全文获取类型
收费全文 | 132篇 |
免费 | 9篇 |
国内免费 | 1篇 |
专业分类
儿科学 | 16篇 |
基础医学 | 14篇 |
临床医学 | 12篇 |
内科学 | 30篇 |
皮肤病学 | 2篇 |
神经病学 | 14篇 |
特种医学 | 3篇 |
外科学 | 15篇 |
综合类 | 1篇 |
预防医学 | 3篇 |
药学 | 20篇 |
肿瘤学 | 12篇 |
出版年
2024年 | 1篇 |
2023年 | 4篇 |
2021年 | 4篇 |
2020年 | 4篇 |
2019年 | 1篇 |
2018年 | 4篇 |
2017年 | 4篇 |
2015年 | 5篇 |
2014年 | 2篇 |
2013年 | 7篇 |
2012年 | 12篇 |
2011年 | 17篇 |
2010年 | 5篇 |
2009年 | 5篇 |
2008年 | 13篇 |
2007年 | 9篇 |
2006年 | 8篇 |
2005年 | 5篇 |
2004年 | 3篇 |
2003年 | 3篇 |
2002年 | 4篇 |
1999年 | 2篇 |
1998年 | 1篇 |
1997年 | 1篇 |
1996年 | 2篇 |
1995年 | 1篇 |
1994年 | 4篇 |
1993年 | 2篇 |
1991年 | 1篇 |
1988年 | 1篇 |
1980年 | 2篇 |
1978年 | 3篇 |
1974年 | 1篇 |
1910年 | 1篇 |
排序方式: 共有142条查询结果,搜索用时 15 毫秒
71.
Koichiro Abe Helmut Fuchs Auke Boersma Wolfgang Hans Philipp Yu Svetoslav Kalaydjiev Matthias Klaften Thure Adler Julia Calzada‐Wack Ilona Mossbrugger Birgit Rathkolb Jan Rozman Cornelia Prehn Miriam Maraslioglu Yoshie Kametani Shin Shimada Jerzy Adamski Dirk H. Busch Irene Esposito Martin Klingenspor Eckhard Wolf Wolfgang Wurst Valerie Gailus‐Durner Matilda Katan Susan Marschall Dian Soewarto Sibylle Wagner Martin Hrab de Angelis 《Arthritis \u0026amp; Rheumatology》2011,63(5):1301-1311
Objective
It is difficult to identify a single causative factor for inflammatory arthritis because of the multifactorial nature of the disease. This study was undertaken to dissect the molecular complexity of systemic inflammatory disease, utilizing a combined approach of mutagenesis and systematic phenotype screening in a murine model.Methods
In a large‐scale N‐ethyl‐N‐nitrosourea mutagenesis project, the Ali14 mutant mouse strain was established because of dominant inheritance of spontaneous swelling and inflammation of the hind paws. Genetic mapping and subsequent candidate gene sequencing were conducted to find the causative gene, and systematic phenotyping of Ali14/+ mice was performed in the German Mouse Clinic.Results
A novel missense mutation in the phospholipase Cγ2 gene (Plcg2) was identified in Ali14/+ mice. Because of the hyperreactive external entry of calcium observed in cultured B cells and other in vitro experiments, the Ali14 mutation is thought to be a novel gain‐of‐function allele of Plcg2. Findings from systematic screening of Ali14/+ mice demonstrated various phenotypic changes: an abnormally high T cell:B cell ratio, up‐regulation of Ig, alterations in body composition, and a reduction in cholesterol and triglyceride levels in peripheral blood. In addition, spermatozoa from Ali14/+ mice failed to fertilize eggs in vitro, despite the normal fertility of the Ali14/+ male mice in vivo.Conclusion
These results suggest that the Plcg2‐mediated pathways play a crucial role in various metabolic and sperm functions, in addition to initiating and maintaining the immune system. These findings may indicate the importance of the Ali14/+ mouse strain as a model for systemic inflammatory diseases and inflammation‐related metabolic changes in humans.72.
