Quercetin and resveratrol are associated with the downregulation of TNFalpha/NF-kB/inos axis-mediated acute liver injury in rats induced by paracetamol poisoning / La quercetina y el resveratrol están asociados con la regulación decreciente de la lesión hepática aguda mediada por el eje TNF-alfa/NF-kB/inos en ratas inducida por envenenamiento con paracetamol

SUMMARY: Paracetamol (known as acetaminophen, or APAP) poisoning causes acute liver damage that can lead to organ failure and death. We sought to determine that APAP overdose can augment tumor necrosis factor-alpha (TNF-α)/ nuclear factor kappa B (NF-kB)/induced nitic oxide synthase (iNOS) axis-mediated hepatotoxicity in rats, and the anti-inflammatory polyphenolic compounds, quercetin (QUR) plus resveratrol (RES) can ameliorate these parameters. Therefore, we induced acute hepatotoxicity in rats using APAP overdose (2 g/kg, orally) and the protective group of rats were treated with 50 mg/kg QUR plus 30 mg/kg RES for one week before APAP ingestion. Animals were killed at day 8. APAP poisoning caused the induction of hepatic tissue levels of TNF-α, NF-kB, and iNOS, which were significantly (p<0.05) decreased by QUR+RES. QUR+RES, also inhibited liver injury biomarkers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additionally, a link between liver injury and TNF-α /NF-kB / iNOS axis mediated hepatotoxicity was observed. Thus, the presented data backing the conclusion that intoxication by paracetamol increases TNF-α / NF-kB / iNOS axis -mediated hepatotoxicity, and is protected by a combination of quercetin and resveratrol.

El envenenamiento por paracetamol (conocido como acetaminofeno o APAP) causa daño hepático agudo que puede provocar una insuficiencia orgánica y la muerte. El objetivo de este trabajo fue determinar si la sobredosis de APAP puede aumentar la hepatotoxicidad mediada por el eje del factor de necrosis tumoral alfa (TNF-α)/factor nuclear kappa B (NF-kB)/óxido nítico sintasa inducida (iNOS) en ratas, y si el polifenólico antiinflamatorio compuesto por quercetina (QUR) más resveratrol (RES) pueden mejorar estos parámetros. Por lo tanto, inducimos hepatotoxicidad aguda en ratas usando una sobredosis de APAP (2 g/kg, por vía oral). El grupo protector de ratas se trató con 50 mg/ kg de QUR más 30 mg/kg de RES durante una semana antes de la ingestión de APAP. Los animales se sacrificaron el día 8. El envenenamiento con APAP en el tejido hepático provocó la inducción de niveles de TNF-α, NF-kB e iNOS, que se redujeron significativamente (p<0,05) con QUR+RES. QUR+RES, también inhibió los biomarcadores de daño hepático, la alanina aminotransferasa (ALT) y el aspartato aminotransferasa (AST). Además, se observó una relación entre la lesión hepática y la hepatotoxicidad mediada por el eje TNF-α /NF-kB/iNOS. Por lo tanto, los datos presentados respaldan la conclusión de que la intoxicación por paracetamol aumenta la hepatotoxicidad mediada por el eje TNF-α /NF-kB / iNOS, y está protegida por una combinación de quercetina y resveratrol.

Avaliação da aterosclerose subclínica em portadores de HDL-colesterol marcadamente elevado / Evaluation of subclinical atherosclerosis in individuals with markedly elevated HDL-cholesterol

O HDL-c é um fator de risco cardiovascular negativo e sua concentração plasmática apresenta relação inversa com a incidência de eventos cardiovasculares. Entretanto, as evidências relativas ao grupo de indivíduos com níveis de HDL-c acima do percentil 95 da população geral ainda são escassas e o impacto da hiperalfalipoproteinemia (HALP) sobre o risco cardiovascular continua representando motivo de controvérsia na literatura médica. Alguns estudos em populações específicas associam a HALP a aumento do risco cardiovascular. Ao mesmo tempo, outros estudos identificaram populações de indivíduos hipoalfalipoproteinêmicos com marcada longevidade. Assim, demonstrou-se aparente dissociação entre níveis de HDL-c e risco cardiovascular em determinadas populações, reconduzível a aspectos disfuncionais da HDL. O objetivo do presente estudo foi verificar o papel da HALP na determinação do risco cardiovascular; comparar a prevalência de doença cardiovascular subclínica, avaliada por meio da quantificação ultrassonográfica da Espessura Íntimo-Medial Carotídea (EIMC), entre portadores de HDL-c >= 90mg/dL (grupo HALP) e portadores de concentrações de HDL-c atualmente consideradas normais (entre 40 e 50mg/dL para os homens e entre 50 e 60mg/dL para as mulheres); e avaliar características e função da HDL em portadores de HALP por meio do estudo de sua composição, de sua capacidade de efluxo de colesterol, e de sua atividade anti-inflamatória e antioxidante, correlacionando estas características com a presença de doença cardiovascular subclínica avaliada por meio da determinação da EIMC, da Velocidade de Onda de Pulso (VOP) e da presença de Calcificação Arterial Coronariana (CAC) avaliada pela TCMD. Para responder estas perguntas, o presente estudo foi articulado em dois braços: Braço 1: Análise da coorte do estudo ELSA com o objetivo de determinar a prevalência de HALP em uma população geral; definir o perfil demográfico, antropométrico e metabólico dos portadores de HALP; e...

