Consensus of the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy (ABHH) and the Brazilian Ministry of Health - General management of blood and blood products on the tests necessary for the release of exceptional medicines for sickle cell disease

Abstract To date, hydroxyurea is the only effective and safe drug that significantly reduces morbidity and mortality of individuals with Sickle cell disease. Twenty years of real-life experience has demonstrated that hydroxyurea reduces pain attacks, vaso-occlusive events, including acute chest syndrome, the number and duration of hospitalizations and the need for transfusion. The therapeutic success of hydroxyurea is directly linked to access to the drug, the dose used and adherence to treatment which, in part, is correlated to the availability of hydroxyurea. This consensus aims to reduce the number of mandatory exams needed to access the drug, prioritizing the requesting physician's report, without affecting patient safety.

Depression and suicide risk during the Covid-19 pandemic at a Brazilian public health psychosocial addiction care center: a preliminary report

Abstract Objective To evaluate the impact of the Covid-19 pandemic on depressive symptoms and suicide risk among patients receiving treatment at a Public Health Psychosocial Addiction Care Center (CAPS AD III) in Porto Alegre, Brazil. Methods Questions from the Coronavirus Health Impact Survey (CRISIS) translated into Brazilian Portuguese were used to evaluate 70 patients' perceptions of and behaviors during the Covid-19 pandemic. Validated Brazilian versions of the Patient Health Questionnaire (PHQ-9) and the General Anxiety Disorder-7 (GAD-7) were used to evaluate the severity of depressive symptoms, suicide risk, and anxiety symptoms. A multiple logistic regression model was used to evaluate predictors of suicide risk in the sample. Results Around 70% of patients reported moderate depressive symptoms and 30% reported severe depressive symptoms, 17% of patients reported having thoughts of suicide or death on more than half of days and 10% reported having them daily. The logistic regression model identified history of alcohol use as the main predictor of suicide risk in (OR 13.0, p = 0.03). Conclusions Individuals with a history of alcohol consumption had significantly higher suicide risk scores at a psychosocial public health care center in Brazil during the Covid-19 pandemic. This result may be important for devising better strategies and interventions to support this specific population profile.

Flow Cytometry Immunophenotyping for Diagnostic Orientation and Classification of Pediatric Cancer Based on the EuroFlow Solid Tumor Orientation Tube (STOT).

Early diagnosis of pediatric cancer is key for adequate patient management and improved outcome. Although multiparameter flow cytometry (MFC) has proven of great utility in the diagnosis and classification of hematologic malignancies, its application to non-hematopoietic pediatric tumors remains limited. Here we designed and prospectively validated a new single eight-color antibody combination-solid tumor orientation tube, STOT-for diagnostic screening of pediatric cancer by MFC. A total of 476 samples (139 tumor mass, 138 bone marrow, 86 lymph node, 58 peripheral blood, and 55 other body fluid samples) from 296 patients with diagnostic suspicion of pediatric cancer were analyzed by MFC vs. conventional diagnostic procedures. STOT was designed after several design-test-evaluate-redesign cycles based on a large panel of monoclonal antibody combinations tested on 301 samples. In its final version, STOT consists of a single 8-color/12-marker antibody combination (CD99-CD8/numyogenin/CD4-EpCAM/CD56/GD2/smCD3-CD19/cyCD3-CD271/CD45). Prospective validation of STOT in 149 samples showed concordant results with the patient WHO/ICCC-3 diagnosis in 138/149 cases (92.6%). These included: 63/63 (100%) reactive/disease-free samples, 43/44 (98%) malignant and 4/4 (100%) benign non-hematopoietic tumors together with 28/38 (74%) leukemia/lymphoma cases; the only exception was Hodgkin lymphoma that required additional markers to be stained. In addition, STOT allowed accurate discrimination among the four most common subtypes of malignant CD45- CD56++ non-hematopoietic solid tumors: 13/13 (GD2++ numyogenin- CD271-/+ nuMyoD1- CD99- EpCAM-) neuroblastoma samples, 5/5 (GD2- numyogenin++ CD271++ nuMyoD1++ CD99-/+ EpCAM-) rhabdomyosarcomas, 2/2 (GD2-/+ numyogenin- CD271+ nuMyoD1- CD99+ EpCAM-) Ewing sarcoma family of tumors, and 7/7 (GD2- numyogenin- CD271+ nuMyoD1- CD99- EpCAM+) Wilms tumors. In summary, here we designed and validated a new standardized antibody combination and MFC assay for diagnostic screening of pediatric solid tumors that might contribute to fast and accurate diagnostic orientation and classification of pediatric cancer in routine clinical practice.

