全文获取类型
收费全文 | 836篇 |
免费 | 55篇 |
国内免费 | 1篇 |
专业分类
耳鼻咽喉 | 3篇 |
儿科学 | 17篇 |
妇产科学 | 11篇 |
基础医学 | 206篇 |
口腔科学 | 19篇 |
临床医学 | 59篇 |
内科学 | 162篇 |
皮肤病学 | 49篇 |
神经病学 | 71篇 |
特种医学 | 14篇 |
外科学 | 65篇 |
综合类 | 1篇 |
预防医学 | 65篇 |
眼科学 | 14篇 |
药学 | 32篇 |
肿瘤学 | 104篇 |
出版年
2023年 | 3篇 |
2022年 | 6篇 |
2021年 | 11篇 |
2020年 | 5篇 |
2019年 | 12篇 |
2018年 | 20篇 |
2017年 | 6篇 |
2016年 | 11篇 |
2015年 | 13篇 |
2014年 | 20篇 |
2013年 | 37篇 |
2012年 | 58篇 |
2011年 | 40篇 |
2010年 | 19篇 |
2009年 | 12篇 |
2008年 | 50篇 |
2007年 | 38篇 |
2006年 | 46篇 |
2005年 | 38篇 |
2004年 | 28篇 |
2003年 | 44篇 |
2002年 | 35篇 |
2001年 | 35篇 |
2000年 | 37篇 |
1999年 | 25篇 |
1998年 | 14篇 |
1997年 | 12篇 |
1996年 | 14篇 |
1995年 | 13篇 |
1994年 | 9篇 |
1993年 | 10篇 |
1992年 | 19篇 |
1991年 | 13篇 |
1990年 | 12篇 |
1989年 | 10篇 |
1988年 | 11篇 |
1987年 | 7篇 |
1986年 | 13篇 |
1985年 | 10篇 |
1984年 | 9篇 |
1983年 | 11篇 |
1982年 | 5篇 |
1981年 | 5篇 |
1979年 | 5篇 |
1977年 | 4篇 |
1973年 | 2篇 |
1970年 | 5篇 |
1968年 | 2篇 |
1966年 | 2篇 |
1932年 | 2篇 |
排序方式: 共有892条查询结果,搜索用时 13 毫秒
1.
Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene. 总被引:3,自引:2,他引:1
下载免费PDF全文
![点击此处可从《The Journal of clinical investigation》网站下载免费的PDF全文](/ch/ext_images/free.gif)
L IJlst J P Ruiter J M Hoovers M E Jakobs R J Wanders 《The Journal of clinical investigation》1996,98(4):1028-1033
Mitochondrial trifunctional protein (MTP) is a recently identified enzyme involved in mitochondrial beta-oxidation, harboring long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and long-chain 3-ketothiolase activity. A deficiency of this protein is associated with impaired oxidation of long-chain fatty acids which can lead to sudden infant death. Furthermore, it is clear that this inborn error of fatty acid oxidation is very frequent, second to medium chain acyl-CoA dehydrogenase deficiency. In most patients only the LCHAD activity of MTP is deficient with near normal activity of the two other enzyme activities of the complex. We recently described the occurrence of a frequent G1528C mutation in the cDNA coding for the a subunit of MTP. Using S. cerevisiae for expression of wild type and mutant protein we show that the G1528C mutation is directly responsible for the loss of LCHAD activity. Furthermore, we describe a newly developed method allowing identification of the G1528C mutation in genomic DNA. The finding of an 87% allele frequency of the G1528C mutation in 34 LCHAD deficient patients makes this a valuable test for prenatal diagnosis. Finally, we show that the gene encoding the alpha subunit of MTP is located on chromosome 2p24.1-23.3. 相似文献
2.
Nicole Y. L. Oei Bernet M. Elzinga Oliver T. Wolf Michiel B. de Ruiter Jessica S. Damoiseaux Joost P. A. Kuijer Dick J. Veltman Philip Scheltens Serge A. R. B. Rombouts 《Brain imaging and behavior》2007,1(1-2):31-41
Glucocorticoids (GCs, cortisol in human) are associated with impairments in declarative memory retrieval. Brain regions hypothesized
to mediate these effects are the hippocampus and prefrontal cortex (PFC). Our aim was to use fMRI in localizing the effects
of GCs during declarative memory retrieval. Therefore, we tested memory retrieval in 21 young healthy males in a randomized
placebo-controlled crossover design. Participants encoded word lists containing neutral and emotional words 1 h prior to ingestion
of 20 mg hydrocortisone. Memory retrieval was tested using an old/new recognition paradigm in a rapid event-related design.
