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1.
In human Y-79 retinoblastoma cells corticotropin-releasing hormone (CRH) produces a marked and rapid increase of adenylate cyclase activity. The concentration of the peptide producing half-maximal stimulation is 60 nM. The effect of CRH is significantly antagonized by the specific CRH receptor antagonist alpha-helical CHR 9-41 and is mimicked by sauvagine and urotensin I, two peptides displaying sequence homology with CRH. These results demonstrate the presence of functional CRH receptors in human Y-79 retinoblastoma cells and suggest that this cell line may be a suitable model in which to study the action of CRH on human retinal cell function. 相似文献
2.
Jun Ishigooka Mitsukuni Murasaki Hirobumi Wakatabe Sadanori Miura Kozo Hikida Masahiro Shibata 《Psychopharmacology》1989,97(3):303-308
The pharmacokinetic properties of the iminodibenzyl antipsychotic drugs clocapramine (CCP, 3-chloro-5-[3-(4-carbamoyl-4-piperidino piperidino) propyl]-10, 11-dihydro-5H-dibenzo[b, f]azepine) and Y-516 (3-chloro-5-[3-(2-oxo-1, 2, 3, 5, 6, 7, 8, 8a-octahydroimidazo [1,2-a] pyridine-3-spiro-4-piperidino) propyl]-10, 11-dihydro-5H-dibenzo[b, f]azepine) were investigated in dog and man. Dogs were administered CCP and Y-516 intravenously, intraperitoneally, and orally, and the concentrations of the parent drugs and their metabolites in the plasma and urine were determined. Half-life (t1/2) was approximately the same by all three administration routes, being approximately 5 h for CCP and 3 h for Y-516. Bioavailability following oral administration was 0.16±0.01 (mean ± SD, n=3) for CCP and 0.29±0.07 for Y-516. The fractions of dose absorbed following oral administration were 0.43±0.07 and 0.79±0.24, and the fractions of dose metabolized in the liver due to the first-pass effect were 0.63±0.05 and 0.63±0.04 for CCP and Y-516, respectively. Y-516 was detected in the plasma after intraperitoneal and oral administration of CCP. The ratio of the AUC of Y-516 to that of CCP was 0.06 following intraperitoneal administration and 0.40 following oral administration. This indicated that while the metabolism of CCP into Y-516 may occur partly in the liver due to the first-pass effect, it occurs mostly within the gastrointestinal tract itself or its mucosa. When CCP and Y-516 were given orally to man, the plasma concentrations of both parent drugs increased in a dose-dependent manner. The t1/2 of CCP at a dose of 50 mg was 46±6 h (n=3) while that of Y-516 at a dose of 25 mg was 15±2 h (n=5), so that elimination from the circulation was slower than in the dog in both cases. As in the dog, Y-516 was detected in the plasma following administration of CCP, but its concentration was approximately one fifth that of CCP and lower than that found in the dog. From the ratios of Y-516 produced upon oral administration of CCP in dog and man, we concluded that Y-516 is involved to a considerable degree in the pharmacological action of CCP in the dog and, though to a lesser degree, in man as well. 相似文献
3.