HDL-c is a negative cardiovascular risk factor and its plasma concentration is inversely related to the incidence of cardiovascular events. However, evidence of benefit among subjects with HDL-c levels above the 95th percentile of the general population is still scarce and the impact of hyperalphalipoproteinemia (HALP) on cardiovascular risk continues to represent matter of debate in the medical literature. Some studies with specific populations indicated an increased cardiovascular risk associated with HALP. In addition, other reports identified groups of patients with marked hypoalphalipoproteinemia and longevity. Hence, there could be a dissociation between HDL-c levels and cardiovascular risk in certain populations, possibly due to dysfunctional HDL particles. The aim of this study was to investigate the role of HALP phenotype in determining cardiovascular risk; to compare the prevalence of subclinical cardiovascular disease, assessed by ultrasound measurement of Carotid Intima-Media Thickness (CIMT) among patients with HDL-c >= 90mg/dL (HALP group) and patients with HDL-c currently considered normal (40-50mg/dL for men and 50-60mg/dL for women); and to evaluate HDL functionality in patients with HALP through the study of its composition, its cholesterol efflux capacity, and its anti-inflammatory and antioxidant activity; correlating those characteristics with the presence of subclinical cardiovascular disease assessed by CIMT, Pulse Wave Velocity (PWV) and Coronary Artery Calcification (CAC). To answer these questions, the present study was articulated into two arms: Arm 1: ELSA-Brasil study cohort analysis in order to assess HALP prevalence in a general population, defining demographic, anthropometric and metabolic profile of HALP individuals; and comparing the prevalence of subclinical vascular disease among HALP subjects with controls with normal HDL-c. Arm 2: Recruitment of 80 healthy volunteers with HALP to study the correlation...

Lack of association among TNF-alfa gene expression, -308 polymorphism (G > A) and virulence markers of Helicobacter pylori

Background Tumor necrosis factor plays a critical role in the pathogenesis of gastric diseases such as gastric cancer, and an abnormal inflammatory response has frequently been observed in dyspeptic patients. Helicobacter pylori infection can induce a gastric mucosal inflammatory response that may be influenced by -308 (G > A) polymorphisms and gene expression of theTNF- gene. Methods One hundred and thirty-four gastric biopsy samples were collected from patients of both genders (61 and 73, mean age 40.3 ± 24.2 years) with gastric symptoms. The -308 (G > A) polymorphism of TNF- was characterized using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). The expression level was measured using real-time PCR, and relative quantification (RQ) was calculated using the comparative CT method (2-CT). Results The analysis revealed an increase in TNF- gene expression in patients with gastritis; on the other hand, no statistical differences were observed in patients with gastric cancer. In addition, no association was found among -308 polymorphism genotypes, virulence markers, or TNF- gene expression. Conclusions Helicobacter pylori induces a large increase in TNF- expression in patients with gastritis, regardless of tissue inflammation, but after the tissue becomes neoplastic, the presence of bacteria did not influence expression. These results suggest that the TNF- pathway may play an important role in the progression from gastritis to gastric cancer.

Los extractos acuoso y metanólico de Berberis darwinii H. (Berberidaceae) inhiben respuestas celulares innatas en monocitos humanos tratados in vitro / Aqueous and methanol extracts of Berberis darwinii H. (Berberidaceae) inhibit innate celular responses in human monocytes in vitro treated

Berberis darwinii H is a native plant of South America, popularly referred to Michay. This species has historically been used by indigenous cultures of Chile as medicinal herb. To preliminarily assess their anti-inflammatory effects was investigated the aqueous and methanolic root extract this plant in human monocytes. The results indicated that the extracts inhibit the production of superoxide anion, the expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1beta) in monocytes activated with lipopolysaccharide. This result suggests the existence of compounds with potential anti-inflammatory action in these extracts.

