virus in Brazil, including its emergence and spread, epidemiological surveillance, vector and non-vector transmission routes, clinical complications, and socio-economic impacts. We discuss gaps in the knowledge and the challenges ahead to anticipate, prevent, and control emerging and re-emerging epidemics of arboviruses in Brazil and worldwide.

Antileishmanial Activity of Dimeric Flavonoids Isolated from Arrabidaea brachypoda

Abstract: Leishmaniasis are diseases caused by parasites belonging to Leishmania genus. The treatment with pentavalent antimonials present high toxicity. Secondary line drugs, such as amphotericin B and miltefosine also have a narrow therapeutic index. Therefore, there is an urgent need to develop new drugs to treat leishmaniasis. Here, we present the in vitro anti-leishmanial activity of unusual dimeric flavonoids purified from Arrabidaea brachypoda. Three compounds were tested against Leishmana sp. Compound 2 was the most active against promastigotes. Quantifying the in vitro infected macrophages revealed that compound 2 was also the most active against intracellular amastigotes of L. amazonensis, without displaying host cell toxicity. Drug combinations presented an additive effect, suggesting the absence of interaction between amphotericin B and compound 2. Amastigotes treated with compound 2 demonstrated alterations in the Golgi and accumulation of vesicles inside the flagellar pocket. Compound 2-treated amastigotes presented a high accumulation of cytoplasmic vesicles and a myelin-like structure. When administered in L. amazonensis-infected mice, neither the oral nor the topical treatments were effective against the parasite. Based on the high in vitro activity, dimeric flavonoids can be used as a lead structure for the development of new molecules that could be useful for structure-active studies against Leishmania.

The Brazilian Longitudinal Study of Aging (ELSI-Brazil): Objectives and Design

Abstract: Brazil is experiencing among the world’s fastest demographic aging worldwide. This demographic transition is occurring in a context of few resources and great social inequalities. The Brazilian Longitudinal Study of Aging (ELSI-Brazil) is a nationally representative study of 9,412 people aged 50 years or older, residing in 70 municipalities across the 5 Brazilian regions. ELSI-Brazil allows investigations of the aging process, its health, psychosocial and economic determinants, and societal consequences. The baseline examination (2015–2016) included detailed household and individual interviews and physical measurements (blood pressure, anthropometry, grip strength, and timed walk and balance tests). Blood tests and sample storage were performed in a subsample of study participants. Subsequent waves are planned for every 3 years. The study adopts a conceptual framework common to other large-scale longitudinal studies of aging in the world, such as the Health and Retirement Study, allowing cross-national comparisons. The goal of ELSI-Brazil is not only to build an understanding of aging in a large, Western, middle-income country in a rapid demographic transition but also to provide scientific data to support and study policy changes that may affect older adults. We describe the methodology of the study and some descriptive results of the baseline survey.

Anti-Inflammatory Effects of Resveratrol: Mechanistic Insights

Abstract: Inflammation is the principal response invoked by the body to address injuries. Despite inflammation constituting a crucial component of tissue repair, it is well known that unchecked or chronic inflammation becomes deleterious, leading to progressive tissue damage. Studies over the past years focused on foods rich in polyphenols with anti-inflammatory and immunomodulatory properties, since inflammation was recognized to play a central role in several diseases. In this review, we discuss the beneficial effects of resveratrol, the most widely investigated polyphenol, on cancer and neurodegenerative, respiratory, metabolic, and cardiovascular diseases. We highlight how resveratrol, despite its unfavorable pharmacokinetics, can modulate the inflammatory pathways underlying those diseases, and we identify future opportunities for the evaluation of its clinical feasibility.

Saúde reprodutiva, materna, neonatal e infantil nos 30 anos do Sistema Único de Saúde (SUS)

Abstract: Resumo Este estudo apresenta um sumario das intervencoes realizadas no âmbito do setor publico e os indicadores de resultado alcancados na saude de mulheres e criancas, destacando-se os avancos no periodo 1990-2015. Foram descritos indicadores de atencao pre-natal, assistencia ao parto e saude materna e infantil utilizando dados provenientes de Sistemas de Informacao Nacionais de nascidos vivos e obitos; inqueritos nacionais; e publicacoes obtidas de diversas outras fontes. Foram tambem descritos os programas governamentais desenvolvidos para a melhoria da saude das mulheres e das criancas, bem como outros intersetoriais para reducao da pobreza. Houve grande queda nas taxas de fecundidade, universalizacao da atencao pre-natal e hospitalar ao parto, aumento do acesso a contracepcao e aleitamento materno, e diminuicao das hospitalizacoes por aborto e da subnutricao. Mantem-se em excesso a sifilis congenita, taxa de cesarianas e nascimentos prematuros. A reducao na mortalidade na infância foi de mais de 2/3, mas nao tao marcada no componente neonatal. A razao de mortalidade materna decresceu de 143,2 para 59,7 por 1000 NV. Embora alguns poucos indicadores tenham demonstrado piora ou mantido a estabilidade, a grande maioria apresentou acentuadas melhoras.

