Involvement of nitric oxide on the pathogenesis of irinotecan-induced intestinal mucositis: role of cytokines on inducible nitric oxide synthase activation.

PURPOSE: Intestinal mucositis and the closely associated diarrhea are common costly side effects of irinotecan. Cytokine modulators, such as thalidomide and pentoxifylline, are found capable of attenuating intestinal mucositis progression. Nitric oxide (NO) seems to be a key mediator of the antineoplastic drug toxicity. The aim of this study was to investigate the role of NO on the pathogenesis of intestinal mucositis, as well as the participation of cytokines upon inducible nitric oxide synthase (iNOS) expression in irinotecan-induced intestinal mucositis. METHODS: iNOS-knockout (iNOS(-/-)) and C57BL/6 (WT, wild type) animals (n = 5-6) were given either saline or irinotecan (60 mg/kg i.p for 4 days), with or without pretreatment with aminoguanidine (50 mg/kg s.c.), thalidomide (60 mg/kg s.c), infliximab (5 mg/kg i.v.), or pentoxifylline (1.7 mg/kg s.c). On day 5, diarrhea was assessed, and following euthanasia, proximal intestinal samples were obtained for myeloperoxidase (MPO) and iNOS activity, morphometric analysis, western blot and immunohistochemistry to iNOS, cytokine dosage, and for in vitro evaluation of gut contractility. RESULTS: Irinotecan induced severe diarrhea and intestinal smooth muscle over-contractility, accompanied with histopathological changes. Additionally, increased MPO and iNOS activity and iNOS immunoexpression were found in WT animals treated with irinotecan. The rise in MPO, smooth muscle over-contractility, and diarrhea were abrogated in aminoguanidine-treated and iNOS(-/-) mice. Moreover, through western blot, we verified that infliximab and pentoxifylline significantly inhibited irinotecan-induced iNOS expression. In addition, cytokine concentration was found only partially decreased in irinotecan-treated iNOS(-/-) mice when compared with wild-type animals that were given irinotecan. CONCLUSIONS: This study suggests a role of nitric oxide in the pathogenesis of irinotecan-induced intestinal mucositis and also provides evidence for the participation of cytokines on iNOS induction.

Associação entre dislipidemia e excesso de peso de crianças e adolescentesatendidos em uma unidade de saúde / Association between dyslipidemia and excess weight in children and adolescents attended in a health care center / Asociación entre dislipidemia y sobrepeso en niños y adolescentes atendidos en un centro de salud

A dislipidemia e o excesso de peso em crianças e adolescentes ocasionam sérios problemas com alto risco para as doenças cardiovasculares. Este artigo tem como objetivo avaliar a associação entre dislipidemia e grau de excesso de peso em crianças e adolescentes. Trata-se de um estudo transversal com abordagem quantitativa. Foram avaliadas 62 crianças e adolescentes de 7 a 19 anos, com excesso de peso, atendidos em um centro de saúde localizado em Fortaleza, Ceará. O grau de excesso de peso foi determinado pelo índice de massa corporal, admitindo-se duas categorias mediante os pontos de corte para idade e sexo: sobrepeso (maior ou igual percentil 85 e menor que 95) e obesidade (maior ou igual percentil 95). Foram realizadas dosagens séricas de colesterol total, LDL-colesterol, HDLcolesterol e triglicerídeos. Os valores foram interpretados como normais ou alterados, segundo os critérios da Sociedade Brasileira de Cardiologia. A distribuição do grupo quanto ao grau de excesso de peso foi similar, havendo mais crianças obesas do que adolescentes (p igual 0,044). A prevalência de dislipidemia foi alta (66,1por cento), sendo detectados, em todas as frações lipídicas, menores percentuais de obesos com valores desejáveis, embora com significância estatística apenas para triglicerídeos. Conclui-se que houve associação entre a trigliceridemia e grau de excesso de peso, evidenciando que, na faixa etária pesquisada, o sobrepeso já acarreta um perfil lipídico de risco.

