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81.
B. Top A. G. Uitterlinden A. van der Zee J. J. P. Kastelein J. A. Gevers Leuven L. M. Havekes R. R. Frants 《Human genetics》1992,89(5):561-565
Summary Denaturing gradient gel electrophoresis (DGGE) was used in combination with the polymerase chain reaction (PCR) to detect sequence variations in the promoter region of the low density lipoprotein receptor (LDLR) gene. On the basis of calculated predictive melting properties we designed primers to amplify a 447-bp fragment of the promoter region from position-512 to -66, containing previously identified regulatory sequences. Using a primer with a GC-clamp in combination with restriction enzyme digestion, two melting domains could be analysed simultaneously. By oligonucleotide-directed mutagenesis artificial mutants were generated to optimize the conditions and to test the sensitivity of the method. All mutants were readily detected by electrophoresis in a 9% polyacrylamide gel containing a 10%–60% linear denaturing gradient. Using this method, we analysed DNA samples of 350 heterozygous familial hypercholesterolaemia (FH) patients. No mutations were detected, suggesting that mutations in the regulatory elements of the promoter sequence do not play a significant role in the etiology of FH. 相似文献
82.
Boekholdt SM Kuivenhoven JA Hovingh GK Jukema JW Kastelein JJ van Tol A 《Current opinion in lipidology》2004,15(4):393-398
PURPOSE OF REVIEW: Over the past decade lowering of low-density lipoprotein-cholesterol levels has been established as the foundation for preventing coronary artery disease, but substantial additional risk reduction remains to be gained by modifying risk factors other than low-density lipoprotein-cholesterol. Raising high-density lipoprotein-cholesterol levels by inhibiting activity of the cholesteryl ester transfer protein (CETP) is a prime target. Research on naturally occurring variants in the CETP gene has yielded numerous insights that have been relevant for understanding lipoprotein metabolism, and crucial to the development of pharmacological CETP inhibition. RECENT FINDINGS: This review discusses a number of recently published studies, including a haplotype analysis of the CETP promoter region confirming that the -629 C-->A variant, not the TaqIB variant, is instrumental in determining CETP activity, as previously suggested. In addition, we discuss a recent meta-analysis which confirms that the I405V and TaqIB variants are indeed associated with lower CETP activity and higher high-density lipoprotein-cholesterol levels. Also, we review two subanalyses of large randomized controlled pravastatin trials which found no evidence for a proposed pharmacogenetic interaction between the CETP TaqIB variant and pravastatin treatment. SUMMARY: The currently available evidence suggests that several genetic variants in the CETP gene are associated with altered CETP plasma levels and activity, high-density lipoprotein-cholesterol plasma levels, low-density lipoprotein and high-density lipoprotein particle size, and perhaps the risk of coronary artery disease. No evidence exists for a pharmacogenetic interaction between the CETP TaqIB variant and pravastatin efficacy. 相似文献
83.
IL-18 receptors, their role in ligand binding and function: anti-IL-1RAcPL antibody, a potent antagonist of IL-18 总被引:12,自引:0,他引:12
Debets R Timans JC Churakowa T Zurawski S de Waal Malefyt R Moore KW Abrams JS O'Garra A Bazan JF Kastelein RA 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(9):4950-4956
IL-18 is critical in eliciting IFN-gamma production from Th1 cells both in vitro and in vivo. Th1 cells have been implicated in the pathogenesis of autoimmune disorders, making antagonists of IL-18 promising therapeutics. However, specificity and binding characteristics of IL-18R components have only been superficially explored. In this study, we show that IL-1R related protein 1 (IL-1Rrp1) and IL-1R accessory protein-like (IL-1RAcPL) confer responsiveness to IL-18 in a highly specific (no response to other IL-1 ligands) and unique manner (no functional pairing with other IL-1Rs and IL-1R-like molecules). Cotransfection with both receptor components resulted in expression of both low and high affinity binding sites for IL-18 (K:(d) of 11 and 0.4 nM, respectively). We prepared anti-IL-1RAcPL mAb TC30-28E3, which, in contrast to soluble R proteins, effectively inhibited the IL-18-induced activation of NF-kappaB. Quantitative PCR showed that Th1 but not Th2 cells are unique in that they coexpress IL-1Rrp1 and IL-1RAcPL. mAb TC30-28E3 inhibited IL-18-induced production of IFN-gamma by Th1 cells, being at least 10-fold more potent than anti-IL-18 ligand mAb. This study shows that IL-1RAcPL is highly specific to IL-18, is required for high affinity binding of IL-18, and that the anti-IL-1RAcPL mAb TC30-28E3 potently antagonizes IL-18 responses in vitro, providing a rationale for the use of anti-IL-1RAcPL Abs to inhibit Th1-mediated inflammatory pathologies. 相似文献
84.
85.
