全文获取类型
收费全文 | 503篇 |
免费 | 33篇 |
出版年
2022年 | 4篇 |
2021年 | 3篇 |
2019年 | 3篇 |
2018年 | 6篇 |
2017年 | 6篇 |
2016年 | 9篇 |
2015年 | 18篇 |
2014年 | 21篇 |
2013年 | 26篇 |
2012年 | 25篇 |
2011年 | 26篇 |
2010年 | 37篇 |
2009年 | 32篇 |
2008年 | 21篇 |
2007年 | 19篇 |
2006年 | 16篇 |
2005年 | 21篇 |
2004年 | 20篇 |
2003年 | 21篇 |
2002年 | 15篇 |
2001年 | 14篇 |
2000年 | 12篇 |
1999年 | 10篇 |
1998年 | 11篇 |
1997年 | 13篇 |
1996年 | 5篇 |
1995年 | 8篇 |
1994年 | 4篇 |
1993年 | 8篇 |
1992年 | 3篇 |
1991年 | 5篇 |
1990年 | 3篇 |
1989年 | 5篇 |
1988年 | 9篇 |
1987年 | 5篇 |
1985年 | 4篇 |
1984年 | 4篇 |
1983年 | 4篇 |
1982年 | 19篇 |
1981年 | 3篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 5篇 |
1976年 | 5篇 |
1975年 | 3篇 |
1971年 | 5篇 |
1967年 | 2篇 |
1965年 | 2篇 |
1953年 | 1篇 |
排序方式: 共有536条查询结果,搜索用时 15 毫秒
51.
Haringman JJ Vinkenoog M Gerlag DM Smeets TJ Zwinderman AH Tak PP 《Arthritis research & therapy》2005,7(4):R862-R867
Analysis of biomarkers in synovial tissue is increasingly used in the evaluation of new targeted therapies for patients with
rheumatoid arthritis (RA). This study determined the intrarater and inter-rater reliability of digital image analysis (DIA)
of synovial biopsies from RA patients participating in clinical trials. Arthroscopic synovial biopsies were obtained before
and after treatment from 19 RA patients participating in a randomized controlled trial with prednisolone. Immunohistochemistry
was used to detect CD3+ T cells, CD38+ plasma cells and CD68+ macrophages. The mean change in positive cells per square millimetre for each marker was determined by different operators
and at different times using DIA. Nonparametric tests were used to determine differences between observers and assessments,
and to determine changes after treatment. The intraclass correlations (ICCs) were calculated to determine the intrarater and
inter-rater reliability. Intrarater ICCs showed good reliability for measuring changes in T lymphocytes (R = 0.87), plasma
cells (R = 0.62) and macrophages (R = 0.73). Analysis by Bland–Altman plots showed no systemic differences between measurements.
The smallest detectable changes were calculated and their discriminatory power revealed good response in the prednisolone
group compared with the placebo group. Similarly, inter-rater ICCs also revealed good reliability for measuring T lymphocytes
(R = 0.68), plasma cells (R = 0.69) and macrophages (R = 0.72). All measurements identified the same cell types as changing
significantly in the treated patients compared with the placebo group. The measurement of change in total positive cell numbers
in synovial tissue can be determined reproducibly for various cell types by DIA in RA clinical trials. 相似文献
52.
Recently, a new heparin disaccharide-binding site on the convex side of cobra cardiotoxin (CTX) was identified by NMR spectroscopy and molecular modeling. To further characterize this site two heparin-like disaccharides were synthesized for binding studies with CTX, and a trisaccharide was synthesized for testing the sequence of the disaccharide binding to CTX. Thus six differentially protected monosaccharide building blocks (three l-iduronic acids and three d-glucosamines) were prepared. These include a l-iduronic acid elongation building block namely methyl 2-O-acetyl-4-O-levulinoyl-3-O-pivaloyl-alpha-l-idopyranosyluronate trichloroacetimidate for which a single-crystal X-ray structure was determined to have M(r)=576.79, a=9.3098(11)A alpha=90 degrees , b=10.3967(12)A beta=90 degrees , c=28.026(3)A gamma=90 degrees , V=2712.7(6)A(3), P2(1)2(1)2(1), Z=4, mu=0.71073A, and R=0.0378 for 7586 observed reflections. It shows that the molecular structure of the donor is in the (1)C(4) conformation with significant 1,3-diaxial interactions between O-1 and O-3 as well as O-2 and O-4. The disaccharides and trisaccharide vary in the degree and position of O- and N-sulfation. The pivaloyl group was used as permanent protecting group of hydroxyl. The levulinoyl group was used as the temporary protecting group to protect the hydroxyl for elongation. 相似文献
53.
