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31.
JB Thomas MJ Fall JB Cooper RB Rothman SW Mascarella H Xu JS Partilla CM Dersch KB McCullough BE Cantrell DM Zimmerman FI Carroll 《Canadian Metallurgical Quarterly》1998,41(26):5188-5197
A three-component library of compounds was prepared in parallel using multiple simultaneous solution-phase synthetic methodology. The compounds were biased toward opioid receptor antagonist activity by incorporating (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (a potent, nonselective opioid pure antagonist) as one of the monomers. The other two monomers, which included N-substituted or unsubstituted Boc-protected amino acids and a range of substituted aryl carboxylic acids, were selected to add chemical diversity. Screening of these compounds in competitive binding experiments with the kappa opioid receptor selective ligand [3H]U69,593 led to the discovery of a novel kappa opioid receptor selective ligand, N-?(2'S)-[3-(4-hydroxyphenyl)propanamido]-3'-methylbutyl?-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (8, RTI-5989-29). Additional structure-activity relationship studies suggested that 8 possesses lipophilic and hydrogen-bonding sites that are important to its opioid receptor potency and selectivity. These sites appear to exist predominantly within the kappa receptor since the selectivity arises from a 530-fold loss of affinity of 8 for the mu receptor and an 18-fold increase in affinity for the kappa receptor relative to the mu-selective ligand, (+)-N-[trans-4-phenyl-2-butenyl]-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (5a). The degree of selectivity observed in the radioligand binding experiments was not observed in the functional assay. According to its ability to inhibit agonist stimulated binding of [35S]GTPgammaS at all three opioid receptors, compound 8 behaves as a mu/kappa opioid receptor pure antagonist with negligible affinity for the delta receptor. 相似文献
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33.
In recent years there has been spectacular progress in the approach to various disorders of the spinal column. Owing to improved methods of osteosynthesis there is no longer so much need for long periods of postoperative bed rest. Of all the scolioses, idiopathic scoliosis is most common. The vast majority of these cases are not clinically significant. What is seen in the remaining cases if left untreated is a progression in the curvature during growth. Progressive idiopathic scoliosis can be effectively treated using conservative methods. Screening at school is an important part of this process. If the curvature proves progressive and skeletal growth is not complete a brace can be prescribed. Use of this strategy and form of treatment can avoid progression of the curvature and development of serious deformities. This conservative therapy has markedly reduced the need for corrective surgery. Scheuermann's disease is characterized by a fixed dorsal thoracic kyphosis. Progressive Scheuermann's kyphosis can be effectively treated using a brace. The majority of fractures of the vertebral bodies can be treated conservatively. However, serious fractures normally require surgical intervention. In the industrialised Western world, low back pain is a major health problem and the foremost cause of disability and unfitness for work. Low back pain caused by degenerative disease of the spinal column should be treated using a multidisciplinary approach. The development of advanced operative techniques and osteosynthesis methods has made it possible to treat metastases of the spine surgically. The effects of this treatment on the quality of life are encouraging. 相似文献
34.
A G protein gamma subunit-like domain shared between RGS11 and other RGS proteins specifies binding to Gbeta5 subunits 总被引:1,自引:0,他引:1
BE Snow AM Krumins GM Brothers SF Lee MA Wall S Chung J Mangion S Arya AG Gilman DP Siderovski 《Canadian Metallurgical Quarterly》1998,95(22):13307-13312
Regulators of G protein signaling (RGS) proteins act as GTPase-activating proteins (GAPs) toward the alpha subunits of heterotrimeric, signal-transducing G proteins. RGS11 contains a G protein gamma subunit-like (GGL) domain between its Dishevelled/Egl-10/Pleckstrin and RGS domains. GGL domains are also found in RGS6, RGS7, RGS9, and the Caenorhabditis elegans protein EGL-10. Coexpression of RGS11 with different Gbeta subunits reveals specific interaction between RGS11 and Gbeta5. The expression of mRNA for RGS11 and Gbeta5 in human tissues overlaps. The Gbeta5/RGS11 heterodimer acts as a GAP on Galphao, apparently selectively. RGS proteins that contain GGL domains appear to act as GAPs for Galpha proteins and form complexes with specific Gbeta subunits, adding to the combinatorial complexity of G protein-mediated signaling pathways. 相似文献
35.
36.
