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OBJECTIVE: Angiotensin-converting enzyme inhibitors are an effective therapy for all stages of heart failure due to reduced systolic left ventricular function. Because sufficient data on intravenous angiotensin-converting enzyme inhibitors following coronary artery bypass surgery complicated by postoperative left ventricular dysfunction are unavailable, the efficacy and safety of intravenously administered enalaprilat were evaluated. DESIGN: A placebo-controlled, randomized, double-blind protocol. SETTING: Postoperative intensive care unit at the German Heart Institute Berlin. PATIENTS: Forty patients with a left ventricular ejection fraction <35% following coronary artery bypass surgery on the second postoperative day or after weaning from intra-aortic balloon counterpulsation. INTERVENTIONS: A loading dose of enalaprilat 0.625 mg infused over 1 hr was followed by 5 mg/24 hrs administered continuously for up to 72 hrs. MEASUREMENTS AND MAIN RESULTS: Systemic and pulmonary hemodynamic variables, blood gases, hormonal variables, renal function, and electrolytes were measured before and repeatedly during therapy. Acute effects were as follows: At 1 hr, enalaprilat increased the cardiac index (p <.001), stroke volume index (p <.001), and right ventricular stroke work index (p <.03) compared with placebo, whereas mean arterial pressure (p <.008) and both systemic (p <.001) and pulmonary (p <.02) vascular resistance decreased. Continuous effects were as follows: Over 72 hrs, enalaprilat decreased diastolic pulmonary artery pressure (p <.019), pulmonary artery occlusion pressure (p <.02), and central venous pressure (p <.02). The cardiac and stroke volume indexes were consistently higher in the enalaprilat group, whereas systemic and pulmonary vascular resistances were lower. The arterial blood-pressure lowering effect was blunted and heart rate remained unchanged. Mixed venous oxygenation (p <.02) was higher and arterial oxygenation was not modified. Finally, enalaprilat increased creatinine clearance (p <.002) and decreased creatinine (p <.02) and urea (p <.03). CONCLUSIONS: Intravenous enalaprilat safely and effectively improves cardiac and renal function following coronary artery bypass surgery complicated by postoperative left ventricular dysfunction. 相似文献
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目的:验证雪灵芝是否具有抑制大鼠肝癌的功效。方法:实验于2003—09/2004—08在广西疾病预防控制中心SPF级动物实验室完成。选用健康成年SD大鼠160只。按体质量分层随机分为5组:空白对照组、模型组、雪灵芝高剂量组、雪灵芝中剂量组和雪灵芝低剂量组,每组32只。雪灵芝高、中、低剂量组大鼠分别灌胃2.500,1.250,0.625mL/kg雪灵芝溶液,阴性对照组和模型组灌胃等量蒸馏水,1次/d,连续60d。第61天开始雪灵芝高、中、低剂量组和模型组灌胃二乙基亚硝胺溶液,对照组灌胃等量的生理盐水。于停止灌胃90d后各组处死一半受试大鼠(雌雄各半),检测血常规及血清主要生化指标,观察各脏器大体形态改变、脏器的癌变程度。1周后给剩余大鼠灌胃雪灵芝溶液(不含二乙基亚硝胺)。7周后处死余下的一半雄性大鼠,进行相同操作。8周后处死余下的全部大鼠,操作及检测方法同前。结果:纳入的160只SD大鼠,145只进入结果分析,15只脱落。①病理切片检查结果:除阴性对照组,其他各组大鼠肝组织均发生癌变或癌前病变。雪灵芝高、中、低剂量组的癌前病变发生率与模型组相近(P〉0.05);癌变的发生率均低于模型组,差异有显著性意义(P〈0.05,0.01)。②大体标本检查结果:阴性对照组大鼠肝脏的大体标本均无异常改变,其他各组大鼠的肝脏有些可见表面粗糙等病理改变。模型组大体标本病理改变的阳性率高于雪灵芝高、中、低剂量组,差异有显著性意义(P〈0.05)。肉眼观模型组癌变发生率高于其他各组。③其他脏器检查结果:模型组2只大鼠有肝癌肺转移。结论:以较大剂量的二乙基亚硝胺连续灌胃30d可以复制大鼠肝癌模型;雪灵芝对二乙基亚硝胺诱导的大鼠肝癌具有预防和抑制的作用。 相似文献
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Martina Nagel Olivia Luu Nicolas Bisson Bojan Macanovic Tom Moss Rudolf Winklbauer 《Developmental dynamics》2009,238(7):1709-1726
The p21 activated kinases (Paks) are prominently involved in the regulation of cell motility. Using a kinase‐dead mutant of xPak1, we show that during Xenopus gastrulation, the kinase activity of Pak1 is required upstream of Cdc42 for the establishment of cell polarity in the migrating mesendoderm. Overactivation of Pak1 function by the expression of constitutively active xPak1 compromises the maintenance of cell polarity, by indirectly inhibiting RhoA function. Inhibition of cell polarization does not affect the migration of single mesendoderm cells. However, Pak1 inhibition interferes with the guidance of mesendoderm migration by directional cues residing in the extracellular matrix of the blastocoel roof, and with mesendoderm translocation in the embryo. Developmental Dynamics 238:1709–1726, 2009. © 2009 Wiley‐Liss, Inc. 相似文献