Platelets in Immune Response to Virus and Immunopathology of Viral Infections

Abstract: Platelets are essential effector cells in hemostasis. Aside from their role in coagulation, platelets are now recognized as major inflammatory cells with key roles in the innate and adaptive arms of the immune system. Activated platelets have key thromboinflammatory functions linking coagulation to immune responses in various infections, including in response to virus. Recent studies have revealed that platelets exhibit several pattern recognition receptors (PRR) including those from the toll-like receptor, NOD-like receptor, and C-type lectin receptor family and are first-line sentinels in detecting and responding to pathogens in the vasculature. Here, we review the main mechanisms of platelets interaction with viruses, including their ability to sustain viral infection and replication, their expression of specialized PRR, and activation of thromboinflammatory responses against viruses. Finally, we discuss the role of platelet-derived mediators and platelet interaction with vascular and immune cells in protective and pathophysiologic responses to dengue, influenza, and human immunodeficiency virus 1 infections.

Child morbidity and mortality associated with alternative policy responses to the economic crisis in Brazil: A nationwide microsimulation study.

Abstract: Background Since 2015, a major economic crisis in Brazil has led to increasing poverty and the implementation of long-term fiscal austerity measures that will substantially reduce expenditure on social welfare programmes as a percentage of the country’s GDP over the next 20 years. The Bolsa Familia Programme (BFP)—one of the largest conditional cash transfer programmes in the world—and the nationwide primary healthcare strategy (Estrategia Saude da Familia [ESF]) are affected by fiscal austerity, despite being among the policy interventions with the strongest estimated impact on child mortality in the country. We investigated how reduced coverage of the BFP and ESF—compared to an alternative scenario where the level of social protection under these programmes is maintained—may affect the under-five mortality rate (U5MR) and socioeconomic inequalities in child health in the country until 2030, the end date of the Sustainable Development Goals. Methods and findings We developed and validated a microsimulation model, creating a synthetic cohort of all 5,507 Brazilian municipalities for the period 2017–2030. This model was based on the longitudinal dataset and effect estimates from a previously published study that evaluated the effects of poverty, the BFP, and the ESF on child health. We forecast the economic crisis and the effect of reductions in BFP and ESF coverage due to current fiscal austerity on the U5MR, and compared this scenario with a scenario where these programmes maintain the levels of social protection by increasing or decreasing with the size of Brazil’s vulnerable populations (policy response scenarios). We used fixed effects multivariate regression models including BFP and ESF coverage and accounting for secular trends, demographic and socioeconomic changes, and programme duration effects. With the maintenance of the levels of social protection provided by the BFP and ESF, in the most likely economic crisis scenario the U5MR is expected to be 8.57% (95% CI: 6.88%–10.24%) lower in 2030 than under fiscal austerity—a cumulative 19,732 (95% CI: 10,207–29,285) averted under-five deaths between 2017 and 2030. U5MRs from diarrhoea, malnutrition, and lower respiratory tract infections are projected to be 39.3% (95% CI: 36.9%–41.8%), 35.8% (95% CI: 31.5%–39.9%), and 8.5% (95% CI: 4.1%–12.0%) lower, respectively, in 2030 under the maintenance of BFP and ESF coverage, with 123,549 fewer under-five hospitalisations from all causes over the study period. Reduced coverage of the BFP and ESF will also disproportionately affect U5MR in the most vulnerable areas, with the U5MR in the poorest quintile of municipalities expected to be 11.0% (95% CI: 8.0%–13.8%) lower in 2030 under the maintenance of BFP and ESF levels of social protection than under fiscal austerity, compared to no difference in the richest quintile. Declines in health inequalities over the last decade will also stop under a fiscal austerity scenario: the U5MR concentration index is expected to remain stable over the period 2017–2030, compared to a 13.3% (95% CI: 5.6%–21.8%) reduction under the maintenance of BFP and ESF levels of protection. Limitations of our analysis are the ecological nature of the study, uncertainty around future macroeconomic scenarios, and potential changes in other factors affecting child health. A wide range of sensitivity analyses were conducted to minimise these limitations. Conclusions The implementation of fiscal austerity measures in Brazil can be responsible for substantively higher childhood morbidity and mortality than expected under maintenance of social protection—threatening attainment of Sustainable Development Goals for child health and reducing inequality.

