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Introduction and objective: Hepatotoxicity during tuberculosis (TB) treatment is frequent and may be related to the Arylamine N-Acetyltransferase (NAT2) acetylator profile, in which allele frequencies differ according to the population. The aim of this study was to investigate functional polymorphisms in NAT2 associated with the development of hepatotoxicity after initiating treatment for TB in people living with HIV/AIDS (PLWHA) in Pernambuco, Northeast Brazil. Material and methods: This was a prospective cohort study that investigated seven single nucleotide polymorphisms located in the NAT2 coding region in 173 PLWHA undergoing TB treatment. Hepatotoxicity was defined as elevated aminotransferase levels and identified as being three times higher than it was before initiating TB treatment, with associated symptoms of hepatitis. A further 80 healthy subjects, without HIV infection or TB were used as a control group. All individuals were genotyped by direct sequencing. Results: The NAT2*13A and NAT2*6B variant alleles were significantly associated with the development of hepatotoxicity during TB treatment in PLWHA (p < 0.05). Individual comparisons between the wild type and each variant genotype revealed that PLWHA with signatures NAT2*13A/NAT2*13A (OR 4.4; CI95% 1.1–18.8; p 0.037) and NAT2*13A/NAT2*6B (OR 4.4; CI95% 1.5–12.7; p 0.005) significantly increased the risk of hepatotoxicity. Conclusion: This study suggests that NAT2*13A and NAT2*6B variant alleles are risk factors for developing hepatotoxicity, and PLWHA with genotypes NAT2*13A/NAT2*13A and NAT2*13A/NAT2*6B should be targeted for specific care to reduce the risk of hepatotoxicity during treatment for tuberculosis.

Dengue has become one of the most important worldwide arthropod-borne diseases. Dengue phenotypes are based on laboratorial and clinical exams, which are known to be inaccurate. Objective : We present a machine learning approach for the prediction of dengue fever severity based solely on human genome data. Methods : One hundred and two Brazilian dengue patients and controls were genotyped for 322 innate immunity single nucleotide polymorphisms (SNPs). Our model uses a support vector machine algorithm to find the optimal loci classification subset and then an artificial neural network (ANN) is used to classify patients into dengue fever or severe dengue. Results : The ANN trained on 13 key immune SNPs selected under dominant or recessive models produced median values of accuracy greater than 86%, and sensitivity and specificity over 98% and 51%, respectively. Conclusion : The proposed classification method, using only genome markers, can be used to identify individuals at high risk for developing the severe dengue phenotype even in uninfected conditions. Significance : Our results suggest that the genetic context is a key element in phenotype definition in dengue. The methodology proposed here is extendable to other Mendelian based and genetically influenced diseases.

Dengue is considered one of the most challenging public health threats in the world. Infection may be clinically asymptomatic but can result in severe forms. The indoleamine 2,3 dioxygenas...

Background Dengue fever is an arthropod-borne viral disease caused by dengue virus (DENV) and transmitted by Aedes mosquitoes. The Northeast region of Brazil is characterized by having one of the highest dengue rates in the country, in addition to being considered the poorest region. Here, we aimed to identify spatial clusters with the highest dengue risk, as well as to analyze the temporal behavior of the incidence rate and the effects of social determinants on the disease transmission dynamic in Northeastern Brazil. Methods This is an ecological study carried out with all confirmed cases of dengue in the Northeast Brazil between 2014 and 2017. Data were extracted from the National Notifiable Diseases Information System (SINAN) and the Brazilian Institute of Geography and Statistics (IBGE). Local empirical Bayesian model, Moran statistics and spatial scan statistics were applied. The association between dengue incidence rate and social determinants was tested using Moran’s bivariate correlation. Results A total of 509 261 cases of dengue were confirmed in the Northeast during the study period, 53.41% of them were concentrated in Pernambuco and Ceará states. Spatial analysis showed a heterogeneous distribution of dengue cases in the region, with the highest rates in the east coast. Four risk clusters were observed, involving 815 municipalities (45.45%). Moreover, social indicators related to population density, education, income, housing, and social vulnerability showed a spatial correlation with the dengue incidence rate. Conclusions This study provides information on the spatial dynamics of dengue in northeastern Brazil and its relationship with social determinants and can be used in the formulation of public health policies to reduce the impact of the disease in vulnerable populations.