Comportamento alimentar e imagem corporal em universitários da área de saúde / Eating behavior and body image in health sciences university students

OBJETIVO: Avaliar a associação da imagem corporal e o comportamento alimentar de universitários de uma capital do Nordeste do Brasil. MÉTODOS: Participaram da pesquisa universitários (n = 1570) da área da saúde de ambos os sexos, de quatro instituições de ensino superior. As dimensões da imagem corporal (i.e., perceptiva e atitudinal) foram avaliadas por meio da Escala de Silhuetas para adultos brasileiros; e o comportamento alimentar por meio da versão brasileira do Dutch Eating Behavior Questionnaire (DEBQ). Para a avaliação do estado nutricional, foram coletados peso corporal e estatura de modo autorreportado. A análise de associação foi feita pela regressão linear múltipla, após estratificação por sexo. RESULTADOS: Notou-se maior prevalência de universitárias do sexo feminino (72,9%), com idade média de 21,8 (DP = 4,1) anos. Foi encontrada associação entre percepção e (in)satisfação corporal com o comportamento alimentar em ambos os sexos. As mulheres que superestimaram o tamanho corporal obtiveram associação inversa com a dimensão alimentar restritiva (p = 0,001); e as insatisfeitas por magreza, associação direta entre alimentação restritiva; e inversa com o comportamento emocional (p < 0,001). Os homens que superestimaram seu tamanho corporal evidenciaram associação direta com a alimentação emocional; e entre os insatisfeitos por excesso de peso houve associação direta com a dimensão emocional (p = 0,032) e global (p = 0,046) do comportamento alimentar. CONCLUSÕES: O presente estudo demonstra que a imagem corporal negativa, considerando as duas dimensões avaliadas (i.e., perceptiva e atitudinal), foi associada ao comportamento alimentar entre universitários de ambos os sexos.

OBJECTIVE: To analyze an association of image and eating behavior of university students from a capital city in Northeast Brazil. METHODS: Participated in university research (n = 1570) in the health area of both sexes, from four higher education institutions. The dimensions of body image (that is, perceptual and attitudinal) were assessed using the Brazilian Adult Silhouettes Scale; and eating behavior using the Brazilian version of the Dutch eating behavior questionnaire (DEBQ). For an assessment of nutritional status, body weight and height were collected automatically reported. An association analysis was performed using the selected linear regression, after stratification by sex. RESULTS: There is no higher prevalence of women (72.9%), with a mean age of 21.8 (SD = 4.1) years. An association was found between perception and (in) body satisfaction with eating behavior in both sexes. Women who overestimated body size had an inverse association with the restrictive dietary dimension (p = 0.001); and as dissatisfied by law, direct association between restrictive eating; and inverse with emotional behavior (p < 0.001). Men who overestimate their body size, showed an association with emotional nutrition; among those dissatisfied with excess weight, there was an association with emotional (p = 0.032) and global (p = 0.046) dimensions of eating behavior. CONCLUSIONS: The present study demonstrates that a negative body image, considering two dimensions evaluated (that is, perceptual and attitudinal), was associated with eating behavior among university students of both sexes.

Screening of COVID-19 in outpatient children with cancer or solid organ transplantation: preliminary report.

