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71.
McCarthy AD Kennedy JL Middleton LT 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2005,360(1460):1579-1588
Over the last two decades, identification of polymorphisms that influence human diseases has begun to have an impact on the provision of medical care. The promise of genetics lies in its ability to provide insights into an individual's susceptibility to disease, the likely nature of the disease and the most appropriate therapy. For much of its history, pharmacogenetics (PGx-the use of genetic information to impact drug choice) has been limited to comparatively simple phenotypes such as plasma drug levels. Progress in genetics technologies has broadened the scope of PGx efficacy and safety studies that can be implemented, impacting on a broad spectrum of drug discovery and development activities. Recent PGx data show the ability of this approach to generate information that can be applied to dose selection, efficacy determination and safety issues. This in turn will lead to significant opportunities to affect both the approach to clinical development and the probability of success--the latter being an important aspect for pharmaceutical companies and for the patients who will benefit from these new medicines. 相似文献
72.
Orsini MJ Nesmelova I Young HC Hargittai B Beavers MP Liu J Connolly PJ Middleton SA Mayo KH 《The Journal of biological chemistry》2005,280(9):8134-8142
Nociceptin, a 17 amino acid opioid-like peptide that has an inhibitory effect on synaptic transmission in the nervous system, is involved in learning, memory, attention, and emotion and is also implicated in the perception of pain and visual, auditory, and olfactory functions. In this study, we investigated the NMR solution structure of nociceptin in membrane-like environments (trifluoroethanol and SDS micelles) and found it to have a relatively stable helix conformation from residues 4-17 with functionally important N-terminal residues being folded aperidoically on top of the helix. In functional assays for receptor binding and calcium flux, alanine-scanning variants of nociceptin indicated that functionally important residues generally followed helix periodicity, consistent with the NMR structural model. Structure-activity relationships allowed identification of pharmacophore sites that were used in small molecule data base searches, affording hits with demonstrated nociceptin receptor binding affinities. 相似文献
73.
The purpose of this study was to verify the performance of recently developed body-worn sensor packs against 3D motion analysis of trunk and lower-limb movements. Five sensor packs, each consisting of rate gyroscope and two 2-D accelerometers controlled by a microprocessor were attached to the trunk, thighs, and shanks of an able bodied subject. A 6-camera motion analysis system (MAS) recorded multiple trials of sit-to-stand movements and normal walking. Time domain signals from each sensor pack were significantly correlated (r = 0.90-0.99;p < 0.05) with a root mean square errors of less than 5 degrees when compared against the same limb angle measurements calculated by the MAS. These data demonstrate that these external sensor packs are accurate devices for measuring trunk and lower-limb sagittal plane orientation in real-time. 相似文献
74.
75.
A HOX gene mutation in a family with isolated congenital vertical talus and Charcot-Marie-Tooth disease 下载免费PDF全文
Shrimpton AE Levinsohn EM Yozawitz JM Packard DS Cady RB Middleton FA Persico AM Hootnick DR 《American journal of human genetics》2004,75(1):92-96
Congenital vertical talus (CVT), also known as "rocker-bottom foot" deformity, is a dislocation of the talonavicular joint, with rigid dorsal dislocation of the navicular over the neck of the talus. This condition is usually associated with multiple other congenital deformities and only rarely is an isolated deformity. The reported familial cases are consistent with an autosomal dominant mode of inheritance with incomplete penetrance. In contrast, Charcot-Marie-Tooth disease (CMT) is thought to be a completely distinct heterogeneous group of disorders, with foot abnormalities that typically develop a high-arched "claw foot" appearance later in life. In the present study, DNA was isolated from 36 members of a single upstate (northern) New York white family of Italian descent in which both CVT and CMT were segregating. Whole-genome linkage analysis with Affymetrix GeneChip Mapping 10K Array defined a 7-Mb critical region on chromosome 2q31, which led to candidate-gene sequencing of six HOX genes and detection of a single missense mutation, M319K (956T-->A), in the HOXD10 gene. In the study family, this mutation was fully penetrant and exhibited significant evidence of linkage (LOD 6.33; theta =0), and it very likely accounts for both CVT and CMT in heterozygotes. 相似文献
76.
目的观察血液磁极化疗法(简称血磁治疗)对糖尿病(DM)的治疗效果和对胰岛功能的影响。方法制备了四氧嘧啶DM兔模型20只,随机分为两组,即DM模型血磁治疗组及DM模型未治疗组,同时设立正常对照组10只,分别测定治疗前后空腹血糖(FPG)、糖化血红蛋白(HbA1c)、胰岛素(INS)及C-肽(C-P),并于观察期结束后处死动物取胰腺组织常规石蜡包埋切片,行HE及Mallory三色法特殊染色观察3组胰岛形态学变化。结果血磁治疗显著降低DM兔的FPG(P<0.001)。DM治疗组INS及C-P水平较治疗前明显升高(P<0.01),与未治疗组相比差异显著(P<0.05)。胰岛病理改变可见治疗组β细胞数量明显多于DM未治疗组,提示血磁疗法具有促进胰岛修复,改善胰岛功能的作用。结论血磁疗法能够促进DM时受损胰岛组织的修复,改善胰岛β细胞分泌功能,降血糖作用明显。 相似文献
77.
