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21.
Steroid actions on the vascular wall have been thought to depend on direct, genomic mechanisms being characterized by a considerable delay and on secondary events, including changes of coagulation, plasma lipids, and renal electrolyte and volume regulation. Recently, rapid effects of steroids on the vascular wall have been reported being clearly incompatible with the classical theory of genomic steroid action. As these effects occur in classical target tissues for genomic steroid action, and modulation of intracellular signaling has been shown to influence genomic steroid action, a two-step model of steroid action was developed integrating both genomic and nongenomic aspects and their possible interaction. This review summarizes recent studies on both types of direct, vascular steroid actions, the swift and the sluggish ones, and discusses the role of these actions in regulation of circulatory homeostasis and their potential therapeutic implications. 相似文献
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RI Connor BT Korber BS Graham BH Hahn DD Ho BD Walker AU Neumann SH Vermund J Mestecky S Jackson E Fenamore Y Cao F Gao S Kalams KJ Kunstman D McDonald N McWilliams A Trkola JP Moore SM Wolinsky 《Canadian Metallurgical Quarterly》1998,72(2):1552-1576
We have studied 18 participants in phase I/II clinical trials of recombinant gp120 (rgp120) subunit vaccines (MN and SF-2) who became infected with human immunodeficiency virus type 1 (HIV-1) during the course of the trials. Of the 18 individuals, 2 had received a placebo vaccine, 9 had been immunized with MN rgp120, and seven had been immunized with SF-2 rgp120. Thirteen of the 18 infected vaccinees had received three or four immunizations prior to becoming infected. Of these, two were placebo recipients, six had received MN rgp120, and five had received SF-2 rgp120. Only 1 of the 11 rgp120 recipients who had multiple immunizations failed to develop a strong immunoglobulin G antibody response to the immunogen. However, the antibody response to rgp120 was transient, typically having a half-life of 40 to 60 days. No significant neutralizing activity against the infecting strain was detected in any of the infected individuals at any time prior to infection. Antibody titers in subjects infected despite vaccination and in noninfected subjects were not significantly different. Envelope-specific cytotoxic T-lymphocyte responses measured after infection were infrequent and weak in the nine vaccinees who were tested. HIV-1 was isolated successfully from all 18 individuals. Sixteen of these strains had a non-syncytium-inducing (NSI) phenotype, while two had a syncytium-inducing (SI) phenotype. NSI strains used the CCR5 coreceptor to enter CD4+ cells, while an SI strain from one of the vaccinees also used CXCR4. Viruses isolated from the blood of rgp120 vaccinees were indistinguishable from viruses isolated from control individuals in terms of their inherent sensitivity to neutralization by specific monoclonal antibodies and their replication rates in vitro. Furthermore, genetic sequencing of the env genes of strains infecting the vaccinees did not reveal any features that clearly distinguished these viruses from contemporary clade B viruses circulating in the United States. Thus, despite rigorous genetic analyses, using various breakdowns of the data sets, we could find no evidence that rgp120 vaccination exerted selection pressure on the infecting HIV-1 strains. The viral burdens in the infected rgp120 vaccine recipients were also determined, and they were found to be not significantly different from those in cohorts of placebo-vaccinated and nonvaccinated individuals. In summary, we conclude that vaccination with rgp120 has had,to date, no obvious beneficial or adverse effects on the individuals we have studied. 相似文献
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AU Rivin 《Canadian Metallurgical Quarterly》1981,56(2):141-143
24.
