Epstein-Barr virus-encoded EBNA1 inhibits the canonical NF-κB pathway in carcinoma cells by inhibiting IKK phosphorylation

Background The Epstein-Barr virus (EBV)-encoded EBNA1 protein is expressed in all EBV-associated tumours, including undifferentiated nasopharyngeal carcinoma (NPC), where it is indispensable for viral replication, genome maintenance and viral gene expression. EBNA1's transcription factor-like functions also extend to influencing the expression of cellular genes involved in pathways commonly dysregulated during oncogenesis, including elevation of AP-1 activity in NPC cell lines resulting in enhancement of angiogenesis in vitro. In this study we sought to extend these observations by examining the role of EBNA1 upon another pathway commonly deregulated during carcinogenesis; namely NF-κB. Results In this report we demonstrate that EBNA1 inhibits the canonical NF-κB pathway in carcinoma lines by inhibiting the phosphorylation of IKKα/β. In agreement with this observation we find a reduction in the phosphorylation of IκBα and reduced phosphorylation and nuclear translocation of p65, resulting in a reduction in the amount of p65 in nuclear NF-κB complexes. Similar effects were also found in carcinoma lines infected with recombinant EBV and in the EBV-positive NPC-derived cell line C666-1. Inhibition of NF-κB was dependent upon regions of EBNA1 essential for gene transactivation whilst the interaction with the deubiquitinating enzyme, USP7, was entirely dispensable. Furthermore, in agreement with EBNA1 inhibiting p65 NF-κB we demonstrate that p65 was exclusively cytoplasmic in 11 out of 11 NPC tumours studied. Conclusions Inhibition of p65 NF-κB in murine and human epidermis results in tissue hyperplasia and the development of squamous cell carcinoma. In line with this, p65 knockout fibroblasts have a transformed phenotype. Inhibition of p65 NF-κB by EBNA1 may therefore contribute to the development of NPC by inducing tissue hyperplasia. Furthermore, inhibition of NF-κB is employed by viruses as an immune evasion strategy which is also closely linked to oncogenesis during persistent viral infection. Our findings therefore further implicate EBNA1 in playing an important role in the pathogenesis of NPC

The Nexus+ approach applied to studies of Impacts, vulnerability and adaptation to climate change in Brazil

This paper aims to present the methodology developed within the Impacts, Vulnerability and Adaptation (IVA) to climate change component of the Fourth National Communication (4CN) of Brazil. The methodological choice of this 4CN involves the application of the nexus+ integrated approach, based on studies of impacts and vulnerabilities for water, energy, food and socio-environmental securities, in the different in the territories of Brazilian biomes, coastal areas and cities. For each of these securities it were identified the observed impacts; analysis of risk conditions; definition and assessments of integrated analysis of key impacts at territorial level; inventory, selection and analysis of adaption options in the context of Nexus+, identifying synergies and trade-offs. This process made possible an integrated assessment among the conditioning risk factors, impacts and interactions among proposed adaptation options.This paper aims to present the methodology developed within the Impacts, Vulnerability and Adaptation (IVA) to climate change component of the Fourth National Communication (4CN) of Brazil. The methodological choice of this 4CN involves the application of the nexus+ integrated approach, based on studies of impacts and vulnerabilities for water, energy, food and socio-environmental securities, in the different in the territories of Brazilian biomes, coastal areas and cities. For each of these securities it were identified the observed impacts; analysis of risk conditions; definition and assessments of integrated analysis of key impacts at territorial level; inventory, selection and analysis of adaption options in the context of Nexus+, identifying synergies and trade-offs. This process made possible an integrated assessment among the conditioning risk factors, impacts and interactions among proposed adaptation options

Desempenho de uma população brasileira no teste de alfabetização funcional para adultos na área de saúde