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Shaw G Price AM Ktori E Bisson I Purkis PE McFaul S Oliver RT Prowse DM 《European urology》2008,54(6):1333-1343
Objectives
Androgen-deprivation therapy effectively shrinks hormone-naïve prostate cancer, both in the prostate and at sites of distant metastasis. However prolonged androgen deprivation generally results in relapse and androgen-independent tumour growth, which is inevitably fatal. The molecular events that enable prostate cancer cells to proliferate in reduced androgen conditions are poorly understood. Here we investigate the role of Hedgehog signalling in androgen-independent prostate cancer (AIPC).Methods
Activity of the Hedgehog signalling pathway was analysed in cultured prostate cancer cells, and circulating prostate tumour cells were isolated from blood samples of patients with AIPC.Results
AIPC cells were derived through prolonged culture in reduced androgen conditions, modelling hormone therapy in patients, and expressed increased levels of Hedgehog signalling proteins. Exposure of cultured AIPC cells to cyclopamine, which inhibits Hedgehog signalling, resulted in inhibition of cancer cell growth. The expression of the Hedgehog receptor PTCH and the highly prostate cancer–specific gene DD3PCA3 was significantly higher in circulating prostate cancer cells isolated from patients with AIPC compared with samples prepared from normal individuals. There was an association between PTCH and DD3PCA3 expression and the length of androgen-ablation therapy.Conclusions
Our data are consistent with reports implicating overactivity of Hedgehog signalling in prostate cancer and suggest that Hedgehog signalling contributes to the androgen-independent growth of prostate cancer cells. As systemic anti-Hedgehog medicines are developed, the Hedgehog pathway will become a potential new therapeutic target in advanced prostate cancer. 相似文献48.
Certain fatty acid N-alkyl amides from the medicinal plant Echinacea activate cannabinoid type-2 (CB2) receptors. In this study we show that the CB2-binding Echinacea constituents dodeca-2E,4E-dienoic acid isobutylamide (1) and dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide (2) form micelles in aqueous medium. In contrast, micelle formation is not observed for undeca-2E-ene-8,10-diynoic acid isobutylamide (3), which does not bind to CB2, or structurally related endogenous cannabinoids, such as arachidonoyl ethanolamine (anandamide). The critical micelle concentration (CMC) range of 1 and 2 was determined by fluorescence spectroscopy as 200-300 and 7400-10000 nM, respectively. The size of premicelle aggregates, micelles, and supermicelles was studied by dynamic light scattering. Microscopy images show that compound 1, but not 2, forms globular and rod-like supermicelles with radii of approximately 75 nm. The self-assembling N-alkyl amides partition between themselves and the CB2 receptor, and aggregation of N-alkyl amides thus determines their in vitro pharmacological effects. Molecular mechanics by Monte Carlo simulations of the aggregation process support the experimental data, suggesting that both 1 and 2 can readily aggregate into premicelles, but only 1 spontaneously assembles into larger aggregates. These findings have important implications for biological studies with this class of compounds. 相似文献
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Anke Bramesfeld Felix Wedegärtner Hermann Elgeti Susanne Bisson 《BMC health services research》2007,7(1):1-12