Single nucleotide polymorphisms of cytokine-related genes and association with clinical outcome in a Chagas disease case-control study from Brazil

BACKGROUND The severity of chronic chagasic cardiomyopathy (CCC), the most frequent clinical outcome of Chagas disease (CD), has been associated with cytokine-enriched heart tissue inflammation, and high serum levels of transforming growth factor (TGFβ), interferon-gamma (IFNγ), and tumour necrosis factor (TNF). Conversely, increased interleukin (IL)-10 serum concentrations have been associated with asymptomatic CD. Cytokines and cytokine-related gene polymorphisms may control cytokine expression and have been proposed to contribute to CCC outcomes. OBJECTIVES We evaluated the association of 13 cytokine-related genes (TGFB: rs8179181, rs8105161, rs1800469; IL10: rs1800890, rs1800871, rs1800896; IFNG: rs2430561; TNF: rs1800629; BAT1: rs3853601; LTA: rs909253, rs2239704; TNFR1: rs767455; TNFR2: rs1061624) with risk and progression of CCC. FINDINGS Four hundred and six seropositive patients from CD endemic areas in the state of Pernambuco, north-eastern Brazil, were classified as non-cardiopathic (A, 110) or cardiopathic (mild, B1, 163; severe, C, 133). We found no evidence of TGFB, IL10, TNF, or TNFR1/2 gene polymorphisms associated with CCC risk or progression. Only BAT1 rs3853601 −22G carriers (B1 vs. C: OR = 0.5; p-value = 0.03) and IFNG rs2430561 +874AT (A vs. C: OR = 0.7; p-value = 0.03; A vs. B1+C: OR = 0.8; p-value = 0.02) showed a significant association with protection from cardiopathy in a logistic regression analysis with adjustment for gender and ethnicity; however, the association disappeared after performing adjustment for multiple testing. A systematic review of TNF rs1800629 −308G>A publications included five studies for meta-analysis (534 CCC and 472 asymptomatic patients) and showed no consensus in pooled odds ratio (OR) estimates for A allele or A carriers (OR = 1.4 and 1.5; p-values = 0.14 and 0.15, respectively). In CD patients, TNF serum levels were increased, but not affected by the TNF rs1800629 −308A allele. MAIN CONCLUSIONS Our data suggest no significant contribution of the analysed gene variants of cytokine-related molecules to development/severity of Chagas' heart disease, reinforcing the idea that parasite/host interplay is critical to CD outcomes.

Early changes in adipokines from overweight to obesity in children and adolescents / Alterações precoces nos níveis de adipocinas de sobrepeso para obesidade em crianças e adolescentes

Abstract Objective: Childhood obesity has been associated with metabolic syndrome and cardiovascular diseases. This study aimed to compare plasma levels of traditional metabolic markers, adipokines and soluble tumor necrosis factor receptor type 1 (sTNFR1) in overweight, obese and lean children. We also assessed the relationships of these molecules with classical metabolic risk factors. Methods: This study included 104 children and adolescents, which were grouped as: lean (n = 24), overweight (n = 30), and obese subjects (n = 50). They were subjected to anthropometrical, clinical and laboratorial measurements. All measurements were compared between groups. Correlation analyses were also performed to evaluate the association between clinical data, traditional metabolic markers, adipokines and sTNFR1. Results: Fasting glucose, insulin, homeostatic model assessment of insulin resistance (HOMA-IR), LDL-cholesterol and triglycerides were comparable in lean, overweight and obese subjects. Plasma levels of sTNFR1 were similar in lean and overweight subjects, but significantly increased in obese group. Leptin, adiponectin and resistin levels did not differ when overweight were compared to obese subjects. However, all adipokines differed significantly when lean subjects were compared to overweight and obese individuals. Plasma levels of adiponectin were negatively correlated with body mass index (BMI), whereas leptin, resistin and sTNFR1 concentrations positively correlated with BMI. Conclusion: Our results showed significant differences in circulating levels of the evaluated markers when lean, overweight and obese individuals were compared, suggesting that these biomarkers may change from lean to overweight and from overweight to obesity.