Clinical presentation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pediatric immunosuppressed patients is unknown. Emerging data describe a milder or asymptomatic course in children compared with adults in this scenario. We present the seroprevalence and clinical features of coronavirus disease 2019 in a prospective cohort of 114 immunosuppressed children and adolescents from three groups: kidney transplantation, liver transplantation, and cancer patients. Among the thirty-five (30.7%) patients who had a positive serological test for SARS-CoV-2, 77% did not report previous symptoms and none of them developed any complications of coronavirus disease 2019 (COVID-19) after 30 or more days of follow-up. Among those who were symptomatic, diarrhea, fever, and cough were the most common findings.Conclusion: Seroprevalence of SARS-CoV-2 infection is high among immunosuppressed children and adolescents. COVID-19 has a mild or asymptomatic course in most of these patients. What is Known: • The number of immunosuppressed patients with coronavirus disease 2019 is increasing. • Viral infections have the potential for greater severity in immunocompromised children. What is New: • Seroprevalence for severe acute respiratory syndrome coronavirus 2 in immunocompromised pediatric patients was 31%. • A quarter of the serology-positive patients reported mild symptoms and none of them developed multisystem inflammatory syndrome in children associated with coronavirus disease 2019.

Intrinsic and Extrinsic Cell Apoptotic Pathways in Patients with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis: A Systematic Review.

We aimed to verify the influence of intrinsic and extrinsic cell apoptotic pathways on the inhibition of cellular apoptosis in patients with tropical spastic paralysis/myelopathy related to human T cell lymphotropic virus type 1. The databases accessed were PubMed, Scopus, Science Direct, and Web of Science. Neither the time of publishing nor the language of the articles was limited. The descriptors used for this systematic literature review were: Tropical Paraparesis, Proto-Oncogenic Protein C, Bcl-2, Bcl-X Protein, Bax protein, Fas ligand (FasL) protein, Fas receptor, TNF-related apoptosis-inducing ligand and Fas-associated protein with death domain (FADD)-like apoptosis regulating. The search resulted in 546 articles from which 9 articles were selected for analysis; ranging from serum levels of Bcl-2, Fas and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) measured by enzyme-linked immunosorbent assay and the levels of cellular expression of Bcl-2 and Bcl-xL the TCD4+ lymphocytes accessed by western blot. Most studies accessed either gene expression or polymorphism of Fas, FasL, and TRAIL in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), whereas one study used flow cytometry and fluorescence to determine Fas expression. Increased Bcl-xL expression inhibited T lymphocyte apoptosis, whereas Bcl-2, serum levels, and cellular expression did not influence T lymphocyte apoptosis and serum levels of Fas were significantly higher and associated with markers of leukocyte activation in patients with HAM/TSP. In addition, Fas polymorphism (FAS-670AA) was associated with higher proviral load. There is a need for additional research on this issue since the number of patients was small and the studies presented higher heterogeneity.

Atividade física e fatores associados em adolescentes estudantes de uma cidade de pequeno porte do sul do Brasil / Physical activity and associated factors in public high-school adolescents from a Southern city in Brazil

O objetivo do estudo foi verificar o nível de atividade física e os fatores associados em adolescentes. Foi realizado um estudo transversal com 114 indivíduos (14 a 21 anos), estudantes do ensino médio, da cidade de Morro Redondo - RS. A atividade física foi mensurada pelo questionário de prática de atividade física para adolescentes (PAQ-A). Os resultados apontaram que na atividade física total, 55,7% dos adolescentes alcançaram as recomendações de atividade física (300 minutos por semana). Sujeitos que relataram percepção de saúde excelente apresentaram uma probabilidade 140% maior de praticar atividade física total quando comparados aos com percepção de saúde regular/ruim. Estudantes que já fumaram em algum momento da vida (RP=1,44; IC 95%= 1,06; 1,96) e aqueles que ingeriram mais de cinco doses de bebidas alcoólicas nos últimos 30 dias foram mais ativos que seus pares (RP=1,40; IC 95%= 1,01; 1,96). Na atividade física de lazer, 43,4% foram considerados ativos. Indivíduos de cor da pele não branca apresentaram 85% mais probabilidade de praticar atividade física no lazer (RP = 1,85; IC 95% = 1,26; 2,72), e a medida que melhora a percepção de saúde dos adolescentes, maior foi a chance de serem ativos. A atividade física mais praticada foi a caminhada como meio de transporte (57,9 %), seguida de andar de bicicleta (33,3%), correr (33,3 %) e jogar futebol (32,5%). Conclui-se que a prevalência de atividade física de lazer e total é semelhante à de estudos com adolescentes em diferentes cidades do país, e sua prática esteve associada a percepção de saúde positiva, ao consumo de bebidas alcóolicas e tabaco. A atividade mais realizada foi a caminhada como meio de transporte.

