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991.
Memantine (1-amino-3,5-dimethyladamantan) was tested as an antagonist of N-methyl-d-aspartate (NMDA) receptors on cultured superior collicular and hippocampal neurones using the patch clamp technique and its actions were compared to those of Mg2+ ions, ketamine, dextrorphan, dextromethorphan, phencyclidine and dizocilpine (MK-801). Memantine (2–33 μM) concentration-dependently antagonized responses to NMDA 100 μM with an IC50 of 2.92 ± 0.05 μM. In contrast, current responses to (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (l-AMPA 50–100 μM) and γ-amino butyric acid (GABA 10 μM) were unaffected by Memantine 8 μM. Memantine 8 μM caused a non-parallel shift of the NMDA concentration-response curve to the right in a manner indicative of uncompetitive open channel block. The effects of memantine were similar to ketamine in that both antagonists were weakly use- and strongly voltage-dependent. In contrast, MK-801, phencyclidine and dextrorphan showed much slower kinetics that was reflected in their marked use- and weaker voltage-dependency. The antagonistic effects of memantine were not reversed by increasing concentrations of glycine (0.1–100 μM) ruling out the possibility of an interaction of memantine with the strychnine-insensitive glycine modulatory site associated with the NMDA receptor-channel complex. Memantine (1–100 μM) also selectively antagonized responses to NMDA (40 μM) in the cortical wedge preparation with IC50 of 12.9 ± 1.5 μM. 相似文献
992.
M Fujita H Egawa T Miyamoto J Nakano J Matsumoto 《European journal of medicinal chemistry》1996,31(12):981-988
Diethyl 1-cyclopropyl-5,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3,6-dicarboxylate 4 as a key-intermediate was synthesized via the Dieckmann reaction. The reaction of 4 with nucleophiles proceeded regioselectively at C-5. Facile cyclization between the C-5 and C-6 side chains of the resulting products gave novel pyrroloquinolones 10 and 12 and pyrazoloquinolones 15. They were converted into a series of cyclic amino-substituted pyrroloquinolones 17–21 and pyrazoloquinolones 22–24, and their in vitro antibacterial activities were tested. 1H-Pyrrolo[2,3-f]quinolone 17a and 2H-pyrrolo[3,4-f]quinolone 21a exhibited a potent in vitro antibacterial activity. 相似文献
993.
健康成年金黄仓鼠腹腔内接种PVH-1(5×106pfu),FCM动态检测肝细胞DNA周期动力学变化,结果显示:PVH-1接种后处于G0+G1期的肝细胞与对照组动物相比无显著差异。S期肝细胞在第3天显著高于对照组动物(P<0.05),且在第7天时仍呈上升趋势,第14天到30天趋于正常水平。G2+M期肝细胞在PVH-1接种后第30天升高(P<0.05)。结果提示,动物在PVH-1接种后第3到第7天是病毒在肝细胞中的复制高峰,并阻滞仓鼠处于S期肝细胞分裂进入G2+M期,但是这种阻滞作用较短暂、并可逆,在PVH-1接种后14~30天自然消失。 相似文献
994.
