Endotoxin tolerance: selective alterations in gene expression and protection against lymphocyte death.

Extensive lymphocyte apoptosis may be an important cause of immune suppression in sepsis. Here we investigated the effect of LPS tolerance on lymphocyte apoptosis in an experimental model of polymicrobial infection. Tolerance was induced by the injection of lipopolysaccharide (1.0mg/kg/subcutaneously) once a day for 5 days. Macroarray analysis of mRNA isolated from T-(CD4) lymphocytes was used to identify genes that are differentially expressed during LPS tolerance. In addition, assessment of the expression of apoptosis-associated lymphocyte gene products and apoptotic events was performed on the 8th day; 6h after the terminal challenge with polymicrobial infection or high-dose LPS administration. Survival studies with polymicrobial infection were also conducted. LPS tolerance induced a broad reprogramming of cell death pathways, including a suppression of receptor-mediated and mitochondrial apoptotic pathways, inflammatory caspases, alternate apoptotic pathways, as well as reduced expression of genes involved in necrosis. These alterations led to a marked resistance of lymphocytes against cell death during the subsequent period of sepsis. In addition, LPS tolerance produced an increased differentiation of T-lymphocytes to T(H)1 and T(H)2, with a T(H)1 differentiation predominance. Thus, in the current study we provide an evidence for a marked reprogramming of gene expression of multiple cell death pathways during LPS tolerance. These alterations may play a significant role in the observed protection of the animals from a subsequent lethal polymicrobial sepsis challenge.

Tolerância à endotoxina em camundongos Balb/c / Endotoxin tolerance in Balb/c mice

A fisiopatologia da sepse grave foi estudada no modelo experimental de tolerância induzida com 1 mg/kg de LPS em camundongos Balb/c. Os animais tolerantes a LPS apresentaram síndrome de animal doente, menor produção de MIP-2, TNF-, IL-1, IL-10 séricas e um aumento de células tronco pluripotentes, linfócitos T auxiliares e linfócitos B. Além disso, foi aumentada a quantidade de todos os linfócitos T com citocinas pró-inflamatórias e de linfócitos T auxiliares com citocinas antiinflamatórias. O estado de tolerância protegeu os animais, mas alterou citologia e o padrão de expressão de citocinas esplênicas / Sepsisis the development of the systemic inflammatory responses syndrome in the presence of infection. The severe sepsis is associated with mortality rate from 45-60 por cento. Endotoxin is external wall of gram-negative bacteria and plays a key role in sepsis pathogenesis...

Gestational trophoblastic disease: one more risk in adolescent pregnancy.

BACKGROUND: An evaluation of the performance of a Referral Center in the diagnosis, treatment and follow up of adolescents with gestational trophoblastic disease. METHODS: In a 13-year prospective cohort study, between March 1987 and March 2000, 124 adolescents with gestational trophoblastic disease were followed up and/or treated by a multidisciplinary team. Adolescents underwent strict clinical and laboratory control after mole evacuation to guarantee adhesion to follow up, early diagnosis, and prompt treatment of persistent disease. The Student-Fischer t-test and the chi-square test were used for the statistic analysis of the results. RESULTS: Adolescents represented 21.3% of the 583 patients with gestational trophoblastic disease: 102 (82.3%) had uncomplicated hydatidiform moles, and 22 (17.7%) underwent chemotherapy for persistent gestational trophoblastic disease or a gestational trophoblastic tumor. Complications were diagnosed earlier (p < 0.001) in patients managed and treated at the referral center. Of the adolescents with complications, 81.8% were low risk, 54.5% were at the International Federation of Gynecology and Obstetrics stage I, and 90.9% were treated with chemotherapy only. Time to remission and follow up were shorter for uncomplicated hydatidiform moles (9.8 +/- 3.4 weeks and 8.8 +/- 1.8 months, respectively) than for persistent disease (16.2 +/- 5.8 weeks and 45 +/- 24.5 months, respectively). Adhesion to follow up was similar in the two groups (84.2% and 91.8%). To this date, 50% of the adolescents have had one or more gestations, and 82% of these pregnancies were normal. CONCLUSIONS: Adolescents comprise approximately 20% of all gestational trophoblastic disease patients and have high adhesion to follow up. The disease did not affect their reproductive capacity, and chances of a normal subsequent gestation were high.

Xenoestrogênios: o exemplo do bisfenol-A / Xenoestrogens: the example of bisphenol-A

Evidências acumuladas indicam que a saúde dos seres humanos, animais e espécies selvagens pode sofrer conseqüências adversas da exposição a produtos químicos presentes no meio ambiente e que interagem com o sistema endócrino, tais como bifenilas policloradas, dioxinas, estrogênios de ocorrência natural e sintéticos. Por outro lado, permanecem incertezas científicas com respeito aos dados relatados e, também, quanto à hipótese de haver níveis suficientemente elevados de exposição a estes agentes, a ponto de exercer efeito estrogênico generalizado sobre a população. Este trabalho revisa os principais tópicos relacionados a um dos xenoestrogênios que vem sendo mais recentemente estudado: o Bisfenol A (BFA), um monômero de plástico policarbonato, com pouca homologia estrutural com o estradiol (E 2 ) mas semelhante ao dietilestilbestrol (DES), hexestriol e componente bisfenólico do tamoxifeno. O presente trabalho comenta e analisa criticamente os efeitos do BFA sobre o trato reprodutivo e função lactotrófica em animais de experimentação, à luz das informações disponíveis e experiência do grupo nesta área, e recomenda algumas necessidades de pesquisa.