The aim of the study was to verify the level of physical activity and associated factors in adolescents. A cross-sectional study was carried out with 114 individuals (age between 14 and 21 years), students of the high school, in the city of Morro Redondo - RS. The physical activity was measured using a physical activity questionnaire for adolescents (PAQ-A). The results showed that concerning total physical activity, 55.7% of the adolescents reached the recommendations of physical activity (300 minutes per week). Subjects who reported excellent health perception presented a 140% higher probability of practicing total physical activity when compared to those with regular/poor health perception. Subjects who have smoked at some point in their life (PR = 1.44, 95% CI = 1.06, 1.96) and those who have consumed more than five doses of alcohol in the last 30 days are more active than their peers (PR = 1.40, 95% CI = 1.01, 1.96). In the leisure time physical activity prevalence of active students was 43.4%. Individuals with non-white skin color had 85% more probability to practice physical activity during leisure time (PR = 1.85, 95% CI = 1.26, 2.72), whereas, as adolescents' health perception improves the greater the chance of being active. The most practiced physical activity was walking as a means of transportation (57.9%), followed by cycling (33.3%), running (33.3%) and playing soccer (32.5%). In conclusion, the prevalence of leisure and total physical activity is similar to studies with adolescents in different cities in the country, and its practice was associated with the positive health perception, consumption of alcoholic beverages and tobacco. The most performed activity was walking as a mode of transport....(AU)

Reduced Expression of IL-1ß and IL-18 Proinflammatory Interleukins Increases the Risk of Developing Cervical Cancer.

Background: The objective of this study was to analyze the gene expression profile of the proinflammatory interleukins, (IL-1ß and IL-18) in patients with premalignant lesions and cervical cancer. Methods: Total IL-1ß and IL-18 mRNA was quantified by qPCR to obtain the expression data in cervical tissues. A total of 74 cervical biopsies were obtained from women undergoing a colposcopy. The samples were divided into: normal (19), low level lesions (LSIL) or NIC I (17), high level lesions (HSIL) or CIN II and CIN III (29) and cancer (9). The normal cervical tissue samples were included as controls. The OR and 95% CI were calculated for the determination of the risk of progression between each type of lesion and cancer using logistic regression. Results: The results showed that an increase in the risk of progression of pre-neoplastic lesions to cancer was between 2.5 and 2.08 times higher in women with lower IL-1ß and IL-18 expression, respectively. Conclusions: This study provided evidence that IL-1ß and IL-18 are potential biomarkers that can be explored in further studies for monitoring the evolution of pre-neoplastic lesions and avoiding overtreatment or undertreatment of the patients.

Metal content in medicinal teas used in the Urubueua de Fátima river community, Abaetetuba-Pará State, Brazil / Contenido de metal en tés terapéuticos utilizados en la comunidad del Río Urubueua de Fátima, estado de Abaetetuba-Pará, Brasil

The content of certain metals in 13 medicinal teas made from 16 plant species was measured by flame photometer and atomic absorption spectrometer with flame methods. The measurements were evaluated against metal intake levels recommended by health authorities. The results indicate that the medicinal teas tested, regularly consumed by inhabitants of the Urubueua de Fátima River Community, Abaetetuba-Para, Brazil, present no risk of poisoning people older than six months. However, decoctions of Mentha sp., Eleutherine bulbosa, Euterpe oleracea, Piper callosum and Hyptis mutabilis, mostly given to children, had Mn values potentially exceeding the recommended maximum intake for infants in the 0-6 months age group, in the quantities customarily administered. Consequently, studies are needed to assess bioavailability for safe human consumption. Results also showed the consumption of medicinal tea alone is not enough to supply an adult's daily metal requirements or treat deficiencies. Additionally, cures emphasized by interviewed Community members might be associated with the bioactivity of organic substances that the medicinal teas contain.