Tian X Iriarte-Diaz J Middleton K Galvao R Israeli E Roemer A Sullivan A Song A Swartz S Breuer K 《Bioinspiration & biomimetics》2006,1(4):S10-S18
Experimental measurements and analysis of the flight of bats are presented, including kinematic analysis of high-speed stereo videography of straight and turning flight, and measurements of the wake velocity field behind the bat. The kinematic data reveal that, at relatively slow flight speeds, wing motion is quite complex, including a sharp retraction of the wing during the upstroke and a broad sweep of the partially extended wing during the downstroke. The data also indicate that the flight speed and elevation are not constant, but oscillate in synchrony with both the horizontal and vertical movements of the wing. PIV measurements in the transverse (Trefftz) plane of the wake indicate a complex 'wake vortex' structure dominated by a strong wing tip vortex shed from the wing tip during the downstroke and either the wing tip or a more proximal joint during the upstroke. Data synthesis of several discrete realizations suggests a 'cartoon' of the wake structure during the entire wing beat cycle. Considerable work remains to be done to confirm and amplify these results. 相似文献
78.
Georges Limbert Carl van Lierde O. Luiza Muraru X. Frank Walboomers Milan Frank Stig Hansson John Middleton Siegfried Jaecques 《Journal of biomechanics》2010,43(7):1251-1261
The first objective of this computational study was to assess the strain magnitude and distribution within the three-dimensional (3D) trabecular bone structure around an osseointegrated dental implant loaded axially. The second objective was to investigate the relative micromotions between the implant and the surrounding bone. The work hypothesis adopted was that these virtual measurements would be a useful indicator of bone adaptation (resorption, homeostasis, formation).In order to reach these objectives, a μCT-based finite element model of an oral implant implanted into a Berkshire pig mandible was developed along with a robust software methodology. The finite element mesh of the 3D trabecular bone architecture was generated from the segmentation of μCT scans. The implant was meshed independently from its CAD file obtained from the manufacturer. The meshes of the implant and the bone sample were registered together in an integrated software environment. A series of non-linear contact finite element (FE) analyses considering an axial load applied to the top of the implant in combination with three sets of mechanical properties for the trabecular bone tissue was devised. Complex strain distribution patterns are reported and discussed. It was found that considering the Young’s modulus of the trabecular bone tissue to be 5, 10 and 15 GPa resulted in maximum peri-implant bone microstrains of about 3000, 2100 and 1400. These results indicate that, for the three sets of mechanical properties considered, the magnitude of maximum strain lies within an homeostatic range known to be sufficient to maintain/form bone. The corresponding micro-motions of the implant with respect to the bone microstructure were shown to be sufficiently low to prevent fibrous tissue formation and to favour long-term osseointegration. 相似文献
79.
Numerous factors influence the increased health risks of seamen. This study investigated sleep (by actigraphy) and the adaptation of the internal clock in watch-keeping crew compared to day workers, as possible contributory factors. Fourteen watch keepers, 4 h on, 8 h off (0800-1200/2000-2400 h, 1200-1600/2400-0400 h, 1600-2000/0400-0800 h) (fixed schedule, n = 6; rotating by delay weekly, n = 8), and 12 day workers participated during a voyage from the United Kingdom to Antarctica. They kept daily sleep diaries and wore wrist monitors for continuous recording of activity. Sleep parameters were derived from activity using the manufacturer's software and analyzed by repeated-measures ANOVA using SAS 8.2. Sequential urine samples were collected for 48 h weekly for 6-sulphatoxymelatonin measurement as an index of circadian rhythm timing. Individuals working watches of 1200-1600/2400-0400 h and 1600-2000/0400-0800 h had 2 sleeps daily, analyzed separately as main sleep (longest) and 2nd sleep. Main sleep duration was shorter in watch keepers than in day workers (p < 0.0001). Objective sleep quality was significantly compromised in rotaters compared to both day workers and fixed watch keepers, the most striking comparisons being sleep efficiency (percentage desired sleep time spent sleeping) main sleep (p < 0.0001) and sleep fragmentation (an index of restlessness) main sleep (p < 0.0001). The 2nd sleep was substantially less efficient than was the main sleep (p < 0.0001) for all watch keepers. There were few significant differences in sleep between the different watches in rotating watch keepers. Circadian timing remained constant in day workers. Timing of the 6-sulphatoxymelatonin rhythm was later for the watch of 1200-1600/2400-0400 h than for all others (1200-1600/2400-0400 h, 5.90 +/- 0.85 h; 1600-2000/0400-0800 h, 1.5 +/- 0.64 h; 0800-1200/ 2000-2400 h, 2.72 +/- 0.76 h; days, 2.09 +/- 0.68 h [decimal hours, mean +/- SEM]: ANOVA, p < 0.01). This study identifies weekly changes in watch time as a cause of poor sleep in watch keepers. The most likely mechanism is the inability of the internal clock to adapt rapidly to abrupt changes in schedule. 相似文献
80.