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981.
Li YW Hill G Wong H Kelly N Ward K Pierdomenico M Ren S Gilligan P Grossman S Trainor G Taub R McElroy J Zazcek R 《The Journal of pharmacology and experimental therapeutics》2003,305(1):86-96
4-(1,3-Dimethoxyprop-2-ylamine)-2,7-dimethyl-8-(2,4-dichlorophenyl)-pyrazolo[1,5-a]-1,3,5-triazine (DMP696) is a highly selective and potent, nonpeptide corticotropin-releasing factor 1 (CRF(1)) antagonist. In this study, we measured in vivo CRF(1) receptor occupancy of DMP696 by using ex vivo ligand binding and quantitative autoradiography and explored the relationship of receptor occupancy with plasma and brain exposure and behavioral efficacy. In vitro affinity (IC(50)) of DMP696 to brain CRF(1) receptors measured using the brain section binding autoradiography in this study is similar to that assessed using homogenized cell membrane assays previously. The ex vivo binding assay was validated by demonstrating that potential underestimation of receptor occupancy with this procedure could be minimized by identifying an appropriate in vitro incubation time (40 min) based upon the dissociation kinetics of DMP696. Orally administrated DMP696 dose dependently occupied CRF(1) receptors in the brain, with ~60% occupancy at 3 mg/kg. In the defensive withdrawal test of anxiety, this dose of DMP696 produced approximately 50% reduction in the exit latency. The time course of plasma and brain drug levels paralleled that of receptor occupancy, with peak exposure at 90 min after dosing. The plasma-free concentration of DMP696 corresponding to 50% CRF(1) receptor occupancy (in vivo IC(50), 1.22 nM) was similar to the in vitro IC(50) (~1.0 nM). Brain concentrations of DMP696 were over 150-fold higher than the plasma-free levels. In conclusion, doses of DMP696 occupying over 50% brain CRF(1) receptors are consistent with doses producing anxiolytic efficacy in the defense withdrawal test of anxiety, and the IC(50) value estimated in vivo based on plasma-free drug concentrations is consistent with the in vitro IC(50) value. 相似文献
982.
C.W. Joyce J.C. Kelly C. Sugrue 《Burns : journal of the International Society for Burn Injuries》2014
The importance of a published paper to a particular area is reflected in the quantity of citations obtained from peers. In burns, it is unknown which papers have been the most influential on this specialty. The purpose of our study was to identify the 100 most cited papers in burns and to analyze their characteristics. Twenty-seven journals were chosen for analysis. These included high impact factor scientific journals and journals dedicated to burns and trauma. Only twelve of these journals contributed to the 100 most cited papers in burns and we analyzed each paper individually looking at its subject matter, authorship, article type, institution, country and year of publication. Our citation analysis revealed an interesting mix of clinical and scientific papers that documents the key landmarks in burn care over the past 66 years. 相似文献
983.
Jane M. Blazeby Emma Hall Neil K. Aaronson Lisa Lloyd Rachel Waters John D. Kelly Peter Fayers 《European urology》2014
Background
Well-developed and well-tested patient-reported outcome measures for non–muscle-invasive bladder cancer (NMIBC) are required.Objective
To test and adapt the scale structure and explore the psychometric properties of the European Organisation for Research and Treatment of Cancer (EORTC) questionnaire for NMIBC.Design, setting, and participants
A total of 433 patients in the Bladder COX-2 Inhibition Trial (BOXIT) completed the EORTC QLQ-C30 and NMIBC questionnaires. BOXIT is evaluating the addition of celecoxib to standard treatment in high- and intermediate-risk NMIBC.Outcome measurements and statistical analysis
Multitrait scaling investigated and adapted the questionnaire scale structure and evaluated the reliability and validity of the revised scales, as well as responsiveness to change.Results and limitations
A total of 410 patients (94.7%) (79.3% men, 74.6% high risk) returned baseline forms, and the questionnaire response rate was 88.2%. Multitrait scaling confirmed six scales and five single items. Scales and items demonstrated significant differences between patients with good and poor performance status scores (p < 0.001). Men reported better sexual function than women (p < 0.001). Scale and single-item module scores were not highly correlated with QLQ-C30 scores (evidence of discriminant validity), and the module was responsive to changes in health over time. International and test–retest data are required.Conclusions
This study demonstrates the evidence-driven adapted scale structure and psychometric data of the EORTC QLQ-NMIBC24 module to use in clinical trials of patients with high- or intermediate-risk bladder cancer. 相似文献984.
985.
986.
987.
Alexander Miric Maria C.S. Inacio Matthew P. Kelly Robert S. Namba 《The Journal of arthroplasty》2014
As the nonagenarian patient population continues to grow, more patients aged 90 and over will become candidates for total knee arthroplasty (TKA). This study evaluated the patient characteristics and incidence of postoperative morbidity and mortality of 216 nonagenarian TKA patients among 81,835 primary TKA patients followed by a total joint replacement registry. Nonagenarians had a greater number of comorbidities preoperatively, experienced a higher rate of deep vein thrombosis and 30 day mortality, and had a longer hospital length of stay. However, nonagenarians did not have an increased risk of infection nor pulmonary embolism and postoperative mortality was within expected rates for individuals 90 years and older. Higher readmission rates, however, highlight the benefits of close follow up during a prolonged postoperative period. 相似文献
988.
989.
990.
J Ahmad AIW Mayne Y Zen MB Loughrey P Kelly M Taylor 《Annals of the Royal College of Surgeons of England》2014,96(5):e18-e20