J. De Vry 《Psychopharmacology》1995,121(1):1-26
During the last decade, serotonin (5-HT)1A receptors have been a major target for neurobiological research and drug development. 5-HT1A receptors have been cloned and a variety of selective agonists, such as the aminotetraline 8-OH-DPAT and the pyrimidinylpiperazine ipsapirone, have become available. Demonstrations of apparent intrinsic activity of these ligands at 5-HT1A receptors, however, depend highly on the particular assay system. This may be due to the possible existence of receptor subtypes and to assay (or brain region)-dependent differences in receptor reserve and the nature of receptor-effector coupling. Nevertheless, the apparent intrinsic activity of 8-OH-DPAT seems to be higher (although possibly not yet maximal) than that of the pyrimidinylpiperazines. In the brain, 5-HT1A receptors are located presynaptically as somatodendritic receptors on 5-HT neurons and postsynaptically in particular limbic and cortical regions. Although it is generally accepted that presynaptic 5-HT1A receptors control 5-HT neuronal activity, recent evidence suggests an additional role of postsynaptic 5-HT1A receptors in cortex as part of a negative feedback loop. Anxiolytic and antidepressive properties of selective 5-HT1A receptor agonists have now been confirmed by clinical studies. Although it is well established that the latter properties depend on theagonistic activity of these compounds, theoptimal level of intrinsic activity is still a matter of debate and may be dependent on the clinical indication. Such compounds may also have antiaggressive effects, and possibly anticraving effects (manifested by their alcohol intake-reducing effects in dependent animals), but the specificity of these so-called anti-impulsivity effects is still controversial and not yet tested clinically. Anticataleptic, antiemetic and neuroprotective properties have been demonstrated in different species. Behavioral studies on the mechanisms underlying the anxiolytic and antidepressive effects have examined the relative contribution of pre-and postsynaptic 5-HT1A receptors by means of local cerebral application and lesion techniques. Most evidence points towards a critical involvement of presynaptic receptors in the anxiolytic effects of 5-HT1A receptor agonists (although a possible contribution of postsynaptic receptors cannot be excluded). With regard to the antidepressive properties, a case can be made for the reverse; i.e., a strong involvement of postsynaptic receptors and a questionable contribution of presynaptic receptors. However, as the therapeutic effects of those 5-HT1A receptor (partial) agonists which have been tested clinically require repeated administration, attention has been directed increasingly towards chronic studies. These studies have shown that a number of electrophysiological, biochemical, behavioral and endocrinological 5-HT1A receptor-related events adapt differentially to repeated or sustained administration. Thus, several hypotheses accounting for the delayed onset of action have been advanced. Among these, time-dependent downregulation /desensitization of eitherpre- orpostsynaptic 5-HT1A receptors, or cortical 5-HT2 receptors have received much attention. However, these hypotheses have their weaknesses, and it is argued thatfunctional sensitization of particular postsynaptic 5-HT1A receptor-mediated events remains a valuable alternate hypothesis. Basic research on the role of 5-HT1A receptors in psychopathology and in the therapeutic effects of clinically effective therapeutics, as well as on the mechanism of action of 5-HT1A receptor ligands, will enable rational design of ligands with particular profiles of intrinsic activity at different 5-HT1A receptor populations, and may contribute to a more efficient treatment of a multiplicity of brain disorders. 相似文献
995.
P物质及其受体在慢性胰腺炎组织的表达和临床意义 总被引:3,自引:1,他引:2
目的 了解P物质及其受体NK-1R在正常胰腺和慢性胰腺炎中的表达,探讨它们与慢性胰腺炎时疼痛发生的关系。方法 25个慢性胰腺炎标本取自慢性胰腺炎手术,男性18例,女性7例,正常胰腺组织取自20个器官捐献者,男性11例,女性9例。应用实时定量逆转录整合酶链反应(RT-PCR)技术,检测正常胰腺和慢性胰腺炎组织中P物质和NK-1R的mRNA水平,应用Western blot技术检测NK-1R的蛋白水平,应用免疫组织化学方法进行NK-1R的组织学定位。将P物质及其受体NK-1R mRNA水平与疼痛的程度,发作频率和病程进行分析,寻找其中的相关性。结果 与正常胰腺相比,慢性胰腺炎组织中P物质和NK-1R mRNA和蛋白都过度表达,NK-1RmRNA水平与疼痛的程度,发作频率和病程明显相关。免疫组化检查显示,NK-1R的表达主要位于胰腺腺泡,胰腺导管,神经纤维和炎性细胞。结论 慢性胰腺炎组织中P物质和NK-1R的表达水平都明显上调,扰乱了神经激肽的作用环节,NK-1R的过度表达与疼痛发生有关。 相似文献
996.
