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11.
The blood–brain barrier (BBB) is an immense neurovascular interface. In neurodegenerative, ischemic, and traumatic disorders of the central nervous system (CNS), the BBB may hinder the delivery of many therapeutic peptides and proteins to the brain and spinal cord. Fortunately, the mistaken dogma that peptides and proteins do not cross the BBB has been corrected during the past two decades by the accumulating evidence that peptides and proteins in the periphery exert potent effects in the CNS. Not only can peptides and proteins serve as carriers for selective therapeutic agents, but they themselves may directly cross the BBB after delivery into the bloodstream. Their passage may be mediated by simple diffusion or specific transport, both of which can be affected by interactions in the blood compartment (outside the BBB) and within the endothelial cells (at the BBB level). Although the majority of current delivery strategies focuses on modification of the molecule to be delivered, understanding the mechanisms of transport will eventually facilitate regulation of the BBB directly. We review the different aspects of interactions and discuss recent advances in the cell biology of peptide/protein transport across the BBB. Better understanding of the nature and regulation of the transport systems at the BBB will provide a new direction to enhance the interactions of peripheral peptides and proteins with the CNS. 相似文献
12.
RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature 总被引:12,自引:0,他引:12
Kai Temming Raymond M. Schiffelers Grietje Molema Robbert J. Kok 《Drug Resistance Updates》2005,8(6):381-402
During the past decade, RGD-peptides have become a popular tool for the targeting of drugs and imaging agents to alphavbeta3-integrin expressing tumour vasculature. RGD-peptides have been introduced by recombinant means into therapeutic proteins and viruses. Chemical means have been applied to couple RGD-peptides and RGD-mimetics to liposomes, polymers, peptides, small molecule drugs and radiotracers. Some of these products show impressive results in preclinical animal models and a RGD targeted radiotracer has already successfully been tested in humans for the visualization of alphavbeta3-integrin, which demonstrates the feasibility of this approach. This review will summarize the structural requirements for RGD-peptides and RGD-mimetics as ligands for alphavbeta3. We will show how they have been introduced in the various types of constructs by chemical and recombinant techniques. The importance of multivalent RGD-constructs for high affinity binding and internalization will be highlighted. Furthermore the in vitro and in vivo efficacy of RGD-targeted therapeutics and diagnostics reported in recent years will be reviewed. 相似文献
13.
腔隙性脑梗死和动脉粥样硬化血栓性脑梗死患者微量蛋白尿的研究 总被引:1,自引:0,他引:1
目的明确脑梗死患者微量蛋白尿(MA)阳性率及腔隙性脑梗死(lacunar infarction,LI)和动脉粥样硬化血栓性脑梗死(atherothrombotic infarction,AI)患者MA阳性率是否存在差别。方法采用竞争性放射免疫分析方法对未合并肝肾功能不全等影响尿蛋白排泄率(UAER)检测结果的83例LI和78例AI患者,以及40例原发性高血压对照者进行UAER测定。统计脑梗死患者MA的阳性率,比较合并高血压的LI、AI与高血压对照组MA阳性率。结果161例脑梗死患者MA阳性率为42·9%;单纯合并高血压病史的45例LI患者和34例AI患者MA阳性率分别为51·1%和58·8%,均高于高血压对照组(P<0·05),但两组间比较无统计学意义。结论脑梗死患者呈现MA高发率;合并高血压病史的LI和AI患者MA阳性率无差别;MA会增加脑梗死的发生风险。 相似文献
14.