Berberis darwinii H. es una planta nativa de América del Sur, conocida popularmente como Michay. Esta especie ha sido históricamente utilizada por las culturas indígenas de Chile como hierba medicinal. Con el fin de evaluar preliminarmente sus efectos anti-inflamatorios, se investigaron dos tipos de extractos; metanólico y acuoso, preparados a partir de la raíz de esta planta. Los resultados indican que estos extractos inhiben la producción de anión superóxido, la expresión del factor de necrosis tumoral-alfa (TNF-alfa) y de interleucina-1beta, (IL-1beta) en monocitos activados con lipopolisacárido. Estos resultados sugieren la existencia de compuestos con potencial acción antiinflamatoria en esta planta.

Estratégia de troca entre agentes anti-TNF-alfa não melhora a capacidade funcional em pacientes com artrite reumatoide de longa evolução / Switching between anti-TNF-alpha agents does not improve functional capacity in patients with long-standing and active rheumatoid arthritis

OBJETIVOS: Avaliar a resposta clínica após a estratégia de troca entre agentes antifator de necrose tumoral alfa (anti-TNF-alfa) em pacientes com artrite reumatoide (AR). PACIENTES E MÉTODOS: Foram incluídos 99 pacientes com diagnóstico de AR (American College of Rheumatology, 1987), em uso de terapia anti-TNF-alfa, para avaliação da resposta terapêutica após 24 semanas. A estratégia de troca foi feita se, após 12 a 24 semanas, houvesse relato de evento adverso sério (T: toxicidade) ou se não ocorresse redução maior que 0,6 do índice de atividade da doença (DAS28) inicial (RI: resposta inadequada). Nesse último caso, o paciente foi considerado como falência primária (FP). Falência secundária (FS) foi definida se houvesse perda de resposta após melhora inicial. Remissão (DAS28 < 2,6), baixa atividade de doença (2,61 < 3,2) e melhora funcional [aumento > 0,2 do questionário de avaliação da saúde (HAQ) inicial] foram avaliadas por análise de regressão linear. P < 0,05 foi considerado significante. RESULTADOS: A estratégia de troca foi realizada em 39 (39,4 por cento) pacientes, especialmente por FP (24,3 por cento), FS (35,1 por cento) e T (40,5 por cento). A taxa de retenção ao primeiro agente foi de 60,1 por cento, e o tempo médio para a troca foi de 14,2 ± 10,9 meses. Após a troca, houve tendência à queda do DAS28 (4,7 ± 1,4; P = 0,08), mas não do HAQ (1,2 ± 0,77; P = 0,11). Cerca de 43 por cento deles alcançaram boa/moderada resposta EULAR. O principal determinante da troca foi o DAS28 inicial mais elevado, independente de idade, tempo de doença e capacidade funcional. CONCLUSÃO: A estratégia de troca entre agentes anti-TNF-alfa é válida para o controle da atividade de doença, embora com baixa probabilidade de remissão e sem melhora significativa da capacidade funcional.

OBJECTIVES: To assess clinical response after switching between anti-tumor necrosis factor-alpha (anti-TNF-alpha) agents in patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: This study included 99 patients diagnosed with RA American College of Rheumatology, 1987), on anti-TNF-alpha therapy, to assess the therapeutic response after 24 weeks. Switching was performed if, after 12 to 24 weeks, a severe adverse event was reported (toxicity: T) or if no reduction greater than 0.6 in the initial Disease Activity Score 28 (DAS28) occurred (inadequate response: IR). In case of IR, the patient was considered as primary failure (PF). Secondary failure (SF) was defined as loss of response after initial improvement. Remission (DAS28 < 2.6), low disease activity (between 2.61 and 3.2), and functional improvement [increase in the initial Health Assessment Questionnaire (HAQ) > 0.2] were assessed by use of linear regression analysis. The significance level adopted was P < 0.05. RESULTS: Switching was performed in 39 (39.4 percent) patients, especially due to PF (24.3 percent), SF (35.1 percent) and T (40.5 percent). The retention rate of the first agent was 60.1 percent, and the mean time for switching was 14.2 ± 10.9 months. After switching, a tendency towards a decrease in DAS28 was observed (4.7 ± 1.4; P = 0.08), but not in the HAQ (1.2 ± 0.77; P = 0.11). Around 43 percent of the patients achieved good/moderate EULAR response. The major determinant of switching was a higher initial DAS28, independent of age, duration of disease, and functional capacity. CONCLUSION: Switching between anti-TNF-alpha agents is a valid strategy to control disease activity, despite the low likelihood of remission and no significant improvement in functional capacity.

