Hepatic Schistosoma mansoni periovular granulomas undergo changes in size, cellular composition and appearance with time. This phenomenom, known as "immunological modulation", has been thought to reflect host immunological status. However, as modulation has not been observed outside the liver, participation of local factors, hitherto little considered, seems crucial. Components of the extracellular matrix of periovular granulomas of the mouse were particularly studied in three different organs (liver, lung and intestine) and during three periods of infection time (acute, intermediate and chronic) by means of histological, biochemical and imunofluorescence techniques, while quantitative data were evaluated by computerized morphometry, in order to investigate participation of local factors in granuloma modulation. Results confirmed modulation as a exclusively hepatic phenomenom, since pulmonary and intestinal granulomas, formed around mature eggs, did not change size and appearance with time. The matricial components which were investigated (Type I, III and IV collagens, fibronectin, laminin, proteoglycans and elastin) were found in all granulomas and in all organs examined. However, their presence was much more prominent in the liver. Elastin was only found in hepatic granulomas of chronic infection. The large amount of extracellular matrix components found in hepatic granulomas was the main change responsible for the morphological aspects of modulation. Therefore, the peculiar environment of the liver ultimately determines the changes identified in schistosomal granuloma as "modulation".

INTRODUÇÃO: Sugere-se a existência de uma faixa de concentração ótima para os níveis sangüíneos da nortriptilina, acima e abaixo da qual os pacientes não respondem ao tratamento ou o fazem pobremente. MÉTODOS: Realizamos metanálise dos estudos publicados com o propósito de verificar a existência de uma faixa de concentração sangüínea ótima (janela terapêutica) para os pacientes deprimidos tratados com nortriptilina. A busca através do MEDLINE envolvendo os anos de 1970 a 1999 foi realizada com o objetivo de identificar artigos originais e de revisão. Dados sobre níveis sangüíneos e percentagem de melhora foram obtidos. Foram realizadas análises uni e multivariadas para a comparação dos dados. Avaliamos possíveis variáveis de confusão como: período de pré-tratamento, ambiente (hospitalar ou ambulatorial) e duração do tratamento. RESULTADOS: Dos 22 estudos publicados que foram identificados, apenas seis que forneceram os dados individuais dos pacientes foram incluídos. Encontramos uma faixa de concentração ótima para a nortriptilina (OR = 2,25, IC 95% = 1,15 a 4,39, p = 0,02). CONCLUSÕES: É possível que exista uma associação de tipo bifásico entre as concentrações de nortriptilina e a resposta clínica, com uma janela terapêutica entre 46 e 236 ng/ml.

INTRODUCTION: An optimum range has been suggested for nortriptyline blood levels, above or below which patients respond poorly or do not respond at all to treatment. METHODS: A meta-analysis of published studies was performed to verify the existence of an optimal blood concentration range or therapeutic window in nortriptyline-treated depression patients. A MEDLINE search through the years 1970-1999 was carried out to identify original papers and review articles. Data concerning blood levels and percentage improvement were obtained concerning all included pacients. Univariate and multivariate analyses were performed for data comparison. Possible confounding variables, such as pre-treatment, setting (in or outpatients), and duration of treatment were also evaluated. RESULTS: From the 22 published studies found, only six of them with patients' individual data were included. We found an optimal range for nortriptyline concentrations (OR= 2.25, 95% CI = 1.15 to 4.39, p= 0.02). CONCLUSIONS: There may be a biphasic relationship of efficacy to plasma concentrations of nortriptyline, with a therapeutic window between 46 to 236 ng/ml.