El contenido de algunos metales en 13 tés medicinales de las 16 especies consumidas por los habitantes de la comunidad del Río Urubueua de Fátima, Abaetetuba-Para, Brasil, se evaluó mediante un fotómetro de llama y un espectrómetro de absorción atómica con métodos de llama, y se comparó con los niveles recomendados por las agencias de la salud. Los tés medicinales evaluados no mostraron riesgo de intoxicación para las personas mayores de seis meses de edad, sino las decocciones de Mentha sp., Eleutherine bulbosa, Euterpe oleracea, Piper callosum y Hyptis mutabilis, en su mayoría dirigidos a la ingesta de niños, informaron valores de Mn superiores a la ingesta máxima recomendada para el grupo de infantes (0-6 meses), debido a que estos estudios son necesarios para evaluar la biodisponibilidad para un consumo humano seguro. Los resultados también mostraron que solo el consumo de té medicinal no es suficiente para satisfacer las necesidades diarias recomendadas de ingesta de minerales o para tratar las deficiencias. Además, los informes de curación, enfatizados por los habitantes, indican que la bioactividad observada podría estar asociada a sustancias orgánicas presentes en el té.

A portrait of germline mutation in Brazilian at-risk for hereditary breast cancer.

PURPOSE: Knowledge about the germline mutational spectrum among Brazilian with hereditary breast and ovarian cancer (HBOC) is limited. Only five studies have performed comprehensive BRCA sequencing, corresponding to 1041 individuals among a Brazilian population of over 207 million people. Herein we aimed to determine the clinical and molecular characteristics of Brazilian patients who underwent oncogenetic counseling and genetic testing of a panel of high-risk and moderate-risk genes from 2009 to 2017. METHODS: Massively parallel sequencing was applied in 157 individuals (132 breast cancer-affected and 25 breast cancer-unaffected individuals) selected according NCCN criteria for hereditary breast cancer. Analysis of mutation segregation in family members was performed by capillary bidirectional sequencing, clinical response after treament and survival analysis was estimated by Kaplan-Meier. RESULTS: Nineteen germline variants were identified,15 pathogenic and 4 VUS (Variants of Uncertain Significance) in 27 individuals (27/157; 17% P < 0.0001) distributed among 7 genes. Sixty-eight percent of patients (13/19) harbor mutation in BRCA genes and 32% (6/19) in moderate risk genes. This is the first study reporting ATR deleterious germline mutation in association with hereditary breast cancer. Cancer-affected patients with moderate- risk mutation present a more aggressive phenotype, with bilateral cancer (25% vs. 13%, P = 0.0305), high-grade tumors (79.2% vs. 46.3%, P = 0.0001) and triple-negative (50% vs. 22.4%, P < 0.0001). However, no difference in the 5 years overall survival was observed between BRCA and moderate risk groups. CONCLUSIONS: This work highlights the benefits of large-scale sequencing for oncogenetic counseling and extends our understanding about the genetics of hereditary breast cancer in the multi-ethnic Brazilian population.

Two sides of a coin: GG genotype of C7 provides protection against fibrosis severity while showing a higher risk for hepatocellular carcinoma in patients with hepatitis C.

