全文获取类型
收费全文 | 359篇 |
免费 | 30篇 |
国内免费 | 3篇 |
专业分类
耳鼻咽喉 | 7篇 |
儿科学 | 24篇 |
妇产科学 | 5篇 |
基础医学 | 56篇 |
口腔科学 | 3篇 |
临床医学 | 27篇 |
内科学 | 88篇 |
皮肤病学 | 2篇 |
神经病学 | 29篇 |
特种医学 | 3篇 |
外科学 | 17篇 |
预防医学 | 35篇 |
眼科学 | 16篇 |
药学 | 9篇 |
肿瘤学 | 71篇 |
出版年
2023年 | 2篇 |
2022年 | 5篇 |
2021年 | 7篇 |
2020年 | 5篇 |
2019年 | 4篇 |
2018年 | 9篇 |
2017年 | 9篇 |
2016年 | 16篇 |
2015年 | 14篇 |
2014年 | 17篇 |
2013年 | 19篇 |
2012年 | 27篇 |
2011年 | 37篇 |
2010年 | 21篇 |
2009年 | 23篇 |
2008年 | 22篇 |
2007年 | 19篇 |
2006年 | 19篇 |
2005年 | 19篇 |
2004年 | 15篇 |
2003年 | 9篇 |
2002年 | 13篇 |
2001年 | 2篇 |
2000年 | 5篇 |
1999年 | 7篇 |
1998年 | 7篇 |
1997年 | 2篇 |
1996年 | 1篇 |
1994年 | 1篇 |
1992年 | 6篇 |
1991年 | 6篇 |
1990年 | 4篇 |
1989年 | 4篇 |
1988年 | 6篇 |
1987年 | 1篇 |
1986年 | 3篇 |
1985年 | 3篇 |
1983年 | 1篇 |
1979年 | 1篇 |
1976年 | 1篇 |
排序方式: 共有392条查询结果,搜索用时 31 毫秒
1.
2.
3.
Nielsen M Franken PF Reinards TH Weiss MM Wagner A van der Klift H Kloosterman S Houwing-Duistermaat JJ Aalfs CM Ausems MG Bröcker-Vriends AH Gomez Garcia EB Hoogerbrugge N Menko FH Sijmons RH Verhoef S Kuipers EJ Morreau H Breuning MH Tops CM Wijnen JT Vasen HF Fodde R Hes FJ 《Journal of medical genetics》2005,42(9):e54
Objective: To investigate the contribution of MYH associated polyposis coli (MAP) among polyposis families in the Netherlands, and the prevalence of colonic and extracolonic manifestations in MAP patients. Methods: 170 patients with polyposis coli, who previously tested negative for APC mutations, were screened by denaturing gradient gel electrophoresis and direct sequencing to identify MYH germline mutations. Results: Homozygous and compound heterozygous MYH mutations were identified in 40 patients (24%). No difference was found in the percentage of biallelic mutation carriers between patients with 10–99 polyps or 100–1000 polyps (29% in both groups). Colorectal cancer was found in 26 of the 40 patients with MAP (65%) within the age range 21 to 67 years (median 45). Complete endoscopic reports were available for 16 MAP patients and revealed five cases with gastro-duodenal polyps (31%), one of whom also presented with a duodenal carcinoma. Breast cancer occurred in 18% of female MAP patients, significantly more than expected from national statistics (standardised morbidity ratio = 3.75). Conclusions: Polyp numbers in MAP patients were equally associated with the attenuated and classical polyposis coli phenotypes. Two thirds of the MAP patients had colorectal cancer, 95% of whom were older than 35 years, and one third of a subset of patients had upper gastrointestinal lesions. Endoscopic screening of the whole intestine should be carried out every two years for all MAP patients, starting from age 25–30 years. The frequent occurrence of additional extraintestinal manifestations, such as breast cancer among female MAP patients, should be thoroughly investigated. 相似文献
4.