Presença do polimorfismo do gene TNFA em pacientes com doença de crohn e com periodontite crônica / Presence of TNFA gene polymorphism in patients with crohn's disease and chronic periodontitis

Indivíduos com doença inflamatória intestinal (DII) apresentam uma maior prevalência de periodontite. O objetivo desse estudo piloto foi investigar a presença do polimorfismo do gene do TNF-A -308 G>A em indivíduos com DII e periodontite comparando com indivíduos sistemicamente saudáveis com periodontite. Nossa hipótese é que nos indivíduos com DII e periodontite, a presença do polimorfismo do fator de necrose tumoral (TNFA) -308 G>A seja mais prevalente. Dez pacientes com Doença de Crohn (DC) e periodontite, 6 pacientes com retocolite ulcerativa idiopática (RCUI) e periodontite e 8 pacientes sem DII com periodontite participaram desse estudo. Foram considerados com periodontite indivíduos com perda de inserção clínica maior ou igual a 3 mm em pelo menos 4 sítios em diferentes dentes. Células epiteliais da mucosa oral foram coletadas com cotonetes esterilizados. O DNA foi extraído através de um kit comercial. O DNA obtido foi utilizado como molde em reações de amplificação das regiões genômicas de interesse através da técnica de reação em cadeia polimerase - PCR, utilizando-se oligonucleotídeos específicos. A comparação entre grupos foi feita com o teste ANOVA e com o teste T. O teste x² foi utilizado para analisar a presença do polimorfismo. O nível de significância foi determinado em 5% (p< 0,05). Nos pacientes com DC, 60% apresentavam 1 alelo polimórfico. Nos com RCUI, não foi encontrado o alelo polimórfico. Nos saudáveis com periodontite, 25% apresentaram o alelo polimórfico. Esse estudo demonstrou que pacientes com DC e periodontite possuíam uma maior prevalência de um alelo polimórfico do TNFA -308 G> A. Esse resultado sugere que apesar de não necessariamente determinar a ocorrência da DII e nem da periodontite, o polimorfismo do TNFA -308 G>A pode exercer um papel na modificação do fenótipo de pacientes com DII e periodontite

Subjects with inflammatory bowel disease (IBD) have a higher prevalence of peridontitis. The aim of this pilot study was to assess the polymorphism of TNFA -308 G>A in IBD patients who had periodontitis and to compare to systemically health individuals who have periodontitis. Our hypothesis is that in subjects with IBD and periodontitis the occurrence of a genetic polymorphism of tumor necrosis factor alpha (TNFA) -308 G>Ais more prevalent. Ten patients with Crohn 's Disease (CD), 6 patients with ulcerative colitis (UC) and 8individuals systemically health otherwise periodontitis were included in this study. Periodontitis was defined by clinical attachment loss equal or higher 3 mm in at least 4 sites in different teeth. Epithelial cells from the oral mucosa were obtained through a sterilized swab. The DNA extraction was realized through a commercial kit. The obtained DNA was used for the aimed region in polymerase chain reaction –PCR using specific oligonucleotides. Comparisons between the groups were analyzed by ANOVA and T tests. To analyze thepresence of the polymorphism x² test was used. Significance was set at 5% (p< 0.05). Sixty per cent of CD patients had one polymorphicalele. None of UC patients had the polymorphic allele. Twenty five per cent of systemically health individuals had the polymorphic allele. This study showed that patientswith Crohn 's Disease who have periodontitis present a higher prevalance of the polymorphic allele of TNA-308. This preliminary result suggests that although this polymorphism is not a risk for occurrence of IBD or periodontitis, this polymorphism may have a role in modifying the phenotype of IBD patients who have periodontitis.

Estrés oxidativo en los músculos soleo y extensor digitorum longus (EDL) de ratas espontáneamente hipertensas / Oxidative stress in soleus and extensor digitorum longus (EDL) muscles of spontaneously hypertensive rats

