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991.
We examine bias in Markov models of diseases, including both chronic and infectious diseases. We consider two common types of Markov disease models: ones where disease progression changes by severity of disease, and ones where progression of disease changes in time or by age. We find sufficient conditions for bias to exist in models with aggregated transition probabilities when compared to models with state/time dependent transition probabilities. We also find that when aggregating data to compute transition probabilities, bias increases with the degree of data aggregation. We illustrate by examining bias in Markov models of Hepatitis C, Alzheimer’s disease, and lung cancer using medical data and find that the bias is significant depending on the method used to aggregate the data. A key implication is that by not incorporating state/time dependent transition probabilities, studies that use Markov models of diseases may be significantly overestimating or underestimating disease progression. This could potentially result in incorrect recommendations from cost-effectiveness studies and incorrect disease burden forecasts. 相似文献
992.
993.
Significant extension of lifespan in important mammalian species is bound to attract the attention not only of the aging research community, but also the media and the wider public. Two recent papers published by Harrison et al. (2009) in Nature and by Colman et al. (2009) in Science report increased longevity of mice fed with rapamycin and of rhesus monkeys undergoing caloric restriction, respectively. These papers have generated considerable debate in the aging community. Here we assess what is new about these findings, how they fit with our knowledge of lifespan extension from other studies and what prospects this new work holds out for improvements in human longevity and human health span. 相似文献
994.
Elizabeth W Karlson Lori B Chibnik Monica McGrath Shun-Chiao Chang Brendan T Keenan Karen H Costenbader Patricia A Fraser Shelley Tworoger Susan E Hankinson I-Min Lee Julie Buring Immaculata De Vivo 《Arthritis research & therapy》2009,11(3):1-12
Introduction
Since current treatment options for patients suffering from active rheumatoid arthritis (RA) remain inadequate, especially for those unresponsive to disease-modifying antirheumatic drugs (DMARDs), new and improved medication is needed. This study evaluates the safety and efficacy of masitinib (AB1010), a potent and selective protein tyrosine kinase inhibitor of c-KIT, in the monotherapy treatment of DMARD-refractory RA.Methods
This was a multicentre, uncontrolled, open-label, randomised, dose-ranging, phase 2a trial. Masitinib was administered orally to 43 patients who had inadequate response to DMARDs, at initial randomised dosing levels of 3 and 6 mg/kg per day over a 12-week period. Dose adjustment was permitted based upon tolerability and response criteria. Efficacy was assessed via American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) responses, disease activity score using 28 joint counts (DAS28), index of improvement in RA (ACRn) and C-reactive protein (CRP) improvement, relative to baseline at week 12.Results
Improvement was observed in all efficacy endpoints, including ACR20/50/70 scores of 54%, 26% and 8%, respectively, and a reduction in CRP level by greater than 50% for approximately half the population. This improvement was sustainable throughout an extension phase (> 84 weeks) and was also independent of initial DMARD resistance (anti-tumour necrosis factor-alpha and/or methotrexate). A relatively high patient withdrawal rate (37%) required the use of last observation carried forward (LOCF) data imputation. Incidence of adverse events was high (95%), although the majority were of mild or moderate severity with a considerable decline in frequency observed after 12 weeks of treatment. Two nonfatal serious adverse events were reported. Dose-response analyses tentatively indicate that an initial dosing level of 6.0 mg/kg per day administered orally in two daily intakes is the most appropriate, based upon potency and tolerability trends.Conclusions
Treatment with masitinib improved DMARD-refractory active RA. Following an initial high incidence of mostly mild to moderate side effects during the first 12 weeks of treatment, masitinib appears to be generally well tolerated. This, together with evidence of a sustainable efficacy response, suggests that masitinib is suitable for long-term treatment regimens. Since this was the first study of masitinib in a nononcologic pathology, the relatively high patient withdrawal rate observed can be partly attributed to a highly cautious response to adverse events. There is sufficient compelling evidence to warrant further placebo-controlled investigation.Trial registration
ClinicalTrials.gov NCT00831922. 相似文献995.
