全文获取类型
收费全文 | 1689篇 |
免费 | 55篇 |
国内免费 | 8篇 |
专业分类
耳鼻咽喉 | 4篇 |
儿科学 | 14篇 |
妇产科学 | 6篇 |
基础医学 | 194篇 |
口腔科学 | 55篇 |
临床医学 | 133篇 |
内科学 | 525篇 |
皮肤病学 | 20篇 |
神经病学 | 119篇 |
特种医学 | 63篇 |
外科学 | 161篇 |
综合类 | 8篇 |
预防医学 | 152篇 |
眼科学 | 51篇 |
药学 | 139篇 |
中国医学 | 3篇 |
肿瘤学 | 105篇 |
出版年
2023年 | 7篇 |
2022年 | 17篇 |
2021年 | 26篇 |
2020年 | 15篇 |
2019年 | 9篇 |
2018年 | 24篇 |
2017年 | 10篇 |
2016年 | 28篇 |
2015年 | 23篇 |
2014年 | 46篇 |
2013年 | 67篇 |
2012年 | 96篇 |
2011年 | 105篇 |
2010年 | 62篇 |
2009年 | 70篇 |
2008年 | 105篇 |
2007年 | 116篇 |
2006年 | 100篇 |
2005年 | 98篇 |
2004年 | 100篇 |
2003年 | 93篇 |
2002年 | 94篇 |
2001年 | 21篇 |
2000年 | 38篇 |
1999年 | 25篇 |
1998年 | 26篇 |
1997年 | 18篇 |
1996年 | 17篇 |
1995年 | 14篇 |
1994年 | 11篇 |
1993年 | 12篇 |
1992年 | 24篇 |
1991年 | 18篇 |
1990年 | 18篇 |
1989年 | 27篇 |
1988年 | 10篇 |
1987年 | 14篇 |
1986年 | 14篇 |
1985年 | 16篇 |
1984年 | 12篇 |
1983年 | 5篇 |
1982年 | 6篇 |
1981年 | 12篇 |
1980年 | 8篇 |
1979年 | 5篇 |
1978年 | 5篇 |
1976年 | 11篇 |
1975年 | 4篇 |
1959年 | 4篇 |
1958年 | 5篇 |
排序方式: 共有1752条查询结果,搜索用时 15 毫秒
21.
Synthesis and structure-activity relationships of new 7-[3-(fluoromethyl)piperazinyl]- and -(fluorohomopiperazinyl)quinolone antibacterials 总被引:1,自引:0,他引:1
C B Ziegler P Bitha N A Kuck T J Fenton P J Petersen Y I Lin 《Journal of medicinal chemistry》1990,33(1):142-146
Some novel 6-fluoro-7-substituted-1,4-dihydro-4-oxoquinoline-3-carboxylic acids have been prepared. At the N-1 position "standard" substitution was employed with the ethyl, cyclopropyl, and p-fluorophenyl groups being used. At C-7 the introduction of some novel piperazines was made. Most notably, 2-(fluoromethyl)piperazine (10) and hexahydro-6-fluoro-1H-1,4-diazepine (16, fluorohomopiperazine) at the quinolone C-7 position produced products with similar in vitro antibacterial activity as the ciprofloxacin reference. The in vivo efficacy of 1-cyclopropyl-6-fluoro-7-[3-(fluoromethyl)piperazinyl]-1,4-dihydro-4- oxoquinoline-3-carboxylic acid (20) was excellent with better oral absorption than ciprofloxacin (2). 相似文献
22.
