PubMed · 9048045
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J Mimaya. 1996. [AIDS].. https://pubmed.ncbi.nlm.nih.gov/9048045/
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Recurrent events are frequently encountered in clinical trials when individuals may experience an event more than once. Examples are common in medical research, including infectious episodes, myocardial infarctions and hospital admissions. However, when only the first event is considered, there is a loss of information. Furthermore, the analysis of recurrent events is complicated by the dependence of the related failure times of each subject, that is, the occurrence of an event influences the risk of other events. Thus, naive statistical methods that consider recurrent events as independent observations will produce misleading conclusions. We recommend the use of a marginal hazards model that is derived from the multivariate generalization of the Cox proportional hazards model. This marginal model allows estimation of the relative risk of recurrence in clinical trials, taking into account the dependence between the recurring events of a same individual without explicit modelling. Two applications are used to compare the results of the marginal model analysis with those of usual methods: (i) a placebo-controlled randomized clinical trial performed to evaluate the efficacy of an immunostimulant in the prevention of recurrences of infectious rhinitis in adults; (ii) a randomized clinical trial comparing transfusions of plasma rich in anti-HIV1 versus transfusions of seronegative plasma in the prevention of opportunist infections. To analyse recurrent events, usual methods are often irrelevant and the marginal model allows use of all the available information to accurately estimate the relative risk of recurrences. Moreover, it enables the estimation of the relative risk for each rank of recurrence.
DL-alpha-Difluoromethylornithine (DFMO) causes polyamines of the AIDS-associated opportunistic pathogen Pneumocystis carinii to diminish 15 times more rapidly than mammalian host cells. The proposed mechanism was that, unlike mammalian cells, P. carinii is unable to regulate polyamine catabolism when synthesis is blocked. To test this, the responses of the polyamine catabolic enzymes spermidine/spermine acetyltransferase (SSAT) and polyamine oxidase (PAO) were determined using a new high-performance liquid chromatography assay to measure the products of these enzymes. The specific activities in untreated Pneumocystis carinii were 1.78 +/- 0.5 pmol min(-1) mg protein(-1) for SSAT, similar to mammalian cells, and 6.42 +/- 0.8 pmol min(-1) mg protein(-1) for PAO, 19% of that of mammalian cells. DFMO treatment for 12 h caused reductions of only 11 and 4% in SSAT and PAO, respectively, despite polyamine reductions of 94, 96, and 90% for putrescine, spermidine, and spermine, respectively. The P. carinii SSAT K(m) value of 25 microM spermidine is 20% of that of mammalian cells, and the PAO K(m) value of 14 nM N(1)-acetylspermidine is 0.01% of that of mammalian cells. Acetylated polyamines continue to be lost from P. carinii even when exposed to DFMO. Collectively, these results support the hypothesis that P. carinii is unable to regulate polyamine catabolism.
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