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921.
Inhibitors of Leishmania mexicana CRK3 cyclin-dependent kinase: chemical library screen and antileishmanial activity 下载免费PDF全文
Grant KM Dunion MH Yardley V Skaltsounis AL Marko D Eisenbrand G Croft SL Meijer L Mottram JC 《Antimicrobial agents and chemotherapy》2004,48(8):3033-3042
The CRK3 cyclin-dependent kinase of Leishmania has been shown by genetic manipulation of the parasite to be essential for proliferation. We present data which demonstrate that chemical inhibition of CRK3 impairs the parasite's viability within macrophages, thus further validating CRK3 as a potential drug target. A microtiter plate-based histone H1 kinase assay was developed to screen CRK3 against a chemical library enriched for protein kinase inhibitors. Twenty-seven potent CRK3 inhibitors were discovered and screened against Leishmania donovani amastigotes in vitro. Sixteen of the CRK3 inhibitors displayed antileishmanial activity, with a 50% effective dose (ED50) of less than 10 microM. These compounds fell into four chemical classes: the 2,6,9-trisubstituted purines, including the C-2-alkynylated purines; the indirubins; the paullones; and derivatives of the nonspecific kinase inhibitor staurosporine. The paullones and staurosporine derivatives were toxic to macrophages. The 2,6,9-trisubstituted purines inhibited CRK3 in vitro, with 50% inhibitory concentrations ranging from high nanomolar to low micromolar concentrations. The most potent inhibitors of CRK3 (compounds 98/516 and 97/344) belonged to the indirubin class; the 50% inhibitory concentrations for these inhibitors were 16 and 47 nM, respectively, and the ED50s for these inhibitors were 5.8 and 7.6 microM, respectively. In culture, the indirubins caused growth arrest, a change in DNA content, and aberrant cell types, all consistent with the intracellular inhibition of a cyclin-dependent kinase and disruption of cell cycle control. Thus, use of chemical inhibitors supports genetic studies to confirm CRK3 as a validated drug target in Leishmania and provides pharmacophores for further drug development. 相似文献
922.
The impact of incontinence on health-related quality of life in a South Australian population sample 总被引:2,自引:0,他引:2
Avery JC Gill TK MacLennan AH Chittleborough CR Grant JF Taylor AW 《Australian and New Zealand journal of public health》2004,28(2):173-179
OBJECTIVE: To assess prevalence of incontinence in a South Australian representative population sample and compare the health-related quality-of-life impact of incontinence with other chronic conditions. METHOD: The 1998 South Australian Health Omnibus Survey interviewed 3,010 male and female respondents aged 15 to 97 years (response rate 70.2%). This representative population survey included questions to determine the prevalence of urinary (stress and urge), and anal (faecal and flatus) incontinence, and other chronic conditions. Respondents also completed the MOS SF-36 questionnaire. RESULTS: Self-reported prevalence of all types of incontinence was 26.0%. The prevalence of anal and urinary incontinence were 10.5% and 20.3% respectively, with 4.8% of respondents experiencing both. Univariate analysis found the prevalence of incontinence was statistically significantly higher among females, and those who were older, widowed, had no post-school education, and lower incomes. After adjusting for differences in age and sex, it was found that people with incontinence were significantly impaired across all dimensions of the SF-36, scoring in the lowest 42% of the population, compared with those people without incontinence. People with incontinence exhibited different SF-36 profiles to those with other chronic conditions. CONCLUSIONS: Incontinence is common in South Australia, affecting more than one-quarter of the population, particularly older women (56.2% for 60 years and over). The impact of incontinence on health-related quality of life is characteristically different to that demonstrated by other chronic conditions. IMPLICATIONS: In an ageing population, identification of the impact of incontinence is necessary to direct policy development and resource allocation to this area. 相似文献
923.
