全文获取类型
收费全文 | 2876篇 |
免费 | 126篇 |
国内免费 | 27篇 |
专业分类
耳鼻咽喉 | 5篇 |
儿科学 | 120篇 |
妇产科学 | 61篇 |
基础医学 | 401篇 |
口腔科学 | 33篇 |
临床医学 | 280篇 |
内科学 | 758篇 |
皮肤病学 | 31篇 |
神经病学 | 177篇 |
特种医学 | 82篇 |
外科学 | 389篇 |
综合类 | 13篇 |
一般理论 | 1篇 |
预防医学 | 179篇 |
眼科学 | 95篇 |
药学 | 240篇 |
中国医学 | 10篇 |
肿瘤学 | 154篇 |
出版年
2023年 | 14篇 |
2022年 | 45篇 |
2021年 | 75篇 |
2020年 | 42篇 |
2019年 | 55篇 |
2018年 | 70篇 |
2017年 | 58篇 |
2016年 | 64篇 |
2015年 | 73篇 |
2014年 | 90篇 |
2013年 | 121篇 |
2012年 | 213篇 |
2011年 | 213篇 |
2010年 | 120篇 |
2009年 | 96篇 |
2008年 | 163篇 |
2007年 | 203篇 |
2006年 | 208篇 |
2005年 | 173篇 |
2004年 | 172篇 |
2003年 | 176篇 |
2002年 | 143篇 |
2001年 | 28篇 |
2000年 | 17篇 |
1999年 | 21篇 |
1998年 | 21篇 |
1997年 | 23篇 |
1996年 | 24篇 |
1995年 | 12篇 |
1994年 | 9篇 |
1993年 | 13篇 |
1992年 | 11篇 |
1991年 | 17篇 |
1990年 | 11篇 |
1989年 | 11篇 |
1987年 | 14篇 |
1986年 | 16篇 |
1985年 | 17篇 |
1984年 | 16篇 |
1983年 | 12篇 |
1982年 | 12篇 |
1981年 | 10篇 |
1980年 | 14篇 |
1979年 | 8篇 |
1977年 | 10篇 |
1976年 | 10篇 |
1975年 | 8篇 |
1974年 | 7篇 |
1973年 | 13篇 |
1972年 | 8篇 |
排序方式: 共有3029条查询结果,搜索用时 0 毫秒
81.
Roosmarijn F. W. De Cock Karel Allegaert Janneke M. Brussee Catherine M. T. Sherwin Hussain Mulla Matthijs de Hoog Johannes N. van den Anker Meindert Danhof Catherijne A. J. Knibbe 《Pharmaceutical research》2014,31(10):2643-2654
Purpose
Since glomerular filtration rate (GFR) is responsible for the elimination of a large number of water-soluble drugs, the aim of this study was to develop a semi-physiological function for GFR maturation from neonates to adults.Methods
In the pharmacokinetic analysis (NONMEM VI) based on data of gentamicin, tobramycin and vancomycin collected in 1,760 patients (age 1 day–18 years, bodyweight 415 g–85 kg), a distinction was made between drug-specific and system-specific information. Since the maturational model for clearance is considered to contain system-specific information on the developmental changes in GFR, one GFR maturational function was derived for all three drugs.Results
Simultaneous analysis of these three drugs showed that maturation of GFR mediated clearance from preterm neonates to adults was best described by a bodyweight-dependent exponent (BDE) function with an exponent varying from 1.4 in neonates to 1.0 in adults (ClGFR?=?Cldrug*(BW/4 kg)BDE with BDE?=?2.23*BW?0.065). Population clearance values (Cldrug) for gentamicin, tobramycin and vancomycin were 0.21, 0.28 and 0.39 L/h for a full term neonate of 4 kg, respectively.Discussion
Based on an integrated analysis of gentamicin, tobramycin and vancomycin, a semi-physiological function for GFR mediated clearance was derived that can potentially be used to establish evidence based dosing regimens of renally excreted drugs in children. 相似文献82.
83.
84.
In vitro profiling of the sensitivity of pediatric leukemia cells to tipifarnib: identification of T-cell ALL and FAB M5 AML as the most sensitive subsets 下载免费PDF全文
Goemans BF Zwaan CM Harlow A Loonen AH Gibson BE Hählen K Reinhardt D Creutzig U Heinrich MC Kaspers GJ 《Blood》2005,106(10):3532-3537
Although the prognosis of pediatric leukemias has improved considerably, many patients still have relapses. Tipifarnib, a farnesyl transferase inhibitor (FTI), was developed to target malignancies with activated RAS, including leukemia. We tested 52 pediatric acute myeloid leukemia (AML) and 36 pediatric acute lymphoblastic leukemia (ALL) samples for in vitro sensitivity to tipifarnib using a total cell-kill assay and compared these results to those obtained with normal bone marrow (N BM) samples (n = 25). AML samples were significantly more sensitive to tipifarnib compared to B-cell precursor ALL (BCP ALL) or N BM samples. Within AML, French-American-British (FAB) M5 samples were most sensitive to tipifarnib. T-cell ALL samples were significantly more sensitive than BCP ALL and N BM samples. In AML there was a marked correlation between tipifarnib resistance and daunorubicin or etoposide resistance, but not to cytarabine or 6-thioguanine. RAS mutations were present in 32% of AML and 18% of ALL samples, but there was no correlation between RAS mutational status and sensitivity to tipifarnib. Future studies are needed to identify biomarkers predictive of tipifarnib sensitivity. In addition, clinical studies, especially in T-cell ALL, seem warranted. 相似文献
85.