研究Rho激酶抑制剂Y27632 对视网膜缺血再灌注损伤大鼠视网膜组织形态学的影响。方法:实验研究。将60只SD大鼠随机分为4组,每组15只:正常对照组(正常组)、急性缺血再灌注损伤组(IRI组)、0.9%氯化钠溶液对照组(生理盐水组)、Y27632治疗组(Y27632组)。再灌注损伤后24 h(10只)和168 h(5只)处死各组动物,行HE染色、ADP酶染色检查,光镜下观察大鼠视网膜组织病理学变化及视网膜厚度变化。数据采用单因素方差分析。结果:正常组大鼠视网膜结构清晰,三层细胞结构排列整齐。IRI组于再灌注24 h后视网膜厚度增加,内外丛状层组织疏松,视网膜节细胞、内外核层细胞水肿明显、排列紊乱,视网膜节细胞减少。168 h后,视网膜水肿消退、厚度变薄、呈萎缩状,神经节细胞及内外核层细胞数量减少,在视网膜前和神经纤维层可见毛细血管。再灌注
24 h后,IRI组视网膜厚度较正常组增加(P=0.005),Y27632组视网膜厚度低于生理盐水组(P=0.032)。再灌注168 h后,IRI组视网膜厚度低于正常组(P<0.001),Y27632组视网膜厚度较生理盐水组增加(P=0.025)。正常组大鼠视网膜血管自视乳头发出,向四周呈放射状均匀分布,毛细血管网结构清晰。再灌注24 h后,IRI组视网膜血管管径变细,走行较僵直,分支减少,视乳头周围及中周部视网膜可见大片无灌注区,无灌注区周围可见新生血管芽渐成网状。Y27632组可见视乳头周围及中周部视网膜局部无灌注区形成,无灌注区周围可见新生血管。后极部4PD无灌注区面积明显小于IRI组及生理盐水组。结论:Y27632玻璃体腔注射可以减轻视网膜缺血再灌注早期的视网膜水肿,减少视网膜神经节细胞的凋亡,减少视网膜新生血管生成,减轻再灌注晚期的视网膜萎缩,具有视神经保护作用。 相似文献
4.
Y‐27632 simplifies the isolation procedure of human primary epidermal cells by selectively blocking focal adhesion of dermal cells 下载免费PDF全文
Jie Wen Tingjian Zu Qian Zhou Xue Leng Xunwei Wu 《Journal of tissue engineering and regenerative medicine》2018,12(2):e1251-e1255
Primary skin epidermal cells isolation and in vitro expansion culture have been widely used for laboratory research and clinical applications. The conventional methods involving sequential enzymatic digestion of adult tissues have given low cell recovery rate and reduced cell viability. We report here an advanced method for human primary epidermal progenitor cells isolation from skin tissues including the Rho kinase inhibitor Y‐27632. Compared with traditional protocols, the current protocol is simple, easy, and faster; moreover, it gives a greater yield of integrin‐expressing epithelial stem cells. In addition, our new methodology does not require a separation of epidermis from dermis because the medium selectively blocks focal adhesion and growth of dermal cells. Importantly, the cells isolated from this method can maintain their regeneration potential and quickly reconstitute a mature human skin in vivo after grafting onto nude mice. In brief, we describe here a simple (one step) and serum‐free method for isolating primary epidermal stem cells from adult tissues. The isolated cells may be widely used for both laboratory studies and clinical application, especially in the field of tissue engineering and regeneration. 相似文献
5.
目的 探讨Rho相关激酶(ROCK)抑制剂Y27632在小鼠腔前卵泡体外发育中的作用。 方法 取出生12.5 d的小鼠卵巢,机械法收集单枚腔前卵泡,采用超低吸附96孔板模拟3D环境对其进行培养。设置对照组和含有Y27632的实验组,通过形态学观察、卵泡直径的变化、成熟卵泡的数量、成熟卵母细胞纺锤体的变化等来评估卵泡的整体发育情况。采用Real-time PCR技术检测颗粒细胞中卵泡刺激素受体(FSHR)、卵母细胞中骨形态发生蛋白15(BMP15)、生长分化因子9(GDF9)等以及凋亡相关基因(Bad、Bax和Caspase-3)的表达情况,同时,用细胞存活染料检测卵泡发育过程中颗粒细胞的凋亡情况。 结果 ROCK抑制剂Y27632对卵泡直径增长和基本发育指标(存活数、成腔率和成熟率)无明显影响(P>0.05),但对照组卵母细胞成熟后纺锤体组装出现异常。培养8 d后,与对照组相比,实验组颗粒细胞特异性基因FSHR上调;卵母细胞特异性基因BMP15和GDF9上调,而叉头框O3(FoxO3)下调;凋亡基因Bax、Bad和Caspase3表达下调,实验组卵泡内的颗粒细胞凋亡明显少于对照组。 结论 小鼠卵泡体外发育过程中,ROCK抑制剂Y27632能够抑制颗粒细胞的凋亡,防止卵母细胞纺锤体组装异常,进而提高卵泡体外发育质量。 相似文献
6.