Las enfermedades sistémicas crónicas afectan el músculo esquelético, siendo la inflamación y el estrés oxidativo algunos de los mecanismos involucrados. El efecto de la hipertensión arterial esencial sobre el músculo esquelético no es bien conocido. Se estudiaron los músculos soleo y extensor digitorum longus (EDL) de ratas espontáneamente hipertensas (SHR), comparadas con las controles normotensas Wistar Kyoto (WKY). Se determinaron los niveles de nitritos y nitratos en µmoles/mg-proteína; las sintasas del óxido nítrico: endotelial (eNOS); neuronal (nNOS); e inducible (iNOS), nitrotirosina y el factor de necrosis tumoral-alfa (TNF-α) en ng/mg-proteína. En las SHR, en el soleo y el EDL respectivamente, se incrementó la nitrotirosina (24,4 ± 5,0 vs. 3,3 ± 0,3, p<0,001; 20,2 ± 4,3 vs. 4,5 ± 0,4, p<0,0037), iNOS (26,6 ± 3,7 vs. 8,3 ± 0,9; 21,3 ± 3,7 vs. 11,0 ± 0,8 ambos p<0,0001), y TNF-α (2,2 ± 0,5 vs. 0,6 ± 0,1, p<0,05; 1,9 ± 0,2 vs. 0,6 ± 0,1, p<0,02); hubo disminución de eNOS en el soleo (20,6 ± 1,4 vs. 30,3 ± 1,2, p<0,00001); de nNOS (soleo 16,8 ± 1,4 vs. 20,7 ± 1,8, p< 0,05; EDL 13,6 ± 1,3 vs. 21,9 ± 1,8, p<0,005) y de nitrito en el EDL (5,8 ± 0,3 vs. 7,1 ± 0,5, p<0,026). En las SHR se observó correlación positiva entre TNF-α vs. nitrotirosina: soleo (r=0,798; p<0,031) y tendencia en EDL (r=0,739; p<0,057); iNOS vs. nitrotirosina (soleo: r=0,908 p<0,0001; EDL: r=0,707; p=0,01), tendencia entre TNF-α vs. iNOS en EDL (r=0,736; p=0,059); y correlación negativa entre eNOS vs. nitrotirosina en soleo (r=-0,816; p=0,0012). En conclusión, las SHR presentan un proceso inflamatorio muscular, evidenciado por el incremento de TNF-α, nitrotirosina, e iNOS. La disminución de las sintasas constitutivas, con incremento de la iNOS es evidencia de la disfunción endotelial.

Systemic diseases affect skeletal muscle, and inflammation and oxidative stress are some of the involved mechanisms. There is scarce information about the effects of essential hypertension on skeletal muscle. The soleus and extensor digitorum longus (EDL) muscles of spontaneously hypertensive rats (SHR) were studied compared to control Wistar Kyoto (WKY) rats. The levels of nitrite and nitrate in µmol/mg-protein; endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) nitric oxide synthases, nitrotyrosine and tumour necrosis factor alpha (TNF-α) in ng/mg-protein were determined. Compared with controls, the SHR showed increased levels of nitrotyrosine (soleus 24.4 ± 5.0 vs. 3.3±0.3, p<0.001; EDL 20.2 ± 4.3 vs. 4.5 ± 0.4, p<0.0037), iNOS (soleus 26.6 ± 3.7 vs. 8.3 ± 0.9; EDL 21.3 ± 3.7 vs. 11.0 ± 0.8, both p<0.0001) and TNF-α (soleus 2.2 ± 0.5 vs. 0.6 ± 0.1, p<0.05; EDL 1.9 ± 0.2 vs. 0.6 ± 0.1, p<0.02). A decrease of eNOS was found in soleus muscle (20.6 ± 1.4 vs. 30.3 ± 1.2, p<0.00001); of nNOS (soleus 16.8 ± 1.4 vs. 20.7 ± 1.8, p< 0.05; EDL 13.6 ± 1.3 vs. 21.9 ± 1.8, p<0.005) and nitrite in EDL (5.8 ± 0.3 vs. 7.1 ± 0.5, p<0.026).There was a positive correlation between TNF-α vs. nitrotyrosine in soleus (r=0.798; p<0.031) and a tendency in EDL (r=0.739; p=0.059); iNOS vs. nitrotyrosine (soleus: r=0.908; p<0.0001; EDL: r=0.707; p<0.01), a tendency between TNF-α and iNOS (EDL: r=0.736; p<0.059); and a negative correlation between eNOS vs. nitrotyrosine in soleus muscle (r=-0.816; p<0.0012). In conclusion, in skeletal muscles of SHR an inflammatory process was found evidenced by the increase in TNF-α, nitrotyrosine and iNOS. The decreased levels of constitutive synthases, together with the higher level of iNOS, are indicative of endothelial dysfunction.