Nicoline Treijtel Arjan Barendregt Andreas P Freidig Bas J Blaauboer Jan C H van Eijkeren 《Drug metabolism and disposition》2004,32(8):884-891
An alternative approach is introduced in determining the in vitro intrinsic clearance of slowly metabolized compounds. The longterm sandwich rat hepatocyte culture was exploited, allowing for sufficient substrate depletion to obtain a reliable clearance estimation; in its physiology, it resembles the in vivo liver, thus allowing in vivo extrapolation of the in vitro clearance value. Substrate depletion of tolbutamide and the formation of its metabolites hydroxytolbutamide and carboxytolbutamide were measured in the medium and sandwich layer. Depletion data from the medium were fitted to a mathematical model incorporating system-dependent parameters (diffusion, protein binding, and partitioning) to calculate the hepatocytes' intrinsic clearance. Based on the decrease of the parent compound in the medium, a specific intrinsic clearance value, i.e., clearance per unit of volume of hepatocytes, of 0.085 min(-1) was fitted. This value was in accordance with in vivo and in vitro values from the literature. The model was verified with substrate depletion data from the sandwich layer. Data on metabolite formation showed an incomplete mass balance. A radiochemical experiment revealed the presence of three additional metabolites. These metabolites were analyzed by liquid chromatography-mass spectometry. One was identified as p-tolysulfonylurea. The structure of the other two needs to be elucidated. After the addition of these compounds to the metabolic pattern, the mass balance was completed. The in vitro clearance value was incorporated in a physiologically based pharmacokinetic literature model of tolbutamide that accurately describes the plasma concentration. The approach used in this study successfully predicts the intrinsic clearance of tolbutamide. In addition, the sandwich rat hepatocyte culture also proves to be useful in the identification of metabolic pathways. 相似文献
5.
Aisha S. Sie Judith B. Prins Liesbeth Spruijt C. Marleen Kets Nicoline Hoogerbrugge 《Familial cancer》2013,12(4):675-682
DNA-testing for BRCA1/2 or Lynch syndrome is possible from the age of 18 years, although surveillance usually starts at 25. Some patients regret their decision of testing before age 25. This retrospective study evaluates whether the testing age should be above 25 years to prevent adverse effects such as regret or decisional conflict, by determining the percentage and characteristics of patients reporting these problems. 111 of 219 patients (51 %) tested for BRCA1/2 mutations or Lynch syndrome between 18 and 25 years from July 1996 to February 2011, returned self-report surveys. Primary measures were regret, decisional conflict and family influence. Secondary measures included quality of life (QoL), coping style, impact of genetic testing, and risk perception. Median age was 27 [21–40] years, with 86 % female. 73 % was tested for BRCA1/2, 27 % for Lynch syndrome. Only 3 % reported regret, however 39 % had moderate (32 %) to severe (7 %) decisional conflict. Regression analysis revealed that decisional conflict was associated with more monitoring/neutral coping style (p < 0.03) or paternal/no family mutation (p < 0.02); there were no differences in QoL, impact or risk perception. 42 % were mutation carriers, showing equal decisional conflict to non-carriers. 68 % would recommend testing <25 years; 77 % desired surveillance <25 years if a mutation carrier. Almost no patient tested for hereditary cancer between 18 and 25 years regretted this decision. A third reported retrospective decisional conflict, especially those actively seeking information when faced with a threat and/or those with a paternal or unknown inheritance. These patients may benefit from decisional support and personalized information. 相似文献
6.
Majke H.D. van Bommel Marieke Arts de Jong Miranda P. Steenbeek Michiel L. Bots Liselore L.M. van Westerop Maria T.E. Hopman Nicoline Hoogerbrugge Joanne A. de Hullu Angela H.E.M. Maas 《Journal of cardiology》2021,77(6):570-575
BackgroundBRCA1/2 mutation carriers are generally exposed to early menopause due to risk-reducing salpingo-oophorectomy (RRSO) around the age of 40 years. This risk-reducing intervention is based on a 10–40% life-time risk of ovarian cancer in this population. Although effective, premature and acute menopause induces non-cancer related morbidity in both the short and long term. Little is known about the impact of RRSO on the cardiovascular system.MethodsThis cross-sectional study explored the relationship between time since RRSO and signs of subclinical atherosclerosis, as measured by carotid intima-media thickness (CIMT) and pulse wave velocity (PWV), in 165 BRCA1/2 mutation carriers. All participants, aged 40 to 63 years, underwent RRSO before the age of 45 years, and at least 5 years ago. Cardiovascular risk factors were assessed by questionnaires and a single screening visit. Data were analyzed using linear regression models.ResultsMean CIMT was 692.7 μm (SD 87.0), and mean central PWV 6.40 m/s (SD 1.42). After adjustment for age and several relevant cardiovascular risk factors, time since RRSO was not associated with CIMT (β=0.68 μm; 95% CI –4.02, 5.38) and PWV (β=44 mm/s; 95% CI –32, 120). Compared to women of a reference group from the general population, lower systolic blood pressure [mean difference 12 mmHg; 95% confidence interval (CI) 10, 14] was found in BRCA1/2 mutation carriers.ConclusionsWe found that, in BRCA1/2 mutation carriers, at 5 to 24 years follow-up, time since RRSO is not related to development of subclinical atherosclerosis. However, the follow-up period in these relatively young women might have been too short. 相似文献
7.