The Family Health Strategy: expanding access and reducinghospitalizations due to ambulatory care sensitive conditions (ACSC).

Abstract: Resumo Criado em 1994, o Programa Saude da Familia gradualmente tornou-se a principal estrategia para a mudanca do modelo assistencial e a ampliacao do acesso de primeiro contato aos servicos de saude no SUS. Pouco mais de dez anos depois foi enunciada como Estrategia de Saude da Familia (ESF) na Politica Nacional de Atencao Basica (PNAB), em 2006. Este artigo avaliou os efeitos da implementacao da ESF ao longo das duas ultimas decadas no Brasil, demonstrando o acesso proporcionado e a tendencia das internacoes por condicoes sensiveis a atencao basica (ICSAB). Trata-se de um estudo do tipo ecologico de series temporais com dados secundarios referentes ao numero de equipes implantadas de saude da familia e as ICSAB no SUS de 2001 a 2016. Os resultados evidenciam a reducao em 45% das taxas padronizadas de ICSAB por 10.000 hab, que passaram de 120 para 66 no periodo de 2001 a 2016. Apesar de nao ser possivel isolar os efeitos da atencao primaria, e bastante plausivel que o resultado da reducao das ICSAB esteja vinculada ao avanco da cobertura da ESF no Brasil, em especial na melhoria do acompanhamento das condicoes cronicas, no aprimoramento do diagnostico e na facilidade do acesso aos medicamentos.

Yellow fever outbreak in Brazil: the puzzle of rapid viral spread and challenges for immunisation.

Abstract: We discuss the complex eco-social factors involved in the puzzle of the unexpected rapid viral spread in the ongoing Brazilian yellow fever (YF) outbreak, which has increased the reurbanisation risk of a disease without urban cases in Brazil since 1942 Indeed, this rapid spatial viral dissemination to the Southeast and South regions, now circulating in the Atlantic Forest fragments close to peri-urban areas of the main Brazilian megalopolises (Sao Paulo and Rio de Janeiro) has led to an exponential increase in the number of yellow fever cases In less than 18 months, 1,833 confirmed cases and 578 deaths were recorded most of them reported in the Southeast region (99,9%) Large epizooties in monkeys and other non-human primates (NHPs) were communicated in the country with 732 YF virus (YFV) laboratory confirmed events only in the 2017/2018 monitoring period We also discuss the peculiarities and similarities of the current outbreak when compared with previous great epidemics, examining several hypotheses to explain the recent unexpected acceleration of epizootic waves in the sylvatic cycle of the YFV together with the role of human, NHPs and mosquito mobility with respect to viral spread We conclude that the most feasible hypothesis to explain this rapidity would be related to human behavior combined with ecological changes that promoted a significant increase in mosquito and NHP densities and their contacts with humans We emphasize the urgent need for an adequate response to this outbreak such as extending immunisation coverage to the whole Brazilian population and developing novel strategies for immunisation of NHPs confined in selected reserve areas and zoos Finally, we stress the urgent need to improve the quality of response in order to prevent future outbreaks and a catastrophic reurbanisation of the disease in Brazil and other South American countries Continuous monitoring of YFV receptivity and vulnerability conditions with effective control of the urban vector Aedes aegypti and significant investments in YF vaccine production capacity and research and development for reduction of adverse effects are of the highest priority

Política Nacional de Atenção Básica 2017: retrocessos e riscos para o Sistema Único de Saúde

Abstract: The article discusses the meanings and implications of the changes introduced by the National Policy of Primary Healthcare 2017, which promote the relativization of universal coverage, the segmentation of access, the recomposition of the teams, the reorganization of the work process and the weakening of the national policy coordination. It is argued that its review indicates serious risks to the achievements obtained with the strengthening of the Primary Health Care in Brazil. In the current conjuncture of strengthening neoliberal ideology, these changes reinforce the subtraction of rights and the process of deconstruction of the Unified Health System in progress in the Country.