Pioderma gangrenoso en paciente con colitis ulcerosa tratada con infliximab / Pyoderma gangrenosum in a patient with ulcerative colitits treated with infliximab

El pioderma gangrenoso (PG) es una dermatitis neutrofílica, que en algunos casos puede ser severa y de difícil manejo. Presentamos el caso de una paciente con múltiples lesiones de PG asociadas a colitis ulcerosa, en la cual, por severidad del cuadro, se optó por adicionar infliximab al tratamiento habitual. La respuesta clínica fue excelente y rápida tras la primera dosis de infliximab, pese a que recibió solo dos de las tres dosis recomendadas habitualmente. La mejoría cutánea y digestiva se ha mantenido un año después de este tratamiento. Infliximab ha demostrado ser, en este y otros reportes, una herramienta muy útil, especialmente en casos de compromiso severo como en nuestra paciente. Se requiere mas evidencia aún para comprobar en cuáles pacientes podría ser beneficioso. Se presenta este caso por su severidad y la rápida y sostenida respuesta obtenida con infliximab.

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis and in some cases can be severe and difficult to manage. We report the case of a patient with multiple lesions of PG associated with ulcerative colitis. Due to the severity of the clinical presentation treatment with infliximab was added to standard therapy. Clinical response was excellent and fast after the first dose of infliximab, although ha received only two of the three doses usually recomended. Skin and digestive improvement has been maintained 1 year after treatment. Infliximab has proven, in this and other reports, as a very useful tool in the treatment of PG, especially in cases of severe involvement as in our patient. More evidence is required to prove in which patients with PG infliximab could beneficial. We present this clinical case because of its severity and the rapid and susteined response obtained with infliximab.

Comprendiendo la inmunopatogenia de las artropatías seronegativas / Understanding the immunopathogenesis of seronegative arthropathy

Las artropatías seronegativas o espondiloartropatías corresponden a un grupo de enfermedades que comparten características clínicas y genéticas, asociadas fuertemente con el complejo mayor de histocompatibilidad clase I HLA-B27. El rol patogénico del HLA-B27 es desconocido; se han propuesto múltiples teorías, entre las cuales cabe destacar tres: 1) péptido artritogénico, 2) cadenas pesadas aberrantes en la superficie celular y 3) estrés en el retículo endoplásmico rugoso. Es conocido que los linfocitos T CD4 tienen un rol primordial en esta patología. Se ha encontrado que en la mayoría de estas artropatías hay una gran producción de citoquinas del perfil Th1, sobre todo de TNF alfa, el que jugaría un rol crucial, pues se ha visto que con los fármacos anti TNF se produce una mejoría en la mayoría de estas patologías.

Seronegative arthropathies or spondyloarthropathy belong to a group of diseases that share clinical and genetic characteristics associated strongly with major histocompatibility complex class I HLA-B27. The pathogenic role of HLA-B27 is unknown, many theories have been proposed, among which we highlight three: 1) arthritogenic peptides, 2) aberrant heavy chains on the cell surface and 3) stress on the rough endoplasmic reticulum. It is known that CD4 T lymphocytes have a pivotal role in this pathology. A great production of Th1 profile cytokines have been found to exist in most of these arthropathies, especially TNF alpha., which may play a crucial role, since anti-TNF drugs have been known to produce an improvement in most of these pathologies.

Produção de fator de necrose tumoral-alfa e peróxido de hidrogênio na infecção pelo Trypanosoma cruzi em camundongos submetidos ao exercício / Production of tumoral necrosis factor-alpha and hydrogen peroxide during Trypanosoma cruzi infection in mice submitted to exercise

Este trabalho teve como objetivo determinar os níveis de fator de necrose tumoral alfa (TNF-alfa) sérico e produção de peróxido de hidrogênio (H2O2) por macrófagos peritoneais em camundongos experimentalmente infectados pelo Trypanosoma cruzi e submetidos ao treinamento físico realizado antes da infecção ou ao exercício físico durante o período de infecção. Foram utilizados camundongos BALB/c fêmeas com 30 dias de idade, inoculados com 1.400 tripomastígotas sanguíneos da cepa Y. O exercício físico consistia em atividade de intensidade moderada em esteira rolante. As dosagens foram realizadas com material coletado no 13º dia de infecção. Para a dosagem de TNF-alfa, foi utilizada a técnica de ELISA de captura. A produção de H2O2 foi expressa por coloração produzida após a incubação de macrófagos peritoneais com peroxidase e a leitura realizada em aparelho de ELISA. Não foram encontradas diferenças significativas nas concentrações de TNF-alfa e produção de H2O2 entre os grupos infectados. O treinamento físico realizado antes da infecção e o exercício físico realizado após a infecção não foram capazes de alterar significativamente os níveis de TNF-alfa e a produção de H2O2 na infecção pelo T. cruzi.