Conjugative transfer and replacement of hundreds of kilobases of a bacterial chromosome can occur in vitro, but replacements in nature are either an order of magnitude smaller or involve the movement of mobile genetic elements. We discovered that two lineages of Staphylococcus aureus, including a pandemic methicillin-resistant lineage, were founded by single chromosomal replacements of at least approximately 244 and approximately 557 kb representing approximately 10 and approximately 20% of the chromosome, respectively, without the obvious involvement of mobile genetic elements. The replacements are unprecedented in natural populations of bacteria because of their large size and unique structure and may have a dramatic impact on bacterial evolution. 相似文献
54.
Lopez-Herrera G Tampella G Pan-Hammarström Q Herholz P Trujillo-Vargas CM Phadwal K Simon AK Moutschen M Etzioni A Mory A Srugo I Melamed D Hultenby K Liu C Baronio M Vitali M Philippet P Dideberg V Aghamohammadi A Rezaei N Enright V Du L Salzer U Eibel H Pfeifer D Veelken H Stauss H Lougaris V Plebani A Gertz EM Schäffer AA Hammarström L Grimbacher B 《American journal of human genetics》2012,90(6):986-1001
Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity. 相似文献
55.
O'Grady SP Valenzuela LO Remien CH Enright LE Jorgensen MJ Kaplan JR Wagner JD Cerling TE Ehleringer JR 《American journal of primatology》2012,74(7):651-660
The stable isotopic composition of drinking water, diet, and atmospheric oxygen influence the isotopic composition of body water ((2)H/(1)H, (18)O/(16)O expressed as δ(2) H and δ(18)O). In turn, body water influences the isotopic composition of organic matter in tissues, such as hair and teeth, which are often used to reconstruct historical dietary and movement patterns of animals and humans. Here, we used a nonhuman primate system (Macaca fascicularis) to test the robustness of two different mechanistic stable isotope models: a model to predict the δ(2)H and δ(18)O values of body water and a second model to predict the δ(2)H and δ(18)O values of hair. In contrast to previous human-based studies, use of nonhuman primates fed controlled diets allowed us to further constrain model parameter values and evaluate model predictions. Both models reliably predicted the δ(2)H and δ(18)O values of body water and of hair. Moreover, the isotope data allowed us to better quantify values for two critical variables in the models: the δ(2)H and δ(18)O values of gut water and the (18)O isotope fractionation associated with a carbonyl oxygen-water interaction in the gut (α(ow)). Our modeling efforts indicated that better predictions for body water and hair isotope values were achieved by making the isotopic composition of gut water approached that of body water. Additionally, the value of α(ow) was 1.0164, in close agreement with the only other previously measured observation (microbial spore cell walls), suggesting robustness of this fractionation factor across different biological systems. 相似文献
56.
