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521.
Richard S. Finkel Kevin M. Flanigan Brenda Wong Carsten B?nnemann Jacinda Sampson H. Lee Sweeney Allen Reha Valerie J. Northcutt Gary Elfring Jay Barth Stuart W. Peltz 《PloS one》2013,8(12)
Background
Approximately 13% of boys with Duchenne muscular dystrophy (DMD) have a nonsense mutation in the dystrophin gene, resulting in a premature stop codon in the corresponding mRNA and failure to generate a functional protein. Ataluren (PTC124) enables ribosomal readthrough of premature stop codons, leading to production of full-length, functional proteins.Methods
This Phase 2a open-label, sequential dose-ranging trial recruited 38 boys with nonsense mutation DMD. The first cohort (n = 6) received ataluren three times per day at morning, midday, and evening doses of 4, 4, and 8 mg/kg; the second cohort (n = 20) was dosed at 10, 10, 20 mg/kg; and the third cohort (n = 12) was dosed at 20, 20, 40 mg/kg. Treatment duration was 28 days. Change in full-length dystrophin expression, as assessed by immunostaining in pre- and post-treatment muscle biopsy specimens, was the primary endpoint.Findings
Twenty three of 38 (61%) subjects demonstrated increases in post-treatment dystrophin expression in a quantitative analysis assessing the ratio of dystrophin/spectrin. A qualitative analysis also showed positive changes in dystrophin expression. Expression was not associated with nonsense mutation type or exon location. Ataluren trough plasma concentrations active in the mdx mouse model were consistently achieved at the mid- and high- dose levels in participants. Ataluren was generally well tolerated.Interpretation
Ataluren showed activity and safety in this short-term study, supporting evaluation of ataluren 10, 10, 20 mg/kg and 20, 20, 40 mg/kg in a Phase 2b, double-blind, long-term study in nonsense mutation DMD.Trial Registration
ClinicalTrials.gov NCT00264888相似文献522.
David F. Ferguson Bryce J. Busenlehner Mark D. Rahm Sachin M. Mehta Juhee Song Matthew L. Davis H. Wayne Sampson Christopher D. Chaput 《Obesity (Silver Spring, Md.)》2013,21(5):997-1003
Objective:
To utilize data from routine CT scans to quantify obesity in polytrauma patients without the need to obtain a height and weight.Design and Methods:
We utilized a comprehensive database including multidetector CT thoracoabdominal images of all polytrauma patients admitted to a Level 1 trauma center. One thousand one hundred seventy‐four patients were reviewed from 2006 to 2008 and of these, 162 had previous documentation of Body Mass Index (BMI) or height and weight measurements as an outpatient within 6 months of trauma activation and with a truncal girth smaller than the scanning area of the CT machine. Truncal Adiposity Volume (TAV) was calculated from three dimensional reconstructions (3DRs) of the CT scans of the thorax and abdomen obtained in the emergency department.Results:
Statistical analysis yielded a fairly good correlation between TAV and BMI (correlation coefficient = 0.77; p‐value < 0.0001). The intra‐observer and inter‐observer correlations in measuring TAV were high; 0.99 and 0.98 respectively. A linear regression equation of BMI on TAV was estimated and it had a form: 3DR BMI = 20.81+0.00064×TAV. In conclusion, TAV provides a reproducible means of evaluating obesity in trauma patients from routinely obtained CT scans.Conclusions:
The TAV eliminates the often problematic task of obtaining a height and weight in a trauma patient and it correlates fairly well with the most commonly used clinical method of quantifying patient adiposity, BMI. This method may provide a more direct measurement of adiposity than does BMI, and holds promise for improving trauma care and research in the obese patient. 相似文献523.
Maria G. Pavlatou Rana Malek Maureen Sampson Alan T. Remaley Philip W. Gold Tomoshige Kino 《Obesity (Silver Spring, Md.)》2013,21(5):960-967
Objective:
Serum cortisol concentrations fluctuate in a circadian fashion, and glucocorticoids exert strong effects on adipose tissue and induce obesity through the glucocorticoid receptor.Design and Methods:
To examine the impact of physiologic levels of circulating cortisol on subcutaneous adipose tissue, 25 overweight and obese subjects were employed, and their serum levels of morning (AM) and evening (PM) cortisol, AM/PM cortisol ratios, and 24‐h urinary‐free cortisol (UFC) were compared with their clinical parameters, serum cytokine levels, and mRNA expression of 93 receptor action‐regulating and 93 glucocorticoid‐responsive genes in abdominal subcutaneous fat.Results and Conclusions:
AM cortisol levels did not correlate with mRNA expression of the all genes examined, whereas PM cortisol levels, AM/PM cortisol ratios, and 24‐h UFC were associated with distinct sets of these genes. Body mass index did not significantly correlate with the four cortisol parameters employed. These results suggest that physiologic levels of AM serum cortisol do not solely represent biological effects of circulating cortisol on the expression of glucocorticoid‐related genes in subcutaneous adipose tissue, whereas PM levels, amplitude, and net amounts of the diurnally fluctuating serum cortisol have distinct effects. Through the genes identified in this study, glucocorticoids appear to influence intermediary metabolism, energy balance, inflammation, and local circadian rythmicity in subcutaneous fat. Our results may also explain in part the development of metabolic abnormality and obesity in subjects under stress or patients with melancholic/atypical depression who demonstrate elevated levels of PM serum cortisol. 相似文献524.