The complement system (CS) is a key element of immunity against pathogens but also seems to influence other events, such as tumorigenesis and tissue repair. Complement component 7 (C7) is a key component of the lytic pathway of CS, leading to the formation of the membrane attack complex (MAC). This study aimed to investigate the existence of the association of a polymorphism in the C7 gene, rs1063499, with hepatic fibrosis and the occurrence of hepatocellular carcinoma (HCC) in patients with hepatitis C. We analyzed 456 samples from patients with chronic hepatitis C. Real-time PCR was used for allelic discrimination. Patients were classified by their METAVIR score as F1 (n = 100), F2 (n = 83), F3 (n = 101) or F4 (n = 66); 106 patients were diagnosed with HCC. Patients carrying the G/G genotype of C7 had a lower chance of developing severe fibrosis in the recessive model (p = 0.042; OR: 0.65 95% CI 0.41-1.02). However, the G/G genotype frequency was higher in patients with HCC (P = 0.01; OR: 2.07 95% CI 1.20-3.53) and in those with larger tumors (p = 0.04). The G/G C7 genotype seems to be a protective factor against advanced fibrosis; however, it was associated with a higher risk of HCC and the occurrence of larger hepatic nodules, suggesting the involvement of C7 in the physiopathogenesis of HCC and fibrosis in patients with hepatitis C virus (HCV).

Enhancement of fermentative hydrogen production from Spirogyra sp. by increased carbohydrate accumulation and selection of the biomass pretreatment under a biorefinery model.

In this work, hydrogen (H2) was produced through the fermentation of Spirogyra sp. biomass by Clostridium butyricum DSM 10702. Macronutrient stress was applied to increase the carbohydrate content in Spirogyra, and a 36% (w/w) accumulation of carbohydrates was reached by nitrogen depletion. The use of wet microalga as fermentable substrate was compared with physically and chemically treated biomass for increased carbohydrate solubilisation. The combination of drying, bead beating and mild acid hydrolysis produced a saccharification yield of 90.3% (w/w). The H2 production from Spirogyra hydrolysate was 3.9 L H2 L-1, equivalent to 146.3 mL H2 g-1 microalga dry weight. The presence of protein (23.2 ± 0.3% w/w) and valuable pigments, such as astaxanthin (38.8% of the total pigment content), makes this microalga suitable to be used simultaneously in both food and feed applications. In a Spirogyra based biorefinery, the potential energy production and food-grade protein and pigments revenue per cubic meter of microalga culture per year was estimated on 7.4 MJ, US $412 and US $15, respectively, thereby contributing to the cost efficiency and sustainability of the whole bioconversion process.

Notas sobre uma ontologia em Lacan: um diálogo com Heidegger / Notes sur une ontologie dans Lacan: un dialogue avec Heidegge / Notas sobre una ontología en Lacan: un diálogo con Heidegger / Notes on an ontology in Lacan: a dialogue with Heidegger

Este estudo busca discutir a questão de uma possível ontologia na obra de Lacan a partir de seu estatuto do inconsciente ético de 1964. Procura-se estabelecer relações entre os conceitos lacanianos de inconsciente, ética e tempo e, através deles, dialogar com a concepção de temporalidade em Heidegger, a fim de demonstrar que o inconsciente lacaniano não é ético apenas por sua natureza linguística, mas também pela ontológica

Cette étude vise à discuter la question d'une ontologie possible dans l'œuvre de Lacan à partir de le statut éthique de l'inconscient présenté par lui en 1964. Nous cherchons à établir des relations entre les concepts lacaniens de l'inconscient, d'éthique et du temps et, à travers d'eux, dialoguer avec la conception de la temporalité chez Heidegger, afin de montrer que l'inconscient lacanien n'est pas éthique seulement du point de vue de la linguistique, mais aussi de la ontologie

Este estudio tiene como objetivo discutir la cuestión de una posible ontología en la obra de Lacan a partir de su estatuto del inconsciente ético de 1964. Tratando de establecer relaciones entre los conceptos lacanianos del inconsciente, ética y tiempo y, mediante estos, dialogar con la concepción de la temporalidad en Heidegger, con el fin de demostrar que el inconsciente lacaniano no es ético solo por su naturaleza lingüística, sino también por la ontológica

This study aims to discuss the possibility of an ontology in Lacan's work, based on the status of ethical unconscious presented by him in 1964. We try to establish relationships between the Lacanian concepts of unconscious, ethics and time and, through them, a dialogue with the conception of temporality in Heidegger, in order to demonstrate that the Lacanian unconscious is not only linguistic, but also ontological

Combined genotypes of the MBL2 gene related to low mannose-binding lectin levels are associated with vaso-occlusive events in children with sickle cell anemia

