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991.
Goepfert PA Horton H McElrath MJ Gurunathan S Ferrari G Tomaras GD Montefiori DC Allen M Chiu YL Spearman P Fuchs JD Koblin BA Blattner WA Frey S Keefer MC Baden LR Corey L;NIAID HIV Vaccine Trials Network 《The Journal of infectious diseases》2005,192(7):1249-1259
BACKGROUND: In clinical trials, canarypox ALVAC-human immunodeficiency virus (HIV) vaccines have been shown to elicit human HIV-specific cytotoxic T lymphocyte (CTL) responses in some but not all healthy uninfected adults.Methods. A clinical trial was conducted to examine whether the vaccine vCP1452 would elicit a greater HIV-specific CTL response when given at a dose of 10(8.0) TCID50 (60 participants) than when given at the regular dose, 10(7.26) TCID50 (40 participants); as a control, a placebo vaccine preparation also was administered (10 participants). RESULTS: Two weeks after the last vaccination in a series, HIV-specific CTL responses were not significantly different when measured by either chromium-release assay (8% and 16% in the high- and regular-dose recipients, respectively) or interferon- gamma ELISpot assay (8% and 15% in the high- and regular-dose recipients, respectively); moreover, recipients of the higher dose had greater local and systemic reactions (P<.001). CONCLUSIONS: High reactogenicity associated with an increased dose of vCP1452 negates the need for further evaluation of this strategy to boost the frequency of HIV-specific CTL response in seronegative human subjects. Development of highly immunogenic canarypox vectors requires further work to optimize vector and insert design, as well as novel ways to increase dosage and to reduce reactogenicity. 相似文献
992.
CUL7: A DOC domain-containing cullin selectively binds Skp1.Fbx29 to form an SCF-like complex
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Dias DC Dolios G Wang R Pan ZQ 《Proceedings of the National Academy of Sciences of the United States of America》2002,99(26):16601-16606
Selective protein degradation targeted by members of the F-box protein family plays pivotal roles in cell biology. It is widely accepted that an F-box protein directs substrate ubiquitination within a Skp1.CUL1.F-box protein.ROC1 (SCF-ROC1) E3 ubiquitin ligase complex. This assembly utilizes the CUL1 molecular scaffold, allowing the F-box protein to position its bound substrate for ubiquitination by a ROC1-recruited E2-conjugating enzyme. Here, we describe an alternative mechanism for assembling an F-box protein-based E3 complex through a previously uncharacterized cullin, CUL7, identified by mass spectrometry as a ROC1-interacting protein. CUL7 is a large polypeptide containing a cullin domain, which is responsible for ROC1 binding, and a DOC domain, which is also present in the anaphase-promoting complex. Remarkably, CUL7 assembles an SCF-ROC1-like E3 ubiquitin ligase complex consisting of Skp1, CUL7, the Fbx29 F-box protein, and ROC1. In contrast to CUL1 that binds Skp1 by itself, CUL7 interacts with the Skp1.Fbx29 complex, but not with Skp1 alone. Strikingly, CUL7 selectively interacts with Skp1.Fbx29 but not with Skp1.betaTRCP2 or Skp1.Skp2. Thus, CUL7 may define a previously uncharacterized, Fbx29-mediated, and ubiquitin-dependent proteolysis pathway. 相似文献
993.
Infliximab for steroid-refractory acute GVHD: a case series 总被引:3,自引:0,他引:3
Jacobsohn DA Hallick J Anders V McMillan S Morris L Vogelsang GB 《American journal of hematology》2003,74(2):119-124
Acute and chronic graft-versus-host disease (GVHD) remain major barriers to successful hematopoietic stem cell transplantation (SCT). TNF-alpha has been implicated in the pathogenesis of GVHD and TNF-alpha blockade has been explored for treatment of GVHD. The development of a chimeric mouse/human monoclonal antibody (infliximab) which binds to cells producing TNF-alpha, allowing for not only the neutralization of TNF-alpha but also lysis of the cells producing the TNF-alpha, makes this an attractive drug to explore in GVHD. We report on 11 patients with acute GVHD who were treated with infliximab after failing other therapies. The survival was very poor, in keeping with previously published reports of steroid-refractory acute GVHD. Two patients with severe diarrhea from acute GI GVHD resolved their symptoms after treatment with infliximab. Only these two patients survived. It appears that of all acute GVHD manifestations, gastrointestinal GVHD may be more responsive to treatment with infliximab than others. Caution is recommended when using this agent since it may exacerbate active infections, particularly aspergillosis. Furthermore, we do not know the correct dose or schedule to use with this drug. Given these data, controlled studies assessing dose and timing of administration may be warranted to study infliximab in acute GVHD. 相似文献
994.
995.
