RESUMO
High-density lipoprotein (HDL) has been found to neutralize LPS activity in vitro and in animals in vivo. We sought to determine the effects of reconstituted HDL (rHDL) on LPS responsiveness in humans in a double-blind, randomized, placebo-controlled, cross-over study. rHDL, given as a 4-h infusion at 40 mg/kg starting 3.5 h before endotoxin challenge (4 ng/kg), reduced flu-like symptoms during endotoxemia, but did not influence the febrile response. rHDL potently reduced the endotoxin-induced release of TNF, IL-6, and IL-8, while only modestly attenuating the secretion of proinflammatory cytokine inhibitors IL-1ra, soluble TNF receptors and IL-10. In addition, rHDL attenuated LPS-induced changes in leukocyte counts and the enhanced expression of CD11b/CD18 on granulocytes. Importantly, rHDL infusion per se, before LPS administration, was associated with a downregulation of CD14, the main LPS receptor, on monocytes. This effect was biologically relevant, since monocytes isolated from rHDL-treated whole blood showed reduced expression of CD14 and diminished TNF production upon stimulation with LPS. These results suggest that rHDL may inhibit LPS effects in humans in vivo not only by binding and neutralizing LPS but also by reducing CD14 expression on monocytes.
Assuntos
Apolipoproteína A-I/metabolismo , Apolipoproteína A-I/uso terapêutico , Colesterol/metabolismo , Colesterol/uso terapêutico , Endotoxemia/tratamento farmacológico , Endotoxinas/metabolismo , Inflamação/tratamento farmacológico , Lipopolissacarídeos/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas HDL/uso terapêutico , Fosfatidilcolinas/metabolismo , Fosfatidilcolinas/uso terapêutico , Adulto , Antígenos CD , Estudos Cross-Over , Método Duplo-Cego , Granulócitos , Humanos , Infusões Intravenosas , Interleucina-6/sangue , Interleucina-8/sangue , Contagem de Leucócitos , Masculino , Monócitos , Náusea , Dor , Placebos , Estremecimento , Fatores de Tempo , Fator de Necrose Tumoral alfa/análise , VômitoRESUMO
High-density lipoproteins (HDL) can bind and neutralize lipopolysaccharides (LPS) in vitro and in vivo. HDL can also affect fibrinolytic activity and can directly influence platelet function by reducing platelet aggregation. In this study, the effects of reconstituted HDL (rHDL) on LPS-induced coagulation, fibrinolysis and platelet activation in humans were investigated. In a double-blind, randomized, placebo-controlled, cross-over study, eight healthy male volunteers were injected with LPS (4 ng/kg) on two occasions, once in conjunction with rHDL (40 mg/kg, given as a 4 h infusion starting 3.5 h prior to LPS injection), and once in conjunction with placebo. rHDL significantly reduced LPS-induced activation of coagulation (plasma levels of prothrombin fragment F1 + 2) and fibrinolysis (plasma levels of tissue type plasminogen activator antigen, t-PA). No effect was observed on LPS-induced inhibition of the fibrinolytic pathway (PAI-1) or on the transient thrombocytopenia elicited by LPS. Furthermore, rHDL treatment significantly enhanced the inhibition of collagen-stimulated inhibition of platelet aggregation during endotoxemia, but had no such effect on arachidonate-stimulated platelet aggregation. rHDL treatment per se also reduced collagen-induced platelet aggregation. These results indicate that rHDL modifies the procoagulant state associated with endotoxemia.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Endotoxemia/tratamento farmacológico , Fibrinólise/efeitos dos fármacos , Lipopolissacarídeos/antagonistas & inibidores , Lipoproteínas HDL/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Adulto , Estudos Cross-Over , Citocinas/sangue , Método Duplo-Cego , Endotoxemia/sangue , Endotoxinas/efeitos adversos , Endotoxinas/antagonistas & inibidores , Humanos , Lipoproteínas HDL/uso terapêutico , Masculino , Fragmentos de Peptídeos/análise , Inibidor 1 de Ativador de Plasminogênio/análise , Agregação Plaquetária , Protrombina/análiseRESUMO
PURPOSE: In a population-based data registry of children with ALL, initial prognostic factors were analyzed with regard to long-term event-free survival. PATIENTS AND METHODS: From 1976-1991 the Swiss Pediatric Oncology Group (SPOG) observed 610 children and adolescents who were diagnosed with ALL before the age of 15 years, and who were prospectively treated according to different study protocols. Immunophenotyping of B-progenitor- or T-lineage ALL was possible in 573 children. Leucocyte count, age, and sex were compared with regard to immunophenotype of lymphoid cells and to event-free survival on Kaplan Meier curves by statistical analyses including multivariate analysis and the Cox regression backward elimination test. RESULTS: Of the 573 patients who were immunophenotyped 86.4% had B-progenitor ALL and 13.6% T-lineage ALL. The differences between B-progenitor ALL and T-lineage ALL with respect to initial white blood cell count, age and gender were significant. A comparison of event-free survival in children with B-progenitor ALL versus T-lineage ALL revealed significant differences in boys (p < 0.001) but not in girls (p = 0.183). Statistical tests showed gender to be an independent risk factor. CONCLUSION: The long-term outcome following identical treatment of both genders was significantly better in girls with T-lineage ALL than in boys. Girls with T-lineage ALL, but not boys with T-lineage ALL, had a prognostic outcome similar to children with B-progenitor ALL.