血红素氧合酶-1对大鼠肾缺血再灌注损伤的保护作用 总被引:8,自引:4,他引:4
目的 探讨钴卟啉 (CoPP)诱导的血红素氧合酶 (HO) 1高表达对大鼠肾缺血再灌注损伤 (IRI)的保护作用。方法 建立大鼠肾缺血再灌注损伤模型 ,随机将动物分为假手术组 ,对照组和实验组。动态检测血尿素氮 (BUN)、肌酐 (Cr)、超氧化物岐化酶 (SOD)、丙二醛 (MDA)的含量以及进行肾组织光镜形态学观察和酶联免疫吸附试验 (ELISA)和Westernblot分析HO 1。结果 对照组BUN、Cr升高 ,SOD下降 ,MDA升高 ,HO 1中度提高 (14 4.5± 13 .6) ,肾组织结构紊乱。实验组除HO 1含量大幅提高外 (62 9.4± 78.9) ,尚能显著逆转上述改变 ,两组间差异具有统计学意义 (P <0 .0 5 )。结论 CoPP预处理诱导HO 1在肾缺血之前高表达可通过清除氧自由基 (OFRs)而减轻大鼠肾IRI。 相似文献
997.
MMP-9和TIMP-1在实验性肺气肿大鼠肺组织中的表达及其意义 总被引:2,自引:0,他引:2
目的研究基质金属蛋白酶(MMP-9)及其组织抑制因子(TIMP-1)在弹性蛋白酶所致肺气肿大鼠肺组织中的表达.方法雄性Wistar大鼠20只,随机分为两组:正常对照组和肺气肿模型组,每组10只.模型组大鼠气管内滴入弹性蛋白酶复制肺气肿模型.25d后,观察各组大鼠肺组织的病理改变,免疫组化方法观察肺组织MMP-9和TIMP-1中的蛋白表达情况.结果肺气肿模型组MMP-9和TIMP-1的表达与正常对照组相比明显增强(P<0.01),且MMP-9/TIMP-1比值失衡.结论MMP-9/TIMP-1失衡在肺气肿形成中起重要作用. 相似文献
998.
目的探讨高糖不同浓度刺激或抑制剂对肾小球系膜细胞表达细胞周期负控蛋白P27的影响.方法不同浓度高糖(5.5 mmol/L和25mmol/L、内皮素-1(10-7mol/L)、白介素-13(10 ng/ml和100 ng/ml)作用于培养的系膜细胞.流式细胞仪检测系膜细胞P27表达水平.结果5.5mol/L浓度组在不同时间P27表达为5.10±0.94和3.84±0.81,较对照级明显降低(P<0.001),而25 mmol/L浓度组在不同时间P27表达为26.82±3.15和30.88±3.68,较对照组明显升高.内皮素-1刺激14 h和18 h后P27的表达分别为14.76±1.49和12.18±1.30,与对照组比较有明显差异(P<0.05,P<0.05).IL-13 10 ng/ml浓度组和100 ng/ml浓度组P27表达为46.74±3.52和23.8±2.56,对对照组比较有明显差异(P<0.001,P<0.05),不同浓度组之间有显著差异(P<0.01).结论细胞周期调节负控蛋白P27在调节系膜细胞增殖过程中起重要作用. 相似文献
999.
重症急性胰腺炎大鼠血清高迁移率族蛋白-1水平的时相变化及意义 总被引:6,自引:2,他引:4
目的 观察重症急性胰腺炎(SAP)大鼠血清肿瘤坏死因子α(TNF-α)、白细胞介素19(IL-19)和高迁移率族蛋白-1(HMGBl)水平的时相变化,探讨HMGBl在SAP病程中的意义。方法采用胰管逆行灌注5%牛磺胆酸钠的方法复制大鼠SAP模型。随机分为正常对照组(N组,n=8)、假手术组(Sham组,n=8)和重症急性胰腺炎组(SAP组,n=80)。用酶联免疫吸附试验(ELISA)检测各组动物血清TNF-α、IL-1β。用Westernblot法检测血清HMGBl水平。结果 SAP组大鼠血清TNF-α和IL-1β在建模后迅速升高,约在4~6h达高峰,之后迅速下降,在建模12h即降至接近正常水平,一直维持至24和48h。SAP组大鼠血清HMGB1水平在建模后12h开始有明显升高,至24和48h仍维持在较高水平。结论 HMGB1可能作为晚期炎症因子参与了SAP的全身炎症反应。 相似文献