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131.
132.
Heidel FH Mack TS Razumovskaya E Blum MC Lipka DB Ballaschk A Kramb JP Plutizki S Rönnstrand L Dannhardt G Fischer T 《Annals of hematology》2012,91(3):331-344
FLT3 kinase has become an attractive drug target in AML with up to 30% of cases harboring internal-tandem-duplication (ITD) mutations. For these, conferring a worse prognosis and decreased overall survival, several FLT3 tyrosine kinase inhibitors (TKIs) are currently being tested in clinical trials. However, when using these drugs as monotherapy, the problem of short duration of remissions and high incidence of TKI resistance has emerged. Here, we investigated two members of a novel class of tyrosine kinase inhibitors, 3,4-diarylmaleimides, for their efficacy on mutated FLT3 kinase. These compounds inhibit FLT3 kinase in an ATP-competitive manner and effectively inhibit phosphorylation of downstream targets. 3,4-Diarylmaleimides (DHF125 and 150) induce apoptosis in FLT3-ITD-dependent cells lines and patient blasts at low micromolar concentrations. They are retained in the cytoplasm of exposed cells for more than 24?h and synergize with chemotherapy and midostaurin. Both 3,4-diarylmaleimides show inhbition of FLT3-ITD-related kinase autophosphorylation at distinct tyrosine residues when compared to midostaurin. In conclusion, this novel group of compounds shows differential inhibition patterns with regard to FLT3 kinase and displays a promising profile for further clinical development. Currently, experiments evaluating toxicity in murine models and unraveling the exact binding mechanism are under way to facilitate a potential clinical application. 相似文献
133.
Seegers J Vos MA Flevari P Willems R Sohns C Vollmann D Lüthje L Kremastinos DT Floré V Meine M Tuinenburg A Myles RC Simon D Brockm?ller J Friede T Hasenfu? G Lehnart SE Zabel M;EUTrigTreat Clinical Study Investigators 《Europace : European pacing, arrhythmias, and cardiac electrophysiology》2012,14(3):416-422
134.
135.
Strand V Burmester GR Ogale S Devenport J John A Emery P 《Rheumatology (Oxford, England)》2012,51(10):1860-1869
Objective. To investigate the effect of tocilizumab on patient-reported outcomes (PROs) in RA patients with inadequate responses to TNF inhibitors (TNFis). Methods. In a Phase III randomized controlled trial, 489 patients received 4 or 8 mg/kg tocilizumab or placebo every 4 weeks plus MTX for 24 weeks. Mean changes from baseline over time and proportions of patients reporting improvements greater than or equal to minimum clinically important differences (MCIDs) in PROs were analyzed. Results. At week 24, 8?mg/kg resulted in significantly greater improvements vs placebo in pain, global assessment of disease activity (P?=?0.001), Health Assessment Questionnaire-Disability Index (HAQ-DI; P?0.0001), Functional Assessment of Chronic Illness Therapy-Fatigue (P?=?0.0150) and Medical Outcomes Survey Short Form 36 (SF-36 v2) Physical Component Summary (PCS; P?=?0.0003) scores, all greater than MCID; 4?mg/kg resulted in greater improvements in pain (P?=?0.0100), HAQ-DI (P?=?0.0030) and SF-36 PCS (P?=?0.0020) scores. Tocilizumab-associated improvements were evident as early as week 2. At week 24, more tocilizumab-treated than control patients reported improvements greater than or equal to MCID in SF-36 domain scores and related PROs (50.9-84.9% vs 35.0-51.7%) and achieved ACR50 responses and/or Disease Activity Score 28 (DAS28) remission with PRO improvements greater than or equal to MCID (36.2-51.2% vs 10-20.7% and 10.7-37.5% vs 0.0-3.4%, respectively). Conclusion. Tocilizumab treatment in patients with inadequate responses to TNFis resulted in rapid and sustained improvements in multiple PROs that were statistically significant and clinically meaningful, consistent with previous efficacy reports. Trial Registration. ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00106522. 相似文献
136.