A spastic thumb can be abusively interpreted as a congenital trigger thumb. This case report describes the rare presentation of bowstringing in a spastic patient after earlier release of the first annular pulley. It is important to recognize bowstringing because of therapeutical consequences. Level of Evidence: Level V, diagnostic study. 相似文献
8.
Differential regulation of IGF-binding proteins in rabbit costal chondrocytes by IGF-I and dexamethasone 总被引:8,自引:0,他引:8
Cartilage is a primary target tissue for the IGFs. The mitogenic activity of these peptides is regulated by a family of high-affinity IGF-binding proteins (IGFBP-1 to -6). We characterized the IGFBPs produced by cultured chondrocytes derived from rib cartilage of prepubertal rabbits. Culture medium, which had been conditioned by these cells for 48 h showed bands of 22 kDa, 24 kDa and a 31/32 kDa doublet by Western ligand blotting with [(125)I]IGF-II. When the cells were grown in the presence of increasing amounts of IGF-I or IGF-II, the 31/32 kDa doublet increased in intensity (reaching a plateau of about 11-fold stimulation between 2 and 10 nM IGF-I). The 22 kDa and 24 kDa bands increased only slightly while a 26 kDa band became faintly visible. By Western immunoblotting the 31/32 kDa doublet was identified as IGFBP-5. An IGF-I analog with reduced affinity for IGFBPs, Long-R3 IGF-I, also induced IGFBP-5, while insulin was less effective (2.2-fold stimulation at 10 nM). IGF-I protected IGFBP-5 against proteolytic degradation by conditioned medium. IGF-I also enhanced the level of IGFBP-5 mRNA. LY294002, a specific inhibitor of the intracellular signaling molecule phosphatidylinositol 3-kinase, inhibited stimulation of IGFBP-5 by IGF-I. Dexamethasone suppressed IGFBP-5 (by 70% at 20 nM) but, at the same time, a 39/41 kDa doublet (presumably IGFBP-3) was induced. IGFBP-5 has been shown in several cell types to enhance the mitogenic activity of IGF-I. IGFBP-3 generally acts as a growth inhibitor. Therefore, the differential effects of dexamethasone on these regulatory proteins could account, at least in part, for the growth-arresting effect of this glucocorticoid. 相似文献
9.
10.
Van Buul-Offers SC Van Kleffens M Koster JG Lindenbergh-Kortleve DJ Gresnigt MG Drop SL Hoogerbrugge CM Bloemen RJ Koedam JA Van Neck JW 《Endocrinology》2000,141(4):1493-1499
The actions of insulin-like growth factor-I (IGF-I) are modulated by IGF binding proteins (IGFBPs). The effects of IGFBP-1 in vivo are insufficiently known, with respect to inhibitory or stimulatory actions on IGF-induced growth of specific organs. Therefore, we studied the effects of IGFBP-1 on IGF-I-induced somatic and organ growth in pituitary-deficient Snell dwarf mice. Human GH, IGF-I, IGFBP-1, and a preequilibrated combination of equimolar amounts of IGF-I and IGFBP-1 were administered sc during 4 weeks. Treatment with IGF-I alone induced a significant increase in body length (108% of control) and weight (112%) as well as an increase in weight of the submandibular salivary glands (135%), kidneys (124%), femoral muscles (111%), testes (129%), and spleen (126%) compared with saline-treated controls. IGFBP-1 alone induced a significant increase in weight of the kidneys (152% of control). Coadministration of IGF-I with IGFBP-1 neutralized the stimulating effects of IGF-I on body length and weight as well as on the femoral muscles and testes. In contrast, the weights of the submandibular salivary glands (143%) were not significantly different from those of IGF-I-treated animals, whereas the weights of the kidneys (171%) and spleen (156%) were significantly increased compared with IGF-I-treated mice. The effect of IGFBP-1 plus IGF-I on kidney weight was not significantly greater than the effect of IGFBP-1 alone. Western ligand blotting showed induction of the IGFBP-3 doublet as well as IGFBPs with molecular masses of 24 kDa, most probably IGFBP-4, by human GH, IGF-I alone, and IGF-I in combination with IGFBP-1. Our data show that coadministration of IGFBP-1 inhibits IGF-I-induced body growth of GH-deficient mice but significantly stimulates the growth promoting effects of IGF-I on the kidneys and the spleen. These data warrant further investigation because differences in concentrations of IGFBP-1 occurring in vivo may influence IGF-I-induced anabolic processes. 相似文献