OBJECTIVE: To analyze the scoring obtained by an instrument, which evaluates the ability to read and understand items in the health care setting, according to education and age. METHODS: The short version of the Test of Functional Health Literacy in Adults was administered to 312 healthy participants of different ages and years of schooling. The study was conducted between 2006 and 2007, in the city of São Paulo, Southeastern Brazil. The test includes actual materials such as pill bottles and appointment slips and measures reading comprehension, assessing the ability to read and correctly pronounce a list of words and understand both prose passages and numerical information. Pearson partial correlations and a multiple regression model were used to verify the association between its scores and education and age. RESULTS: The mean age of the sample was 47.3 years(sd=16.8) and the mean education was 9.7 years(sd=5; range: 1 - 17). A total of 32.4% of the sample showed literacy/numeracy deficits, scoring in the inadequate and marginal functional health literacy ranges. Among the elderly (65 years or older) this rate increased to 51.6%. There was a positive correlation between schooling and scores (r=0.74; pOBJETIVO: Analizar los escores de instrumento que evalúa habilidad de lectura y comprensión de materiales del área de salud según escolaridad y edad. MÉTODOS: Fueron evaluados 312 participantes saludables de diferentes edades por medio de la versión reducida del instrumento Test of Functional Health Literacy in Adults. El estudio fue realizado entre 2006 y 2007 en la ciudad de Sao Paulo (Sureste de Brasil). El instrumento incluye materiales como frascos de medicamentos y cartones de para marcar consultas, evaluando la comprensión de lectura y de conceptos numéricos. Las pruebas de correlación parcial y de Pearson y un modelo de regresión múltiple fueron usados para verificar la asociación entre los escores en el instrumento, escolaridad y edad. RESULTADOS: Los promedios de edad y de escolaridad de la muestra fueron respectivamente 47,3 (dp=16,8) y 9,7 (dp=5; de uno a 17 años de estudio). El total de 32,4% de la muestra mostraron déficit de alfabetización funcional/uso de conceptos numéricos en el área de salud, con desempeño inadecuado o limítrofe en el instrumento. Entre ancianos (65 años o más) esta tasa afectó 51,6%. Se encontró correlación positiva entre años de estudio y escores en el instrumento (r=0,740; p< 0,01) y correlación negativa entre edad y escores en el instrumento (r=-0,259; p< 0,01).La correlación entre escores en el instrumento y edad no fue significativa cuando los efectos de la escolaridad fueron controlados (r=-0,031, p=0,584). Una asociación significativa (B=3,877, Beta=0,733; p< 0,001) fue encontrada entre años de estudio y escores en el instrumento. La edad no fue una variable predictiva en el modelo (B=-0,035, Beta=-0,22; p=0,584). CONCLUSIONES: El instrumento es adecuado para evaluar la alfabetización funcional en salud en la población brasilera. El elevado número de individuos clasificados como analfabetos funcionales indica la importancia de adopción de medidas especiales para ayudar estos individuos a comprender correctamente las orientaciones para cuidados de salud.OBJETIVO: Analisar os escores de instrumento que avalia habilidade de leitura e compreensão de materiais da área da saúde segundo escolaridade e idade. MÉTODOS: Foram avaliados 312 participantes saudáveis de diferentes idades por meio da versão reduzida do instrumento Test of Functional Health Literacy in Adults. O estudo foi realizado entre 2006 e 2007 na cidade de São Paulo (SP). O instrumento envolve materiais como frascos de medicamentos e cartões de agendamento de consultas, avaliando a compreensão de leitura e de conceitos numéricos. Os testes de correlação parcial e de Pearson e um modelo de regressão múltipla foram usados para verificar a associação entre os escores no instrumento, escolaridade e idade. RESULTADOS: As médias de idade e de escolaridade da amostra foram respectivamente 47,3 (dp=16,8 ) e 9,7 (dp=5; de um a 17 anos de estudo). O total de 32,4% da amostra mostraram déficits de alfabetização funcional/ uso de conceitos numéricos na área de saúde, com desempenho inadequado ou limítrofe no instrumento. Entre idosos (65 anos ou mais) esta taxa atingiu 51,6%. Encontrou-se correlação positiva entre anos de estudo e escores no instrumento (r=0,740;

Low prevalence of renal, cardiac, pulmonary, and neurological extra-articular clinical manifestations in spondyloarthritis: analysis of the Brazilian Registry of Spondyloarthritis

