排序方式: 共有75条查询结果,搜索用时 140 毫秒
71.
Roger D. Kouyos C. Jessica E. Metcalf Ruthie Birger Eili Y. Klein Pia Abel zur Wiesch Peter Ankomah Nimalan Arinaminpathy Tiffany L. Bogich Sebastian Bonhoeffer Charles Brower Geoffrey Chi-Johnston Ted Cohen Troy Day Bryan Greenhouse Silvie Huijben Joshua Metlay Nicole Mideo Laura C. Pollitt Andrew F. Read David L. Smith Claire Standley Nina Wale Bryan Grenfell 《Proceedings. Biological sciences / The Royal Society》2014,281(1794)
The evolution of resistance to antimicrobial chemotherapy is a major and growing
cause of human mortality and morbidity. Comparatively little attention has been paid
to how different patient treatment strategies shape the evolution of resistance. In
particular, it is not clear whether treating individual patients aggressively with
high drug dosages and long treatment durations, or moderately with low dosages and
short durations can better prevent the evolution and spread of drug resistance. Here,
we summarize the very limited available empirical evidence across different pathogens
and provide a conceptual framework describing the information required to effectively
manage drug pressure to minimize resistance evolution. 相似文献
72.
Silvie Huijben William A. Nelson Andrew R. Wargo Derek G. Sim Damien R. Drew Andrew F. Read 《Evolution; international journal of organic evolution》2010,64(10):2952-2968
A major determinant of the rate at which drug‐resistant malaria parasites spread through a population is the ecology of resistant and sensitive parasites sharing the same host. Drug treatment can significantly alter this ecology by removing the drug‐sensitive parasites, leading to competitive release of resistant parasites. Here, we test the hypothesis that the spread of resistance can be slowed by reducing drug treatment and hence restricting competitive release. Using the rodent malaria model Plasmodium chabaudi, we found that low‐dose chemotherapy did reduce competitive release. A higher drug dose regimen exerted stronger positive selection on resistant parasites for no detectable clinical gain. We estimated instantaneous selection coefficients throughout the course of replicate infections to analyze the temporal pattern of the strength and direction of within‐host selection. The strength of selection on resistance varied through the course of infections, even in untreated infections, but increased immediately following drug treatment, particularly in the high‐dose groups. Resistance remained under positive selection for much longer than expected from the half life of the drug. Although there are many differences between mice and people, our data do raise the question whether the aggressive treatment regimens aimed at complete parasite clearance are the best resistance‐management strategies for humans. 相似文献
73.
74.
Frank A.E. Kruyt Linda J. van der Veer Silvie Mader Christina E. van den Brink Alie Feijen Luigi J.C. Jonk Wiebe Kruijer Paul T. van der Saag 《Differentiation; research in biological diversity》1992,49(1):27-37
P19 embryonal carcinoma (EC) cells differentiate when treated with retinoic acid (RA). The P19 EC-derived mutant cell line RAC65 is resistant to the differentiation-inducing activity of RA. We show that these cells express a truncated retinoic acid receptor alpha(mRAR alpha-RAC65), probably due to the integration of a transposon-like element in the RAR alpha gene. This receptor lacks 71 C-terminal amino acids and terminates in the ligand-binding domain. In CAT assays in RAC65 cells, mRAR alpha-RAC65 fails to trans-activate the RAR beta promoter, which contains a RA-response element. In wild-type P19 EC cells mRAR alpha-RAC65 functions as a dominant-negative repressor of RA-induced RAR beta activation. Gel retardation assays demonstrate that mRAR alpha-RAC65 is still able to bind to the RA-response element of the RAR beta promoter, indicating that competition with functional RARs for the same binding site leads to the observed dominant-negative effect. In addition, in two RAC65 clones in which wild-type hRAR alpha was stably transfected RA-sensitivity was restored and in one RAR beta expression could be induced by RA. Taken together, these data show that the primary cause of RA-resistance of RAC65 cells is the expression of a defective RAR alpha, which prevents the trans-activation of RA-responsive genes and results in a loss of the ability to differentiate. 相似文献
75.
Silvie Huijben Andrew S. Bell Derek G. Sim Danielle Tomasello Nicole Mideo Troy Day Andrew F. Read 《PLoS pathogens》2013,9(9)
Drug resistant pathogens are one of the key public health challenges of the 21st century. There is a widespread belief that resistance is best managed by using drugs to rapidly eliminate target pathogens from patients so as to minimize the probability that pathogens acquire resistance de novo. Yet strong drug pressure imposes intense selection in favor of resistance through alleviation of competition with wild-type populations. Aggressive chemotherapy thus generates opposing evolutionary forces which together determine the rate of drug resistance emergence. Identifying treatment regimens which best retard resistance evolution while maximizing health gains and minimizing disease transmission requires empirical analysis of resistance evolution in vivo in conjunction with measures of clinical outcomes and infectiousness. Using rodent malaria in laboratory mice, we found that less aggressive chemotherapeutic regimens substantially reduced the probability of onward transmission of resistance (by >150-fold), without compromising health outcomes. Our experiments suggest that there may be cases where resistance evolution can be managed more effectively with treatment regimens other than those which reduce pathogen burdens as fast as possible. 相似文献