全文获取类型
收费全文 | 721篇 |
免费 | 47篇 |
专业分类
耳鼻咽喉 | 21篇 |
儿科学 | 53篇 |
妇产科学 | 20篇 |
基础医学 | 130篇 |
口腔科学 | 9篇 |
临床医学 | 110篇 |
内科学 | 129篇 |
皮肤病学 | 10篇 |
神经病学 | 93篇 |
特种医学 | 7篇 |
外科学 | 30篇 |
综合类 | 6篇 |
预防医学 | 66篇 |
眼科学 | 6篇 |
药学 | 44篇 |
肿瘤学 | 34篇 |
出版年
2024年 | 4篇 |
2023年 | 11篇 |
2022年 | 18篇 |
2021年 | 12篇 |
2020年 | 10篇 |
2019年 | 18篇 |
2018年 | 36篇 |
2017年 | 25篇 |
2016年 | 24篇 |
2015年 | 15篇 |
2014年 | 24篇 |
2013年 | 58篇 |
2012年 | 60篇 |
2011年 | 70篇 |
2010年 | 49篇 |
2009年 | 42篇 |
2008年 | 63篇 |
2007年 | 45篇 |
2006年 | 33篇 |
2005年 | 41篇 |
2004年 | 26篇 |
2003年 | 29篇 |
2002年 | 24篇 |
2001年 | 3篇 |
2000年 | 2篇 |
1999年 | 4篇 |
1998年 | 2篇 |
1997年 | 3篇 |
1996年 | 4篇 |
1995年 | 2篇 |
1994年 | 2篇 |
1993年 | 4篇 |
1992年 | 1篇 |
1990年 | 2篇 |
1984年 | 1篇 |
1982年 | 1篇 |
排序方式: 共有768条查询结果,搜索用时 0 毫秒
1.
2.
Pennings RJ Te Brinke H Weston MD Claassen A Orten DJ Weekamp H Van Aarem A Huygen PL Deutman AF Hoefsloot LH Cremers FP Cremers CW Kimberling WJ Kremer H 《Human mutation》2004,24(2):185
Usher syndrome type II (USH2) is characterised by moderate to severe high-frequency hearing impairment, progressive visual loss due to retinitis pigmentosa and intact vestibular responses. Three loci are known for USH2, however, only the gene for USH2a (USH2A) has been identified. Mutation analysis of USH2A was performed in 70 Dutch USH2 families. Ten mutations in USH2A were detected, of which three are novel, c.949C>A, c.2242C>T (p.Gln748X) and c.4405C>T (p.Gln1468X). Including 9 previously published Dutch USH2a families, estimates of the prevalence of USH2a in the Dutch USH2 population were made. Mutations were identified in 62% of the families. In 28% both mutated alleles were identified, whereas in 34% the mutation in only one allele was found. It is estimated that about 28% of the Dutch USH2 families have a different causative gene. Analysis of deduced haplotypes suggests that c.1256G>T (p.Cys419Phe) is a Dutch ancestral mutation, occurring in 16% of the alleles. 相似文献
3.
Reiners J van Wijk E Märker T Zimmermann U Jürgens K te Brinke H Overlack N Roepman R Knipper M Kremer H Wolfrum U 《Human molecular genetics》2005,14(24):3933-3943
Usher syndrome (USH) is the most frequent cause of combined deaf-blindness in man. USH is clinically and genetically heterogeneous with at least 11 chromosomal loci assigned to the three USH types (USH1A-G, USH2A-C, USH3A). Although the different USH types exhibit almost the same phenotype in human, the identified USH genes encode for proteins which belong to very different protein classes and families. We and others recently reported that the scaffold protein harmonin (USH1C-gene product) integrates all identified USH1 molecules in a USH1-protein network. Here, we investigated the relationship between the USH2 molecules and this USH1-protein network. We show a molecular interaction between the scaffold protein harmonin (USH1C) and the USH2A protein, VLGR1 (USH2C) and the candidate for USH2B, NBC3. We pinpoint these interactions to interactions between the PDZ1 domain of harmonin and the PDZ-binding motifs at the C-termini of the USH2 proteins and NBC3. We demonstrate that USH2A, VLGR1 and NBC3 are co-expressed with the USH1-protein harmonin in the synaptic terminals of both retinal photoreceptors and inner ear hair cells. In hair cells, these USH proteins are also localized in the signal uptaking stereocilia. Our data indicate that the USH2 proteins and NBC3 are further partners in the supramolecular USH-protein network in the retina and inner ear which shed new light on the function of USH2 proteins and the entire USH-protein network. These findings provide first evidence for a molecular linkage between the pathophysiology in USH1 and USH2. The organization of USH molecules in a mutual 'interactome' related to the disease can explain the common phenotype in USH. 相似文献
4.