It was found that hydrocortisone decreased brain activity in both the hippocampus and PFC during successful retrieval of neutral
words. These observations are consistent with previous animal and human studies suggesting that glucocorticoids modulate both
hippocampal and prefrontal brain regions that are crucially involved in memory processing.
Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
3.
B. Ruiter V. Trégoat L. M''Rabet J. Garssen C. A. F. M. Bruijnzeel-Koomen E. F. Knol E. van Hoffen 《Clinical and experimental allergy》2006,36(3):303-310
BACKGROUND: One to two percent of infants suffer from IgE-mediated allergic reactions against cow's milk proteins. Most children develop clinical tolerance, but approximately 15% are still allergic by the age of 10 years. Little is known about the T cell epitopes in individual cow's milk protein in relation to allergy and tolerance. OBJECTIVE: To identify T cell epitopes in alphas1-casein, the most abundant milk protein, and to investigate T cell responses toward these epitopes in allergic, atopic and non-atopic children. METHODS: Allergen-specific T cell lines (TCLs) were derived from peripheral blood mononuclear cells of 11 cow's milk allergic, nine atopic and nine non-atopic children. T cell responses were measured to alphas1-casein and to overlapping peptides (18-mers), spanning the alphas1-casein molecule. Proliferation was determined by incorporation of (3)H-thymidine, and cytokine production (IL-10, IL-13 and IFN-gamma) was measured by ELISA. RESULTS: Four main regions (amino acid (AA) residues 43-66, 73-96, 91-114 and 127-180) in the alphas1-casein molecule were immunogenic to T cells, among which the AA residues 133-156 spanned the immunodominant part. Only subtle differences were found in peptide recognition between the subject groups. Some of the peptides induced slightly Th1- or Th2-skewed cytokine responses. The increased levels of IL-10 in response to alphas1-casein observed in TCLs from atopic children appeared not to be linked to recognition of specific IL-10-inducing epitopes. CONCLUSIONS: The immunodominant sequence in alphas1-casein is spanned by AA residues 133-156. Tolerance towards alphas1-casein in atopic children may be mediated by an overall induction of IL-10 and not by recognition of certain T cell epitopes. The identified T cell epitopes in children with cow's milk allergy may be useful targets in developing peptide immunotherapy. 相似文献
4.
George G. J. M. Kuiper Petra E. de Ruiter J. Anton Grootegoed Albert O. Brinkmann 《Molecular and cellular endocrinology》1991,80(1-3):65-73
Androgen receptor synthesis and modification were studied in the human LNCaP cell line. Immunoblotting with a specific polyclonal antibody showed that the androgen receptor migrated as a closely spaced 110–112 kDa doublet on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gels. Most of the receptor protein is present in the higher molecular mass form. Pulse labelling experiments with [35S]methionine showed that the androgen receptor is synthesized as a single 110 kDa protein which is rapidly converted to a 112 kDa protein. Alkaline phosphatase treatment of cytosols from [35S]methionine pulse labelled cells caused a gradual elimination of the 112 kDa isoform with a concomitant increase of the 110 kDa isoform. This indicates that the observed 110 to 112 kDa upshift of the newly synthesized androgen receptor reflects receptor phosphorylation. Both isoforms can bind hormone and can undergo a hormone dependent transformation to a tight nuclear binding form, indicating that the 110 to 112 kDa conversion is not an obligatory step for hormone binding or receptor transformation. 相似文献
5.