Ryanne JM Lemmens Annick AA Timmermans Yvonne JM Janssen-Potten Rob JEM Smeets Henk AM Seelen 《BMC neurology》2012,12(1):1-17
Background
Loss of arm-hand performance due to a hemiparesis as a result of stroke or cerebral palsy (CP), leads to large problems in daily life of these patients. Assessment of arm-hand performance is important in both clinical practice and research. To gain more insight in e.g. effectiveness of common therapies for different patient populations with similar clinical characteristics, consensus regarding the choice and use of outcome measures is paramount. To guide this choice, an overview of available instruments is necessary. The aim of this systematic review is to identify, evaluate and categorize instruments, reported to be valid and reliable, assessing arm-hand performance at the ICF activity level in patients with stroke or cerebral palsy.Methods
A systematic literature search was performed to identify articles containing instruments assessing arm-hand skilled performance in patients with stroke or cerebral palsy. Instruments were identified and divided into the categories capacity, perceived performance and actual performance. A second search was performed to obtain information on their content and psychometrics.Results
Regarding capacity, perceived performance and actual performance, 18, 9 and 3 instruments were included respectively. Only 3 of all included instruments were used and tested in both patient populations. The content of the instruments differed widely regarding the ICF levels measured, assessment of the amount of use versus the quality of use, the inclusion of unimanual and/or bimanual tasks and the inclusion of basic and/or extended tasks.Conclusions
Although many instruments assess capacity and perceived performance, a dearth exists of instruments assessing actual performance. In addition, instruments appropriate for more than one patient population are sparse. For actual performance, new instruments have to be developed, with specific focus on the usability in different patient populations and the assessment of quality of use as well as amount of use. Also, consensus about the choice and use of instruments within and across populations is needed. 相似文献57.
Reinout Raijmakers Joyce JBC van Beers Mahmoud El-Azzouny Natasja FC Visser Borut Bo?i? Ger JM Pruijn Albert JR Heck 《Arthritis research & therapy》2012,14(3):R114-10
Introduction
Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation of the joints and the presence of autoantibodies directed against proteins containing the non-standard arginine-derived amino acid citrulline. The protein fibrinogen, which has an essential role in blood clotting, is one of the most prominent citrullinated autoantigens in RA, particularly because it can be found in the inflamed tissue of affected joints. Here, we set out to analyze the presence of citrullinated endogenous peptides in the synovial fluid of RA and arthritic control patients.Methods
Endogenous peptides were isolated from the synovial fluid of RA patients and controls by filtration and solid phase extraction. The peptides were identified and quantified using high-resolution liquid chromatography-mass spectrometry.Results
Our data reveal that the synovial fluid of RA patients contains soluble endogenous peptides, derived from fibrinogen, containing significant amounts of citrulline residues and, in some cases, also phosphorylated serine. Several citrullinated peptides are found to be more abundantly present in the synovial fluid of RA patients compared to patients suffering from other inflammatory diseases affecting the joints.Conclusions
The increased presence of citrullinated peptides in RA patients points toward a possible specific role of these peptides in the immune response at the basis of the recognition of citrullinated peptides and proteins by RA patient autoantibodies. 相似文献58.
Parts L Hedman ÅK Keildson S Knights AJ Abreu-Goodger C van de Bunt M Guerra-Assunção JA Bartonicek N van Dongen S Mägi R Nisbet J Barrett A Rantalainen M Nica AC Quail MA Small KS Glass D Enright AJ Winn J;MuTHER Consortium Deloukas P Dermitzakis ET McCarthy MI Spector TD Durbin R Lindgren CM 《PLoS genetics》2012,8(5):e1002704
59.
S Chen AJ de Craen Y Raz E Derhovanessian AC Vossen WG Rudi G Pawelec AB Maier 《Immunity & ageing : I & A》2012,9(1):18-7
ABSTRACT: BACKGROUND: Cytomegalovirus (CMV) infection has been reported to contribute to the pathogenesis of type 1 diabetes and post-transplantation diabetes. However, CMV infection has not been evaluated as a possible risk factor for type 2 diabetes. Our aim was to investigate potential associations between CMV seropositivity, CMV IgG antibody level and glucose regulation in the oldest old. RESULTS: CMV seropositive subjects were more likely to have type 2 diabetes (17.2% vs 7.9%, p = 0.016), had a higher level of HbA1c (p = 0.014) and higher non-fasting glucose (p = 0.024) in the oldest olds. These associations remained significant after adjustment for possible confounders. CMV IgG antibody level was not significantly associated with glucose regulation (all p > 0.05). CONCLUSIONS: In the oldest old, CMV seropositivity is significantly associated with various indicators of glucose regulation. This finding suggests that CMV infection might be a risk factor for the development of type 2 diabetes in the elderly. 相似文献
60.