Eckhard Jähde Karl-Heinz Glüsenkamp Manfred F. Rajewsky 《Cancer chemotherapy and pharmacology》1991,27(6):440-444
Summary The cytotoxicity of many alkylating anticancer drugs is increased at reduced intracellular pH (pHi). The therapeutic index of such agents could therefore be improved by lowering pHi in the target cells prior to their application. We have previously demonstrated that the formation of lactic acid can be selectively enhanced in malignant tissues via glucose-mediated stimulation of tumor cell glycolysis. However, the resulting reduction in pHi is partly compensated by the extrusion of H+ equivalents into the extracellular space, with pHi remaining closer to the physiological value than extracellular pH (pHe). For full exploitation of the proton-mediated increase in the cytotoxicity of alkylating agents, pHi should therefore be equilibrated with pHe in lactic acid-producing cells. In the present study we investigated the question as to whether nigericin, an H+/K+ antiporter enabling the entry into cells of H+ ions at low pHe, can be used to enhance the cytotoxic effect of mafosfamide (MAFO; a precursor of activated cyclophosphamide) on cultured M1R rat mammary carcinoma cells. At pHe 7.4, the cytotoxic effect of combined treatment with MAFO and nigericin was not superior to treatment with MAFO alone. At acidic pHe, however, MAFO cytotoxicity was potentiated by nigericin as indicated by the colony-forming capacity of M1R cells. For example, at pHe 6.2 (corresponding to the approximate mean aggregated pH in actively glycolyzing tumors), the colonyforming fraction of cells treated with a combination of MAFO and nigericin was 3×10–5 that of controls, as compared with a value of 5×10–2 found for cells exposed to MAFO alone. These results suggest that agents counteracting cellular mechanisms that control pHi may be candidate compounds for investigations aimed at the enhancement of alkylating drug cytotoxicity following glucosemediated pH reduction in malignant tumors in vivo.This work was supported by grants from the Dr. Mildred Scheel-Stiftung für Krebsforschung and by the Federal Ministry for Research and Technology (0318849 A) 相似文献
23.
Reinhard Wölfel Karl-Heinz Graefe 《Naunyn-Schmiedeberg's archives of pharmacology》1992,345(2):129-136
Summary The aim of the present study was to answer the question whether amines other than 5-hydroxytryptamine (5-HT) and tryptamine act as substrates of the platelet 5-HT transporter. To this end, a large number of tryptamines, 5-HT receptor agonists and phenethylamines (which had IC50 values for 3H-5-HT uptake inhibition of 145–24500 nmol l–1) was examined in rabbit platelets in order to determine their ability to induce an outward transport of 3H-5-HT Platelets (the MAO of which was blocked) from reserpine-pretreated animals were loaded with 3H-5-HT and then exposed for 5 min to various concentrations (ranging from 0.25 to 40 times the IC50) of each compound. The concentration-effect curves for the drug-induced increase in 3H-5-HT efflux served to determine values of Emax (maximum increase in efflux expressed in % of the 3H-5-HT content of cells) and EC50 (drug concentration producing Emax/2).For the 24 compounds studied here (which included the 5-HT uptake inhibitors imipramine, citalopram, fluoxetine and cocaine) a linear correlation between EC50 and IC50 (r = 0.975) and a mean ratio of EC50/IC50 of 2.4 was found. Most of the compounds [e.g., (±)8-hy-ydroxy-2-(N,N-dipropylamino)tetralin, S(+)-methyl-5-HT, 5-carboxamidotryptamine and 5-methoxytryptamine] gave rise to Emax values (15.8–32.5%) that exceeded that brought about by imipramine (6.6%), indicating that they act as substrates of the 5-HT transporter; the 3H-5-HT outward transport observed in response to these substances was abolished in the presence of imipramine. Others (e.g., 2-methyl-5-HT and 5-methylurapidil) produced Emax values (3.4–14.3%) not significantly different from that of imipramine and, therefore, can be classified either as poor substrates or as inhibitors of the 5-HT transporter.Hence, many tryptamines and 5-HT receptor agonists are substrates of the platelet 5-HT transporter. The property of being substrates gives them the latent capacity to bring about release of endogenous 5-HT and, as a result, to cause indirect 5-HT receptor-mediated effects.Abbreviations MAO
monoamine oxidase
- 5-HT
5-hydroxytryptamine
- 2-M-5-HT
2-methyl-5-HT
- N-M-5-HT
N-methyl-5-HT
- N,N-DM-5-HT
N,N-dimethyl-5-HT
- S(+)-M-5-HT
S(+)-methyl-5-HT
- 5-CT
5-carboxamidotryptamine
- 5-M-tryptamine
5-methyltryptamine
- 5-MO-tryptamine
5-methoxytryptamine
- 7-M-tryptamine
7-methyltryptamine
- N-M-tryptamine
N-methyltryptamine
- N,N-DM-tryptamine
N,N-dimethyltryptamine
- N,N-DM-5-MO-tryptamine
N,N-dimethyl-5-methoxytryptamine
- (±)8-OH-DPAT
(±)8-hydroxy-2-2-(N,N-dipropylamino)tetralin
- 5-M-urapidil
5-methyl-urapidil
Send offprint requests to R. Wölfel at the above address 相似文献
24.