Resumo Objetivo: A obesidade na infância tem sido associada à síndrome metabólica e a doenças cardiovasculares. O objetivo deste estudo foi comparar níveis plasmáticos de marcadores metabólicos tradicionais, adipocinas e do receptor solúvel de fator de necrose tumoral tipo 1 (sTNFR1) em crianças com sobrepeso, obesas e magras. Também avaliamos as relações dessas moléculas com fatores de risco metabólico clássicos. Métodos: Este estudo incluiu 104 crianças e adolescentes, agrupados da seguinte forma: indivíduos magros (n = 24), com sobrepeso (n = 30) e obesos (n = 50). Eles foram submetidos a medições antropométricas, clínicas e laboratoriais. Todas as medições foram comparadas entre os grupos. Também foram feitas análises de correlação para avaliar a associação entre dados clínicos, marcadores metabólicos tradicionais, adipocinas e sTNFR1. Resultados: Glicemia de jejum, insulina, modelo de avaliação da homeostase da resistência à insulina (HOMA-IR), colesterol LDL e triglicerídeos foram comparáveis em indivíduos magros, com sobrepeso e obesos. Os níveis plasmáticos de sTNFR1 foram similares em indivíduos magros e com sobrepeso, porém significativamente maiores no grupo obeso. Os níveis de leptina, adiponectina e resistina não diferiram quando indivíduos com sobrepeso foram comparados aos obesos. Contudo, todas as adipocinas diferiram significativamente quando indivíduos magros foram comparados a indivíduos com sobrepeso e obesos. Os níveis plasmáticos de adiponectina estavam negativamente correlacionados ao índice de massa corporal (IMC), ao passo que as concentrações de leptina, resistina e sTNFR1 estavam positivamente correlacionadas ao IMC. Conclusão: Nossos resultados mostraram diferenças significativas nos níveis circulantes dos marcadores avaliados ao comparar indivíduos magros, com sobrepeso e obesos. Isso sugere que esses biomarcadores poderão mudar de indivíduos magros para indivíduos com sobrepeso e de indivíduos com sobrepeso para obesos.

Oxidative stress and skeletal muscle dysfunction are present in healthy smokers

Chronic exposure to cigarette smoke seems to be related to an increase of pro-inflammatory cytokines, oxidative stress and changes in muscular and physical performances of healthy smokers. However, these parameters have not yet been evaluated simultaneously in previous studies. The participants of this study were healthy males divided into two groups: smokers (n=20) and non-smokers (n=20). Inflammation was evaluated by measuring plasma levels of the cytokines IL-10, IL-6 e TNF-α, and of the soluble receptors sTNFR1 and sTNFR2. Oxidative stress was evaluated by determination of thiobarbituric acid reactive substances (TBARS) plasma levels, total antioxidant capacity of plasma and erythrocytes activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase. Muscular performance was evaluated by measuring the peak torque of knee flexors and extensors, and by determining the total work of the knee extensors. Physical performance was assessed by measuring the peak oxygen uptake (VO2 peak), the maximum heart rate (HRmax) and the walking distance in the shuttle walking test. Smokers showed an increase in the levels of the sTNFR1 and TBARS and a decrease in the total antioxidant capacity of plasma, in the catalase activity and in the total work (P<0.05). IL-6, IL-10, sTNFR2, SOD, peak torque, VO2 peak, HRmax and walking distance were similar between groups. Smokers presented increased oxidative stress and skeletal muscle dysfunction, demonstrating that the changes in molecular and muscular parameters occur simultaneously in healthy smokers.

Serial measurement of the circulating levels of tumour necrosis factor and its soluble receptors 1 and 2 for monitoring leprosy patients during multidrug treatment

Leprosy is an infectious and contagious spectral disease accompanied by a series of immunological events triggered by the host response to the aetiologic agent, Mycobacterium leprae . The induction and maintenance of the immune/inflammatory response in leprosy are linked to multiple cell interactions and soluble factors, primarily through the action of cytokines. The purpose of the present study was to evaluate the serum levels of tumour necrosis factor (TNF)-α and its soluble receptors (sTNF-R1 and sTNF-R2) in leprosy patients at different stages of multidrug treatment (MDT) in comparison with non-infected individuals and to determine their role as putative biomarkers of the severity of leprosy or the treatment response. ELISA was used to measure the levels of these molecules in 30 healthy controls and 37 leprosy patients at the time of diagnosis and during and after MDT. Our results showed increases in the serum levels of TNF-α and sTNF-R2 in infected individuals in comparison with controls. The levels of TNF-α, but not sTNF-R2, decreased with treatment. The current results corroborate previous reports of elevated serum levels of TNF-α in leprosy and suggest a role for sTNF-R2 in the control of this cytokine during MDT.