Gonzalo Grazioli Beatriz Merino Silvia Montserrat Bàrbara Vidal Manel Azqueta Carles Pare Georgia Sarquella-Brugada Xavier Yangüas Ramon Pi Lluis Til Jaume Escoda Josep Brugada Marta Sitges 《Revista espa?ola de cardiología》2014
Introduction and objectives
Despite the established diagnostic value of the electrocardiogram in preparticipation screening of athletes, some cardiac structural changes can be missed, particularly in early disease stages. The aim of this study was to evaluate the prevalence of cardiac structural changes via the systematic use of echocardiography in preparticipation screening of competitive athletes.Methods
Professional athletes or participants in a competitive athletic program underwent a screening that included family and personal medical history, physical examination, electrocardiography, exercise testing, and Doppler echocardiography.Results
A total of 2688 athletes (67% men; mean age [standard deviation], 21 [10] years) were included. Most of the echocardiographic evaluations (92.5%) were normal and only 203 (7.5%) showed changes; the most frequent change was left ventricular hypertrophy, seen in 50 athletes (1.8%). Cessation of athletic activity was indicated in 4 athletes (0.14%): 2 for hypertrophic cardiomyopathy (electrocardiography had shown changes that did not meet diagnostic criteria), 1 pectus excavatum with compression of the right ventricle, and 1 significant pulmonary valve stenosis; the rest of the changes did not entail cessation of athletic activity and only indicated periodic monitoring.Conclusions
Although rare, some cardiac structural changes can be missed on physical examination and electrocardiography; in contrast, they are easily recognized with echocardiography. These findings suggest the use of echocardiography in at least the first preparticipation screening of competitive athletes to improve the effectiveness of programs aimed at preventing sudden death in athletes.Full English text available from:www.revespcardiol.org/en 相似文献996.
Sophie Mavrogeni Petros P. Sfikakis Georgia Karabela Efthymios Stavropoulos Georgios Spiliotis Elias Gialafos Stylianos Panopoulos Vasiliki Bournia Dionisia Manolopoulou Genovefa Kolovou George Kitas 《International journal of cardiology》2014
Background–aim
Recent LBBB in connective tissue diseases (CTDs) is challenging, due to high incidence of underlying pathology that may remain undetected, due to limitations of imaging tests. We hypothesized that cardiovascular magnetic resonance (CMR) may be of diagnostic value in CTDs with recent LBBB and normal echocardiogram.Patients–methods
26 CTDs, aged 32 ± 7 yrs (19 F) and 26 controls without CTDs, aged 60 ± 4 yrs (10 F) with recent LBBB and normal echo were evaluated by CMR. The CTDs included 6 sarcoidosis (SRC), 4 systemic sclerosis (SSc), 6 systemic lupus erythematosus (SLE), 6 rheumatoid arthritis (RA) and 4 inflammatory myopathies (IM). CMR was performed by 1.5 T. LVEF, T2 ratio (oedema imaging) and late gadolinium enhancement (LGE) (fibrosis imaging) were evaluated. Acute and chronic lesions were characterised by T2 > 2 and positive LGE and T2 < 2 and positive LGE, respectively. According to LGE, lesions were characterised as diffuse subendo-, subepicardial/intramural not following and subendocardial/transmural following the distribution of coronaries, indicative of vasculitis, myocarditis and myocardial infarction, respectively.Results
CTDs were younger (p < 0.001), with higher incidence of abnormal CMR (42.31 vs 30.77%, p = NS), including dilated cardiomyopathy (11.54%), diffuse subendocardial fibrosis (11.54%), myocardial infarction (7.69%) and acute myocarditis (11.54%) vs dilated cardiomyopathy (19.23%), myocardial infarction (7.69%) and acute myocarditis (3.85%), detected in non-CTDs.Conclusions
In CTDs with recent LBBB, CMR documented acute and chronic cardiac pathology, particularly myocarditis. CMR should be considered as an adjunct to conventional diagnostic workup in both patient groups, more so in CTDs. 相似文献997.
998.
Grigorios Tsigkas Georgia KopsidaIoanna Xanthopoulou MD Periklis DavlourosNikolaos Koutsogiannis MD Georgios MakrisKonstantinos Theodoropoulos MD George KassimisVasileios Gkizas MD George HahalisDimitrios Alexopoulos MD PhD 《The Canadian journal of cardiology》2014
Background
We aimed to examine the diagnostic value of ST-segment depression in patients with rapid atrial fibrillation (AF) for the prediction of coronary artery disease (CAD).Methods
Hemodynamically stable patients with AF, and a heart rate > 80% of their maximum predicted according to their age, were allocated to 2 groups according to their electrocardiographic findings on admission: group A included patients without any ST-segment abnormalities and group B, patients with downward or horizontal ST-segment depression ≥ 1 mm in 2 or more contiguous leads. Group A patients were subjected to a dobutamine stress echo or Tl-201 myocardial single-photon emission computed tomography, followed by coronary angiography in case of abnormal results and Group B patients to coronary angiography. CAD was defined angiographically as stenosis of ≥ 50% in any major epicardial coronary vessel.Results
Out of 115 consecutive patients, with a mean age of 65.9 ± 10.2 years, 42.6% were male, 18.3% smokers, 68.7% hypertensive, 21.7% had diabetes, and 40% had hyperlipidemia. We enrolled 71 and 44 patients in group A and B, respectively. Prevalence of significant CAD among studied patients was 21.7%, 3/71 (4.2%) and 22/44 (50.0%) in group A and B, respectively. Overall ST-segment depression during rapid AF had 88.0% sensitivity (95% confidence interval [CI], 67.7%-96.8%) and 75.6% specificity (95% CI, 65.2%-83.7%) in predicting presence of CAD, and positive and negative predictive value was 50.0% (95% CI, 34.8%-65.2%) and 95.8% (95% CI, 87.3%-98.7%), respectively.Conclusions
In consecutive patients with rapid AF, the absence of ST-segment depression might indicate absence of CAD. 相似文献999.