Abstract Sickle cell anemia (SCA) presents heterogenous clinical manifestations that cannot be explained solely by alterations to hemoglobin (Hb); other components such as endothelial adhesion, thrombosis and inflammation may be involved. The mannose-binding lectin (MBL) has an important role in innate immunity and inflammatory diseases. In this report, we describe an association between MBL2 polymorphism related to low production of serum MBL and the frequency of vasoocclusive events (FVOE) in children ≤ 5 years old with SCA (p = 0.0229; OR 5.55; CI 1.11-27.66). Further studies are needed to explore the role of low MBL2 in the pathophysiology of vasoocclusive events in SCA.

Association of rs1285933 single nucleotide polymorphism in CLEC5A gene with dengue severity and its functional effects.

Outbreaks of the Zika, dengue, and chikungunya viruses, especially in the Americas, pose a global threat due to their rapid spread and difficulty controlling the vector. Extreme phenotypes are often observed, from asymptomatic to severe clinical manifestations, which are well-studied in dengue. Host variations are also important contributors to disease outcomes, and many case-control studies have associated single nucleotide polymorphisms (SNPs) with severe dengue. Here, we found that the TC genotype and T-carriers for SNP rs1285933 in the C-type lectin superfamily member 5 (CLEC5A) gene was associated with severe dengue in a Northern Brazilian population (OR=2.75 and p-value=0.01, OR=2.11 and p-value=0.04, respectively). We also tested the functional effect of the CLEC5A protein and found that it is upregulated on the surface of human monocytes after in vitro dengue infection. CLEC5A was correlated with viral load inside the monocytes (Spearman r=0.55, p=0.008) and TNF production in culture supernatants (Spearman r=0.72, p=0.03). Analysis of mRNA in blood samples from DENV4-infected patients exhibiting mild symptoms showed that CLEC5A mRNA expression is correlated with TNF (r=0.67, p=0.0001) and other immune mediators. Monocytes from rs1285933 TT/TC individuals showed lower CLEC5A expression compared to CC genotypes. However, in these cells, CLEC5A was not correlated with TNF production. In summary, we confirmed that CLEC5A is genetically associated with dengue severity outcome, playing a central role during the immune response triggered by a dengue viral infection, and rs1285933 is a relevant SNP that is able to regulate signaling pathways after interactions between the dengue virus and CLEC5A receptors.

Mediators Go Together: High Production of CXCL9, CXCL10, IFN-γ, and TNF-α in HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis.

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic demyelinating and disabling syndrome caused by human T lymphotropic virus 1 (HTLV-1). Although the pathogenic mechanisms that lead to HAM/TSP outcome have not been elucidated, genetic and immunological factors may be involved in the myelopathy occurrence. This study aimed to compare cytokines, chemokines, and nitric oxide (NO) levels in asymptomatic and HAM/TSP HTLV-1-infected patients. The study group consisted of 21 HAM/TSP and 48 asymptomatic HTLV-1 patients. Chemokines (CCL5, CCL2, CXCL8, CXCL9, and CXCL10) and cytokines [IL-2, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), IL-4, IL-6, and IL-10] were measured using cytometric bead array, whereas NO production was measured after reaction of supernatants with nitrate reduction solution. CXCL9 and CXCL10 chemokines levels were found to be higher in the HAM/TSP group. CXCL9 was also strongly correlated with CXCL10 and both CXCL9 and CXCL10 were moderately correlated with CCL2 and CCL5 levels, in both HAM/TSP and asymptomatic groups. There was no significant difference related to NO, IL-4, IL-6, and IL-10 levels between the clinical groups but TNF-α and IFN-γ levels were increased in HAM/TSP patients. Thus, factors such as CXCL9, CXCL10, TNF-α, and IFN-γ could be good prognostic biomarker candidates, and further studies may help to clarify their association with HAM/TSP immunopathogenesis.