骨髓细胞移植上调血管内皮生长因子及其受体的表达并改善缺血心脏功能 总被引:14,自引:1,他引:13
目的:通过骨髓细胞移植对心肌梗死大鼠模型血管内皮生长因子及其受体表达的影响,探讨骨髓细胞移植改善缺血心脏功能的可能机制。方法:利用左前降支冠状动脉结扎术制备大鼠心肌梗死模型,然后行异体骨髓细胞移植;分别于术后1d,3d,7d,14d和28d取材;利用免疫荧光和RT—PCR技术分析细胞移植对血管内皮生长因子(VEGF)及其受体(Flk一1)表达的影响和移植细胞的分化情况;通过免疫组化计算血管数量;应用血流动力学检测大鼠心脏功能在术后各时间点的变化。结果:VEGF和Flk-1在移植组动物的心肌梗死区残存细胞、梗死周边区细胞以及部分移植细胞内表达。移植组VEGF和Flk-1的mRNA表达明显高于对照组。分别于术后3d和14d达到高峰,以后逐渐减弱。术后7d,14d和28d移植组血管数量较同期对照组明显增加,移植组心脏功能较对照组明显改善。术后14d可在部分移植细胞中检测到心肌细胞或血管内皮细胞特异性蛋白的表达。结论:骨髓细胞移植通过上调移植细胞及受者内源性VEGF和Flk—1的表达,促进血管新生,进而改善缺血心脏功能。 相似文献
15.
16.
Coronary vasomotion in patients with syndrome X: evaluation with positron emission tomography and parametric myocardial perfusion imaging 总被引:1,自引:1,他引:0
Joan G. Meeder Paul K. Blanksma Ernst E. van der Wall Antoon T. M. Willemsen Jan Pruim Rutger L. Anthonio Richard M. de Jong Willem Vaalburg Kong I. Lie 《European journal of nuclear medicine and molecular imaging》1997,24(5):530-537
The aim of this study was to elucidate further the causative mechanism of abnormal coronary vasomotion in patients with syndrome X. In patients with syndrome X, defined as angina pectoris and documented myocardial ischaemia during stress testing with normal findings at coronary angiography, abnormal coronary vasomotion of either the micro- or the macrocirculation has been suggested as the causative mechanism. Accordingly, we evaluated endothelial function, vasodilator reserve, and perfusion heterogeneity in these patients. Twenty-five patients with syndrome X (definitely normal coronary arteriogram, group A), 15 patients with minimal coronary artery disease (group B) and 21 healthy volunteers underwent [13N]ammonia positron emission tomography at rest, during cold pressor stimulation (endothelial function) and during dipyridamole stress testing (vasodilator reserve). Heterogeneity of myocardial perfusion was analysed by parametric polar mapping using a 480-segment model. In both patient groups, resting perfusion was increased compared to the normal subjects: group A, 127±31 ml·min–1·100 g–1; group B, 124±30 ml·min–1·100 g–1 normal subjects, 105±21 ml·min–1·100 g–1 (groups A and B vs normals,P<0.05). These differences were abolished after correction for rate-pressure product. During cold pressor stimulation, the perfusion responses (ratio of cold pressor perfusion to resting perfusion) were similar among the patients and the control subjects (group A, 1.20±0.23; group B, 1.24±0.22; normal subjects, 1.23±0.14). Likewise, during dipyridamole stress testing, perfusion responses were similar among the three groups (group A, 2.71±0.67; group B, 2.77±1.29; normal subjects, 2.91±1.04). In group A the heterogeneity of resting perfusion, expressed as coefficient of variation, was significantly different from the volunteers (20.1±4.5 vs 17.0±3.0,P<0.05). In group B (coefficient of variation 19.4±3.9) the difference from normal volunteers was not significant. In this study, patients with syndrome X and patients with minimal coronary artery disease showed normal perfusion responses during cold pressor stimulation and dipyridamole stress testing. Our findings therefore suggest that endothelial dysfunction and impaired vasodilator reserve are of no major pathophysiological relevance in patients with syndrome X. Rather, other mechanisms such as increased sympathetic tone and focal release of vasoactive substances may play a role in the pathogenesis of syndrome X. 相似文献
17.
目的研究骨髓基质细胞源内皮细胞移植对大鼠局灶性脑损伤超微结构的影响,探讨骨髓基质细胞源内皮细胞移植修复大鼠脑损伤的机制。方法制备大鼠局灶性脑损伤动物模型,进行骨髓基质细胞源内皮细胞移植,通过透射电镜观察损伤局部超微结构的变化。结果脑损伤后微血管内皮细胞胞浆广泛空泡变,细胞器明显减少,并出现核固缩,血管壁破坏。骨髓基质细胞源内皮细胞移植后微循环得到改善。结论脑损伤后出现微循环障碍是产生继发性脑缺血、脑水肿的病理基础。骨髓基质细胞源内皮细胞移植促进了损伤区微循环的改善。 相似文献
18.
