全文获取类型
收费全文 | 7480篇 |
免费 | 592篇 |
国内免费 | 27篇 |
专业分类
耳鼻咽喉 | 54篇 |
儿科学 | 216篇 |
妇产科学 | 165篇 |
基础医学 | 1209篇 |
口腔科学 | 229篇 |
临床医学 | 681篇 |
内科学 | 1520篇 |
皮肤病学 | 220篇 |
神经病学 | 724篇 |
特种医学 | 366篇 |
外国民族医学 | 2篇 |
外科学 | 749篇 |
综合类 | 186篇 |
一般理论 | 5篇 |
预防医学 | 684篇 |
眼科学 | 48篇 |
药学 | 472篇 |
中国医学 | 55篇 |
肿瘤学 | 514篇 |
出版年
2023年 | 39篇 |
2022年 | 66篇 |
2021年 | 135篇 |
2020年 | 109篇 |
2019年 | 121篇 |
2018年 | 168篇 |
2017年 | 118篇 |
2016年 | 153篇 |
2015年 | 164篇 |
2014年 | 211篇 |
2013年 | 285篇 |
2012年 | 392篇 |
2011年 | 392篇 |
2010年 | 271篇 |
2009年 | 248篇 |
2008年 | 325篇 |
2007年 | 322篇 |
2006年 | 321篇 |
2005年 | 334篇 |
2004年 | 285篇 |
2003年 | 280篇 |
2002年 | 270篇 |
2001年 | 236篇 |
2000年 | 253篇 |
1999年 | 214篇 |
1998年 | 139篇 |
1997年 | 127篇 |
1996年 | 139篇 |
1995年 | 92篇 |
1994年 | 79篇 |
1993年 | 88篇 |
1992年 | 134篇 |
1991年 | 147篇 |
1990年 | 153篇 |
1989年 | 130篇 |
1988年 | 116篇 |
1987年 | 104篇 |
1986年 | 105篇 |
1985年 | 110篇 |
1984年 | 107篇 |
1983年 | 52篇 |
1982年 | 46篇 |
1981年 | 37篇 |
1980年 | 32篇 |
1979年 | 38篇 |
1978年 | 30篇 |
1977年 | 40篇 |
1972年 | 28篇 |
1968年 | 31篇 |
1967年 | 28篇 |
排序方式: 共有8099条查询结果,搜索用时 31 毫秒
61.
Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability 总被引:1,自引:15,他引:1
La Spada AR; Peterson KR; Meadows SA; McClain ME; Jeng G; Chmelar RS; Haugen HA; Chen K; Singer MJ; Moore D; Trask BJ; Fischbeck KH; Clegg CH; McKnight GS 《Human molecular genetics》1998,7(6):959-967
X-linked spinal and bulbar muscular atrophy (SBMA) is caused by a CAG
repeat expansion in the first exon of the androgen receptor (AR) gene.
Disease-associated alleles (37-66 CAGs) change in length when transmitted
from parents to offspring, with a significantly greater tendency to shift
size when inherited paternally. As transgenic mice carrying human AR cDNAs
with 45 and 66 CAG repeats do not display repeat instability, we attempted
to model trinucleotide repeat instability by generating transgenic mice
with yeast artificial chromosomes (YACs) carrying AR CAG repeat expansions
in their genomic context. Studies of independent lines of AR YAC transgenic
mice with CAG 45 alleles reveal intergenerational instability at an overall
rate of approximately 10%. We also find that the 45 CAG repeat tracts are
significantly more unstable with maternal transmission and as the
transmitting mother ages. Of all the CAG/CTG repeat transgenic mice
produced to date the AR YAC CAG 45 mice are unstable with the smallest
trinucleotide repeat mutations, suggesting that the length threshold for
repeat instability in the mouse may be lowered by including the appropriate
flanking human DNA sequences. By sequence-tagged site content analysis and
long range mapping we determined that one unstable transgenic line has
integrated an approximately 70 kb segment of the AR locus due to
fragmentation of the AR YAC. Identification of the cis - acting elements
that permit CAG tract instability and the trans -acting factors that
modulate repeat instability in the AR YAC CAG 45 mice may provide insights
into the molecular basis of trinucleotide repeat instability in humans.
相似文献
62.