Cindy Strehl Timo Gaber Mark Lwenberg Daniel W. Hommes Auke P. Verhaar Saskia Schellmann Martin Hahne Monique Fangradt Markus Wagegg Paula Hoff Alexander Scheffold Cornelia M. Spies Gerd‐Rüdiger Burmester Frank Buttgereit 《Arthritis \u0026amp; Rheumatology》2011,63(12):3779-3788
Objective
Glucocorticoids (GCs) exert their antiinflammatory and immunosuppressive effects in humans primarily via the cytosolic GC receptor (cGR) but also via rapid, nongenomic mechanisms. Most likely, membrane‐bound GRs (mGR) are involved in nongenomic GC signaling. The aim of this study was to investigate the origin and functional activity of mGR.Methods
We analyzed the origin of mGR using mGR‐expressing HEK 293T cells, by transient and stable RNA interference–mediated GR reduction. GR messenger RNA (mRNA) and cGR and mGR protein levels were analyzed by real‐time quantitative polymerase chain reaction, immunoblotting, and high‐sensitivity immunofluorescence staining. Furthermore, we analyzed the functional activity of mGR, using membrane‐impermeable bovine serum albumin (BSA)–bound dexamethasone (DEX‐BSA) in human monocytes. Membrane‐bound GR–expressing monocytes were treated with DEX, DEX‐BSA, or BSA. Cell lysates were analyzed using PepChip arrays in order to identify kinases triggered by DEX‐BSA, with validation using Bio‐Plex assays and immunoblotting.Results
Our data showed that transient reduction of GR mRNA in HEK 293T cells decreased cGR protein levels but not mGR protein levels. However, stably transfected cells showed reduced cGR protein expression and significantly reduced mGR protein expression. Furthermore, 51 kinase substrates were identified for which phosphorylation was either reduced or increased. We observed p38 MAP kinase (MAPK) as one possible upstream kinase. Validation of these data by Bio‐Plex phosphoprotein assay and immunoblotting showed increased phosphorylation of p38 MAPK after treatment with DEX‐BSA.Conclusion
Our data demonstrate that the human GR gene encodes for both cGR and mGR. Membrane‐bound GR retains functional activity, as indicated by induced phosphorylation of p38 MAPK due to DEX‐BSA treatment. Membrane‐bound GR–mediated cellular signaling needs to be investigated further in order to clarify its therapeutic potential.73.
Radi M Adema AD Daft JR Cho JH Hoebe EK Alexander LE Peters GJ Chu CK 《Journal of medicinal chemistry》2007,50(9):2249-2253
l-1,3-Dioxolane-cytidine, a potent anticancer agent against leukemia, has limited efficacy against solid tumors, perhaps due to its hydrophilicity. Herein, a library of prodrugs were synthesized to optimize in vitro antitumor activity against non-small cell lung cancer. N4-Substituted fatty acid amide prodrugs of 10-16 carbon chain length demonstrated significantly improved antitumor activity over l-1,3-dioxolane-cytidine. These in vitro results suggest that the in vivo therapeutic efficacy of l-1,3-dioxolane-cytidine against solid tumors may be improved with prodrug strategies. 相似文献
74.
75.
Te Poele EM de Bont ES Marike Boezen H Revesz T Bökkerink JP Beishuizen A Nijhuis IJ Oude Nijhuis CS Veerman AJ Kamps WA 《European journal of cancer (Oxford, England : 1990)》2007,43(17):2532-2536
We report an increased incidence of infectious deaths during maintenance treatment of the ninth protocol for acute lymphoblastic leukaemia of the Dutch Childhood Oncology Group (DCOG-ALL-9). The main difference in maintenance treatment between DCOG-ALL-9 and the DCOG-ALL-7 and DCOG-ALL-8 protocols is the interruption of methotrexate and 6-mercaptopurine by vincristine (2mg/m(2) weekly) and dexamethasone (6mg/m(2) daily) for 14 days every 7 weeks in the DCOG-ALL-9 protocol. The 1107 children treated with the DCOG-ALL-7, DCOG-ALL-8 or DCOG-ALL-9 protocol were included and screened for infectious death during maintenance treatment (July 1988-July 2002). Seven of the 510 children died of severe infections during the maintenance phase of DCOG-ALL-9, compared to none of the 597 patients during the DCOG-ALL-7 and DCOG-ALL-8 protocols (1.37% versus 0.0%; p=0.013). Results from the current study suggest that repeated, prolonged exposure to dexamethasone results in an increase of lethal infections from 0% to 1.37%. In the dosing-schedule used, the advantage of dexamethasone may not outweigh the higher risk of infectious death. 相似文献
76.
Chatterjea A Renard AJ Jolink C van Blitterswijk CA de Boer J 《Journal of tissue engineering and regenerative medicine》2012,6(2):103-112
Mesenchymal stromal cells are present in very low numbers in the bone marrow, necessitating their selective expansion on tissue culture plastic prior to their use in tissue-engineering applications. MSC expansion is laborious, time consuming, unphysiological and not economical, thus calling for automated bioreactor-based strategies. We and others have shown that osteogenic grafts can be cultured in bioreactors by seeding either 2D-expanded cells or by direct seeding of the mononuclear fraction of bone marrow. To further streamline this protocol, we assessed in this study the possibility of seeding the cells onto porous calcium phosphate ceramics directly from unprocessed bone marrow. Using predetermined volumes of bone marrow from multiple human donors with different nucleated cell counts, we were able to grow a confluent cell sheath on the scaffold surface in 3 weeks. Cells of stromal, endothelial and haematopoietic origin were detected, in contrast to grafts grown from 2D expanded cells, where only stromal cells could be seen. Upon implantation in nude mice, similar quantities of bone tissue were generated as compared to that obtained by using the conventional number of culture expanded cells from the same donor. We conclude that human osteogenic grafts can be efficiently prepared by direct seeding of cells from unprocessed bone marrow. 相似文献
77.