Background The spread of Dengue virus (DENV) infections, as well as their signs and symptoms, are the result of a complex interaction between several factors. In Brazil, especially in the Northeastern, dengue is an important public health problem. Here, we report an epidemiological analysis of dengue cases in Pernambuco state, Northeastern Brazil, during 2015–2017. Methods This work is a retrospective cross-sectional observational study on the epidemiological profile of all dengue cases confirmed and reported to the Health Secretary of Pernambuco between 2015 and 2017. These data cover all municipalities of Pernambuco, except Fernando de Noronha. DENV-positive individuals were classified according to the dengue type (without and with warning signs, or severe dengue), age, gender, ethnicity and intermediate geographic region of residence (Recife, Caruaru, Serra Talhada or Petrolina). The distribution of cases over the years was assessed by χ2 test. Temperature and rainfall data were evaluated by Unpaired t-test. p-value Results Most dengue cases was without warning signs. The most observed characteristics in the less severe dengue phenotypes were: female, mulatto ethnicity and age between 20 and 39 years old; this profile was more clearly observed in 2015. In 2016 and 2017, however, the numbers of dengue without and with warning signs were more evenly distributed and the difference in cases within groups decreased significantly. Regarding severe dengue, mulattoes were the most affected, but it is possible to note a trend towards a more uniform distribution between the genders and ages. Recife was the region with the highest numbers of both total cases and incidence rates and the highest rainfall levels. Overall, over the years, there has been a decrease in dengue cases in all regions of Pernambuco. Conclusions We identified the epidemiological profile of dengue in Pernambuco, Brazil, reporting the gender, age, ethnicity and regions most affected by different dengue types. In addition, we observed that these cases were probably more influenced by rainfall than by temperature. Finally, we believe that this epidemiological knowledge is important to direct public health policies to the reality of each population.

Dengue is considered one of the most challenging public health threats in the world. Infection may be clinically asymptomatic but can result in severe forms. The indoleamine 2,3 dioxygenase (

Dengue has become one of the most important worldwide arthropodborne diseases around the world. Here, one hundred and two Brazilian dengue virus (DENV) III patients and controls were genotyped for 322 innate immunity gene loci. All biological data (including age, sex and genome background) were analyzed using Machine Learning techniques to discriminate tendency to severe dengue phenotype development. Our current approach produces median values for accuracy greater than 86%, with sensitivity and specificity over 98% and 51%, respectively. Genome data information from 13 key immune polymorphic SNPs was used under different dominant or recessive models. Our approach is a valuable tool for early diagnosis of the severe form of dengue infection and can be used to identify individuals at high risk of developing this form of the disease even in uninfected individuals. The model also identifies various genes involved dengue severity.

BACKGROUND Lymphatic filariasis (LF) is a parasitic disease caused mainly by the Wuchereria bancrofti worm and that affects up to 120 million people worldwide. LF is the second cause of chronic global deformity, responsible for 15 million people with lymphedema (elephantiasis) and 25 million men with scrotal hydrocele. Its diagnosis is still associated with numerous difficulties, such as the sample collection periods (microfilaria nocturnal periodicity) and limited diagnostic kits. OBJECTIVES The aim of this work was to evaluate two recombinant antigens (Wb14 and WbT) as part of an enzyme-linked immunosorbent assay (ELISA) based antibody capture tests for LF. METHODS The recombinant antigens rWb14 and rWbT were expressed in Escherichia coli BL21 and an antibody capture ELISA was performed. For this, sera were used from microfilaremic individuals with W. bancrofti (MF), chronic pathology (CP), individuals infected with Strongyloides (SP) and healthy controls from endemic (EN) and non-endemic (NE) areas. FINDINGS Both tests showed similar results, with 90% sensitivity and 96.6% specificity. In comparison with the BM14 ELISA commercial test, the Wb14 and WbT antigens performed with identical sensitivity but greater specificity. Reduced positivity with the CP suggested a potential to monitor cure. This was not confirmed, however, when sera from individuals up to seven years after treatment were assayed. MAIN CONCLUSIONS The Wb14 and WbT ELISAs were considered efficient and promising diagnostic tests. Due to the importance of antibody capture analysis to evaluate the Global Program to Eliminate Lymphatic Filariasis (GPELF), the tests proposed here appear as great alternatives to the available commercial system.