High responsiveness of HLA-B57-restricted Gag-specific CD8+ T cells in vitro may contribute to the protective effect of HLA-B57 in HIV-infection 总被引:1,自引:0,他引:1
Jansen CA Kostense S Vandenberghe K Nanlohy NM De Cuyper IM Piriou E Manting EH Miedema F van Baarle D 《European journal of immunology》2005,35(1):150-158
HLA-B57 has been shown to be associated with long-term asymptomatic HIV-1 infection. To investigate the biological mechanism by which the HLA-B57 allele could protect from HIV-1 disease, we studied both the number of CD8(+) T cells as well as CD8(+) T cell responsiveness directed to different HIV-1 Gag peptides presented by HLA-A2, -B8 or -B57. T cells specific for the HLA-B57 peptide KAFSPEVIPMF responded more readily and to a higher extend to antigenic stimulation in vitro than T cells specific for the HLA-A2 peptide SLYNTVATL or the HLA-B8 peptide EIYKRWII. This phenomenon was reproducible with T cells from individuals expressing HLA-B57 in combination with one or both of the other alleles and was persistent during long-term follow-up. Lower reactivity of A2- and B8-restricted T cells was not explained by mutations in the B8- or A2-restricted Gag-peptides. Moreover, no correlation between peptide mutation frequency and IFN-gamma production by the corresponding Gag-specific T cells was observed. In conclusion, functional differences were observed between T cells specific for HIV epitopes derived from the same protein presented by different HLA molecules. B57-restricted KAFSPEVIPMF-specific CD8(+) T cells have relatively high responsiveness, which could contribute to the protective effect of HLA-B57 in HIV infection. 相似文献
63.
van Muiswinkel FL de Vos RA Bol JG Andringa G Jansen Steur EN Ross D Siegel D Drukarch B 《Neurobiology of aging》2004,25(9):1253-1262
Dopamine (DA) autooxidation, and consequent formation of neurotoxic DA-derived quinones and reactive oxygen species, has been implicated in dopaminergic cell death and, hence, in the pathogenesis of Parkinson's disease (PD). Stimulation of pathways involved in the detoxication of DA-quinones in the brain is hypothesized to be an effective means to limit oxidative stress and to confer neuroprotection in PD. In this respect, the inducible flavoprotein NAD(P)H:quinone oxidoreductase (NQO1) is of particular interest as it is directly implicated in the detoxication of DA-quinones and, in addition, has broad spectrum anti-oxidant properties. To study the potential pathophysiological role of NQO1 in PD, the cellular expression of NQO1 was examined in the mesencephalon of PD patients and age-matched controls. In the substantia nigra pars compacta (SNpc), NQO1 was found to be expressed in astroglial and endothelial cells and, albeit less frequently, also in dopaminergic neurons. Moreover, while overt NQO1 immunoreactivity was absent in the surrounding nervous tissue, in the Parkinsonian SNpc a marked increase in the astroglial and neuronal expression of NQO1 was consistently observed. 相似文献
64.
David Tarrag Julio Casal Jesús Ruiz-Contreras J. Toms Ramos Pablo Rojo Harm Snippe Wouter T. M. Jansen 《Clinical and Vaccine Immunology : CVI》2005,12(1):165-170
We investigated antibody responses against pneumococci of serotypes 6B, 14, and 23F in 56 children and adolescents with perinatal human immunodeficiency virus (HIV) infection who were vaccinated with 7-valent pneumococcal conjugate vaccine. Overall immune responses differed greatly between serotypes. Correlation coefficients between immunoglobulin G (IgG) measured by enzyme-linked immunosorbent assay (ELISA) and functional antibodies measured by a flow cytometry opsonophagocytosis assay (OPA) varied with serotype and time points studied. After 3 months of administering a second PCV7 dose we got the highest correlation (with significant r values of 0.754, 0.414, and 0.593 for serotypes 6B, 14, and 23F, respectively) but no significant increase in IgG concentration and OPA titers compared to the first dose. We defined a responder to a serotype included in the vaccine with two criteria: frequency of at least twofold OPA and ELISA increases for each serotype and frequency of conversion from negative to positive OPA levels. Responders varied from 43.9% to 46.3%, 28.5% to 50.0%, and 38.0% to 50.0% for serotypes 6B, 14, and 23F, respectively, depending on the response criterion. The present research highlights the importance of demonstrating vaccine immunogenicity with suitable immunological endpoints in immunocompromised patients and also the need to define how much antibody is required for protection from different serotypes, since immunogenicity differed significantly between serotypes. 相似文献
65.
O serogroups, biotypes, and eae genes in Escherichia coli strains isolated from diarrheic and healthy rabbits. 总被引:2,自引:0,他引:2
下载免费PDF全文
![点击此处可从《Journal of clinical microbiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
J E Blanco M Blanco J Blanco A Mora L Balaguer M Mourio A Juarez W H Jansen 《Journal of clinical microbiology》1996,34(12):3101-3107
A total of 305 Escherichia coli strains isolated from diarrheic and healthy rabbits in 10 industrial fattening farms from different areas of Spain were serotyped, biotyped, and tested for the presence of the eae gene and toxin production. The characteristics found in strains isolated from healthy rabbits were generally different from those observed in E. coli strains associated with disease. Thus, strains with the eae gene (74% versus 22%); strains belonging to serogroups O26, O49, O92, O103, and O128 (64% versus 12%); rhamnose-negative strains (51% versus 5%); and rhamnose-negative O103 strains with eae genes present (41% versus 1%) were significantly (P < 0.001 in all cases) more frequently detected in isolates from diarrheic animals than in those from healthy rabbits. Whereas a total of 35 serogroups and 17 biotypes were distinguished, the majority of the strains obtained from diarrheic rabbits belonged to only four serobiotypes, which in order of frequency were O103:B14 (72 strains), O103:B6 (16 strains), O26:B13 (12 strains), and O128:B30 (12 strains). These four serobiotypes accounted for 48% (112 of 231) and 5% (4 of 74) of the E. coli strains isolated from diarrheic and healthy rabbits, respectively. Only six strains were toxigenic (three CNF1+, two CNF2+, and one VT1+). We conclude that enteropathogenic E. coli strains that possess the eae gene are a common cause of diarrhea in Spanish rabbit farms and that the rhamnose-negative highly pathogenic strains of serotype O103:K-:H2 and biotype B14 are especially predominant. Detection of the eae gene is a useful method for the identification of enteropathogenic E. coli strains from rabbits. However, a combination of serogrouping and biotyping may be sufficient to accurately identify the highly pathogenic strains for rabbits. 相似文献
66.