Eirini Katodritou Chrysanthi Vadikolia Chrysavgi Lalagianni Maria Kotsopoulou Georgia Papageorgiou Marie-Christine Kyrtsonis Panagiota Matsouka Nikolaos Giannakoulas Despoina Kyriakou Georgios Karras Nikolaos Anagnostopoulos Evridiki Michali Evangelos Briasoulis Eleftheria Hatzimichael Emmanouil Spanoudakis Panagiotis Zikos Anastasia Tsakiridou Konstantinos Tsionos Konstantinos Anargyrou Argiris Symeonidis Alice Maniatis Evangelos Terpos 《Annals of hematology》2014,93(1):129-139
Lenalidomide and dexamethasone (RD) is a standard of care for relapsed/refractory multiple myeloma (RRMM), but there is limited published data on its efficacy and safety in the “real world” (RW), according to the International Society of Pharmacoeconomics and Outcomes Research definition. We studied 212 RRMM patients who received RD in RW. Objective response (≥PR (partial response)) rate was 77.4 % (complete response (CR), 20.2 %). Median time to first and best response was 2 and 5 months, respectively. Median time to CR when RD was given as 2nd or >2nd-line treatment at 4 and 11 months, respectively. Quality of response was independent of previous lines of therapies or previous exposure to thalidomide or bortezomib. Median duration of response was 34.4 months, and it was higher in patients who received RD until progression (not reached versus 19 months, p?<?0.001). Improvement of humoral immunity occurred in 60 % of responders (p?<?0.001) and in the majority of patients who achieved stable disease. Adverse events were reported in 68.9 % of patients (myelosuppression in 49.4 %) and 12.7 % of patients needed hospitalization. Peripheral neuropathy was observed only in 2.5 % of patients and deep vein thrombosis in 5.7 %. Dose reductions were needed in 31 % of patients and permanent discontinuation in 38.9 %. Median time to treatment discontinuation was 16.8 months. Performance status (PS) and initial lenalidomide dose predicted for treatment discontinuation. Extra-medullary relapses occurred in 3.8 % of patients. Our study confirms that RD is effective and safe in RRMM in the RW; it produces durable responses especially in patients who continue on treatment till progression and improves humoral immunity even in patients with stable disease. 相似文献
1000.
Yiqiang Cai Sorin V. Fedeles Ke Dong Georgia Anyatonwu Tamehito Onoe Michihiro Mitobe Jian-Dong Gao Dayne Okuhara Xin Tian Anna-Rachel Gallagher Zhangui Tang Xiaoli Xie Maria D. Lalioti Ann-Hwee Lee Barbara E. Ehrlich Stefan Somlo 《The Journal of clinical investigation》2014,124(12):5129-5144
The most severe form of autosomal dominant polycystic kidney disease occurs in patients with mutations in the gene (PKD1) encoding polycystin-1 (PC1). PC1 is a complex polytopic membrane protein expressed in cilia that undergoes autoproteolytic cleavage at a G protein–coupled receptor proteolytic site (GPS). A quarter of PKD1 mutations are missense variants, though it is not clear how these mutations promote disease. Here, we established a cell-based system to evaluate these mutations and determined that GPS cleavage is required for PC1 trafficking to cilia. A common feature among a subset of pathogenic missense mutations is a resulting failure of PC1 to traffic to cilia regardless of GPS cleavage. The application of our system also identified a missense mutation in the gene encoding polycystin-2 (PC2) that prevented this protein from properly trafficking to cilia. Using a Pkd1-BAC recombineering approach, we developed murine models to study the effects of these mutations and confirmed that only the cleaved form of PC1 exits the ER and can rescue the embryonically lethal Pkd1-null mutation. Additionally, steady-state expression levels of the intramembranous COOH-terminal fragment of cleaved PC1 required an intact interaction with PC2. The results of this study demonstrate that PC1 trafficking and expression require GPS cleavage and PC2 interaction, respectively, and provide a framework for functional assays to categorize the effects of missense mutations in polycystins. 相似文献