SILVA, André Filipe Pastor da, também é conhecido(a) em citações bibliográficas por: PASTOR, André Filipe CAPES A Filariose Linfática (FL) é uma doença que afeta 120 milhões de pessoas no mundo, sendo a Wuchereria bancrofti (WB) o agente etiológico no Brasil. O diagnóstico apresenta inúmeras dificuldades, como horário de coleta para exames parasitológicos (entre 23h-1h), problemas de importação e altos custos para kits de imunodiagnóstico. Sendo assim, o objetivo detse trabalho foi produzir antígenos recombinantes e anticorpos para o desenvolvimento de diagnósticos para FL. Para tanto, a partir dos antígenos recombinantes Wb14 e WbT foram desenvolvidos dois testes de captura de anticorpos IgG4, os ELISAs anti-Wb14 e anti-WbT. Além disso, foram produzidos anticorpos policlonais e monoclonais contra a proteína rWb14, que deram origem a um ELISA sanduiche de captura de antígenos. Os testes ELISA anti-Wb14 e anti-WbT mostraram sensibilidade e especificidade semelhantes ao Og4C3, POC-ICT e melhor especificidade do que o kit comercial de captura de anticorpos, o BM14. Enquanto que o ELISA sanduiche desenvolvido mostrou ser uma opção viável para o diagnóstico da LF, pois detectou até 15ng rWb14. Devido a importância do imunodiagnóstico para avaliar o Programa Global para a eliminação da Filariose Linfática (PGELF), os testes propostos aqui aparecem como uma ótima alternativa. A expectativa é o ELISA sanduiche reconheça os indivíduos MF e que os ELISAs anti-Wb14 e ant-WbT sejam testados por outros grupos de pesquisas para validar os kits como eficientes em diferentes países endêmicos. Lymphatic filariasis (LF) is a parasitic disease caused mainly by Wuchereria bancrofti that affects 120 million of people in the world. The diagnosis presents numerous difficulties, such as the hour to collect samples for parasitological exams (between 11 pm and 1 am) and high costs of immunodiagnostic kits. Thus, the objective of this work is to produce recombinant antigens and antibodies for the development of FL diagnoses. To this end, two IgG4 antibody capture assays were prepared from the recombinant Wb14 and WbT antigens, the anti-Wb14 and anti-WbT ELISAs. In addition, polyclonal and monoclonal antibodies were raised against the rWb14 protein, resulting in an antigen capture sandwich ELISA. Anti-Wb14 and anti-WbT ELISAs showed sensitivity and specificity similar to Og4C3, POC-ICT and better specificity than the commercial antibody capture kit, BM14. While the sandwich ELISA was shown to be a viable option for LF diagnosis, because it detected up to 15ng rWb14. Due to the immunodiagnosis importance to evaluate the Global Program for the Elimination of Lymphatic Filariasis (PGELF), the tests proposed here appear as a great alternative. The expectation is that the ELISA sandwich recognizes the MF individuals and that the anti-Wb14 and anti-WbT ELISAs be tested by other research groups to validate these assays as effective in different endemic countries.

This study investigated the anti-inflammatory effects of DEC on the CCl4-induced hepatotoxicity in C57BL/6 mice. Chronic inflammation was induced by i.p. administration of CCl40.5 μL/g of body weight through two injections a week for 6 weeks. DEC (50 mg/kg) was administered by gavage for 12 days before finishing the CCl4induction. Histological analyses of the DEC-treated group exhibited reduced inflammatory process and prevented liver necrosis and fibrosis. Immunohistochemical and immunofluorescence analyses of the DEC-treated group showed reduced COX-2, IL1β, MDA, TGF-β, andαSMA immunopositivity, besides exhibiting decreased IL1β, COX-2, NFκB, IFNγ, and TGFβexpressions in the western blot analysis. The DEC group enhanced significantly the IL-10 expression. The reduction of hepatic injury in the DEC-treated group was confirmed by the COX-2 and iNOS mRNA expression levels. Based on the results of the present study, DEC can be used as a potential anti-inflammatory drug for chronic hepatic inflammation.

Four genetic polymorphisms located at the promoter (C-257T) and coding regions of CFH gene (exon 2 G257A, exon 14 A2089G and exon 19 G2881T) were investigated in 121 dengue patients (DENV-3) in order to assess the relationship between allele/haplotypes variants and clinical outcomes. A statistical value was found between the CFH-257T allele (TT/TC genotypes) and reduced susceptibility to severe dengue (SD). Statistical associations indicate that individuals bearing a T allele presented significantly higher protein levels in plasma. The −257T variant is located within a NF-κB binding site, suggesting that this variant might have effect on the ability of the CFH gene to respond to signals via the NF-κB pathway. The G257A allelic variant showed significant protection against severe dengue. When CFH haplotypes effect was considered, the ancestral CG/CG promoter-exon 2 SNP genotype showed significant risk to SD either in a general comparison (ancestral × all variant genotypes), as well as in individual genotypes comparison (ancestral × each variant genotype), where the most prevalent effect was observed in the CG/CG × CA/TG comparison. These findings support the involvement of −257T, 257A allele variants and haplotypes on severe dengue phenotype protection, related with high basal CFH expression.