目的:探讨Rho激酶抑制剂Y-27623对心肌缺血再灌注损伤(MIRI)中细胞凋亡的影响,以及对丝裂原活化蛋白激酶(Mitogen-activated protein kinase,MAPK)和凋亡相关蛋白表达水平的变化和意义。方法:成年雄性SD大鼠60只, 随机分为4组(n=15):正常对照组(Sham组) 、缺血再灌注组(ischemia-reperfusion即I/R组) 、Dil组( diltiazem即地尔硫卓组)、Y-27632组。Dil组每日给予地尔硫卓(10mg/kg)灌胃, Y-27632组每日给予Y-27632(5mg/kg),其余两组给予等体积清水。给药五天后Sham组只穿线,不结扎冠状动脉左前降支,I/R组、Dil组和Y-27632组建立MIRI模型。TUNEL法检测各组心肌凋亡,计算心肌细胞凋亡指数(AI),western blotting 法检测心肌组织中MAPK信号传导途径相关蛋白(p-JNK/ERK/P38)和凋亡相关蛋白(Bcl-2、Bax、Caspase-3和Caspase-9)的表达。结果:相对于Sham组,I/R组AI明显增加(P<0.01),MAPK信号传导途径和心肌促凋亡相关蛋白(Bax、Caspase-3和Caspase-9)表达显著增加(均为P<0.05),心肌抗凋亡蛋白Bcl-2表达显著减少(P<0.05);相对于I/R组,Y-27632治疗组AI明显下降(P<0.01),与Dil治疗组没有显著差异(P>0.05),Y-27632治疗组MAPK信号传导途径相关蛋白和Bax、Caspase-3和Caspase-9表达均显著降低(P<0.05),Bcl-2表达显著增加(P<0.05),与Dil治疗组没有显著差异(P>0.05)。结论:Y-27632通过抑制JNK/ERK/P38的磷酸化,抑制Bax、Caspase-3和Caspase-9的表达,加强Bcl-2的表达,来减少心肌细胞的凋亡,从而减轻心肌缺血再灌注损伤。 相似文献
7.
Timo KIRSCHSTEIN Chris PROTZEL Katrin PORATH Tina SELLMANN Rudiger KOHLING Oliver W HAKENBERG 《Acta pharmacologica Sinica》2014,35(1):74-81
Aim: Activation of muscarinic receptors on the detrusor smooth muscle is followed by contraction, which involves both myosin light chain kinase (MLCK) and Rho kinase (ROCK). The aim of this study was to determine the relative contributions of MLCK and ROCK to carbachol-induced contraction of human detrusor smooth muscle in vitro.
Methods: Detrusor smooth muscle strips were prepared from the macroscopically unaffected bladder wall of patients underwent cystectomy. The strips were fixed in an organ bath, and carbachol or KCl-induced isometric contractions were measured by force transducers.
Results: Addition of carbachol (0.4-4 μmol/L) into the bath induced concentration-dependent contractions of detrusor specimens, which was completely abolished by atropine (1 μmol/L). Pre-incubation of detrusor specimens with either the MLCK inhibitor ML-9 or the ROCK inhibitors HA1100 and Y-27632 (each at 10 μmol/L) significantly blocked carbachol-induced contractions as compared to the time-control experiments. Moreover, MLCK and ROCK inhibition were equally effective in reducing carbachol-induced contractions. The residual carbachol-induced contractions in the presence of both MLCK and ROCK inhibitors were significantly smaller than the contractions obtained when only one enzyme (either MLCK or ROCK) was inhibited, suggesting an additive effect of the two kinases. Interestingly, ROCK-mediated carbachol-induced contractions were positively correlated to the age of patients (r=0.52, P〈0.05).
Conclusion: Both MLCK and ROCK contribute to carbachol-induced contractions of human detrusor smooth muscle. ROCK inhibitors may be a new pharmacological approach to modulate human bladder hyperactivity. 相似文献
Methods: Detrusor smooth muscle strips were prepared from the macroscopically unaffected bladder wall of patients underwent cystectomy. The strips were fixed in an organ bath, and carbachol or KCl-induced isometric contractions were measured by force transducers.