OBJECTIVE: To describe the extra-articular manifestations (cardiac, renal, pulmonary, and neurological), usually not related to spondyloarthritis (SpA), in a large cohort of Brazilian patients. MATERIALS AND METHODS: This retrospective study analyzed 1,472 patients diagnosed with SpA and cared for at 29 health care centers distributed in the five major geographic regions in the country, participating in the Brazilian Registry of Spondyloarthritis (BRS). All patients were assessed for the prevalence of major extra-articular manifestations (cardiac, renal, pulmonary, and neurological), classified according to the diagnosis [ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA), arthritis associated with inflammatory bowel disease (IBD), undifferentiated spondyloarthritis (uSpA), and juvenile SpA], and according to the clinical presentation (axial, peripheral, mixed, and enthesitis). RESULTS: Of the patients with SpA assessed, 963 had AS, 271 PsA, 49 ReA, 48 arthritis associated with IBD, 98 uSpA, and 43 juvenile SpA. Cardiac involvement was reported in 44 patients (3.0%), pulmonary involvement in 19 (1.3%), renal involvement in 17 (1.2%), and neurological involvement in 13 patients (0.9%). Most patients with visceral involvement had AS or PsA, and the mixed (axial + peripheral) and/or predominantly axial clinical form. CONCLUSION: Cardiac, renal, pulmonary, and neurological extra-articular manifestations are quite infrequent in SpA, ranging from 0.9% to 3% in this large Brazilian cohort, and affected predominantly patients with AS and PsA.OBJETIVO: Descrever as manifestações extra-articulares (cardíacas, renais, pulmonares e neurológicas) geralmente não relacionadas às espondiloartrites (EpA) em uma grande coorte de pacientes brasileiros. MÉTODOS: Este estudo retrospectivo analisou 1.472 pacientes com o diagnóstico de EpA atendidos em 29 centros distribuídos pelas cinco principais regiões geográficas do Brasil, integrantes do Registro Brasileiro de Espondiloartrites. Todos os pacientes foram avaliados para a prevalência das principais manifestações extra-articulares (cardíacas, renais, pulmonares e neurológicas), divididas por diagnóstico [espondilite anquilosante (EA), artrite psoriásica (AP), artrite reativa (ARe), artrite associada a doença inflamatória intestinal (DII), EpA indiferenciada (EI) e EpA juvenil] e por forma clínica (axial, periférica, mista e entesítica). RESULTADOS: Dentre os pacientes avaliados com EpA, 963 apresentavam EA, 271 AP, 49 ARe, 48 artrite associada a DII, 98 EI e 43 EpA juvenil. Acometimento cardíaco foi observado em 44 pacientes (3,0%), seguido por acometimento pulmonar em 19 (1,3%), renal em 17 (1,2%) e neurológico em 13 pacientes (0,9%). A maioria dos casos de acometimento visceral ocorreu nos pacientes com EA ou AP e naqueles com forma clínica mista (axial e periférica) e/ou predominantemente axial. CONCLUSÃO: As manifestações extra-articulares cardíacas, renais, pulmonares e neurológicas são muito pouco frequentes nas EpA, variando de 0,9%-3% nesta grande coorte brasileira, estando mais associadas a EA e AP.37938

Phlebotomine sand fly survey in the focus of leishmaniasis in Madrid, Spain (2012-2014): seasonal dynamics, Leishmania infantum infection rates and blood meal preferences

BACKGROUND: An unusual increase of human leishmaniasis cases due to Leishmania infantum is occurring in an urban area of southwestern Madrid, Spain, since 2010. Entomological surveys have shown that Phlebotomus perniciosus is the only potential vector. Direct xenodiagnosis in hares (Lepus granatensis) and rabbits (Oryctolagus cuniculus) collected in the focus area proved that they can transmit parasites to colonized P. perniciosus. Isolates were characterized as L. infantum. The aim of the present work was to conduct a comprehensive study of sand flies in the outbreak area, with special emphasis on P. perniciosus. METHODS: Entomological surveys were done from June to October 2012-2014 in 4 stations located close to the affected area. Twenty sticky traps (ST) and two CDC light traps (LT) were monthly placed during two consecutive days in every station. LT were replaced every morning. Sand fly infection rates were determined by dissecting females collected with LT. Molecular procedures applied to study blood meal preferences and to detect L. infantum were performed for a better understanding of the epidemiology of the outbreak. RESULTS: A total of 45,127 specimens belonging to 4 sand fly species were collected: P. perniciosus (75.34%), Sergentomyia minuta (24.65%), Phlebotomus sergenti (0.005%) and Phlebotomus papatasi (0.005%). No Phlebotomus ariasi were captured. From 3203 P. perniciosus female dissected, 117 were infected with flagellates (3.7%). Furthermore, 13.31% and 7.78% of blood-fed and unfed female sand flies, respectively, were found infected with L. infantum by PCR. The highest rates of infected P. perniciosus were detected at the end of the transmission periods. Regarding to blood meal preferences, hares and rabbits were preferred, although human, cat and dog blood were also found. CONCLUSIONS: This entomological study highlights the exceptional nature of the Leishmania outbreak occurring in southwestern Madrid, Spain. It is confirmed that P. perniciosus is the only vector in the affected area, with high densities and infection rates. Rabbits and hares were the main blood meal sources of this species. These results reinforce the need for an extensive and permanent surveillance in this region, and others of similar characteristics, in order to control the vector and regulate the populations of wild reservoirs.This study was partially sponsored and funded by: Dirección General de Salud Pública, Consejería de Sanidad, Comunidad de Madrid; Colegio de Veterinarios de Madrid; Colegio de Biólogos de Madrid and EU grant FP7-261504 EDENext (http://www.edenext.eu).S