Kaisa Nieminen Juha Immanen Marjukka Laxell Leila Kauppinen Petr Tarkowski Karel Dolezal Sari Thtiharju Annakaisa Elo Mlanie Decourteix Karin Ljung Rishikesh Bhalerao Kaija Keinonen Victor A. Albert Yk Helariutta 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(50):20032-20037
Although a substantial proportion of plant biomass originates from the activity of vascular cambium, the molecular basis of radial plant growth is still largely unknown. To address whether cytokinins are required for cambial activity, we studied cytokinin signaling across the cambial zones of 2 tree species, poplar (Populus trichocarpa) and birch (Betula pendula). We observed an expression peak for genes encoding cytokinin receptors in the dividing cambial cells. We reduced cytokinin levels endogenously by engineering transgenic poplar trees (P. tremula × tremuloides) to express a cytokinin catabolic gene, Arabidopsis CYTOKININ OXIDASE 2, under the promoter of a birch CYTOKININ RECEPTOR 1 gene. Transgenic trees showed reduced concentration of a biologically active cytokinin, correlating with impaired cytokinin responsiveness. In these trees, both apical and radial growth was compromised. However, radial growth was more affected, as illustrated by a thinner stem diameter than in WT at same height. To dissect radial from apical growth inhibition, we performed a reciprocal grafting experiment. WT scion outgrew the diameter of transgenic stock, implicating cytokinin activity as a direct determinant of radial growth. The reduced radial growth correlated with a reduced number of cambial cell layers. Moreover, expression of a cytokinin primary response gene was dramatically reduced in the thin-stemmed transgenic trees. Thus, a reduced level of cytokinin signaling is the primary basis for the impaired cambial growth observed. Together, our results show that cytokinins are major hormonal regulators required for cambial development. 相似文献
86.
Marten Munneke Zuzana de Jong Aeilko H. Zwinderman Annemarie Jansen H. Karel Ronday Wilfred F. H. Peter Dies C. G. Boonman Cornelia H. M. van den Ende Theodora P. M. Vliet Vlieland Johanna M. W. Hazes 《Arthritis care & research》2003,49(5):665-672
Objective
To evaluate adherence and satisfaction of patients with rheumatoid arthritis (RA) in a long‐term intensive dynamic exercise program.Methods
A total of 146 RA patients started an intensive (strength and endurance training for 75 minutes, twice a week, for 2 years) exercise program (Rheumatoid Arthritis Patients In Training) aimed at improving physical fitness. Program attendance and satisfaction were examined. Additional assessments at baseline were done to find possible predictors of attendance.Results
Median (interquartile range) age and disease duration of the patients were 54 (45–61) and 5 (3–10) years, respectively. After 2 years, 118 (81%) patients still participated in an exercise class. The median attendance rate of all patients was 74%. Low attendance was weakly associated with high disease activity, low functional ability, and low quality of life at baseline but not with the severity of joint damage at baseline. At the end, 78% of all participants would (strongly) recommend the program to other RA patients.Conclusion
Adherence and satisfaction of RA patients with an intensive dynamic exercise program over a prolonged time can be high. Disease severity parameters do not strongly predict the compliance of participants in an intensive exercise program.87.
A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis 总被引:15,自引:0,他引:15 下载免费PDF全文
De Gendt K Swinnen JV Saunders PT Schoonjans L Dewerchin M Devos A Tan K Atanassova N Claessens F Lécureuil C Heyns W Carmeliet P Guillou F Sharpe RM Verhoeven G 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(5):1327-1332
Androgens control spermatogenesis, but germ cells themselves do not express a functional androgen receptor (AR). Androgen regulation is thought to be mediated by Sertoli and peritubular myoid cells, but their relative roles and the mechanisms involved remain largely unknown. Using Cre/loxP technology, we have generated mice with a ubiquitous knockout of the AR as well as mice with a selective AR knockout in Sertoli cells (SC) only. Mice with a floxed exon 2 of the AR gene were crossed with mice expressing Cre recombinase ubiquitously or selectively in SC (under control of the anti-Müllerian hormone gene promoter). AR knockout males displayed a complete androgen insensitivity phenotype. Testes were located abdominally, and germ cell development was severely disrupted. In contrast, SC AR knockout males showed normal testis descent and development of the male urogenital tract. Expression of the homeobox gene Pem, which is androgen-regulated in SC, was severely decreased. Testis weight was reduced to 28% of that in WT littermates. Stereological analysis indicated that the number of SC was unchanged, whereas numbers of spermatocytes, round spermatids, and elongated spermatids were reduced to 64%, 3%, and 0% respectively of WT. These changes were associated with increased germ cell apoptosis and grossly reduced expression of genes specific for late spermatocyte or spermatid development. It is concluded that cell-autonomous action of the AR in SC is an absolute requirement for androgen maintenance of complete spermatogenesis, and that spermatocyte/spermatid development/survival critically depends on androgens. 相似文献
88.