D. D. Thomas A. M. Fogelman J. N. Miller M. A. Lovett 《European journal of epidemiology》1989,5(1):15-21
Syphilis is a chronic disease characterized by hematogenous dissemination of Treponema pallidum into tissues such as the cardiovascular and central nervous systems. In order to test whether these aspects of the pathogenesis of syphilis reflect an ability of T. pallidum to invade vascular entothelial surfaces, we explored the association of T. pallidum with human and rabbit endothelial cells in vitro. Using radiolabeled motile organisms, we found that treponemal attachment was two times greater to rabbit aortic endothelial cells and human umbilical endothelial cells than to HeLa cells. Mild trypsinization of attached treponemes resulted in release from cells of all organisms detectable by darkfield microscopy without visible damage to the monolayer. Nevertheless, 25% of the counts representing T. pallidum remained associated with the cell monolayers. Further trypsin treatment to release the monolayer and differential centrifugation showed that 80% of the remaining cell-associated counts were not within the cells. These results suggest that some treponemes had associated with the monolayer in a trypsin resistant niche. Additionally, motile T. pallidum passed through tight functioned endothelial cell monolayers on membrane filters under conditions were heat-killed T. pallidum and the host indigenous nonpathogen. T. phagedenis biotype Reiter failed to do so. Electron micrographs of transverse sections through the monolayers showed many T. pallidum in junctions between endothelial cells. These studies suggest that T. pallidum may leave the circulation by passing between endothelial cells. 相似文献
19.
Summary
The compartment syndrome (cs) is characterized by an increased tissue pressure in a limited space. Pathophysiologically, it
is a multifactorial disease that is potentially induced by an initial trauma and develops according to the existence of cofactors.
Cofactors are, for instance, the circulation of the patient and the initial treatment of the impending cs. In particular,
the microcirculation is altered with endothelial destruction, development of a capillary leak, protein loss from intravasal
space and the development of an interstitial and intracellular third space. An impaired drainage of the lymphatic and venous
system causes a venous infarction. An arterial infarction results if the tissue pressure exceeds the arteriolar pressure.
An accompanying ischemia reperfusion mechanism increases the trauma load. In disadvantageous cases, the patients are in danger
of developing a multi-organ deficiency syndrome (MODS) by an uncontrolled inflammatory reaction, by intravasal volume loss
and by a myonephropathic systemic reaction. Clinically, the patients suffer a disproportionate amount of pain, followed by
neurological signs. Especially in noncompliant patients, tissue pressure measurement is useful. Resuscitation of the circulation
as well as splitting of casts is important. In case of a manifest cs, dermatofasciotomy has to be performed as an emergency
operation. Even if cs is diagnosed early and fasciotomy is carried out early, the development of sequellae cannot be avoided
in every single case.
相似文献
20.
目的 对比观察2型糖尿病(DM)及糖尿病肾病(DN)患者血管内皮损害标志物,分析其与白蛋白尿相关性。方法 6 8例2型糖尿病患者根据尿白蛋白排泄率分为正常白蛋白尿组(Ⅰ组)和微量白蛋白尿组(Ⅱ组) ,同时以健康成人作为对照组(Ⅲ组) ,分别检测其循环内皮细胞(CEC)、vonWillebrand因子(vWF)、内皮素- 1 (ET - 1 )的变化,并分析其相关性。结果 DM患者CEC、vWF和ET - 1明显增高,尤其是DN组(P <0 .0 5 ) ,各指标间以及与尿白蛋白排泄呈正相关。结论 2型DM患者在出现白蛋白尿前已存在血管内皮功能异常,其白蛋白排泄与血管内皮功能障碍程度有一定相关性。 相似文献