Serum levels of soluble TNF-a receptors but not BDNF are associated with apathy symptoms in mild Alzheimer's disease and amnestic mild cognitive impairment / Níveis Séricos de receptores Solúveis Do TNF-a mas não de BDNF estão associados a sintomas de apatia na doença de Alzheimer leve e no comprometimento cognitivo leve amnéstico

Apathy is intimately associated with dementia. Unfortunately, its pathophysiology remains poorly understood. The motivational impairment that characterizes this disorder might share the same inflammatory mechanisms, as suggested by the sickness behavior theory. OBJECTIVE: The primary aim of this study was to investigate the association between apathy symptoms and serum levels of tumor necrosis factor alpha (TNF-a) and its soluble receptors. Brain-derived neurotrophic factor (BDNF) levels were also analyzed since these have been associated with depression, a condition which shares abulic features with apathy. METHODS: The sample consisted of 27 subjects with mild Alzheimer's disease or amnestic mild cognitive impairment, who were submitted to specific apathy evaluation using the Apathy Scale (AS) and provided blood samples for biomarker analysis. Participants were categorized into two groups according to median AS scores (17 points). RESULTS: Subjects with higher apathy symptoms (n=13) displayed higher levels of TNF-a soluble receptors (type 1: p=0.03; type 2: p=0.04). No other difference was found between groups. CONCLUSION: These findings point to the involvement of inflammatory mediators in the genesis of apathy symptoms, as suggested by the sickness behavior theory.

Apatia está intimamente associada à demência. Lamentavelmente, sua fisiopatologia ainda é pouco compreendida. O comprometimento motivacional que caracteriza este transtorno poderia compartilhar mecanismos inflamatórios como sugere a teoria do comportamento associado à doença. OBJETIVO: O principal objetivo deste estudo foi investigar a associação entre apatia e os níveis séricos do fator de necrose tumoral alfa (TNF-a) e de seus receptores solúveis. Os níveis de fator neurotrófico derivado do cérebro também foram analisados já que estes foram associados à depressão, que compartilha aspectos abúlicos com a apatia. MÉTODOS: A amostra consistiu de 27 indivíduos com doença de Alzheimer leve ou com comprometimento cognitivo leve amnéstico, que foram submetidos à avaliação de apatia pela Escala de Apatia (EA), e proveram amostra de sangue para análise de biomarcadores. De acordo com a mediana de escores na EA (17 pontos), a amostra foi divida em dois grupos. RESULTADOS: O grupo com mais sintomas de apatia apresentou maiores níveis séricos de receptores solúveis de TNF-a (tipo 1: p=0,03 ; tipo 2: p=0,04). Nenhuma outra diferença foi encontrada entre os grupos.CONCLUSÃO: Estes achados sugerem o envolvimento de mediadores inflamatórios na gênese de sintomas de apatia, assim como sugere a teoria do comportamento associado à doença.

Increased serum levels of soluble tumor necrosis factor receptor-2 (sTNFR2) in patients with active toxoplasmic retinochoroiditis

This study aimed to investigate the serum levels of the cytokine TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in patients with toxoplasmosis retinochoroidits (TR) and controls. 37 patients with TR and 30 subjects with positive serology for toxoplasmosis but without history and signs of uveitis were included in this study. Serum concentrations of TNF-α, sTNFR1, and sTNFR2 were determined by ELISA. Serum concentrations of TNF-α and sTNFR1 were similar in controls (mean ± SD median values; 56.57 ± 141.96 and 504.37 ± 163.87, respectively) and TR patients (mean ± SD values, 121.62 ± 217.56 and 511.15 ± 189.30, respectively). Serum concentrations of sTNFR2 were higher in the uveitis group when compared to the control group (respectively, mean ± SD values, 1734.84 ± 379.32 and 1442.75 ± 309.47; p=0.002). There was no association between the serum levels of the molecules and the time of first symptoms, severity of vitreous haze, size or localization of active lesions, levels of visual acuity, and presence of vasculitis. These results suggest that TR is associated with changes in the circulating levels of inflammatory biomarkers, but they are not correlated with local/ocular signs.