Primary dengue haemorrhagic fever in patients from northeast of Brazil is associated with high levels of interferon-β during acute phase

Dengue is an acute febrile disease caused by the mosquito-borne dengue virus (DENV) that according to clinical manifestations can be classified as asymptomatic, mild or severe dengue. Severe dengue cases have been associated with an unbalanced immune response characterised by an over secretion of inflammatory cytokines. In the present study we measured type I interferon (IFN-I) transcript and circulating levels in primary and secondary DENV infected patients. We observed that dengue fever (DF) and dengue haemorrhagic fever (DHF) patients express IFN-I differently. While DF and DHF patients express interferon-α similarly (52,71 ± 7,40 and 49,05 ± 7,70, respectively), IFN- β were associated with primary DHF patients. On the other hand, secondary DHF patients were not able to secrete large amounts of IFN- β which in turn may have influenced the high-level of viraemia. Our results suggest that, in patients from our cohort, infection by DENV serotype 3 elicits an innate response characterised by higher levels of IFN- β in the DHF patients with primary infection, which could contribute to control infection evidenced by the low-level of viraemia in these patients. The present findings may contribute to shed light in the role of innate immune response in dengue pathogenesis.

Association of Catalase and Glutathione Peroxidase 1 Polymorphisms with Chronic Hepatitis C Outcome.

The hepatic damage caused by hepatitis C virus (HCV) infection is associated with the host immune response and viral regulatory factors. Catalase (CAT) and glutathione peroxidase 1 (GPX1) are antioxidant enzymes located in the peroxisomes and mitochondria, respectively, and are responsible for the control of intracellular hydrogen peroxide levels. Polymorphisms in CAT (C-262T) and GPX1 (Pro198Leu) are correlated with serum levels and enzyme activity. This study aimed to investigate the association of genetic polymorphisms of CAT C-262T (rs1001179) and GPX1 Pro198Leu (rs1050450) with different stages of liver fibrosis and development of hepatocellular carcinoma (HCC). This study included 445 patients with chronic hepatitis C, of whom 139 patients had mild fibrosis (F0-F1), 200 had moderate/severe fibrosis (F2-F4), and 106 had HCC. Genotyping of SNPs was performed by real-time PCR using TaqMan probes. The Pro/Pro genotype of GPX1 was significantly associated with fibrosis severity, HCC, Child Pugh score, and BCLC staging. Additionally, patients carrying both CT+TT genotypes in the CAT gene and the Pro/Pro genotype in the GPX1 gene had higher risk for developing moderate/severe fibrosis or HCC (p = 0.009, OR 2.40 and p = 0.002, OR 3.56, respectively). CAT and GPX1 polymorphisms may be implicated in the severity of liver fibrosis and HCC caused by HCV.

TNF-α and IL-10 polymorphisms increase the risk to hepatocellular carcinoma in HCV infected individuals.

Hepatitis C virus (HCV) is the major cause of hepatocellular carcinoma (HCC). The risk to develop HCC increases with the severity of liver inflammation and hepatic fibrosis. It is believed that a balance between the releases of pro- and anti-inflammatory cytokines will determine the clinical course of HCV and the risk to develop HCC. The inteleukin-10 (IL-10) and the tumor necrosis factor alpha (TNF-α) play key roles in the Th1 and Th2 balance during the inflammatory response against HCV. The aim of the present study was to investigate the association between polymorphisms in TNF-α -308 G>A (rs1800629), IL-10 -1082 G>A (rs1800896) and -819/-592 (rs1800871/rs1800872) with HCC risk in individuals with HCV. The present study evaluated 388 chronic HCV patients. Polymorphisms were determined by real-time PCR. Diplotypes associated with low IL-10 production and the TNF-α GG genotype were significantly associated with HCC occurrence after multivariate logistic regression analysis (P = 0.027 and P = 0.029, respectively). Additionally, the IL-10 -819 (-592) TT (AA) genotype was significantly associated with multiple nodules and HCC severity according to BCLC staging (P = 0.044 and P = 0.025, respectively). Patients carrying low production haplotypes of IL-10 and the TNF-α GG genotype have higher risk to develop HCC. J. Med. Virol. 88:1587-1595, 2016. © 2016 Wiley Periodicals, Inc.