Assuntos
Linfócitos B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Células-Tronco/imunologia , Linfócitos T/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Prognóstico , Fatores Sexuais , Análise de Sobrevida , Fatores de TempoRESUMO
The incidence of isolated CNS-relapse in the SPOG ALL studies 1976-1986 was analyzed and the prophylaxis of meningosis leucaemica of the different studies was compared. In the SPOG ALL high-risk study 1979-1983, the incidence of isolated CNS-relapse was significantly higher (17/71, 24%) than in the other studies. In this period, radiotherapy was omitted and the prophylactic treatment consisted only of moderately high doses of intravenous methotrexate and intrathecal methotrexate. In other studies, it was shown that the prophylactic combination of CNS-radiotherapy and intrathecal methotrexate, or the periodic administration of combined intrathecal chemotherapy alone, during the whole therapy of 2 1/2 years, produced comparably good results. The prophylaxis with the combined intrathecal chemotherapy was less neurotoxic and allowed the use of a curative radiotherapy in case of a CNS-relapse.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças do Sistema Nervoso Central , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/radioterapia , Criança , Pré-Escolar , Terapia Combinada , Citarabina/administração & dosagem , Feminino , Humanos , Hidrocortisona/administração & dosagem , Lactente , Injeções Intravenosas , Injeções Espinhais , Masculino , Metotrexato/administração & dosagem , Estudos Multicêntricos como Assunto , Recidiva Local de Neoplasia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Estudos Retrospectivos , SuíçaRESUMO
Of 54 children with acute lymphoblastic leukemia (ALL) and first hematological recurrence observed between 1985 and 1989, 31 relapsed while still on treatment and 23 after cessation of therapy. Of the former, only one survived. Of the latter, 11 children survived after a minimum follow-up of 25 months. During the same period, a first isolated testicular relapse was observed in nine boys, of whom six survived, and an isolated CNS relapse in eight patients, of whom three survived. As a rule, survivors of a bone marrow or testicular relapse were doing well while those surviving a CNS relapse had considerable neuropsychological sequelae. These results, compared with those of two preceding studies, suggest that with intensification of front-line treatments, it becomes more difficult to rescue children who relapse, particularly those with a bone marrow relapse while on therapy.
Assuntos
Doenças da Medula Óssea/terapia , Neoplasias do Sistema Nervoso Central/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Neoplasias Testiculares/terapia , Adolescente , Doenças da Medula Óssea/mortalidade , Neoplasias do Sistema Nervoso Central/mortalidade , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Qualidade de Vida , Recidiva , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias Testiculares/mortalidade , Resultado do TratamentoRESUMO
Of 656 patients with ALL (all types) diagnosed in Switzerland during 4 consecutive 4-year periods (1976-1979, 1980-1983, 1984-1987, 1988-1991), 507 were officially registered on protocols ("study" patients) while 149 were not ("nonstudy" patients). The mean incidence of 3.8/100,000 children < 15 years/year is higher than reported for other Western countries. Evidence is presented suggesting that the 656 patients represent only approximately 90% of all children with ALL residing in Switzerland, indicating that the true incidence of ALL might even be higher. The fraction of "nonstudy" patients fell from 40% (1976-1979) to 15% (1984-1987). The rate of survival at 4 years of all patients with ALL ("study" and "nonstudy") increased by 17% during the three consecutive periods 1976-1979, 1980-1983, and 1984-1987. As expected, a higher increase (20%) was observed in "study" patients and a statistically nonsignificant lower one (10%) in "nonstudy" patients.