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11.
J. P. VAVALLE C. P. RUSCONI S. ZELENKOFSKE W. A. WARGIN J. H. ALEXANDER R. C. BECKER 《Journal of thrombosis and haemostasis》2012,10(7):1303-1311
Summary. Background: The REG2 anticoagulation system consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous control agent, anivamersen. Objectives: To assess the safety, tolerability and pharmacokinetic and pharmacodynamic responses of REG2. Patients/Methods: In this phase 1a study, 36 healthy volunteers were enrolled into five cohorts and given one dose of pegnivacogin. Cohorts 1 (n = 6) and 1A (n = 4) received 0.5 mg kg?1; cohort 2 (n = 6) received 1.0 mg kg?1; cohort 3 (n = 6) received 3.0 mg kg?1; and cohort 4 (n = 8) received 2.0 mg kg?1. In cohorts 1–3, two subjects were randomized to placebo. Cohort 4 subjects were subsequently randomized to single‐dose (n = 4) or multidose (n = 4) anivamersen. Results: The mean maximum observed concentrations of pegnivacogin in cohorts 1, 1A, 2 and 3 at median time were 5.16 μg mL?1 at 84 h, 5.19 μg mL?1 at 72 h, 9.32 μg mL?1 at 90 h, and 32.5 μg mL?1 at 84 h, respectively. The maximum relative activated partial thromboplastin time and time needed to achieve this were 1.18 at 2 days, 1.16 at 2 days, 1.27 at 3 days, and 1.85 at 2 days, respectively. The calculated mean half‐life and mean residence times of pegnivacogin were 6.12 days and 9.6 days, respectively. There was rapid reversal with intravenous anivamersen, although subsequent reaccumulation of pegnivacogin was observed. Conclusions: In our first‐in‐human study, REG2 was well tolerated and provided dose‐proportional anticoagulation for several days after a single subcutaneous dose, with complete, although transient, reversal by its control agent. This study demonstrates the first application of a subcutaneously administered aptamer, and represents a potential advance in aptamer therapeutics. 相似文献
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Summary. Inhibitor development continues to be a major problem in the treatment of haemophilia. Immune tolerance induction (ITI) continues to be the most effective approach to managing this complication. This study reviews the practice and outcome of ITI at a single centre over a 17‐year period. All 31 inhibitor patients have haemophilia A. Two patients with haemophilia A underwent two trials of ITI and a third patient underwent three trials of ITI for a total of 35 courses of ITI in these 31 patients. Most patients had high responding inhibitors, 22 of 31. Seventy‐one percent of haemophilia patients achieved tolerance. Courses of ITI in African American (AA) patients with haemophilia A were much less likely to achieve tolerance compared with non‐AAs, 57.9% and 92% (P = 0.04) respectively. Most trials of ITI were carried out with recombinant products (25 of 35). While ITI continues to be an effective therapy for patients with inhibitors, it is less effective in AA patients, and patients with higher inhibitor titres. In this refractory group of patients, new approaches are needed. 相似文献
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BackgroundThe mechanism underlying the increased levels of protoporphyrin IX in bladder cancer remains unclear. Here, we focus on proteins associated with protoporphyrin IX accumulation in bladder cancer cells and investigate the protein that plays a key role in increased protoporphyrin IX accumulation in bladder cancer cells.MethodsWestern blotting was used to determine the expression of peptide transporter 1, hydroxymethylbilane synthase, ferrochelatase, ATP-binding cassette 2, and heme oxygenase-1 in bladder cancer cell line cells. We evaluated the correlation between the expression of each protein and accumulated protoporphyrin IX in these cells using Pearson's correlation analysis. Immunohistochemistry was used to estimate the expression of the same five proteins in samples from 75 patients who underwent transurethral resection of bladder tumors. The correlation between the expression of each protein in cells from resected bladder specimens and accumulated protoporphyrin IX in bladder cancer cells in voided urine was evaluated using Pearson's correlation analysis.ResultsThe expression of ferrochelatase showed a significant negative correlation with protoporphyrin IX accumulation in vitro (p = 0.04). The expression of peptide transporter 1 (p < 0.01, R = 0.39), heme oxygenase-1 (p < 0.01, R = 0.33), and ferrochelatase (p < 0.01, R = 0.75) in resected bladder specimens by immunohistochemistry was correlated with protoporphyrin IX accumulation in bladder cancer cells in voided urine. On multivariate analysis, the expression of ferrochelatase (p = 0.03) was significant factors to predict positive 5-aminolevulinic acid-induced fluorescent cytology.ConclusionThe expression of ferrochelatase has a strong correlation in protoporphyrin IX accumulation with photodynamic detection of bladder cancer. 相似文献
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《Expert opinion on therapeutic targets》2013,17(12):1593-1605
Objective: Hypoxia-inducible factor 1, a regulator of CA IX activity, is often overexpressed in human osteosarcoma (OS) but not in normal tissues, and its expression levels correlate with prognosis. In this study, we investigated the therapeutic potential of newly synthesized CA IX sulfonamide inhibitors in OS.Methods: CA IX expression was evaluated in OS cell lines and bone marrow stromal cells (BMSC). After treatment with CA IX inhibitors, cell proliferation, apoptosis, cell cycle, extracellular and cytosolic pH changes were evaluated both in vitro and in mouse OS xenografts.Results: CA IX expression levels were significantly higher in OS than in BMSC. Accordingly, CA IX inhibitor 3 induced remarkable cytotoxicity on OS cells without affecting BMSC proliferation. This activity was increased under hypoxia, and was mediated by cell cycle arrest and by the modulation of cytosolic and extracellular pH. In vivo, CA IX inhibitor 3 reduced tumor growth by inducing significant necrosis.Conclusions: Our results provide a strong rationale for the clinical use of the newly synthesized CA IX inhibitor 3 in human OS. 相似文献
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Key NS 《British journal of haematology》2004,127(4):379-391
The development of inhibitory 'allo' antibodies to a deficient coagulation factor is arguably now the most severe and important complication of clotting factor concentrate exposure in haemophilia and other congenital coagulation disorders. Furthermore, development of an inhibitor to the factor VIII or factor IX transgene product remains a significant concern in gene therapy protocols for haemophilia. Although the development of an inhibitor does not usually change the rate, initial severity or pattern of bleeding, it does compromise the ability to manage haemorrhage in affected individuals, resulting in a greater rate of complications, cost and disability. The purpose of this review is to summarize current understanding of the epidemiology, immunobiology, laboratory evaluation and management of inhibitors arising in patients with congenital coagulation disorders. An attempt has been made to focus on recent advances in the immunology of inhibitors, and to speculate on their potential clinical application. 相似文献
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The chaperone‐like sodium phenylbutyrate improves factor IX intracellular trafficking and activity impaired by the frequent p.R294Q mutation 下载免费PDF全文
S. Pignani A. Todaro M. Ferrarese S. Marchi S. Lombardi D. Balestra P. Pinton F. Bernardi M. Pinotti A. Branchini 《Journal of thrombosis and haemostasis》2018,16(10):2035-2043
Essentials
- Missense mutations often impair protein folding, and thus intracellular trafficking and secretion.
- Cellular models of severe type I hemophilia B were challenged with chaperone‐like compounds.
- Sodium phenylbutyrate improved intracellular trafficking and secretion of the frequent p.R294Q.
- The increased coagulant activity levels (~3%) of p.R294Q would ameliorate the bleeding phenotype.