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1.
Relaxin down-regulates renal fibroblast function and promotes matrix remodelling in vitro. 总被引:1,自引:0,他引:1
Rosemary Masterson Tim D Hewitson Kristen Kelynack Marina Martic Laura Parry Ross Bathgate Ian Darby Gavin Becker 《Nephrology, dialysis, transplantation》2004,19(3):544-552
BACKGROUND: Renal fibroblasts are important effector cells in tubulointerstitial fibrosis, with experimental antifibrotic strategies focusing on the functional down-regulation of these cells. Several experimental models of fibrosis have provided evidence for the effectiveness of the polypeptide hormone relaxin as a potential antifibrotic agent. This study was conducted to further elucidate the antifibrotic mechanisms of relaxin on renal fibroblasts in vitro. METHODS: Rat cortical fibroblasts were obtained from outgrowth culture of renal tissue isolated from kidneys 3 days post-unilateral ureteric obstruction and constituted 100% of cells studied. A relaxin radio-receptor assay was used to establish binding of relaxin to renal fibroblasts in vitro. Functional studies then examined the effects of H2 relaxin (0, 1, 10 and 100 ng/ml) on fibroblast kinetics, expression of alpha-smooth muscle actin (alpha-SMA), total collagen synthesis, collagenase production and collagen-I lattice contraction. CTGF mRNA expression was also measured by northern analysis. RESULTS: H2 relaxin bound with high affinity to rat renal fibroblasts, but receptor numbers were low. Consistent with its previously reported bimodal effect, transforming growth factor (TGF-beta 1) reduced fibroblast proliferation, an effect abrogated by H2 relaxin. Fibroblasts exposed to H2 relaxin (100 ng/ml) for 24 h demonstrated decreased immunostaining for alpha-SMA and reduced alpha-SMA protein expression compared with controls. There was a trend for a relaxin-mediated reduction in total collagen synthesis and alpha 1(I) mRNA expression with large dose-related increases in collagenase protein expression being observed. TGF-beta 1-stimulated collagen-I lattice contraction was significantly inhibited following co-incubation with 100 ng/ml relaxin. Incremental doses of H2 relaxin had no significant effect on CTGF mRNA expression. CONCLUSIONS: The findings of this study suggest that the antifibrotic effects of relaxin involve down-regulation of fibroblast activity, increase in collagenase synthesis and restructuring of collagen-I lattices, which are consistent with its known physiological role of matrix remodelling. Although there appears to be an interaction between TGF-beta 1 and H2 relaxin, this does not appear to involve a reduction in CTGF mRNA expression. 相似文献
2.
Timson C Appanna Shareen H Doak Spencer A Jenkins Howard G Kynaston Timothy P Stephenson James M Parry 《International journal of urology》2007,14(6):539-544
OBJECTIVE: Tumors arising within augmentation cystoplasties are aggressive, have poor prognosis and the majority are not detected at follow-up cystoscopy. Genetic changes in tumors precede morphological abnormalities. Therefore, the aim of this study was to investigate whether genetic abnormalities detected by comparative genomic hybridization (CGH) could be used to identify those patients with augmentation cystoplasties at increased risk of tumorigenesis. METHODS: Bladder biopsy samples were obtained from 16 augmentation cystoplasty patients both distant from and near to the enterovesical anastomosis. CGH was used to detect genetic abnormalities in DNA extracted from the biopsies, archival specimens of two augmentation cystoplasties and two de novo bladder adenocarcinomas. RESULTS: A greater number of amplifications on 2p, 3q, 8q, 9p, 17p, 18pq and 20pq, were observed in bladder biopsies obtained near to the enterovesical anastomosis compared to those taken distant to the suture line. CGH of archival augmentation cystoplasty tumor DNA indicated abnormalities at several loci with amplifications at 2q, 5q, 10p and 21pq, while deletions occurred at 5p and 16p. CONCLUSIONS: The results of this study suggest that the urothelium adjacent to the bladder and/or bowel anastomosis in augmentation cystoplasties is genetically unstable. Furthermore, longitudinal studies are required to establish whether or not patients exhibiting genetic instability following augmentation cystoplasty are at greater risk of developing tumors than those with genetically stable epithelia. 相似文献
3.