The T393C polymorphism of the G alpha s gene (GNAS1) is a novel prognostic marker in bladder cancer. 总被引:2,自引:0,他引:2
Ulrich H Frey Andreas Eisenhardt Gerd Lümmen Herbert Rübben Karl-Heinz J?ckel Kurt W Schmid Winfried Siffert 《Cancer epidemiology, biomarkers & prevention》2005,14(4):871-877
The G protein G(alpha)s pathway is linked to proapoptotic signaling in cancer cell lines. To assess the role of the GNAS1 locus encoding G(alpha)s as a genetic factor for disease progression of transitional cell carcinoma (TCC) of the bladder, we genotyped the synonymous T393C polymorphism in 254 patients with TCC (minor allele frequency: 0.43) to examine a potential association between genotypes and disease progression. Using Kaplan-Meier estimates to calculate 5-year probabilities of follow-up, we could show that progression-free survival, metastasis-free survival, and cancer-specific survival was significantly increased in TT genotypes (56%, 84%, 82%) compared with CC genotypes (35%, 53%, 58%). In multivariate Cox proportional hazard analysis, the T393C polymorphism was an independent prognostic factor for clinical outcome. Homozygous CC patients were at highest risk for progression [odds ratio (OR), 1.94; P = 0.020], metastasis (OR, 3.49; P = 0.005), and tumor-related death (OR, 2.49; P = 0.031) compared with TT genotypes. Heterozygous patients had an intermediate risk compatible with a gene-dose effect. Real-time PCR analysis of urothelial tumor tissue as well as adipose and heart tissue revealed that G(alpha)s mRNA expression was highest in TT genotypes, indicating a proapoptotic effect in these genotypes. In conclusion, the GNAS1 T393C status associated with differential G(alpha)s mRNA expression is a novel independent prognostic marker for clinical outcome supporting a functional role of G(alpha)s in bladder cancer progression. 相似文献
25.
Identifying nanomaterial-bio-interactions are imperative due to the broad introduction of nanoparticle (NP) applications and their distribution. Here, we demonstrate that silica NPs effect widespread protein aggregation in the soil nematode Caenorhabditis elegans ranging from induction of amyloid in nucleoli of intestinal cells to facilitation of protein aggregation in body wall muscles and axons of neural cells. Proteomic screening revealed that exposure of adult C. elegans with silica NPs promotes segregation of proteins belonging to the gene ontology (GO) group of “protein folding, proteolysis and stress response” to an SDS-resistant aggregome network. Candidate proteins in this group include chaperones, heat shock proteins and subunits of the 26S proteasome which are all decisively involved in protein homeostasis. The pathway of protein homeostasis was validated as a major target of silica NPs by behavioral phenotyping, as inhibitors of amyloid formation rescued NP-induced defects of locomotory patterns and egg laying. The analysis of a reporter worm for serotonergic neural cells revealed that silica NP-induced protein aggregation likewise occurs in axons of HSN neurons, where presynaptic accumulation of serotonin, e.g. disturbed axonal transport reduces the capacity for neurotransmission and egg laying. The results suggest that in C. elegans silica NPs promote a cascade of events including disturbance of protein homeostasis, widespread protein aggregation and inhibition of serotonergic neurotransmission which can be interrupted by compounds preventing amyloid fibrillation. 相似文献
26.
The endophytic fungus Piriformospora indica reprograms barley to salt-stress tolerance, disease resistance, and higher yield 总被引:1,自引:0,他引:1 下载免费PDF全文
Waller F Achatz B Baltruschat H Fodor J Becker K Fischer M Heier T Hückelhoven R Neumann C von Wettstein D Franken P Kogel KH 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(38):13386-13391
Disease resistance strategies are powerful approaches to sustainable agriculture because they reduce chemical input into the environment. Recently, Piriformospora indica, a plant-root-colonizing basidiomycete fungus, has been discovered in the Indian Thar desert and was shown to provide strong growth-promoting activity during its symbiosis with a broad spectrum of plants. Here, we report on the potential of P. indica to induce resistance to fungal diseases and tolerance to salt stress in the monocotyledonous plant barley. The beneficial effect on the defense status is detected in distal leaves, demonstrating a systemic induction of resistance by a root-endophytic fungus. The systemically altered "defense readiness" is associated with an elevated antioxidative capacity due to an activation of the glutathione-ascorbate cycle and results in an overall increase in grain yield. Because P. indica can be easily propagated in the absence of a host plant, we conclude that the fungus could be exploited to increase disease resistance and yield in crop plants. 相似文献
27.