O'Shea S Chrystie I Cranston R Mullen J Corbett K Murphy G Parry JV De Ruiter A Banatvala J 《Journal of medical virology》2000,61(2):187-194
During routine monitoring of human immunodeficiency virus (HIV) viral load, two problems arose. First, a number of patients, the majority being African, were found to have low viral loads by the Chiron branched-chain DNA assay in conjunction with low CD4(+) cell numbers. In order to determine whether this was due to failure of the branched-chain DNA assay to detect non-B subtypes of HIV, selected samples were subtyped and HIV RNA quantified by branched-chain DNA, NASBA, and the Roche Monitor RT-PCR assay. Twenty-eight (97%) of 29 Africans were infected with a non-B subtype of HIV and 15 (93.7%) of 16 non-Africans with subtype B. Twenty-three samples had a low viral load by branched-chain DNA, which was confirmed by the NASBA and RT-PCR assays. All three assays detected B and non-B subtypes with similar efficiency; NASBA failed to detect HIV RNA in a small number of non-B samples. Discrepancies between viral load and CD4(+) cell numbers did not appear therefore to be related to subtype. Second, while quantification of HIV RNA was being conducted using version 2 of the branched-chain DNA assay (lower detection limit 500 HIV RNA copies/ml) the manufacturers had developed a more sensitive assay and a comparative evaluation was therefore conducted. In approximately 30% of samples the viral load was up to 10 times higher with the more sensitive assay. These experiences emphasise the importance of close collaboration between the clinic and the laboratory. 相似文献
6.
Hogg S Hof M Würbel H Steimer T de Ruiter A Koolhaas J Sluyter F 《Behavior genetics》2000,30(6):439-446
Artificially selected aggressive (SAL) and non-aggressive (LAL) male house mice were tested in a hexagonal tunnel maze and light-dark preference (LD) box to determine if the bidirectional selection for aggressive behavior leads to a coselection for different levels of trait anxiety. The tunnel maze consists of an open, brightly lit central arena surrounded by a complex system of interconnecting tunnels. As in the LD box, animals which spend less time and are less active in the brightly illuminated section of the maze are considered to have higher anxiety levels. In the tunnel maze, the LAL mice showed more exploration and spent more time in the central arena than the SAL animals, but only during the final 2 min of the 6-min test. This reduced preference for the central arena was not due to general inactivity or a failure of the SAL to find the central arena and indicates a higher level of state anxiety in the aggressive animals. In contrast, no anxiety-like differences were found in the LD box, either for the percentage of time spent in the light compartment or for the number of crossings. SAL males actually showed higher levels of moving and rearing, and lower levels of freezing, than did LAL males. 相似文献
7.
Maintenance of tolerance to cow''s milk in atopic individuals is characterized by high levels of specific immunoglobulin G4 总被引:1,自引:0,他引:1
B. Ruiter E. F. Knol R. J. J. van Neerven J. Garssen C. A. F. M. Bruijnzeel-Koomen A. C. Knulst E. van Hoffen 《Clinical and experimental allergy》2007,37(7):1103-1110
BACKGROUND: The central role of specific IgE in cow's milk allergy (CMA) is well documented. However, less is known about the function of other immunoglobulin isotypes in allergy and tolerance to cow's milk proteins (CMPs). OBJECTIVE: To determine differences in the antibody responses that are associated with allergy and tolerance to cow's milk in allergic, atopic and non-atopic individuals of different age groups. METHODS: Nineteen infants (<1 year), 18 children (6-14 years) and 41 adults (21-68 years) were included. Each age group was comprised of subjects with CMA, atopic individuals without a history of CMA and non-atopic subjects. Levels of specific IgE, IgG4, IgG1 and IgA to whole cow's milk and the six most abundant individual CMPs were determined in plasma by ELISA. For comparison, specific IgE and IgG4 were measured to ovomucoid and house dust mite (HDM) in individuals allergic for the respective allergens, and in atopic and non-atopic subjects without allergy. RESULTS: In infants and children with CMA, alphas1-casein and beta-lactoglobulin induced the highest specific IgE response, whereas alphas1-casein was the most allergenic CMP in adult patients. Specific IgG4 and IgG1 responses were the highest to alphas1-casein and beta-lactoglobulin in all age groups, while kappa-casein and alpha-lactalbumin induced the highest levels of IgA. CMP-specific IgG4 was higher in atopic children and adults without CMA, as compared with non-atopic individuals. A similar difference between tolerant atopic and non-atopic subjects was observed for IgG4 specific to ovomucoid, whereas HDM-specific IgG4 was not detectable in these subjects. CONCLUSION: Maintenance of tolerance to cow's milk in atopic children and adults without CMA is associated with elevated levels of specific IgG4, in combination with low specific IgE. The up-regulation of specific IgG4 in tolerant atopic individuals may be related to the type of allergen and its regular dose of exposure. 相似文献
8.