Susan Yung Heinz Hausser Gareth Thomas Liliana Schaefer Hans Kresse Malcolm Davies 《Peritoneal dialysis international》2004,24(2):147-155
OBJECTIVE: Previous studies have shown that decorin and biglycan account for over 70% of the proteoglycans (PGs) synthesized by human peritoneal mesothelial cells (HPMCs). Since these PGs are involved in the control of cell growth, cell differentiation, and matrix assembly, we investigated their turnover in cultured HPMCs. METHODS: Confluent HPMCs were metabolically labeled with [35S]-sulfate and the labeled products isolated from the cell medium and the cell layer characterized by sensitivity to bacterial eliminases. Experiments were undertaken with exogenous labeled decorin, and its metabolic state was studied. RESULTS: In a 24-hour labeling period, 75% of the newly synthesized chondroitin sulfate/dermatan sulfate (CS/DS) PGs appeared in the culture medium, the majority of which (90%) was decorin. In the cell layer, protein-free glycosaminoglycan (GAG) chains accounted for 21% of the total CS/DS at 24 hours and exhibited constant specific activity at 12-16 hours. The latter material was turned over with a half-life of approximately 2.5 hours. Exogenous decorin underwent receptor-mediated endocytosis and subsequent intracellular degradation. Uptake but not degradation could be inhibited by heparin. CONCLUSIONS: HPMCs are distinguished by a rapid turnover of decorin. A characteristic metabolic feature is the existence of a large intracellular pool of protein-free DS-GAGs. Understanding the control of decorin turnover in HPMCs might lead to delineation of its potential role in both the physiology and pathophysiology of the membrane in PD patients. 相似文献
4.
Hans C. Andersson Dilys M. Parry John J. Mulvihill 《American journal of medical genetics. Part A》1995,56(1):72-75
Hereditary lymphedemas that are not associated with other malformations usually affect the lower limbs and are inherited in an autosomal dominant fashion. These non-syndromic hereditary lymphedemas are categorized by their age of onset, being either congenital (Milroy disease) or having an onset in childhood or around puberty (Meige disease). We describe a family in which three individuals in three generations had unusually late onset of lym-phedema in their mid-twenties or thirties. The proband additionally developed a very rare lymphangiosarcoma. This tumor, usually associated with post-mastectomy lym-phedema, has not been described in late-onset hereditary lymphedema. Because of an unusually high incidence of multiple primary tumors in association with lymphangiosarcoma in the literature (approximately 10%) and the proband's own familial cancer background, we speculate that an inherited predisposition to malignancy may underlie the development of lymphedema-associated lymphangiosarcoma. © 1995 Wiley-Liss, Inc. 相似文献
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Dennis M Mello MD Doff B McElhinney MS Andrew J Parry MD Norman H Silverman MD Frank L Hanley MD 《The Annals of thoracic surgery》1997,64(6):1808-1810
In hearts with a common arterial trunk (truncus arteriosus), there is almost always an inverse development of the aortic arch and the ductus arteriosus. Truncus with a normal aortic arch and a patent ductus is a rare echocardiographic and surgical finding. In this report, we describe 2 neonates in whom truncus arteriosus with a normal aortic arch and a medium or large patent ductus was diagnosed by preoperative echocardiography (without catheterization) and confirmed intraoperatively. 相似文献
9.
Through the analysis of questionnaire data, this study examines the strategic management styles of 114 nonprofit hospitals and the relationship between each of these styles and hospital marketing tactics. The analysis has important implications for nonprofit hospitals and other health care organizations. 相似文献
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