Taxonomy based on science is necessary for global conservation

Abstract: Taxonomy is a scientific discipline that has provided the universal naming and classification system of biodiversity for centuries and continues effectively to accommodate new knowledge. A recent publication by Garnett and Christidis [1] expressed concerns regarding the difficulty that taxonomic changes represent for conservation efforts and proposed the establishment of a system to govern taxonomic changes. Their proposal to “restrict the freedom of taxonomic action” through governing subcommittees that would “review taxonomic papers for compliance” and their assertion that “the scientific community’s failure to govern taxonomy threatens the effectiveness of global efforts to halt biodiversity loss, damages the credibility of science, and is expensive to society” are flawed in many respects. They also assert that the lack of governance of taxonomy damages conservation efforts, harms the credibility of science, and is costly to society. Despite its fairly recent release, Garnett and Christidis' proposition has already been rejected by a number of colleagues [2,3,4,5,6,7,8]. Herein, we contribute to the conversation between taxonomists and conservation biologists aiming to clarify some misunderstandings and issues in the proposition by Garnett and Christidis.

SUS: supply, access to and use of health services over the last 30 years.

Abstract: Resumo Ao longo dos ultimos 30 anos, o Sistema Unico de Saude brasileiro se caracterizou por importantes mudancas na atencao a saude. No presente artigo, sao apresentados dados relativos a evolucao das estruturas ambulatorial e hospitalar, e dos recursos humanos, bem como acerca da utilizacao dos servicos de saude. A expansao da rede publica ocorreu principalmente entre as unidades que dao suporte aos programas de atencao basica, ampliando o acesso as consultas medicas e a reducao das internacoes para um conjunto de doencas, mas persiste uma carencia de profissionais, especialmente no cuidado odontologico. Entretanto, a despeito do avanco na cobertura, permanecem os desafios a continuidade do SUS e a melhoria da qualidade do cuidado, particularmente no tocante ao financiamento publico, oferta de servicos, e na relacao com o setor privado.

Species distribution modelling: Contrasting presence-only models with plot abundance data

Abstract: Species distribution models (SDMs) are widely used in ecology and conservation. Presence-only SDMs such as MaxEnt frequently use natural history collections (NHCs) as occurrence data, given their huge numbers and accessibility. NHCs are often spatially biased which may generate inaccuracies in SDMs. Here, we test how the distribution of NHCs and MaxEnt predictions relates to a spatial abundance model, based on a large plot dataset for Amazonian tree species, using inverse distance weighting (IDW). We also propose a new pipeline to deal with inconsistencies in NHCs and to limit the area of occupancy of the species. We found a significant but weak positive relationship between the distribution of NHCs and IDW for 66% of the species. The relationship between SDMs and IDW was also significant but weakly positive for 95% of the species, and sensitivity for both analyses was high. Furthermore, the pipeline removed half of the NHCs records. Presence-only SDM applications should consider this limitation, especially for large biodiversity assessments projects, when they are automatically generated without subsequent checking. Our pipeline provides a conservative estimate of a species’ area of occupancy, within an area slightly larger than its extent of occurrence, compatible to e.g. IUCN red list assessments.

Obesity following ART initiation is common and influenced by both traditional and HIV-/ART-specific risk factors.

Abstract: Author(s): Bakal, David R; Coelho, Lara E; Luz, Paula M; Clark, Jesse L; De Boni, Raquel B; Cardoso, Sandra W; Veloso, Valdilea G; Lake, Jordan E; Grinsztejn, Beatriz | Abstract: Background:Obesity rates are increasing among HIV-infected individuals, but risk factors for obesity development on ART remain unclear. Objectives:In a cohort of HIV-infected adults in Rio de Janeiro, Brazil, we aimed to determine obesity rates before and after ART initiation and to analyse risk factors for obesity on ART. Methods:We retrospectively analysed data from individuals initiating ART between 2000 and 2015. BMI was calculated at baseline (time of ART initiation). Participants who were non-obese at baseline and had ≥90 days of ART exposure were followed until the development of obesity or the end of follow-up. Obesity incidence rates were estimated using Poisson regression models and risk factors were assessed using Cox regression models. Results:Of participants analysed at baseline (n = 1794), 61.3% were male, 48.3% were white and 7.9% were obese. Among participants followed longitudinally (n = 1567), 66.2% primarily used an NNRTI, 32.9% a PI and 0.9% an integrase strand transfer inhibitor (INSTI); 18.3% developed obesity and obesity incidence was 37.4 per 1000 person-years. In multivariable analysis, the greatest risk factor for developing obesity was the use of an INSTI as the primary ART core drug (adjusted HR 7.12, P l 0.0001); other risk factors included younger age, female sex, higher baseline BMI, lower baseline CD4+ T lymphocyte count, higher baseline HIV-1 RNA, hypertension and diabetes mellitus. Conclusions:Obesity following ART initiation is frequent among HIV-infected adults. Key risk factors include female sex, HIV disease severity and INSTI use. Further research regarding the association between INSTIs and the development of obesity is needed.