La mutación R92Q del gen TNFRSF1A se asocia con manifestaciones extra-intestinales en la enfermedad de Crohn / The TNFRSF1A gene R92Q mutation is associated with extra-intestinal manifestations of Crohn’s disease

It has been suggested that the R92Q mutation of the tumour necrosis factor receptor superfamily 1A (TNFRS1A) gene may be implicated in different inflammatory disorders. The aim of this study was to establish the role of this mutation as a determinant of Crohn`s disease (CD) susceptibility and/or clinical phenotype. One hundred and sixty-five CD patients and 203 healthy controls were prospectively included. The frequency of individuals carrying the R92Q mutation was similar between CD patients (4.24 percent) and controls (4.43 percent) (OR: 0.95; 95 percent CI = 0.34-2.62). In the genotype-phenotype evaluation, the univariate analysis showed that extra-intestinal manifestations were positively associated with the presence of R92Q mutation (p = 0.025; OR: 5.56; 95 percent CI = 1.04-29.6). In the multivariate analysis, presence of R92Q mutation was independently associated to extra-intestinal manifestations of CD, specially cutaneous manifestations (p = 0.02; OR: 5.17, 95 percent CI = 1.07-24.8). The R92Q mutation of TNFRSF1A gene is not a determinant of CD susceptibility, but contributes to the appearance of extra-intestinal manifestations of the disease.

Se ha sugerido que la mutación R92Q del gen de la super-familia del receptor del factor de necrosis tumoral 1A (TNFRS1A) podría estar relacionada con diversos trastornos inflamatorios. El objetivo de este estudio fue determinar el papel de esta mutación como factor determinante de la susceptibilidad y/o fenotipo clínico de la enfermedad de Crohn (EC). Ciento sesenta y cinco pacientes con EC y 203 controles sanos fueron incluidos de manera prospectiva. La frecuencia de individuos portadores de la mutación R92Q fue similar entre los pacientes con EC (4,24 por ciento) y los controles (4,43 por ciento) (OR: 0,95; 95 por ciento IC = 0,34-2,62). En la evaluación genotipo-fenotipo, el análisis univariado indicó que las manifestaciones extra-intestinales estaban relacionadas con la presencia de la mutación R92Q (p = 0,025; OR: 5,56; 95 por ciento IC = 1,04-29,6). En el análisis multivariado, la presencia de la mutación R92Q estuvo relacionada de manera independiente con las manifestaciones extra-intestinales de la EC, especialmente manifestaciones cutáneas (p = 0,02; OR: 5,17, 95 por ciento IC = 1,07-24,8). La mutación R92Q del gen TNFRSF1A no es un factor determinante de susceptibilidad a EC, pero contribuye a la aparición de manifestaciones extra-intestinales de la enfermedad.

Plasma levels of procalcitonin and eight additional inflammatory molecules in febrile neutropenic patients

OBJECTIVE: This study aimed to examine the association between different inflammatory markers and specific clinical endpoints in patients with febrile neutropenia. METHOD: We prospectively evaluated the expression of procalcitonin (PCT), interleukin 8 (IL-8), induced protein-10, tumor necrosis factor alpha (TNF-a), two soluble TNF-a receptors (sTNF-R I and sTNF-R II), monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1 alpha, and eotaxin in 37 episodes of febrile neutropenia occurring in 31 hospitalized adult onco-hematologic patients. Peripheral blood samples were collected in the morning at inclusion (day of fever onset) and on days 1, 3, and 7 after the onset of fever. Approximately 2-3 ml of plasma was obtained from each blood sample and stored at -80°C. RESULTS: The sTNF-R II level at inclusion (day 1), the PCT level on the day of fever onset, and the change (day 3 - day 1) in the IL-8 and eotaxin levels were significantly higher in patients who died during the 28-day follow-up. A requirement for early adjustment of antimicrobial treatment was associated with higher day 3 levels of IL-8, sTNF-R II, PCT, and MCP-1. CONCLUSION: Procalcitonin, sTNF-R II, IL-8, MCP-1, and eotaxin could potentially be used to assess the risk of death and the requirement for early adjustment of antimicrobial treatment in febrile, neutropenic onco-hematologic patients. The levels of the other markers showed no association with any of the evaluated endpoints.