TRIAGEM NEONATAL DE IMUNODEFICIÊNCIAS GRAVES COMBINADAS POR MEIO DE TRECS E KRECS: SEGUNDO ESTUDO PILOTO NO BRASIL

RESUMO Objetivo: Validar a quantificação de T-cell receptor excision circles (TRECs) e kappa-deleting recombination circles (KRECs) por reação em cadeia de polimerase (polymerase chain reaction, PCR) em tempo real (qRT-PCR), para triagem neonatal de imunodeficiências primárias que cursam com defeitos nas células T e/ou B no Brasil. Métodos: Amostras de sangue de recém-nascidos (RN) e controles foram coletadas em papel-filtro. O DNA foi extraído e os TRECs e KRECs foram quantificados por reação duplex de qRT-PCR. O valor de corte foi determinado pela análise de Receiver Operating Characteristics Curve, utilizando-se o programa Statistical Package for the Social Sciences (SSPS) (IBM®, Armonk, NY, EUA). Resultados: 6.881 amostras de RN foram analisadas quanto à concentração de TRECs e KRECs. Os valores de TRECs variaram entre 1 e 1.006 TRECs/µL, com média e mediana de 160 e 139 TRECs/µL, respectivamente. Três amostras de pacientes diagnosticados com imunodeficiência grave combinada (severe combined immunodeficiency, SCID) apresentaram valores de TRECs abaixo de 4/µL e um paciente com Síndrome de DiGeorge apresentou TRECs indetectáveis. Os valores de KRECs encontraram-se entre 10 e 1.097 KRECs/µL, com média e mediana de 130 e 108 KRECs/µL, e quatro pacientes com diagnóstico de agamaglobulinemia tiveram resultados abaixo de 4 KRECs/µL. Os valores de corte encontrados foram 15 TRECs/µL e 14 KRECs/µL, e foram estabelecidos de acordo com a análise da Receiver Operating Characteristics Curve, com sensibilidade de 100% para detecção de SCID e agamaglobulinemia, respectivamente. Conclusões: A quantificação de TRECs e KRECs foi capaz de diagnosticar crianças com linfopenias T e/ou B em nosso estudo, validando a técnica e dando o primeiro passo para a implementação da triagem neonatal em grande escala no Brasil

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Mapping development and health effects of cooking with solid fuels in low-income and middle-income countries, 2000-18 : a geospatial modelling study

Background More than 3 billion people do not have access to clean energy and primarily use solid fuels to cook. Use of solid fuels generates household air pollution, which was associated with more than 2 million deaths in 2019. Although local patterns in cooking vary systematically, subnational trends in use of solid fuels have yet to be comprehensively analysed. We estimated the prevalence of solid-fuel use with high spatial resolution to explore subnational inequalities, assess local progress, and assess the effects on health in low-income and middle-income countries (LMICs) without universal access to clean fuels.Methods We did a geospatial modelling study to map the prevalence of solid-fuel use for cooking at a 5 km x 5 km resolution in 98 LMICs based on 2.1 million household observations of the primary cooking fuel used from 663 population-based household surveys over the years 2000 to 2018. We use observed temporal patterns to forecast household air pollution in 2030 and to assess the probability of attaining the Sustainable Development Goal (SDG) target indicator for clean cooking. We aligned our estimates of household air pollution to geospatial estimates of ambient air pollution to establish the risk transition occurring in LMICs. Finally, we quantified the effect of residual primary solid-fuel use for cooking on child health by doing a counterfactual risk assessment to estimate the proportion of deaths from lower respiratory tract infections in children younger than 5 years that could be associated with household air pollution.Findings Although primary reliance on solid-fuel use for cooking has declined globally, it remains widespread. 593 million people live in districts where the prevalence of solid-fuel use for cooking exceeds 95%. 66% of people in LMICs live in districts that are not on track to meet the SDG target for universal access to clean energy by 2030. Household air pollution continues to be a major contributor to particulate exposure in LMICs, and rising ambient air pollution is undermining potential gains from reductions in the prevalence of solid-fuel use for cooking in many countries. We estimated that, in 2018, 205000 (95% uncertainty interval 147000-257000) children younger than 5 years died from lower respiratory tract infections that could be attributed to household air pollution.Interpretation Efforts to accelerate the adoption of clean cooking fuels need to be substantially increased and recalibrated to account for subnational inequalities, because there are substantial opportunities to improve air quality and avert child mortality associated with household air pollution. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.Peer reviewe