Soravia C van der Klift H Bründler MA Blouin JL Wijnen J Hutter P Fodde R Delozier-Blanchet C 《American journal of medical genetics. Part A》2003,(2):159-162
The recognized urologic tumor spectrum in hereditary non-polyposis colon cancer includes ureteral and renal pelvis malignancies. Here, we report a family in which the proband, who had three metachronous adenocarcinomas of the colon and rectum (at ages 54, 57, and 60), presented with an adenocarcinoma of the prostate at age 61. Immunohistochemical (IHC) staining of colonic, rectal, and prostatic tumor tissues demonstrated lack of expression of both MSH2 and MSH6. Accordingly, microsatellite instability (MSI) was found in the rectal, colonic, and prostatic tumors. The kindred complies with the Amsterdam criteria for HNPCC, as five members over three generations had colorectal cancer. Molecular investigations were initiated when the proband's son presented with an adenocarcinoma of the colon at age 35. Southern blotting analysis of genomic DNA led to identification of a novel genomic deletion encompassing exon 5 of the MSH2 gene. Although prostate cancer has occasionally been described in HNPCC families, to the best of our knowledge, this is the first report where the MSI and IHC analysis of the prostatic adenomcarcinoma clearly link its aetiology to the germline mismatch repair mutation. Hence, prostate cancer should be included in the HNPCC tumor spectrum. 相似文献
5.
6.
Corine C Visser Sanja Stevanovi? L Heleen Voorwinden Louis van Bloois Pieter J Gaillard Meindert Danhof Daan J A Crommelin Albertus G de Boer 《European journal of pharmaceutical sciences》2005,25(2-3):299-305
In this study, we aim to target pegylated liposomes loaded with horseradish peroxidase (HRP) and tagged with transferrin (Tf) to the BBB in vitro. Liposomes were prepared with the post-insertion technique: micelles of polyethylene glycol (PEG) and PEG-Tf were inserted into pre-formed liposomes containing HRP. Tf was measured indirectly by measuring iron via atomic absorption spectroscopy. All liposomes were around 100 nm in diameter, contained 5-13 microg HRP per mumol phospholipid and 63-74 Tf molecules per liposome (lipo Tf) or no Tf (lipo C). Brain capillary endothelial cells (BCEC) were incubated with liposomes at 4 degrees C (to determine binding) or at 37 degrees C (to determine association, i.e. binding+endocytosis) and the HRP activity, rather than the HRP amount was determined in cell lysates. Association of lipo Tf was two- to three-fold higher than association of lipo C. Surprisingly, the binding of lipo Tf at 4 degrees C was four-fold higher than the association of at 37 degrees C. Most likely this high binding and low endocytosis is explained by intracellular degradation of endocytosed HRP. In conclusion, we have shown targeting of liposomes loaded with protein or peptide drugs to the BCEC and more specifically to the lysosomes. This is an advantage for the treatment of lysosomal storage disease. However, drug targeting to other intracellular targets also results in intracellular degradation of the drug. Our experiments suggest that liposomes release some of their content within the BBB, making targeting of liposomes to the TfR on BCEC an attractive approach for brain drug delivery. 相似文献
7.
Anke Smits Maud Steins Sebastiaan van Koeverden Stuart Rundle Heleen Dekker Petra Zusterzeel 《The oncologist》2023,28(1):e19
ObjectiveThe objective of this study was to compare staging by MRI to clinical staging in patients with cervical cancer and to determine the histological accuracy of staging by MRI and examination under anesthesia (EUA) in early stage disease.MethodsThis was a retrospective cohort study of patients diagnosed with cervical cancer between 2010 and 2020 at the Radboud University Medical Centre, the Netherlands. Pretreatment stage (FIGO 2009) by MRI was compared with staging by EUA. Diagnostic accuracy in terms of sensitivity, specificity, positive, and negative predictive value was calculated for MRI and EUA in patients undergoing surgery (early stage disease) with histological results as a reference standard.ResultsA total of 358 patients were included in the study and MRI-based stage differed from EUA stage in 30.7%. In 12.3% this meant a discrepancy in treatment assignment between MRI and EUA. Diagnostic accuracy of MRI in terms of sensitivity and specificity for detecting early stage disease was comparable to EUA in surgical patients. Further analyses showed that premenopausal status, early stage disease and a tumor diameter of <2 cm were associated with improved comparability of MRI and EUA (98%).ConclusionThere is still a large discrepancy between MRI and EUA. In patients with suspected early stage disease, diagnostic accuracy of MRI is similar to EUA, especially for premenopausal women with early stage disease and a tumor diameter of <2 cm. 相似文献
8.