de Ruiter CJ Elzinga MJ Verdijk PW van Mechelen W de Haan A 《Pflügers Archiv : European journal of physiology》2004,447(4):436-444
The purpose of the present study was to relate the expected inter-subject variability in voluntary drive of the knee extensor muscles during a sustained isometric contraction to the changes in firing rates of single motor units. Voluntary activation, as established with superimposed electrical stimulation was high (range: 91–99%, n=8) during a short maximal contraction, but was lower (range: 69–100%) in most subjects at the point of force failure during a sustained (49.1±10.1 s) fatiguing contraction at 50% of maximum force. On a different experimental day the firing behaviour of 27 single motor units was recorded with wire electrodes in the vastus lateralis muscle, 24 of which could be monitored from the time of recruitment to the point of force failure (53.6±9.8 s). Motor unit firing behaviour differed considerably among subjects. During the second half of the sustained, fatiguing contraction the changes in firing rate firing rate variability of early recruited units ranged from –10% to +100% and from –50% to +160% respectively among subjects. There were significant positive linear relations between voluntary activation, on the one hand, and rectified surface electromyogram (rsEMG, r=0.82), the changes in motor unit firing rate (r=0.49) and firing rate variability (r=0.50) towards the point of force failure on the other. The present data suggest that differences in voluntary drive that appear among subjects during fatigue may be an important determinant of motor unit firing behaviour.Abbreviations
EMG
electromyogram
-
ER unit
early recruited unit
-
MFGC
maximal force-generating capacity
-
MPF
mean power frequency
-
MVC
maximum voluntary contraction
-
NR unit
newly recruited unit
-
rsEMG
rectified surface electromyogram
-
SMUAP
single motor unit action potential 相似文献
9.
Eva-Bettina Brcker Ludwig Suter Josef Brüggen Dirk J. Ruiter Egon Macher Clemens Sorg 《International journal of cancer. Journal international du cancer》1985,36(1):29-35
The phenotypic changes in human melanoma cells during the course of tumor progression were studied with monoclonal antibodies (MAbs) against the melanoma-associated antigens (MAA) M.2.2.4, H.2.8.10, K.1.2, A.1.43, and A.10.33, and HLA-(A,B,C and D). Cryostat sections of 172 primary melanomas of the skin, 157 melanoma metastases and 56 nevi were investigated with an indirect immunoperoxidase method. Phenotypic heterogeneity was observed within lesions at all stages, and also within different tumors of the same patients. Despite this heterogeneity, principles of antigen expression were found. From the reaction pattern of MAbs, the following classifications of antigens were derived: "constitutive" markers of nevomelanocytic cells (M.2.2.4 and H.2.8.10) were found expressed over a wide range of local and systemic tumors. One MAA, K.1.2 (Suter et al., 1985), that declines with progression of melanoma, was classified as an "early" antigen, whereas MAA that appear in primary melanoma in proportion to invasiveness, and which are expressed in metastases of lymph nodes and visceral organs (A.1.43, and A.10.33), were classified as "late" markers of tumor progression. HLA-antigens were classified as "intermediate" markers, HLA-A,B,C, as an "early-intermediate", and HLA-DR as a "late-intermediate" marker. The occurrence of class II HLA, A.1.43-, and A.10.33-positive tumor cells in primary melanoma indicates a high metastatic potential of tumors, independent of tumor thickness. The data show that local and systemic progression of melanoma is associated with qualitative changes in tumor cells which can be recognized by MAbs. 相似文献
10.
The velo-cardio-facial syndrome (VCFS), caused by a submicroscopic deletion of chromosome 22q11, is the most common syndrome that has palatal anomalies as a major feature. A possible strategy for early detection of VCFS is routine screening for 22q11 deletions in all infants with cleft palate (CP). The purpose of this study was to evaluate whether this strategy is preferable to testing on clinical suspicion. At the Nijmegen Cleft Palate Craniofacial Center, 58 new patients with overt CP were routinely tested, using fluorescence in situ hybridization (FISH), for a 22q11 deletion. One deletion was identified in a newborn girl with an overt CP who was clinically not suspected of having VCFS. Based on this study (n = 45) and the literature (n = 54), the prevalence of 22q11 deletions among children with CP, but without any other symptoms of VCFS, is estimated to be one in 99. We take the view that this figure is rather low and that early discovery will rarely have significant clinical or genetic consequences. Because CP patients remain under medical attention, almost all of the infants with isolated CP and VCFS will be recognized as having the syndrome at a later age when additional features have developed. Therefore, we conclude that routine FISH testing for 22q11 deletions in infants with overt CP is not indicated, provided clinical follow-up is guaranteed. 相似文献