AM Pollock 《Canadian Metallurgical Quarterly》1995,310(6994):1580-1584
The Association of Metropolitan Authorities has recently proposed that responsibility for the NHS should pass from health authorities to local authorities. One of the fiercest debates at the outset of the NHS was whether the hospitals should be run by local authorities. In the end the minister for health, Aneurin Bevan, decided against local democracy and in favour of a national health service. His arguments included the fact that equality of treatment could not be guaranteed if facilities varied with local finances and that even the largest authorities were not big enough to pool risks and expertise. All these arguments still apply today, and the recent changes in community care provide an insight into how a market model of local authority control might work. The changes have been accompanied by a shift from public to private sector provision and the introduction of charges for services that the NHS once provided free. As important, the willingness and ability of local authorities to raise extra revenue from local taxes and charges affect the service they can provide, so leading to inequalities of provision. Local authorities have yet to make the case that they can preserve the fundamental principles and benefits of the NHS, including its reliance on central taxation and unified funding formulas. 相似文献
37.
X Chen DJ Kempf HL Sham BE Green A Molla M Korneyeva S Vasavanonda NE Wideburg A Saldivar KC Marsh E McDonald DW Norbeck 《Canadian Metallurgical Quarterly》1998,8(24):3531-3536
The 2-isopropyl thiazolyl group is a highly optimized P3 ligand for C2 symmetry-based HIV protease inhibitors, as exemplified in the drug ritonavir. Here we report that incorporation of this P3 ligand into a piperazine hydroxyethylamine series also yielded novel, highly potent inhibitors. In tissue culture assays, the presence of human serum was less deleterious to the activity of these inhibitors than to that of ritonavir. Furthermore, potent activity against ritonavir resistant HIV was observed. 相似文献
38.
In a Danish population-based non-Hodgkin's lymphoma registry, 2687 newly diagnosed patients were registered from 1983 to 1992. 39 had testicular involvement (TL) (incidence 0.26/10(5)/year). Median age was 71 years. 24 cases had localised and 15 had disseminated disease. Histologically, all cases were diffuse (65% diffuse centroblastic type). Of the 27 tested, 11% were of T- and 89% of B-immunophenotype. In localised cases, where surgery was supplemented by combination chemotherapy (CCT), the relapse rate was 15.4%. The relapse rate for cases with localised disease treated with other regimens (orchiectomy and/or radiotherapy) was 63.6% (P < 0.05). Median relapse-free survival was 28 and 14 months, respectively. Overall 5-year survival for all cases was 17%. Adverse prognostic factors at the univariate level were stage IV, constitutional symptoms, serum lactic dehydrogenase elevation and performance score (WHO 3-4). It is suggested that the treatment of stage IE/IIE TL should include early CCT and CNS prophylaxis. 相似文献
39.
Pollock B Burton M Kelly JW Gilbert S Winer E 《IEEE transactions on visualization and computer graphics》2012,18(4):581-588
Stereoscopic depth cues improve depth perception and increase immersion within virtual environments (VEs). However, improper display of these cues can distort perceived distances and directions. Consider a multi-user VE, where all users view identical stereoscopic images regardless of physical location. In this scenario, cues are typically customized for one "leader" equipped with a head-tracking device. This user stands at the center of projection (CoP) and all other users ("followers") view the scene from other locations and receive improper depth cues. This paper examines perceived depth distortion when viewing stereoscopic VEs from follower perspectives and the impact of these distortions on collaborative spatial judgments. Pairs of participants made collaborative depth judgments of virtual shapes viewed from the CoP or after displacement forward or backward. Forward and backward displacement caused perceived depth compression and expansion, respectively, with greater compression than expansion. Furthermore, distortion was less than predicted by a ray-intersection model of stereo geometry. Collaboration times were significantly longer when participants stood at different locations compared to the same location, and increased with greater perceived depth discrepancy between the two viewing locations. These findings advance our understanding of spatial distortions in multi-user VEs, and suggest a strategy for reducing distortion. 相似文献
40.
Murray Sean P. Raeker Evan B. Pusch Kira M. Frey Carolina Torbet Chris J. Zhou Ning Forsik Stéphane A. J. Dicus Austin D. Colombo Gian A. Kirka Michael M. Pollock Tresa M. 《Metallurgical and Materials Transactions A》2022,53(8):2943-2960
Metallurgical and Materials Transactions A - A high $$\gamma ^{\prime }$$ volume fraction CoNi-base superalloy with roughly equal amounts of cobalt and nickel was successfully processed through... 相似文献