525.
526.
Petra A. Prins Michael F. Hill David Airey Sam Nwosu Prudhvidhar R. Perati Hagai Tavori MacRae F. Linton Valentina Kon Sergio Fazio Uchechukwu K. Sampson 《PloS one》2014,9(1)
Objective
Understanding variations in size and pattern of development of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) may inform translational research strategies. Thus, we sought insight into the temporal evolution of AAA in apolipoprotein (apo)E−/− mice.Approach
A cohort of mice underwent a 4-week pump-mediated infusion of saline (n = 23) or 1500 ng/kg/min of Ang II (n = 85) and AAA development was tracked via in vivo ultrasound imaging. We adjusted for hemodynamic covariates in the regression models for AAA occurrence in relation to time.Results
The overall effect of time was statistically significant (p<0.001). Compared to day 7 of AngII infusion, there was no decrease in the log odds of AAA occurrence by day 14 (−0.234, p = 0.65), but compared to day 21 and 28, the log odds decreased by 9.07 (p<0.001) and 2.35 (p = 0.04), respectively. Hemodynamic parameters were not predictive of change in aortic diameter (Δ) (SBP, p = 0.66; DBP, p = 0.66). Mean total cholesterol (TC) was higher among mice with large versus small AAA (601 vs. 422 mg/ml, p<0.0001), and the difference was due to LDL. AngII exposure was associated with 0.43 mm (95% CI, 0.27 to 0.61, p<0.0001) increase in aortic diameter; and a 100 mg/dl increase in mean final cholesterol level was associated with a 12% (95% CI, 5.68 to 18.23, p<0.0001) increase in aortic diameter. Baseline cholesterol was not associated with change in aortic diameter (p = 0.86).Conclusions
These are the first formal estimates of a consistent pattern of Ang II-induced AAA development. The odds of AAA occurrence diminish after the second week of Ang II infusion, and TC is independently associated with AAA size. 相似文献527.
Robert J. Sampson 《Ethnic and racial studies》2014,37(10):1732-1738
In this response I focus on two major themes in Wacquant's trilogy: (1) punishment and the state; and (2) territorial stigmatization. I discuss evidence that supports elements of Wacquant's argument, while at the same time demonstrating the need for an account that brings mediating institutional processes of the state, violence, the civil sphere and neighbourhood mechanisms more fully into the larger theoretical picture. I conclude that ‘bottom-up’ processes of inequality must be integrated with ‘top-down’ forces of the state to advance our theoretical understanding of penality and spatial marginality in federated and unitary governments alike. 相似文献
528.
529.
With the completion of numerous genome projects, new high-throughput methods are required to ascribe gene function and interactions. A method proven successful in yeast for protein interaction studies is tandem affinity purification (TAP) of native protein complexes followed by MS. Here, we show that TAP, using Protein A and CBP tags, is not generally suitable for the purification and identification of proteins from tissues. A head-to-head comparison of tags shows that two others, FLAG and His, provide protein yields from Drosophila tissues that are an order of magnitude higher than Protein A and CBP. FLAG-His purification worked sufficiently well so that two cofactors of the Drosophila nuclear receptor protein dHNF4 could be purified from whole animals. These proteins, Hsc70 and Hsp83, are important chaperones and cofactors of other nuclear receptor proteins. However, this is the first time that they have been shown to interact with a non-steroid binding nuclear receptor. We show that the two proteins increase the ability of dHNF4 to bind DNA in vitro and to function in vivo. The tags and approaches developed here will help facilitate the routine purification of proteins from complex cells, tissues and whole organisms. 相似文献
530.
We have examined the detection by a 125I-labeled basic protein, cationized cytochrome c, of selected proteoglycans (PGs) and standard preparations of glycosaminoglycans (GAGs) immobilized on Nylon 66 and also on positively charged Nylon 66. Immobilization on Nylon 66 appears to allow a relative freedom of interaction between PGs or GAGs and 125I-cationized cytochrome c, but a more restricted reaction was observed when PGs and GAGs were immobilized to positively charged Nylon 66. On this support PGs with large numbers of GAG side chains reacted well with 125I-cationized cytochrome c, but GAGs were minimally reactive. By taking advantage of some of the properties of large-pore agarose-acrylamide gels, rapid partial characterization of some PGs can be accomplished in the 10-ng range, and therefore at a sensitivity equal to PGs with internal biosynthetic labels. 相似文献