Reed JZ Chambers C Hunter CJ Lockyer C Kastelein R Fedak MA Boutilier RG 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》2000,170(1):1-10
The respiratory physiology, heart rates and metabolic rates of two captive juvenile male harbour porpoises (both 28 kg) were
measured using a rapid-response respiratory gas analysis system in the laboratory. Breath-hold durations in the laboratory
(12 ± 0.3 s, mean ± SEM) were shorter than field observations, although a few breath-holds of over 40 s were recorded. The
mean percentage time spent submerged was 89 ± 0.4%. Relative to similarly-sized terrestrial mammals, the respiratory frequency
was low (4.9 ± 0.19 breaths · min−1) but with high tidal volumes (1.1 ± 0.01 l), enabling a comparatively high minute rate of gas exchange. Oxygen consumption
under these experimental conditions (247 ± 13.8 ml O2 · min−1) was 1.9-fold higher than predicted by standard scaling relations. These data together with an estimate of the total oxygen
stores predicted an aerobic dive limit of 5.4 min. The peak end-tidal O2 values were related to the length of the previous breath-hold, demonstrating the increased oxygen uptake from the lung for
the longer dives. Blood oxygen capacity was 23.5 ± 1.0 ml · 100 ml−1, and the oxygen affinity was high, enabling rapid oxygen loading during ventilation.
Accepted: 11 August 1999 相似文献
86.
Sankatsing RR de Groot E Jukema JW de Feyter PJ Pennell DJ Schoenhagen P Nissen SE Stroes ES Kastelein JJ 《Current opinion in lipidology》2005,16(4):434-441
PURPOSE OF REVIEW: Novel treatment modalities for cardiovascular prevention are emerging rapidly. Since it is virtually impossible to evaluate all these new compounds in long-term trials using clinical end points, there is an urgent need for validated surrogate markers of atherosclerosis to save both time and costs. Over the last decade, the use of imaging markers has been widely introduced into drug-development strategies. Here we will discuss the most commonly used techniques. RECENT FINDINGS: Whereas both testing of endothelial function, assessed as flow-mediated dilation, and assessment of carotid intima-media thickness have been shown to predict future cardiovascular events, predominantly intima-media thickness has been used successfully as a surrogate marker in intervention studies. More recently, standardization of intravascular ultrasound has also enabled reproducible assessment of coronary atheroma volume. Multidetector computed tomography and electron-beam computed tomography have proven useful in providing quantitative information on plaque burden and coronary calcium content, respectively. Although cardiovascular magnetic resonance (CMR) is improving continuously, additional technical improvements will be mandatory before this technique can be implemented in multicenter clinical studies. SUMMARY: The imaging modalities reviewed here all provide specific information on either functionality or morphology of the vasculature. The value of carotid intima-media thickness for cardiovascular risk prediction has been studied most extensively. Whereas assessment of plaque burden using intravascular ultrasound appears to be the most direct way to quantify coronary changes, its predictive value for future cardiovascular events remains to be established. Awaiting further technical improvements, CMR is expected to provide the most valuable information for the evaluation of atherosclerosis in the near future. 相似文献
87.
Nieuwdorp M Meuwese MC Vink H Hoekstra JB Kastelein JJ Stroes ES 《Current opinion in lipidology》2005,16(5):507-511
PURPOSE OF REVIEW: Although cardiovascular prevention has improved substantially, we still face the challenge of finding new targets to reduce the sequelae of atherosclerosis further. In this regard, optimizing the vasculoprotective effects of the vessel wall itself warrants intensive research. In particular, the endothelial glycocalyx, consisting of proteoglycans, glycoproteins and adsorbed plasma proteins, may play an essential role in protecting the vessel wall from atherosclerosis. RECENT DEVELOPMENTS: In this review, we will discuss the different vasculoprotective effects exerted by the endothelial glycocalyx, the factors that damage it, and the first preliminary data on the glycocalyx dimension in humans. Whereas most glycocalyx research has traditionally focused on the microvasculature, more recent data have underscored the importance of the glycocalyx in protecting the macrovasculature against pro-atherogenic insults. It has been shown that glycocalyx loss is accompanied by a wide array of unfavourable changes in both small and larger vessels. Pro-atherogenic stimuli increase the shedding of glycocalyx constituents into the circulation, contributing to the progressive loss of the vasculoprotective properties of the vessel wall. Novel techniques have facilitated reproducible measurements of systemic glycocalyx volume in humans. Consistent with experimental data, the volume of the human glycocalyx is also severely perturbed by exposure to atherogenic risk factors. SUMMARY: Cumulating evidence suggests that an intact glycocalyx protects the vessel wall, whereas disruption of the glycocalyx upon atherogenic stimuli increases vascular vulnerability for atherogenesis. 相似文献
88.
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90.
Stephanie Maiwald Suthesh Sivapalaratnam Mahdi M. Motazacker Julian C. van Capelleveen Ilze Bot Saskia C. de Jager Miranda van Eck Jennifer Jolley Johan Kuiper Jonathon Stephens Cornelius A. Albers C. Ruben Vosmeer Heleen Kruize Daan P. Geerke Allard C. van der Wal Chris M. van der Loos John J. P. Kastelein Mieke D. Trip Willem H. Ouwehand Geesje M. Dallinga-Thie G. Kees Hovingh 《PloS one》2014,9(5)