Dyslipidemia and excess weight in children and adolescents cause serious problems with a high risk for cardiovascular disease. The purpose of this study was to evaluate the degree of association between dyslipidemia and excessive weight among children and teenagers. This was a cross-sectional study with a quantitative approach. Sixty-two patients, with ages from 7 to 19 yearsold, all with excessive weight, seen at a health care center in the Brazilian city of Fortaleza, Ceara, were evaluated. The degree of excessive weight was determined by the body mass index, and two categories were admitted by cut-off points for age and sex: overweight (greater than or equal percentil 85 and less than 95) and obesity (greater than or equal percentil 95). Serum dosages of total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides were taken. The values obtained were interpreted as ônormalõ or ôaltered,õ according to criteria of the Brazilian Society of Cardiology. The distribution of the group according to the degree of weight excess was similar, but there were more obese children than adolescents (p equal 0.044). The prevalence of dyslipidemia was high (66.1percent), but in all lipid fractions there were fewer percentages of obesity with desirable values in comparison with the individuals who were overweight, although the statistical significance was only for triglycerides. It was concluded that there was an association between dyslipidemia and the degree of excess weight among the studied group, indicating that, in this age range, excessive weight already causes a lipid-risk profile.

La dislipidemia y sobrepeso en niños y adolescentes causan problemas graves con alto riesgo de enfermedades cardiovasculares. El objetivo de este estudio fue evaluar la asociación entre dislipidemia y el grado de exceso de peso en niños y adolescentes. Se trata de un estudio transversal con un enfoque cuantitativo. Fueron evaluadas 62 niños y adolescentes de 7 a 19 años de edad, con exceso de peso, atendidos en un centro de atención de la salud en la ciudad de Fortaleza, Ceará. El grado de exceso de peso fue determinado por el índice de masa corporal, y dos categorías fueron admitidos mediante los puntos de corte para edad y sexo: sobrepeso (mayor o igual percentil 85 y menos que 95) y obesidad (percentil mayor o igual 95). Fueron tomadas dosificaciones séricas de colesterol total, LDL-colesterol, HDL-colesterol y triglicéridos. Los valores obtenidos fueron interpretados como normales o alterados, de acuerdo con los criterios de la Sociedad Brasileña de Cardiología. La distribución de los grupos según el grado de exceso de peso fue similar, habiendo más niños obesos de que adolescentes (p igual 0,044). La prevalencia de la dislipidemia fue elevada (66,1por ciento), y fue detectada en todas las fracciones de lípido menor porcentaje de pacientes obesos con valores deseables, aunque con significancia estadística sólo para los triglicéridos. Se concluye que hubo asociación entre la dislipidemia y el grado de exceso de peso entre el grupo estudiado, lo que indica que, en este rango de edad, el sobrepeso ya causa un perfil de lípido de riesgo.

Role of cytokines (TNF-alpha, IL-1beta and KC) in the pathogenesis of CPT-11-induced intestinal mucositis in mice: effect of pentoxifylline and thalidomide.

INTRODUCTION: Irinotecan (CPT-11) is an inhibitor of DNA topoisomerase I and is clinically effective against several cancers. A major toxic effect of CPT-11 is delayed diarrhea; however, the exact mechanism by which the drug induces diarrhea has not been established. PURPOSE: Elucidate the mechanisms of induction of delayed diarrhea and determine the effects of the cytokine production inhibitor pentoxifylline (PTX) and thalidomide (TLD) in the experimental model of intestinal mucositis, induced by CPT-11. MATERIALS AND METHODS: Intestinal mucositis was induced in male Swiss mice by intraperitoneal administration of CPT-11 (75 mg/kg) daily for 4 days. Animals received subcutaneous PTX (1.7, 5 and 15 mg/kg) or TLD (15, 30, 60 mg/kg) or 0.5 ml of saline daily for 5 and 7 days, starting 1 day before the first CPT-11 injection. The incidence of delayed diarrhea was monitored by scores and the animals were sacrificed on the 5th and 7th experimental day for histological analysis, immunohistochemistry for TNF-alpha and assay of myeloperoxidase (MPO) activity, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and KC ELISA. RESULTS: CPT-11 caused significant diarrhea, histopathological alterations (inflammatory cell infiltration, loss of crypt architecture and villus shortening) and increased intestinal tissue MPO activity, TNF-alpha, IL-1beta and KC level and TNF-alpha immuno-staining. PTX inhibited delayed diarrhea of mice submitted to intestinal mucositis and reduced histopathological damage, intestinal MPO activity, tissue level of TNF-alpha, IL-1beta and KC and TNF-alpha immuno-staining. TLD significantly reduced the lesions induced by CPT-11 in intestinal mucosa, decreased MPO activity, TNF-alpha tissue level and TNF-alpha immuno-staining, but did not reduce the severity of diarrhea. CONCLUSION: These results suggest an important role of TNF-alpha, IL-1beta and KC in the pathogenesis of intestinal mucositis induced by CPT-11.