Mummery K Schofield G Caperchione C 《Australian and New Zealand journal of public health》2004,28(2):188-192
OBJECTIVE: The purpose of this study was to examine the dose-response relationship between physical activity and mental health, comparing two recommended levels of physical activity involvement. The two current physical activity recommendations used to study the dose-response relationships in a sample of older adults were 150 minutes per week and 420 minutes per week. METHOD: Data were collected on a sample (n=337) of independent living older adults ranging from 55 to 89 years of age (mean age 65.2 years) using a computer-assisted telephone interview (CATI) survey. Activity status was assessed using the Active Australia questionnaire, whereas health status was assessed using the SF-12 health survey questionnaire. RESULTS: Participants classed as moderately active (150-420 minutes per week) and highly active (>420 minutes per week) displayed significantly higher mental health status than those who were classified as inactive (<150 minutes per week) when controlling for physical health status. Further analysis failed to reveal any significant difference in mental health status between moderately and highly active participants. CONCLUSION: When controlling for the variability in mental health status relating to physical health, individuals meeting current guidelines of 150 minutes of physical activity per week displayed higher mental health than those who did not. Increased levels of activity showed no reliable increase in health status. IMPLICATIONS: The benefits of moderate levels of physical activity were supported for older adults. In terms of mental health, recent recommendations for increased amounts of daily activity were not supported. 相似文献
924.
Relation between physical activity and energy expenditure in a representative sample of young children 总被引:4,自引:0,他引:4
Montgomery C Reilly JJ Jackson DM Kelly LA Slater C Paton JY Grant S 《The American journal of clinical nutrition》2004,80(3):591-596
BACKGROUND: Strategies for the prevention and treatment of childhood obesity require a better understanding of the relation between the pattern of free-living physical activity and total energy expenditure (TEE). OBJECTIVE: We assessed the relations between TEE and physical activity level (PAL) during engagement in different intensities of physical activity. DESIGN: We used a cross-sectional study of 104 children (median age: 5.4 y) in Scotland. TEE was measured with use of doubly labeled water (DLW), and resting energy expenditure was predicted to determine PAL. Time spent sedentary and in light-intensity activity and in moderate- and vigorous-intensity physical activity (MVPA) was assessed by accelerometry concurrent with DLW measurements. Correlation and regression were used to assess the relations between measures of sedentary behavior, intensities of activity, and PAL as the dependent variable. RESULTS: Time spent sedentary was negatively correlated with PAL (r = -0.33, P < 0.01), and time spent in light-intensity activity was positively correlated with PAL (r = 0.31, P < 0.01). In multiple regression analyses, both time spent sedentary and in light-intensity activities were significantly associated with PAL. Time spent in MVPA was not associated with PAL; engagement in MVPA was limited in this sample (median: 3% of waking hours; range: 0-14%). PAL was significantly higher in boys than in girls. CONCLUSION: In this sample and setting, PAL was not influenced by engagement in MVPA but was influenced by time spent sedentary and in light-intensity activities. This study suggests that in young children, MVPA could make only a minor contribution to free-living TEE and PAL. 相似文献
925.
Thyroid nodules and thyroid cancer 总被引:8,自引:0,他引:8
Russell GM 《The Medical journal of Australia》2004,180(12):654-5; author reply 655
926.
Spencer S Grant AD Piola P Tukpo K Okia M Garcia M Salignon P Genevier C Kiguli J Guthmann JP 《Transactions of the Royal Society of Tropical Medicine and Hygiene》2004,98(12):719-727
Malaria is a key health problem among displaced populations in malaria-endemic areas. Mass distribution of insecticide-treated bednets (ITN) to prevent malaria is often carried out in complex emergencies, but there are few data on the outcome or operational effectiveness of such programmes. In June 2001, Medecins Sans Frontieres completed a mass distribution of ITNs (Permanet) to internally displaced persons in Bundibugyo, southwest Uganda, distributing one to four nets per household, and aiming to provide coverage for all residents. In July 2002, we did a cross-sectional survey using three-stage cluster sampling to evaluate the programme. A total of 1245 individuals from 835 households were interviewed. An ITN was present in 75.6% (95% CI 72.7-78.5) of the households, but only 56.5% (95% CI 52.3-60.4) of individuals were sleeping under an ITN, and nets were often damaged. The prevalence of malarial parasitaemia was 11.2% (95% CI 9.4-13.0), and was significantly lower in ITN users compared to non-users (9.2% vs. 13.8%, relative risk [RR] 0.63, 95% CI 0.46-0.87); ITNs with severe damage remained effective (RR for severely damaged net 0.58, 95% CI 0.35-0.98). There was no significant difference in haemoglobin concentration between ITN users and non-users. 相似文献
927.