DNA electrotransfer to muscle tissue yields long-term, high levels of gene expression; showing great promise for future gene
therapy. We want to characterize the novel far-red fluorescent protein Katushka as a marker for gene expression using time
domain fluorescence in vivo imaging. Highly efficient transgenic expression was observed after DNA electrotransfer with 100-fold
increase in fluorescent intensity. The fluorescent signal peaked 1 week after transfection and returned to background level
within 4 weeks. Katushka expression was not as stable as GFP expression, which was detectable for 8 weeks. Depth and 3D analysis
proved that the expression was located in the target muscle. In vivo bio-imaging using the novel Katushka fluorescent protein
enables excellent evaluation of the transfection efficacy, and spatial distribution, but lacks long-term stability. 相似文献
996.
Matthew W. VanBrocklin James P. Robinson Todd Whitwam Adam R. Guilbeault Julie Koeman Pamela J. Swiatek George F. Vande Woude Joseph D. Khoury Sheri L. Holmen 《Pigment cell & melanoma research》2009,22(4):454-460
While many genetic alterations have been identified in melanoma, the relevant molecular events that contribute to disease progression are poorly understood. Most primary human melanomas exhibit loss of expression of the CDKN2A locus in addition to activation of the canonical mitogen‐activated protein kinase signaling pathway. In this study, we used a Cdkn2a‐deficient mouse melanocyte cell line to screen for secondary genetic events in melanoma tumor progression. Upon investigation, intrachromosomal gene amplification of Met, a receptor tyrosine kinase implicated in melanoma progression, was identified in Cdkn2a‐deficient tumors. RNA interference targeting Met in these tumor cells resulted in a significant delay in tumor growth in vivo compared with the control cells. MET expression is rarely detected in primary human melanoma but is frequently observed in metastatic disease. This study validates a role for Met activation in melanoma tumor progression in the context of Cdkn2a deficiency. 相似文献
997.
998.
Philip L. Leopold Michael J. O'Mahony X. Julie Lian Ann E. Tilley Ben-Gary Harvey Ronald G. Crystal 《PloS one》2009,4(12)
Background
Whereas cilia damage and reduced cilia beat frequency have been implicated as causative of reduced mucociliary clearance in smokers, theoretically mucociliary clearance could also be affected by cilia length. Based on models of mucociliary clearance predicting that cilia length must exceed the 6–7 µm airway surface fluid depth to generate force in the mucus layer, we hypothesized that cilia height may be decreased in airway epithelium of normal smokers compared to nonsmokers.Methodology/Principal Findings
Cilia length in normal nonsmokers and smokers was evaluated in aldehyde-fixed, paraffin-embedded endobronchial biopsies, and air-dried and hydrated samples were brushed from human airway epithelium via fiberoptic bronchoscopy. In 28 endobronchial biopsies, healthy smoker cilia length was reduced by 15% compared to nonsmokers (p<0.05). In 39 air-dried samples of airway epithelial cells, smoker cilia length was reduced by 13% compared to nonsmokers (p<0.0001). Analysis of the length of individual, detached cilia in 27 samples showed that smoker cilia length was reduced by 9% compared to nonsmokers (p<0.05). Finally, in 16 fully hydrated, unfixed samples, smoker cilia length was reduced 7% compared to nonsmokers (p<0.05). Using genome-wide analysis of airway epithelial gene expression we identified 6 cilia-related genes whose expression levels were significantly reduced in healthy smokers compared to healthy nonsmokers.Conclusions/Significance
Models predict that a reduction in cilia length would reduce mucociliary clearance, suggesting that smoking-associated shorter airway epithelial cilia play a significant role in the pathogenesis of smoking-induced lung disease. 相似文献999.
1000.
Yi Han Aaron Miller Julie Mangada Ying Liu Andrzej Swistowski Ming Zhan Mahendra S. Rao Xianmin Zeng 《PloS one》2009,4(9)