Expression of death cellular receptors FAS/CD95 and DR4 during porcine placentation / Expresión de los receptores de muerte celular FAS/CD95 y DR4 durante la placentación porcina

Apoptosis is a permanent and dynamic physiological process by which an organism eliminates the undesirable cells without causing an inflammatory response. The objective of this work was to study the expression of FAS, DR4 and other members of the TNF-R1 superfamily extrinsic route apoptotic receptors the DNA fragmentation and the cellular apoptosis in placental samples at the early, mid and late pregnancy on +/- 30, +/- 55 and +/- 114 gestational days, respectively. We used placental histological sections of samples fixed in buffered saline formaldehyde. Immunohistochemical techniques were performed to detect the apoptotic receptors, whereas the DNA fragmentation was detected by TUNEL reaction and apoptotic cellular ultrastructure was detected by TEM conventional techniques. Apoptosis related receptors were immunolocalized in the early pig gestation and correlated with apoptosis, suggesting a role in the cellular remodelling of the placenta. At gestation day 55, apoptosis might be correlated to FAS route, but not by DR4-mediating pathway. At the end of gestation, increased apoptosis and both receptors markers were detected showing cellular death due to the extrinsic route through FAS and DR4 receptors. In conclusion, the immunolocalization of FAS and TNF R-1 receptors along the pig placental development correlates with TUNEL reaction and with apoptotic ultrastructure observed by TEM and seems to occur through different pathways along gestation.

La apoptosis es un proceso fisiológico, dinámico y permanente a través del cual un organismo elimina células indeseables sin provocar una respuesta inflamatoria. El objetivo del presente trabajo fue estudiar la expresión de los receptores de la vía extrínseca de apoptosis, FAS, DR4 y otros miembros de la superfamilia TNF-R1, la fragmentación del ADN y la apoptosis celular a través de TEM, en muestras placentarias del inicio, la mitad y el final de la gestación, hacia el día +/- 30, +/- 55 y +/- 114 de preñez, respectivamente. Se realizaron cortes histológicos de las muestras placentarias fijadas en formol tamponado. Para la detección de los receptores de apoptosis se realizaron técnicas inmunohistoquímicas, para el estudio de la fragmentación del ADN se utilizó el ensayo TUNEL y para el análisis de la ultraestructura celular apoptótica la técnica convencional de TEM. La inmunolocalización de los receptores de muerte celular al inicio de la preñez porcina sugiere el rol de la apoptosis en la remodelación celular placentaria. Hacia el día 55 de preñez, la apoptosis detectada ocurriría únicamente a través de la vía del receptor FAS, no del receptor DR4. Al final de la gestación, se detectó un incremento de la apoptosis y la expresión de ambos receptores, indicando que la muerte celular a través de la vía de señalización extrínseca estaría inducida por los receptores FAS y DR4. En conclusión, la inmunolocalización de los receptores FAS y otros miembros del TNF-R1, los resultados de TUNEL y la ultraestructura celular apoptótica observada en la placentación porcina, indican que la apoptosis detectada ocurre por diferentes vías de inducción a lo largo de la gestación.

Serum cytokine levels in patients with chronic low back pain due to herniated disc: analytical cross-sectional study / Concentrações plasmáticas de citocinas em pacientes com lombalgia crônica por hérnia de disco: estudo transversal analítico