This study aimed to determine the levels of seric tumor necrosis factor-alpha (TNF-alpha) and production of hydrogen peroxide (H2O2) by peritoneal macrophages in mice experimentally infected with T. cruzi and submitted to pre-infection exercise training and to post-infection acute exercise. Female 30-day-old BALB/c mice were inoculated with 1,400 blood trypomastigotes of Y-strain T. cruzi. Exercise programs consisted in moderate-intensity activity and were carried out in a treadmill. The measurements were performed with material collected at the 13th day after infection Serum TNF-alpha was evaluated using capture ELISA. H2O2 production was expressed by coloration produced after incubation of peritoneal macrophages and the measurement was performed using an ELISA reader. There were no statistically significant differences in TNF-alpha levels and H2O2 production between the trained and non-trained infected groups. Thus, the physical training performed before infection and physical exercise performed after the infection were not able to change the levels of TNF-alpha and production of H2O2 in the infection by T. cruzi.

Serum levels of interleukin-6, tumor necrosis factor-alpha and interferon-gama in infants with and without dengue

This study compared the serum levels of IL-6, TNF-alpha and IFN-gamma, in children under 1 year of age with and without dengue. Sera were collected from a total of 41 children living in the Department of Antioquia, Colombia (27 patients with dengue and 14 controls). The results showed higher cytokine levels in children with dengue than without dengue, with statistically significant differences for IL-6 and IFN-gamma. No statistically significant differences were found between clinical forms, although IL-6 and IFN-gamma levels were higher in dengue fever cases than in dengue hemorrhagic fever cases. On the other hand, TNF-alpha levels were higher in dengue hemorrhagic fever than in dengue fever. The levels of IL-6 and TNF-alpha were higher in secondary infection than in primary infection, although IFN-gamma levels were higher in primary infection. These results suggest that IL-6, TNF-alpha and IFN-gamma are involved in dengue infection independently of the clinical form.

Este estudo comparou os níveis séricos de IL-6, TNF-alfa e IFN-gama, em crianças menores de um ano com e sem dengue. Os soros foram coletados de um total de 41 crianças residentes no Departamento de Antioquia, Colômbia (27 pacientes com dengue e 14 controles). Os resultados mostraram níveis de citoquinas mais elevadas em crianças com dengue do que naquelas sem dengue, com diferenças estatisticamente significativas para IL-6 and IFN-gama. Não houve diferenças estatisticamente significativas entre formas clínicas, embora os níveis de IL-6 e IFN-gama estivessem mais elevados nos casos de febre do dengue que nos casos de febre hemorrágica do dengue. Por outro lado, os níveis de TNF-alfa estavam mais elevados na febre hemorrágica do dengue que na febre do dengue. Os níveis de IL-6 and TNF-alfa estavam mais elevados em infecções secundárias que em infecções primarias, embora os níveis de IFN-gama estivessem mais elevados em infecções primárias. Estes resultados sugerem que IL-6, TNF-alfa e IFN-gama estejam envolvidos na infecção do dengue, independentemente da forma clínica.

Endotoxemia por lipopolissacarídeo de Escherichia coli, em eqüinos: efeitos de antiinflamatórios nas concentrações sérica e peritoneal do fator de necrose tumoral alfa (TNF-alfa) / Escherichia coli lipopolisacharide (LPS) induced endotoxemia in horses: effects of anti-inflammatory drugs on seric and peritoneal tumor necrosis factor alpha (TNF-alpha) concentrations

Avaliou-se a inibição da produção do fator de necrose tumoral alfa (TNF-alfa) devido ao pré-tratamento com antiinflamatório esteroidal (dexametasona) e não esteroidal (diclofenaco sódico) em eqüinos com endotoxemia induzida experimentalmente. Foram utilizados 15 cavalos machos não castrados, distribuídos em três grupos de cinco animais: controle (C), diclofenaco sódico (DS) e dexametasona (DM). A endotoxemia subletal foi induzida pela infusão intravenosa (IV) de 0,1mg/kg/pv de lipopolissacarídeo (LPS) de Escherichia coli 055:B5, administrado em 250ml de solução estéril de cloreto de sódio a 0,9 por cento, durante 15min. Os cavalos do grupo-controle foram tratados com solução de cloreto de sódio a 9 por cento IV. Nos animais do grupo DS, administraram-se, por via oral, 2,2mg/kg de diclofenaco sódico e, nos do grupo DM, 1,1mg/kg de dexametasona IV, respectivamente, 60 e 30min antes da infusão da endotoxina. Mensurou-se, por meio de ensaio de toxicidade com células da linhagem L929, a concentração de TNF-alfa no soro e no líquido peritoneal às 0, 1», 3 e 6 horas após injeção do LPS. No grupo-controle, observou-se aumento significativo de TNF-alfa sérico, em relação ao valor basal e aos grupos DS e DM, 1,15 horas após a indução da endotoxemia. No líquido peritoneal, as concentrações observadas estavam abaixo daquelas da curva padrão de TNF-alfa, não havendo diferença entre os grupos (P>0,05)