Results: Addition of carbachol (0.4-4 μmol/L) into the bath induced concentration-dependent contractions of detrusor specimens, which was completely abolished by atropine (1 μmol/L). Pre-incubation of detrusor specimens with either the MLCK inhibitor ML-9 or the ROCK inhibitors HA1100 and Y-27632 (each at 10 μmol/L) significantly blocked carbachol-induced contractions as compared to the time-control experiments. Moreover, MLCK and ROCK inhibition were equally effective in reducing carbachol-induced contractions. The residual carbachol-induced contractions in the presence of both MLCK and ROCK inhibitors were significantly smaller than the contractions obtained when only one enzyme (either MLCK or ROCK) was inhibited, suggesting an additive effect of the two kinases. Interestingly, ROCK-mediated carbachol-induced contractions were positively correlated to the age of patients (r=0.52, P〈0.05).
Conclusion: Both MLCK and ROCK contribute to carbachol-induced contractions of human detrusor smooth muscle. ROCK inhibitors may be a new pharmacological approach to modulate human bladder hyperactivity. 相似文献
8.
The low plasticity of high strength Mg-Gd-Y alloy has become the main obstacle to its application in engineering. In this paper, the origin, propagation and fracture processes of cracks of a solution of treated Mg-13Gd-5Y-3Zn-0.3Zr alloy were observed and studied with scanning electron microscopy (SEM) in an in situ tensile test to provide theoretical references for the development of a new high-performance Mg-Gd-Y alloy. The results showed that there was still some bulk long period stacking order (LPSO) phase remaining in solid solution Mg-13Gd-5Y-3Zn-0.3Zr alloy. Most importantly, it was found that the locations of micro-cracks vary with the different solution treatment processes, mainly including the following three types. (1) At 480 × 10 h and 510 °C × 10 h, much bulk LPSO phase with higher elastic modulus remains in the alloy, which can lead to micro-cracks in the LPSO phase due to stress concentration. (2) At 510 °C × 13 h and 510 °C × 16 h, the phase structure of bulk LPSO changes, and the stress concentration easily appears at the LPSO/α-Mg interface, which leads to micro-cracks at the interface. (3) At 510 °C × 19 h and 510 °C × 22 h, the grain size increases, and the stress concentration is obvious at the grain boundary of coarse grains, which leads to the formation of micro-cracks. 相似文献
9.
Comparison exercises involving 90Y and 177Lu were performed during 2009 and 2012, respectively, to assess the measurement capability of hospitals in the UK and Europe. The results from the measurement of a typical liquid solution of 90Y show that only 40% of participants could measure the solution to within 5% of the certificated value and that a significant −6% bias was present due to the use of non-standard geometries for the calibration of equipment. The results from the measurement of a standard liquid solution of 177Lu show that 81% of participants could measure to within 5% of the certificated value and in fact 65% of these results were within 2% of the certificated value, showing administered activities can be far more accurately measured for 177Lu than for 90Y and that 177Lu has a far smaller geometry dependence. These studies were performed to identify specific measurement issues in the user community and to identify areas where future research should be focused. In addition to this the work allows the participants to adjust measurement practice and identify key measurement issues. 相似文献
10.
The role of Rho kinase activation in the regulation of cardiac contractility and Ca2+ signaling remains unclear, whereas its role in smooth muscle regulation has been well documented. To study the potential role of Rho kinase in the regulation of cardiac contractility and Ca2+ transients induced by endothelin-1 (ET-1) and isoproterenol, we used the Rho kinase inhibitor Y-27632 in rabbit ventricular myocardium and myocytes loaded with indo-1/AM. Y-27632 (3–30 M) inhibited significantly the baseline contractility and Ca2+ transients. Furthermore, Y-27632 suppressed the increase in contractility and Ca2+ transients induced by ET-1 in a concentration-dependent manner, when it was used in a concentration at which it did not affect the effects of isoproterenol via -adrenoceptors. In the presence of Y-27632, ET-1 increased cell shortening in the absence of an increase in Ca2+ transients. This is an indication that the increase in myofilament Ca2+ sensitivity induced by ET-1 is less susceptible to the inhibitory action of Y-27632. These findings imply that the Rho kinase activation may partially contribute to the ET-1-induced regulation of contractility, primarily due to an ET-1-induced increase in Ca2+ transients in rabbit ventricular myocardium. 相似文献