A novel approach to treat bleeding episodes in patients with Glanzmann thrombasthenia (GT) and perhaps also in patients receiving alpha IIb beta 3 inhibitors is the administration of recombinant factor VIIa (rFVIIa). The mechanism of action of rFVIIa in these patients is, however, still unclear. We studied the effect of rFVIIa-mediated thrombin formation on adhesion of alpha IIb beta 3-deficient platelets under flow conditions. Adhesion of alpha IIb beta 3-deficient platelets to the extracellular matrix (ECM) of stimulated human umbilical vein endothelial cells or to collagen type III was studied using a model system with washed platelets and red cells. When alpha IIb beta 3-deficient platelets were perfused over the surface at arterial shear rate for 5 minutes, a low surface coverage was observed (GT platelets, mean +/- SEM, 37.5% +/- 5.0%; normal platelets preincubated with an RGD-containing peptide, 7.4% +/- 2.1%). When rFVIIa, together with factors X and II, was added to the perfusate, platelet deposition significantly increased (GT platelets, mean +/- SEM, 67.0% +/- 4.3%; normal platelets preincubated with an RGD-containing peptide, 48.2% +/- 2.9%). The same effect was observed when normal platelets were pretreated with the commercially available anti-alpha IIb beta 3 drugs abciximab, eptifibatide, or tirofiban. It was shown that tissue factor-independent thrombin generation (presumably induced by binding of rFVIIa to adhered platelets) was responsible for the increase in platelet deposition. In conclusion, defective adhesion of alpha IIb beta 3-deficient platelets to ECM can be restored by tissue factor-independent rFVIIa-mediated thrombin formation. The enhanced generation of platelet procoagulant surface facilitates fibrin formation, so that lack of platelet aggregate formation might be compensated for. 相似文献
89.
Survivin: a novel neuroendocrine marker for pheochromocytoma 总被引:10,自引:0,他引:10
Koch CA Vortmeyer AO Diallo R Poremba C Giordano TJ Sanders D Bornstein SR Chrousos GP Pacak K 《European journal of endocrinology / European Federation of Endocrine Societies》2002,146(3):381-388
OBJECTIVE: To study survivin expression in human adrenal medulla and in benign and malignant pheochromocytoma tissue as a tool to predict tumor metastatic potential and prognosis. DESIGN: Blinded study to assess the role of the anti-survivin antibody in chromaffin cells. METHODS: We performed immunohistochemistry with a purified rabbit-polyclonal anti-survivin antibody on 39 formalin-fixed and paraffin-embedded pheochromocytoma/paraganglioma specimens, and on 10 normal adrenal medulla samples from patients unaffected by a chromaffin cell tumor. Fourteen samples were from 14 patients with benign pheochromocytoma (<8 year follow-up, mean 5.2 years), 18 specimens were from 12 patients with malignant pheochromocytoma (<13 year follow-up, mean 6.3 years), 5 samples were from 2 patients with malignant paraganglioma (<6 year follow-up, mean 4 years), and 2 specimens from 2 patients with benign paraganglioma (<7 year follow-up, mean 5.5 years). Malignancy was defined by metastases in non-chromaffin tissues. Staining intensity with the anti-survivin antibody was scored from 0 (none) to 3+ (heavy). Tissues from human kidney, breast, and melanoma served as controls. RESULTS: All pheochromocytoma/paraganglioma specimens stained either 2+ or 3+. By analysis of variance (ANOVA), there was no statistically significant difference between the staining intensity of benign and malignant samples. All normal adrenal medulla specimens stained positively with anti-survivin but to a lesser degree than the chromaffin cell tumors (P<0.01). CONCLUSIONS: Based on these findings, we conclude that (i) survivin may represent a novel neuroendocrine marker for chromaffin cell tumors, and (ii) survivin does not appear to reliably distinguish benign from malignant pheochromocytomas/paragangliomas and thus does not identify patients at risk of recurrent disease. 相似文献
90.
Mark F J Stolk Marco C J M Becx Karel C Kuypers Cees A Seldenrijk 《Clinical gastroenterology and hepatology》2006,4(7):908-911
BACKGROUND AND AIMS: Ezetimibe was introduced recently as a new class of cholesterol-lowering drugs. Until now only limited increases of transaminase levels were reported. METHODS: We studied 2 patients with severe hepatic side effects of ezetimibe in a general community hospital. RESULTS: Ezetimibe may lead to 2 distinct types of severe hepatic side effects. CONCLUSIONS: Ezetimibe may rarely cause hepatotoxicity, severe cholestatic hepatitis, or acute autoimmune hepatitis. 相似文献