CONTEXT AND OBJECTIVE: The role of immune response and proinflammatory cytokines in the pathogenesis of chronic pain has been of growing interest. In order to evaluate whether there is any association between disc herniation and elevated cytokine levels, we measured cytokine levels in patients with chronic low back pain and in healthy subjects. DESIGN AND SETTING: Analytical cross-sectional study at the Pain Clinic of Universidade Federal da Bahia (UFBA). METHODS: Cytokine levels were measured using the enzyme-linked immunosorbent assay (ELISA) technique on 23 patients with low back pain (G1) and on 10 healthy subjects (G2). RESULTS: The levels of tumor necrosis factor-alpha [TNF-alpha] (G1 = 5.6 ± 2.3 pg/ml; G2 = 1.6 ± 0.5 pg/ml; P = 0.01) and interleukin-6 [IL-6] (G1 = 4.1 ± 3.0 pg/ml; G2 = 0.9 ± 0.4 pg/ml; P = 0.01) were higher in G1. There were no statistically significant differences in relation to interleukin-1 [IL-1] (G1 = 0.5 ± 0.3 pg/ml; G2 = 0.5 ± 0.1 pg/ml; P = 1) or soluble tumor necrosis factor receptor [sTNF-R] (G1 = 572 pg/ml ± 36; G2 = 581 ± 50 pg/ml; P = 0.87). CONCLUSION: The patients with chronic low back pain due to disc herniation presented higher levels of TNF-alpha and IL-6, but not of IL-1 or sTNF-R.

CONTEXTO E OBJETIVO: A função da resposta imunológica e das citocinas pró-inflamatórias na patogênese da dor crônica tem tido interesse crescente. Para avaliar se há correlação entre hérnia de disco e aumento de citocinas, foi medida a concentração de citocinas em pacientes com lombalgia crônica e em indivíduos sadios. TIPO DE ESTUDO E LOCAL: Estudo transversal analítico realizado na Clínica de Dor da Universidade Federal da Bahia (UFBA). MÉTODO: As concentrações de citocinas foram medidas pela técnica de ELISA (enzyme linked immunosorbent assay) em 23 pacientes com lombalgia (G1) e 10 sadios (G2). RESULTADOS: As concentrações de fator-alfa de necrose tumoral [TNF-alpha] (G1 = 5.6 ± 2.3 pg/ml; G2 = 1.6 ± 0.5 pg/ml; P = 0,01) e interleucina-6 [IL-6] (G1 = 4.1 ± 3.0 pg/ml; G2 = 0.9 ± 0.4 pg/ml; P = 0,01) foram maiores no G1. Não houve diferença estatisticamente significante para interleucina-1 [IL-1] (G1 = 0.5 ± 0.3 pg/ml; G2 = 0.5 ± 0.1 pg/ml; P = 1) e receptor solúvel do factor de necrose tumoral [sTNF-R] (G1 = 572 pg/ml ± 36; G2 = 581 ± 50 pg/ml; P = 0,87). CONCLUSÃO: Os pacientes com lombalgia crônica por hérnia de disco apresentam concentrações maiores de TNF-alpha e IL-6, mas não de IL-1 ou sTNF-R.

Soluble inflammatory markers as predictors of hepatocellular damage and therapeutic response in chronic hepatitis C

Hepatitis C is an important burden worldwide being an important cause of cirrhosis and liver cancer in different parts of the world. Host immune response, especially T helper type 1 (Th1) cell-mediated, seems to play an important role in disease progression but is also crucial for viral elimination following specific therapy. Immune activation can be evaluated using peripheral levels of different cytokines, such as different chemokines (e.g. CCL5, CXCL10) and tumor necrosis factor alpha (TNF-á), and their soluble receptors (e.g. soluble TNF-á receptors 1 (sTNF-R1) and 2 (sTNF-R2). This review article focuses on the potential use of peripheral inflammatory markers as predictors of liver histological changes and therapeutic response among patients with chronic hepatitis C.

Perfil neuro-hormonal de pacientes reumáticos com insuficiência aórtica crônica importante / Perfil neurohormonal de pacientes reumáticos con insuficiencia aórtica crónica severa / Neurohormonal profile of rheumatic patients with significant chronic aortic regurgitation