Jan Philipp Kolb Rebecca A. Kueny Klaus Püschel Andreas Boger Johannes M. Rueger Michael M. Morlock Gerd Huber Wolfgang Lehmann 《European spine journal》2013,22(7):1650-1656
Purpose
Normal progression of osteoporosis or the rigid reinforcement of the fractured vertebral body with polymethyl methacrylate (PMMA) cement is being discussed as a cause for adjacent-level fractures after vertebroplasty. The purpose of this study was to investigate whether augmentation with low stiffness cement can decrease the risk of adjacent-level fractures in low-quality bone.Methods
Eighteen female osteoporotic lumbar specimens (L1–L5) were harvested and divided into three groups according to bone mineral density: (I) native; (II) PMMA; (III) modified PMMA (lower stiffness). For the PMMA and modified PMMA groups, a compression fracture was first mechanically induced in L3, and then the fracture received vertebroplasty treatment. The cement stiffness reduction of the modified PMMA group was achieved via an addition of 8 mL of serum to the typical PMMA base. All specimens were exposed to cyclic loading (4 Hz) and a stepwise increasing applied peak force. Cement stiffness was tested according to ISO 5833.Results
A 51 % decrease in cement stiffness was achieved in the modified PMMA group (954 ± 141 vs. 1,937 ± 478 MPa, p < 0.001). Fatigue fracture force (the force level during cyclic loading at which the deformation experienced a sudden increase; FFF) was significantly affected by bone quality (r 2 = 0.39, p = 0.006) and by the initial fracture force (the force necessary to create the initial fracture in L3 prior to augmentation; r 2 = 0.82, p < 0.001). Using initial fracture force as a covariate, the FFF of the modified PMMA group (1,764 ± 49 N) was significantly higher than in the PMMA group (1,544 ± 55 N; p = 0.03).Conclusions
A possible method to reduce adjacent-level fractures after vertebroplasty in patients with reduced bone quality could be the use of a lower modulus cement. Therefore, mixing cement with biocompatible fluids could prove useful to tailor cement properties in the operating theater. 相似文献137.
Sanjum P. Samagh Erik J. Kramer Gerd Melkus Dominique Laron Blake M. Bodendorfer Kyle Natsuhara Hubert T. Kim Xuhui Liu Brian T. Feeley 《Journal of orthopaedic research》2013,31(3):421-426
Rotator cuff pathology is the most common shoulder problem seen by orthopedic surgeons. Rotator cuff muscle fatty infiltration and muscle atrophy are common in larger tears and are considered predicting factors for the prognosis of cuff repair. Clinically, MRI is the gold standard in determining fatty infiltration and muscle atrophy; however, analysis for MRI imaging is primarily qualitative in nature with the results lacking further validation. We have recently developed a mouse model of rotator cuff tears. The goal of this study is to quantify and verify rotator cuff muscle atrophy and fatty infiltration using high‐resolution MRI in our mouse model. The rotator cuff muscles were analyzed for fat using a triglyceride quantification assay (TQA), muscle volume was measured through water displacement (WD), and histology. The study revealed that MRI had a high correlation with fat as measured with histology and TQA (R2 = 098). MRI also correlated well with atrophy measured with WD and wet weight. This suggests that MRI is a reliable modality in evaluating the progression of fatty infiltration and muscle atrophy following rotator cuff tears in a small animal model. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 421–426, 2013 相似文献
138.