The inhibition of tumor necrosis factor alpha (TNF-alpha) production due to pre-treatment with steroidal (dexamethazone) and non-steroidal (sodium diclofenac) anti-inflammatories was studied in horses under experimentally induced endotoxemy. Fifteen stallions were allotted into three groups of five animals each: control (C), sodium diclofenac (SD) and dexamethazone (DM). Sublethal endotoxemy was induced with 0.1mg/kg/bw Escherichia coli 055:B5 lipopolysaccharide (LPS), IV, administrated in 250ml of 0.9 percent sterile sodium chloride, during 15 minutes. Control group horses received 9 percent sodium chloride, IV. SD group animals were orally administrated 2.2mg/kg sodium diclofenac and DM horses received 1.1mg/kg dexamethazone, IV, 30 and 60 minutes before endotoxin infusion, respectively. TNF-alpha concentration was measured in serum and peritoneal fluid by toxicity assay using L929 lineage cells at 0, 1», 3 and 6 hours after LPS injection. Ninety minutes after endotoxemy induction, it was verified a significant increase of serum TNF-a concentration in horses from control group in relation to the basal values as well as results of horses from SD and DM groups. In peritoneal fluid, the measured concentrations were lower than those from TNF-a standard curve and difference among the groups was not verified (P>0.05)

Influencia de alelos y haplotipos del complejo principal de histocompatibilidad en la susceptibilidad a lupus eritematoso generalizado en la población mexicana / Influence of alleles and haplotypes of the main histocompatibility complex on the susceptibility to systemic lupus erythematosus in the Mexican population

A pesar de que se han asociado algunos alelos del complejo principal de histocompatibilidad (MHC) con la susceptibilidad a lupus eritematoso generalizado (LEG) en diferentes grupos étnicos, aún se desconoce la contribución de otros genes como los HSP70 y TNF-α en la susceptibilidad a esta enfermedad. Además, las asociaciones genéticas varían con base en el grupo étnico estudiado, lo que sugiere que la etnicidad tiene un papel importante en la susceptibilidad. En este estudio se analizaron las frecuencias de los genes HLA-DRB1, DQA1, DQB1, HSP70-2 y polimorfismos del promotor de TNF-α en 81 pacientes mexicanos con LEG. Como grupo control se estudiaron 99 sujetos mexicanos mestizos sanos. El haplotipo DRB1*0301- DQA1*0501-DQB1*0201 se asoció con LEG. El alelo DRB1*1501 se encontró con mayor frecuencia en los pacientes con LEG en comparación con los grupos control. Además se observó menor frecuencia de marcadores autóctonos como el alelo DRB1*0802 en los pacientes con LEG. Los alelos del MHC asociados con LEG son poco frecuentes en las poblaciones indígenas mexicanas. Esto podría sugerir que los marcadores de susceptibilidad a LEG se incorporaron a la población mestiza mexicana por flujo genético de poblaciones no indígenas.

HLA alelles with susceptibility to systemic lupus erythematosus (SLE) have been found in many ethnic groups. In addition, some neighboring genes such as TNF-alpha and HSP70, that may contribute to this disease have also been described. Interestingly some of the genetic associations differ among several ethnic groups, which might suggest that ethnicity plays an important role in the predisposition to SLE. In this study, we analyze gene frequencies of HLA-DRB1, DQA1, DQB1, HSP70-2 alelles and the polymorphism of TNF-alpha promoter region among 81 Mexican mestizo SLE patients. A control group of 99 healthy Mexican mestizos was included. We found that the HLA-DRB1*0301-DQA1*0501-DQB1*0201 haplotype was significantly increased in SLE patients compared to healthy controls (p=0.01, OR=2.97, IC 95%=1.18-7.68). The DRB1*1501 allele was more frequent among patients than among controls. A significantly decreased frequency of the HLA-DRB1*0802 alelle in SLE patients was also observed. Since the HLA alelles associated with SLE are uncommon in Mexican ethnic groups, we performed admixture estimates analysis and found that the incorporation of SLE susceptibility markers in Mexican mestizo groups might have come from genetic admixture with Caucasian populations.