Ruben Y.G. Tijssen Rene J. van der Schaaf Robin P. Kraak Maarten A. Vink Sjoerd H. Hofma E. Karin Arkenbout Auke P.J.D. Weevers Laura S.M. Kerkmeijer Yoshinobu Onuma Patrick W. Serruys Marcel A.M. Beijk Karel T. Koch Jan Baan M. Marije Vis Jan J. Piek Jan G.P. Tijssen Jose P.S. Henriques Robbert J. de Winter Joanna J. Wykrzykowska 《Catheterization and cardiovascular interventions》2020,95(1):89-96
- The clinical impact of concurrently administered morphine and P2Y12 inhibitors in primary percutaneous coronary intervention (PCI) is not well understood.
- Large, randomized clinical trials are required to assess clinical outcomes with concurrent morphine and P2Y12 inhibitor use in ST‐segment elevation myocardial infarction patients undergoing PCI.
- Based on the currently available pharmacologic data, cautious use of morphine in primary PCI would seem prudent.
78.
Dineke Westra Eiske M. Dorresteijn Auke Beishuizen Lambert P. W. J. van den Heuvel Paul P. T. Brons Nicole C. A. J. van de Kar 《Pediatric nephrology (Berlin, Germany)》2013,28(2):349-352
Background
The hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy leading to acute kidney injury in children. In most cases it is triggered by an infection caused by Shiga-like toxin-producing Escherichia coli (STEC). Endothelial damage plays a central role in the pathogenesis of disease. Hemophilia A is a genetic disorder leading to factor VIII (FVIII) deficiency, an important factor in the coagulation system.Case
Here we describe a hemophilia A patient who developed HUS due to a STEC O26 infection. The patient developed not only acute kidney injury, but also severe gastro-intestinal and neurological complications. Increased amounts of recombinant FVIII (rFVIII) had to be administered during the acute phase of the disease to reach acceptable blood levels of FVIII, in order to control the hemorrhagic colitis and to prevent severe neurological complications.Conclusion
The patient’s treatment schedule of rFVIII during the HUS period was a serious challenge, and we cannot exclude that it contributed to the severity of the HUS by enhancing the thrombotic microangiopathic process. The role of factor VIII administration in the severe outcome of this disease is discussed. 相似文献79.
Auke Jan Ijspeert 《Neural networks》2008,21(4):642-653
The problem of controlling locomotion is an area in which neuroscience and robotics can fruitfully interact. In this article, I will review research carried out on locomotor central pattern generators (CPGs), i.e. neural circuits capable of producing coordinated patterns of high-dimensional rhythmic output signals while receiving only simple, low-dimensional, input signals. The review will first cover neurobiological observations concerning locomotor CPGs and their numerical modelling, with a special focus on vertebrates. It will then cover how CPG models implemented as neural networks or systems of coupled oscillators can be used in robotics for controlling the locomotion of articulated robots. The review also presents how robots can be used as scientific tools to obtain a better understanding of the functioning of biological CPGs. Finally, various methods for designing CPGs to control specific modes of locomotion will be briefly reviewed. In this process, I will discuss different types of CPG models, the pros and cons of using CPGs with robots, and the pros and cons of using robots as scientific tools. Open research topics both in biology and in robotics will also be discussed. 相似文献
80.
Olaf van Tellingen Jos H. Beijnen Willem J. Nooijen Auke Bult 《Cancer chemotherapy and pharmacology》1993,32(4):286-292
We have developed and validated a selective analytical procedure, based on ion-exchange normal-phase liquid chromatography with fluorescence detection and liquid-liquid extraction, for the analysis of vinblastine (VBL) in biological matrices. The assay is suitable for the determination of the parent compound and its metabolites in plasma, tissue, faeces and urine specimens. Pharmacokinetics studies were performed in male FVB mice receiving VBL by intravenous (i.v.) bolus injection at a dose of 6 mg/kg. Plasma concentrations were monitored until 48 h after drug administration. Urine and faeces samples were collected in 24-h portions for up to 72 h and tissue samples were obtained at 4, 24, 72 and 168 h after drug administration. To facilitate a comparison between the findings we obtained by high-performance liquid chromatography (HPLC) and the results of previous studies using radiolabeled drug monitoring, some of the animals were also given radiolabeled drug. Large discrepancies were observed between the results obtained by the two methods. Excretion of the radiolabel in faeces and urine was 85% of the dose within 72 h. HPLC revealed that only 18% of the dose was excreted as unchanged drug and 19%, as measurable metabolites [O4-deacetylvinblastine (DVBL) and two unknown compounds]. In most of the tissues taken at 4 h after drug administration, virtually all of the radioactivity represented VBL or DVBL. In all tissues taken at 72 h after drug administration, however, only very little of the radioactivity remained in the form of these compounds. Following the administration, VBL and DVBL were distributed extensively to most tissues. Many tissues appeared to possess effective means of extruding the cytotoxic drug with decreasing plasma levels. However, in some organs, including those from the genital tract and lymphatic tissues, VBL and DVBL were retained for prolonged periods. Our studies confirm previous indications that selective retention may be the basis of the activity of VBL against malignant transformations derived from these tissues. 相似文献