Martin F. Sprinzl Arndt Weinmann Nikola Lohse Hanna Tönissen Sandra Koch Jörn Schattenberg Maria Hoppe‐Lotichius Tim Zimmermann Peter R. Galle Torsten Hansen Gerd Otto Marcus Schuchmann 《Transplant international》2013,26(1):67-74
The metabolic syndrome (MetS) might contribute to morbidity after orthotopic liver transplantation (OLT). For this reason, we searched for MetS‐associated risk factors and analyzed the link with nonalcoholic fatty liver disease (NAFLD) in OLT recipients. De novo MetS affected 32.9% of our cohort (n = 170) within 2 years after OLT. Multivariate analysis identified glycosylated hemoglobin (HbA1c) levels ≥5% [odds ratio (OR) = 3.5; 95% confidence interval (CI) = 1.56–8.13, P = 0.003], diabetes mellitus (OR = 4.31, CI = 1.69–10.99, P = 0.002), and arterial hypertension (OR = 4.59, CI = 1.46–14.49, P = 0.009) as independent risk factors for de novo MetS. MetS incidence correlated with steroid dosage after OLT (5.2 ± 2.4 mg/day vs. 7.1 ± 4.7 mg/day, P = 0.014), and was linked to NAFLD (P = 0.001) via obesity (OR = 4.67, CI = 1.55–14.1, P = 0.006) and dyslipidemia (OR = 4.23, CI = 1.35–13.3, P = 0.013) post‐OLT. In conclusion, we were able to identify low threshold HbA1c as a novel risk factor for MetS after OLT and described a link of MetS with NAFLD in transplant organs. This study also indicated that steroid treatment is associated with MetS rates after OLT. 相似文献
139.
Mareike Lankeit Claudia Dellas Viola Benz Gerd Hasenfuß Stavros Konstantinides 《Thrombosis research》2013
Background
Heart-type fatty acid-binding protein (H-FABP) is a useful biomarker for risk stratification of patients with pulmonary embolism (PE). In patients with acute myocardial infarction, H-FABP plasma concentrations rise after 30 minutes and return to normal within 20-24 hours. We tested whether the predictive value of H-FABP is affected by the duration of symptoms prior to diagnosis in patients with PE.Material and Methods
We prospectively studied 257 consecutive normotensive patients with confirmed symptomatic PE.Results
Patients with acute (< 24 hours; n = 150) symptom onset presented more often with syncope (28.7% vs. 6.5%; p < 0.001) compared to patients with symptoms ≥ 24 hours (n = 107); other baseline characteristics, comorbidities, and risk factors were distributed equally. Patients with an adverse 30-day outcome (6.6%) had higher H-FABP levels (11.84 [3.57-19.62] ng/ml) compared to patients with a favorable course (3.42 [1.92-5.42] ng/ml; p < 0.001). However, the proportion of patients with H-FABP levels ≥ 6 ng/ml did not differ among patients with acute symptom onset and late presentation (p = 0.104). Only tachycardia and elevation of H-FABP were associated with an increased risk of an adverse 30-day outcome both in patients with acute symptom onset (H-FABP: OR, 5.8; 95% CI, 1.4-24.5; p = 0.016; tachycardia: 7.0 [1.4-36.0]; p = 0.018) and late presentation (H-FABP: 9.3 [2.0-43.2]; p = 0.004 and tachycardia: 12.3 [1.5-103.6]; p = 0.021). The prognostic value could further be improved by the use of a simple H-FABP-based clinical prediction score.Conclusions
Our findings indicate that H-FABP is a useful biomarker for risk stratification of normotensive patients with PE regardless of symptom duration prior to diagnosis. 相似文献140.
Gerd Fabian Volk MD Nadja Wystub Martin Pohlmann MD Mira Finkensieper MD Heather J. Chalmers DVM Orlando Guntinas-Lichius MD 《Muscle & nerve》2013,47(6):878-883
Introduction: There is no standardized method for examination of facial muscles with ultrasound. The purpose of this study was to identify those facial muscles accessible for reliable identification and to provide reference data. Methods: In healthy subjects all facial muscles were screened for visibility, separation from adjacent muscles, and reliability of landmarks. Bilateral scans of reliable muscles were performed in 40 adult volunteers. Results: Six facial muscles were clearly demarcated with ultrasound. These were: frontalis, orbicularis oculi, orbicularis oris, depressor anguli oris, depressor labii inferioris, and mentalis muscles. Cross-sectional area and muscle thickness showed gender differences and were independently related to age for some muscles. A significant left–right side difference was only seen for the orbicularis oculi muscle in women. Conclusions: These data demonstrate the usefulness of ultrasonography to assess facial muscles and provide reference values that can be applied in the clinical setting. Muscle Nerve 47: 878–883, 2013 相似文献