Höpp HW Baer FM Ozbek C Kuck KH Scheller B 《Journal of the American College of Cardiology》2000,36(6):1853-1859
OBJECTIVES: The AtheroLink registry sought to observe the effect of plaque burden reduction by directional coronary atherectomy (DCA) prior to stenting on acute lesion success rate, on the clinical success rate and on the incidence of in-stent restenosis six months after intervention. BACKGROUND: Although coronary stenting has reduced restenosis, its effect has been less favorable in complex lesions with a high plaque burden that results from suboptimal stent expansion. Therefore, plaque removal by DCA may improve the results of coronary stenting. METHODS: A total of 167 patients with >60% stenosis in a native coronary artery of 2.8 to 4.0 mm in diameter were enrolled in 10 study centers on an intention-to-treat basis. All patients underwent DCA aimed at an optimal result (residual diameter stenosis <20%) followed by stenting. Angiographic follow-up was performed in 120 (71.8%) patients at 5.3+/-2.8 months. RESULTS: Lesion success was achieved in 164/167 (98.2%) patients, and the clinical success rate was 95.2% (159/167 patients). The overall restenosis rate in the 120 patients with angiographic follow-up was 10.8% (13/120). Incidence of restenosis was lower (8.4%) in patients with optimal stent deployment following DCA compared to patients with a persisting caliber reduction >15% (restenosis rate 15.3.%) and restenosis occurred with a significantly higher frequency (p<0.04) in distal lesions (37.5%) compared to proximal stenoses (9.0%). CONCLUSIONS: This observational multicenter registry points to a potential reduction in restenosis by a synergistic approach of DCA and stenting performed under routinely accessible angiographic guidance. Therefore, multicenter-based randomized clinical trials are clearly warranted to finally clarify the validity of this complex approach versus conventional angioplasty plus stenting. 相似文献
28.
Philipp Bohm Jürgen Scharhag Florian Egger Karl-Heinz Tischer David Niederseer Christian Schmied Tim Meyer 《The Canadian journal of cardiology》2021,37(1):105-112
BackgroundKnowledge about causes of sports-related sudden cardiac arrest (SrSCA) may influence national strategies to prevent such events. Therefore, we established a prospective registry on SrSCA to estimate the incidence and in particular describe the etiologies of SrSCA in the general population in Germany.MethodsThe registration of SrSCA based upon 4 pillars: a web-based platform to record SrSCA cases in competitive and recreational athletes, media-monitoring, cooperation with the German Resuscitation Registry, and 15 institutes of forensic medicine.ResultsAfter an observation period of 6 years, a total of 349 cases was recorded (mean age 48.0 ± 12.7 years); 109 subjects survived. Most of the cases occurred during nonelite competitive or recreational sports. Bystander cardiopulmonary resuscitation (CPR) was initiated in 262 cases (75%); however, rhythm analysis and defibrillation (if indicated) was mainly performed by medical services. In patients ≤ 35 years of age, premature coronary artery disease (CAD) and sudden arrhythmic death syndrome (SADS) prevailed, followed by myocarditis. In athletes ≥ 35 years of age, CAD predominated.ConclusionsCountry-specific registries are necessary to define the national screening and prevention strategy optimally. In Germany, premature CAD, SADS, and myocarditis are the leading causes of SrSCA in young athletes, reinforcing the great disparity of the prevalence of cardiac diseases among different countries. Extension of on-site SCD-prevention campaigns, with training of CPR and explanation of the efficient use of automated external defibrillators (AEDs), may decrease the burden of SrSCD. 相似文献
29.
Christian-Hendrik Heeger MD Jan-Eric Bohnen MD Sorin Popescu Roza Meyer-Saraei PhD Thomas Fink MD Vanessa Sciacca Bettina Kirstein MD Sascha Hatahet MD Anna Traub MD Lisbeth D. Lopez MD Michael Schlüter Karl-Heinz Kuck MD Charlotte Eitel MD Julia Vogler MD Roland Richard Tilz MD 《Journal of cardiovascular electrophysiology》2021,32(6):1553-1560