Corine C. Visser L. Heleen Voorwinden Liesbeth R. Harders Mohamed Eloualid Louis van Bloois Daan J.A. Crommelin 《Journal of drug targeting》2013,21(9-10):569-573
Liposomes for drug delivery are often prepared with maleimide groups on the distal end of PEG to enable coupling of homing devices, such as antibodies, or other proteins. EDTA is used to stabilize the thiol group in the homing device for attachment to the maleimide. However, when using a homing device that contains a metal, EDTA inactivates this by scavenging of the metal. Holo-transferrin (Tf) containing two iron atoms (Fe3+), has a much higher affinity for the Tf receptor than apo-Tf (which does not contain any Fe3+). To couple Tf to a liposome, the introduction of a thiol group is necessary. During this process, by using N-succinimidyl S-acetylthioacetate (SATA), followed by 2–3 h coupling to the liposomes, Fe3+ is scavenged by EDTA. This causes a decreased affinity of Tf for its receptor, resulting in a decreased targeting efficiency of the liposomes.Tris(2-carboxyethyl)phosphine (TCEP) hydrochloride is a sulfhydryl reductant that is often used in protein biochemistry. We found that TCEP (0.01 mM) does not scavenge Fe3+ from Tf and is able to protect thiol groups for the coupling to maleimide. Furthermore, TCEP does not interfere with the maleimide coupling itself.In this communication, we describe the preparation of liposomes, focussing on the coupling of Tf to the maleimide linker at the distal end of PEG, without loosing Fe3+ from Tf. This method can be applied to other metal-containing homing devices as well. 相似文献
9.
10.
Leif Bo? Dirk Lehr Dorota Reis Christiaan Vis Heleen Riper Matthias Berking David Daniel Ebert 《Journal of medical Internet research》2016,18(8)
BackgroundThe perspective of users should be taken into account in the evaluation of Web-based health interventions. Assessing the users’ satisfaction with the intervention they receive could enhance the evidence for the intervention effects. Thus, there is a need for valid and reliable measures to assess satisfaction with Web-based health interventions.ObjectiveThe objective of this study was to analyze the reliability, factorial structure, and construct validity of the Client Satisfaction Questionnaire adapted to Internet-based interventions (CSQ-I).MethodsThe psychometric quality of the CSQ-I was analyzed in user samples from 2 separate randomized controlled trials evaluating Web-based health interventions, one from a depression prevention intervention (sample 1, N=174) and the other from a stress management intervention (sample 2, N=111). At first, the underlying measurement model of the CSQ-I was analyzed to determine the internal consistency. The factorial structure of the scale and the measurement invariance across groups were tested by multigroup confirmatory factor analyses. Additionally, the construct validity of the scale was examined by comparing satisfaction scores with the primary clinical outcome.ResultsMultigroup confirmatory analyses on the scale yielded a one-factorial structure with a good fit (root-mean-square error of approximation =.09, comparative fit index =.96, standardized root-mean-square residual =.05) that showed partial strong invariance across the 2 samples. The scale showed very good reliability, indicated by McDonald omegas of .95 in sample 1 and .93 in sample 2. Significant correlations with change in depressive symptoms (r=−.35, P<.001) and perceived stress (r=−.48, P<.001) demonstrated the construct validity of the scale.ConclusionsThe proven internal consistency, factorial structure, and construct validity of the CSQ-I indicate a good overall psychometric quality of the measure to assess the user’s general satisfaction with Web-based interventions for depression and stress management. Multigroup analyses indicate its robustness across different samples. Thus, the CSQ-I seems to be a suitable measure to consider the user’s perspective in the overall evaluation of Web-based health interventions. 相似文献