Colfax G Vittinghoff E Husnik MJ McKirnan D Buchbinder S Koblin B Celum C Chesney M Huang Y Mayer K Bozeman S Judson FN Bryant KJ Coates TJ;EXPLORE Study Team 《American journal of epidemiology》2004,159(10):1002-1012
Prior reports associating substance use with sexual risk behavior have generally used summary measures and have not adjusted for participants' background levels of substance use. In this 1999-2001 US study (the EXPLORE study), the authors determined whether substance use during sex was independently associated with sexual risk during recent sexual episodes, as reported by 4,295 human immunodeficiency virus-negative men who have sex with men. The main outcome measure was serodiscordant unprotected anal sex (SDUA). The influence of participant-level characteristics was examined by using repeated-measures logistic models. In assessing the influence of episode-level predictors on SDUA, the influence of participant-level characteristics, including 6-month substance use, was removed by using conditional logistic regression, in effect making each participant his own control. The authors also adjusted for partner characteristics. Eleven percent of participants reported heavy alcohol use, 37% used poppers, 19% sniffed cocaine, and 13% used amphetamines. In the participant-level analysis, use of poppers, amphetamines, and sniffed cocaine as well as heavy alcohol use in the prior 6 months were independently associated with SDUA. In the conditional analysis, consumption of > or = 6 alcoholic drinks or use of poppers, amphetamines, or sniffed cocaine just before or during sex was independently associated with SDUA. The authors concluded that programs aimed at preventing human immunodeficiency virus transmission should emphasize the influence of substance use during sex on increased risk behavior. 相似文献
928.
929.
930.
It is now clear that reactive oxygen species (ROS) can act as signalling molecules in the cerebral circulation under both physiological and pathological conditions. Some major products of superoxide (O(2)(.)(-)) metabolism, such as hydrogen peroxide (H(2)O(2)) and hydroxyl radical (OH(.)), appear to be particularly good cerebral vasodilators and may, surprisingly, represent important molecules for increasing local cerebral blood flow. A major determinant of overall ROS levels in the cerebral circulation is the rate of generation of the parent molecule, O(2)(.)(-). Although the major enzymatic source of O(2)(.)(-) in cerebral arteries is yet to be conclusively established, the two most likely candidates are cyclo-oxygenase and nicotinamide adenine dinucleotide phosphate (reduced form) [NADPH] oxidase. The activity of endogenous superoxide dismutases (SODs) play a vital role in determining levels and effects of all individual ROS derived from metabolism of O(2)(.)(-). The term 'oxidative stress' may be an over-simplification that hides the complexity and diversity of the ROS family in cerebrovascular health and disease. Although a generalised increase in ROS levels seems to occur during several vascular disease states, the consequences of this for cerebrovascular function are still unclear.Because enhanced breakdown of O(2)(.)(-) by SOD will increase the generation of the powerful cerebral vasodilator H(2)O(2), this latter molecule could conceivably act as a compensatory vasodilator mechanism in the cerebral circulation under conditions of elevated O(2)(.)(-) production. Some recent clinical data support the concept of a protective role for cerebrovascular NADPH oxidase activity. Although it is quite speculative at present, if NADPH oxidase were to emerge as a major source of beneficial vasodilator ROS in the cerebral circulation, this may represent a significant dilemma for treatment of ischaemic cerebrovascular conditions, as excessive NADPH oxidase activity is associated with the progression of several systemic vascular disease states, including hypertension and atherosclerosis. Despite data suggesting that antioxidant vitamins can have beneficial effects on vascular function and that their plasma levels are inversely correlated with risk of cardiovascular disease and stroke, the results of several recent large-scale clinical trials of antioxidant supplementation have been disappointing. Future work must establish whether or not increased ROS generation is necessarily detrimental to cerebral vascular function, as has been generally assumed, or whether localised increases in ROS in the vicinity of the arterial wall could be beneficial in disease states for the maintenance of cerebral blood flow. 相似文献