FUNDAMENTO: Os neuro-hormônios estão envolvidos na fisiopatologia da insuficiência cardíaca, mas pouco se sabe sobre seu comportamento na insuficiência aórtica crônica importante (IAo). OBJETIVO: Analisar o comportamento desses mediadores na IAo. MÉTODOS: Analisamos 89 pacientes com IAo, com média etária de 33,6±11,5 anos, 84,6 por cento do sexo masculino, 60 por cento assintomáticos, todos de etiologia reumática. Após avaliação clínica e ecocardiográfica, realizaram-se dosagens plasmáticas de fator de necrose tumoral (TNF), seus antagonistas receptores solúveis tipos I e II (sTNFRI e sTNFRII), interleucina-6 (IL-6), seu receptor solúvel, endotelina-1 e peptídeo natriurético tipo B (BNP). Doze indivíduos saudáveis serviram como controle. RESULTADOS: O valor médio de diâmetro diastólico (DD) do ventrículo esquerdo (VE) foi de 71,9±8,3 mm, e o do diâmetro sistólico (DS) do VE, de 50,4±9,3 mm. Os níveis de neuro-hormônios estavam elevados nos pacientes com IAo: TNF 92,65±110,24 pg/ml vs. 1,67±1,21 pg/ml nos controles, p<0,001; IL-6 7,17±7,78 pg/ml vs. 0,81±0,38 pg/ml nos controles, p = 0,0001; e TNFRI 894,75±348,87 pg/ml vs. 521,42±395,13 pg/ml, p = 0,007. Com exceção dos níveis de BNP, os pacientes sintomáticos e assintomáticos apresentaram perfil neuro-hormonal semelhante. Houve correlação entre TNFRII e diâmetro diastólico do ventrículo esquerdo (DDVE) (r = -0,329, p = 0,038) e diâmetro sistólico do ventrículo esquerdo (DSVE) (r = -0,352, p = 0,027). Os níveis de BNP estavam significativamente mais altos em pacientes sintomáticos, e apenas nestes foi possível correlação entre BNP e diâmetros ventriculares. CONCLUSÃO: Pacientes com insuficiência aórtica crônica importante apresentam altos níveis neuro-hormônios, sem correlação com o status sintomático. Os níveis de TNFRII e BNP puderam ser correlacionados com diâmetros ventriculares, mas apenas este último com sintomas.

TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-á blockade

In Chagas disease, understanding how the immune response controls parasite growth but also leads to heart damage may provide insight into the design of new therapeutic strategies. Tumor necrosis factor-alpha (TNF-á) is important for resistance to acute Trypanosoma cruzi infection; however, in patients suffering from chronic T. cruzi infection, plasma TNF-á levels correlate with cardiomyopathy. Recent data suggest that CD8-enriched chagasic myocarditis formation involves CCR1/CCR5-mediated cell migration. Herein, the contribution of TNF-á, especially signaling through the receptor TNFR1/p55, to the pathophysiology of T. cruzi infection was evaluated with a focus on the development of myocarditis and heart dysfunction. Colombian strain-infected C57BL/6 mice had increased frequencies of TNFR1/p55+ and TNF-á+ splenocytes. Although TNFR1-/- mice exhibited reduced myocarditis in the absence of parasite burden, they succumbed to acute infection. Similar to C57BL/6 mice, Benznidazole-treated TNFR1-/- mice survived acute infection. In TNFR1-/- mice, reduced CD8-enriched myocarditis was associated with defective activation of CD44+CD62Llow/- and CCR5+ CD8+ lymphocytes. Also, anti-TNF-á treatment reduced the frequency of CD8+CCR5+ circulating cells and myocarditis, though parasite load was unaltered in infected C3H/HeJ mice. TNFR1-/- and anti-TNF-á-treated infected mice showed regular expression of connexin-43 and reduced fibronectin deposition, respectively. Furthermore, anti-TNF-á treatment resulted in lower levels of CK-MB, a cardiomyocyte lesion marker. Our results suggest that TNF/TNFR1 signaling promotes CD8-enriched myocarditis formation and heart tissue damage, implicating the TNF/TNFR1 signaling pathway as a potential therapeutic target for control of T. cruzi-elicited cardiomyopathy.

TRAPS, un síndrome autoinflamatorio: Casos cínicos / Tumor necrosis factor receptor associated periodic syndrome (TRAPS): Report of two cases

Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) is an autoinflammatory disorder associated to a mutation of the Tumor Necrosis Factor Receptor 1 (TNFR1) whose clinical presentation consists on recurrent episodes of prolonged fever, abdominal pain, myalgias, migratory cutaneous erythema, conjunctivitis or periorbitary edema. The diagnosis is confirmed by genetic analysis of the TNFR1 gene. Its main complication is amyloidosis and the treatment is based on the use of corticosteroids or anti-TNF antibodies. We report a 17 year-old male and 23 year-old female with the syndrome. Both cases had heterozygous mutations of the TNFR1 gene, C30R in the first case and T50M in the second case.