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Mode of action of iron (III) chelators as antimalarials: II. Evidence for differential effects on parasite iron-dependent nucleic acid synthesis 总被引:1,自引:0,他引:1
Iron chelation treatment of red blood cells infected with Plasmodium falciparum selectively intervenes with iron-dependent metabolism of malaria parasites and inhibits their development. Highly permeant hydroxamate iron chelator RSFileum2 affects all parasite stages when cultures are continuously exposed to drug, but affects primarily ring stages when assessed for irreversible effects, ie, sustained inhibition remaining after drug removal. On the other hand, the hydrophilic and poorly permeant desferrioxamine (DFO) affects primarily trophozoite/schizont stages when tested either in the continuous mode or irreversible mode. Unlike parasites, mammalian cells subjected to similar drug treatment show complete growth recovery once drugs are removed. Our studies indicate that parasites display a limited capacity to recover from intracellular iron depletion evoked by iron chelators. Based on these findings we provide a working model in which the irreversible effects of RSFs on rings are explained by the absence of pathways for iron acquisition/utilization by early forms of parasites. Trophozoite/schizonts can partially recover from RSFileum2 treatments, but show no DNA synthesis following DFO treatment even after drug removal and iron replenishment by permeant iron carriers. At trophozoite stage, the parasite uses a limited pathway for refurnishing its iron-containing enzymes, thus overcoming iron deprivation caused by permeant RSFileum2, but not by DFO because this latter drug is not easily removable from parasites. Their DNA synthesis is blocked by the hydroxamate iron chelators probably by affecting synthesis of ribonucleotide reductase (RNRase). Presumably in parasites, prolonged repression of the enzyme leads also to irreversible loss of activity. The action profiles of RSFileum2 and DFO presented in this study have implications for improved chemotherapeutic performance by combined drug treatment and future drug design based on specific intervention at parasite DNA synthesis. 相似文献
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V Fuster R L Frye D C Connolly M A Danielson L R Elveback L T Kurland 《Heart (British Cardiac Society)》1975,37(12):1250-1255
Coronary arteriography in 300 patients within one year of onset of symptoms of coronary arterial disease revealed already severe anatomical coronary disease in three patient groups: those with angina pectoris alone (164 patients), with subendocardial myocardial infarction (63 patients), and with transmural myocardial infarction (73 patients). The number of vessels diseased (larger than or equal to 50% obstruction), distribution of obstruction, and degree of stenosis were similar in the three groups. However, total occlusion of at least one artery was much more common in transmural myocardial infarction and in subendocardial myocardial infarction with elevation of enzyme levels. We suggest that such occlusions occurred at the time of the infarction. Similarities in coronary anatomy between patient subgroups with angina (on exercise or at rest and nocturnal) indicate that factors other than coronary anatomy intervene in precipitating the different types of angina. Vessel disease was not related to smoking, hyperlipidaemia, or hypertension but coronary disease was manifest earlier in life in smokers or those with hyperlipidaemia. 相似文献
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Kapadia F Frye V Bonner S Emmanuel PJ Samples CL Latka MH 《AIDS education and prevention》2012,24(1):27-40
We investigated the association between perceived peer norms and safer sexual behaviors among substance using Latino youth. Between 2005 and 2006, cross-sectional data were collected from 92 Latino adolescents recruited from clinic- and community-based settings in two U.S. cities. Separate multivariate logistic regression models were used to assess the relationship between perceived peer norms around safer sex and two different outcomes: consistent condom use and multiple sexual partnerships. Among these participants, perceived peer norms encouraging safer sex were associated with consistent condom use even after controlling for individual- and partner-related factors. Perceived peer norms supporting safer sex were inversely associated with recently having two or more sexual partners after controlling for demographic characteristics. Perceived peer norms around safer sexual behavior contribute to a lower likelihood of engaging in two HIV/STI risk behaviors: inconsistent condom use and multiple partnering. These findings suggest that further development of peer-based interventions for Latino youth is warranted. 相似文献
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Robert M. Post Lori Altshuler Gabriele Leverich Willem Nolen Ralph Kupka Heinz Grunze Mark Frye Trisha Suppes Sue McElroy Paul Keck Mike Rowe 《Psychiatry research》2013
Considerable data suggest that compared to some European countries, in the U.S. there are more childhood onset bipolar disorders, more adverse courses of illness, and greater treatment resistance. Psychosocial variables related to these findings have not been adequately explored. Therefore we analyzed psychosocial stressors in three time domains: childhood; the year prior to illness Onset; and the Last Episode from questionnaires in 968 outpatients (mean age 41) with bipolar I or II disorder; 676 from four sites in the U.S. and 292 from three in the Netherlands and Germany (abbreviated here as Europe). Compared to the Europeans, those from the U.S. had significantly more stressors in childhood and prior to the last episode. Stressors prior to the last episode were related to: childhood stressors; an earlier age at illness onset; anxiety and substance abuse comorbidity; lower income; both parents having an affective illness; and feeling more stigma. These data suggest a greater prevalence of adverse life events in childhood and over the course of bipolar illness in the U.S. compared to the Netherlands and Germany. Clinical, therapeutic, and public health approaches to these illness-relevant stressors require further exploration. 相似文献
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Aimen Kasasbeh Osama A. Abulseoud Joseph Y. Matsumoto Squire M. Stead Stephan J. Goerss Bryan T. Klassen John Huston Hoon-Ki Min Kendall H. Lee Mark A. Frye 《Journal of clinical neuroscience》2013,20(11):1520-1526
Deep brain stimulation (DBS) has emerged as a viable therapy for Parkinson’s disease (PD). The impact of subthalamic nucleus (STN) lead placement (lateral versus medial) on motor outcome, however, has not been systematically evaluated. Forty-eight patients with PD underwent STN-DBS surgery and were evaluated postoperatively for 48 weeks for motor improvement as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) part III (standardized motor examination) and levodopa equivalent daily dose (LEDD). Postoperative MRI was used to identify the location of the active stimulating contact and motor outcome was analyzed. STN-DBS was associated with significant improvement in motor outcome as determined by a reduction in the UPDRS part III subscore from 34.44 ± 1.29 at baseline to 18.76 ± 1.06 at end visit (p < 0.0001) and a reduction in LEDD from 1721 ± 152 mg/day at baseline to 1134 ± 119 mg/day at end visit (p = 0.0024). Patients with stimulating contacts in the medial STN compared to the lateral STN did not demonstrate any significant differences in motor outcome (UPDRS, p = 0.5811; LEDD, p = 0.7341). No significant differences were found in motor outcome between patients with STN stimulation compared to stimulation of surrounding fiber tracts (p = 0.80). No significant difference in stimulation voltage was noted with respect to lead location. Our study did not find a significant effect for the location of active contact and motor outcome neither within the subregions of the STN nor between the STN and surrounding fibers. Further research is needed to better understand the neurophysiological basis for these results. 相似文献