Freeman-Sheldon's syndrome is a rare genetic disease inherited as an autosomal dominant trait in some families but showing sporadic appearance in the majority of the reported cases. In the present paper we report a family having two affected children from normal consanguineous parents suggesting that Freeman-Sheldon's syndrome may be heterogeneous from the genetic point of view. 相似文献
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R Ziyal AU Ziganshin P Nickel U Ardanuy E Mutschler G Lambrecht G Burnstock 《Canadian Metallurgical Quarterly》1997,120(5):954-960
1. The effects of NF023, the symmetrical 3'-urea of 8-(benzamido)naphthalene-1,3,5-trisulphonic acid), and its parent compound suramin were investigated on vasoconstrictor responses to alpha, beta-methylene ATP in rabbit isolated saphenous artery and vasodilator responses to ATP in noradrenaline-precontracted rabbit isolated thoracic aorta. 2. In rabbit isolated saphenous artery, alpha, beta-methylene ATP-induced vasoconstrictor responses via P2X-receptors were concentration-dependently and competitively antagonised by NF023 (30-300 microM; pA2 = 5.69 +/- 0.04). Suramin (100-1000 microM) also competitively blocked vasoconstrictor responses to alpha, beta-methylene ATP, albeit with lower potency (pA2 = 4.79 +/- 0.05). In contrast, NF023 (100 microM) did not significantly affect contractile responses to noradrenaline or histamine in the saphenous artery. 3. In noradrenaline-precontracted rabbit isolated thoracic aorta preparations, ATP (3-3000 microM) concentration-dependently induced relaxations via endothelium-dependent or smooth muscle P2Y-receptor subtypes. NF023 (30-300 microM) failed to block relaxant responses to ATP at endothelium-dependent P2Y-receptors, whereas suramin (100-1000 microM) did antagonise endothelium-dependent vasodilator responses to ATP. Neither NF023 (100 microM) nor suramin (300 microM) influenced vasorelaxant responses to ATP via endothelium-independent P2Y-receptors. 4. In conclusion, this study outlines the selectivity of NF023 as an effective P2X-receptor antagonist in rabbit isolated blood vessels without affecting endothelium-dependent or endothelium-independent P2Y-receptor subtypes, adrenoceptors or histamine receptors. 相似文献
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提出了一种基于I_c数据自动划分土层的贝叶斯方法,所提方法不仅能够在考虑I_c的空间变异性的条件下自动划分土层,识别最可能的土层界面,而且能够定量地表征土层界面的不确定性,为制定下一步勘探方案和岩土工程设计提供参考依据。本文采用基于子集模拟的贝叶斯更新方法(CBUS)求解贝叶斯方程,产生土层厚度的后验分布样本,并计算每个可能的土层数目对应的模型证据,确定最可能土层数和最可能的土层界面深度,计算界面深度的标准差作为土层界面不确定性的量化指标。最后,通过上海市轨道交通10号线伊犁站基坑开挖现场的I_c数据和模拟I_c数据说明了所提方法的有效性和正确性。结果表明:所提方法划分的土层合理地反映了不同土层I_c的统计特性。相邻土层I_c的统计特性差异越大,界面深度的标准差越小,识别出的土层界面越可靠,反之亦然。 相似文献
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JM Pawlotsky G Germanidis AU Neumann M Pellerin PO Frainais D Dhumeaux 《Canadian Metallurgical Quarterly》1998,72(4):2795-2805
A 40-amino-acid sequence located in the nonstructural 5A (NS5A) protein of hepatitis C virus genotype 1b (HCV-1b) was recently suggested to be the interferon sensitivity-determining region (ISDR), because HCV-1b strains with an ISDR amino acid sequence identical to that of the prototype strain HCV-J were found to be resistant to alpha interferon (IFN-alpha) whereas strains with amino acid substitutions were found to be sensitive (N. Enomoto, I. Sakuma, Y. Asahina, M. Kurosaki, T. Murakami, C. Yamamoto, N. Izumi, F. Marumo, and C. Sato, J. Clin. Invest. 96:224-230, 1995; N. Enomoto, I. Sakuma, Y. Asahina, M. Kurosaki, T. Murakami, C. Yamamoto, Y. Ogura, N. Izumi, F. Marumo, and C. Sato, N. Engl. J. Med. 334:77-81, 1996). We used single-strand conformation polymorphism (SSCP) analysis, combined with cloning and sequencing strategies, to characterize NS5A quasispecies in HCV-1b-infected patients and determine the relationships between pre- and posttreatment NS5A quasispecies mutations and the IFN-alpha sensitivity of HCV-1b. The serine residues involved in phosphorylation of NS5A protein were highly conserved both in the various patients and in quasispecies in a given patient, suggesting that phosphorylation is important in NS5A protein function. A hot spot for amino acid substitutions was found at positions 2217 to 2218; it could be the result of either strong selection pressure or tolerance to these amino acid replacements. The proportion of synonymous mutations was significantly higher than the proportion of nonsynonymous mutations, suggesting that genetic variability in the region studied was the result of high mutation rates and viral replication kinetics rather than of positive selection. Sustained HCV RNA clearance was associated with low viral load and low nucleotide sequence entropy, suggesting (i) that the replication kinetics when treatment is started plays a critical role in HCV-1b sensitivity to IFN-alpha and (ii) that HCV-1b resistance to IFN-alpha could be conferred by numerous and/or related mutations that could be patient specific and located at different positions throughout the viral genome and could allow escape variants to be selected by IFN-alpha-stimulated immune responses. No NS5A sequence appeared to be intrinsically resistant or sensitive to IFN-alpha, but the HCV-J sequence was significantly more frequent in nonresponder quasispecies than in sustained virological responder quasispecies, suggesting that the balance between NS5A quasispecies sequences in infected patients could have a subtle regulatory influence on HCV replication. 相似文献