Opsonic antibodies to outer membrane protein P2 of nonencapsulated Haemophilus influenza are strain specific. 总被引:3,自引:5,他引:3
下载免费PDF全文
![点击此处可从《Infection and immunity》网站下载免费的PDF全文](/ch/ext_images/free.gif)
A Troelstra L Vogel L van Alphen P Eijk H Jansen J Dankert 《Infection and immunity》1994,62(3):779-784
The ability of monoclonal antibodies (MAbs) specific for variable and conserved epitopes of outer membrane protein (OMP) P2 (b,c) of nonencapsulated Haemophilus influenza to promote opsonophagocytosis of this bacterium by human polymorphonuclear leucocytes (PMNs) was determined by flow cytometry. MAbs rendering PMNs fluorescent because of association with fluorescein isothiocyanate-labelled bacteria were defined as stimulating opsonophagocytosis. Opsonophagocytosis was dependent on the presence of both antibodies and complement. Of the 14 MAbs directed to the variable parts of OMP P2 (L. van Alphen, P. Eijk, L. Geelen-van den Broek, and J. Dankert, Infect. Immun. 59:247-252, 1991), 9 stimulated opsonophagocytosis. Four of the five nonopsonophagocytic MAbs that were immunoglobulin G1 were unable to cause complement activation. The MAbs promoting opsonophagocytosis included MAbs specific for one or more OMP P2 antigenic variants of H. influenzae strains isolated from patients with chronic bronchitis during persistent infection. MAbs cross-reacting in enzyme-linked immunosorbent assays with nonrelated H. influenzae did not promote opsonophagocytosis of strains from other patients. Opsonophagocytosis was not observed in the presence of three MAbs reacting with OMP P2 epitopes common in H. influenzae. These results indicate that OMP P2-dependent opsonophagocytosis of nonencapsulated H. influenzae is strictly strain specific. 相似文献
67.
Prenatal diagnosis of the fragile X syndrome: loss of mutation owing to a double recombinant or gene conversion event at the FMR1 locus.
下载免费PDF全文
![点击此处可从《Journal of medical genetics》网站下载免费的PDF全文](/ch/ext_images/free.gif)
M Losekoot E Hoogendoorn R Olmer C C Jansen J C Oosterwijk A M van den Ouweland D J Halley S T Warren R Willemsen B A Oostra E Bakker 《Journal of medical genetics》1997,34(11):924-926
The fragile X syndrome, an X linked mental retardation syndrome, is caused by an expanded CGG repeat in the first exon of the FMR1 gene. In patients with an expanded repeat the FMR1 promoter is methylated and, consequently, the gene is silenced and no FMR1 protein (FMRP) is produced, thus leading to the clinical phenotype. Here we describe a prenatal diagnosis performed in a female from a fragile X family carrying a large premutation. In chorionic villus DNA of the male fetus the normal maternal CGG allele and a normal pattern on Southern blot analysis were found in combination with the FRAXAC2 and DXS297 allele of the maternal at risk haplotype. A second chorionic villus sampling was performed giving identical results on DNA analysis and, in addition, expression of FMRP was shown by immunohistochemistry. We concluded that the male fetus was not affected with the fragile X syndrome. Subsequent detailed haplotype analysis showed a complex recombination pattern resembling either gene conversion or a double crossover within a 20 kb genomic region. 相似文献
68.
Secretion of Igs and surface expression of HLA antigens was examined in lymphoid cells as a function of temp. Upon reducing the temp from 37 to 20 degrees C a progressive decrease in the secretion of Ig and surface expression of HLA antigens was noted. When the status of the oligosaccharides present on these glycoproteins was examined, conversion of high-mannose [endo-beta-N-acetylglucosaminidase-(Endo H) sensitive] to complex-type (Endo H resistant) oligosaccharides diminished with decreasing temp. At no time was an accumulation of Endo H resistant glycoproteins seen intracellularly. These results show that the phenomenon observed for synthesis and intracellular transport of viral glycoproteins in epithelial cells at reduced temp, namely intracellular accumulation of viral glycoproteins carrying complex sugar moieties, does not necessarily apply to glycoprotein transport in lymphoid cells. A difference in subcellular organization of epithelial and lymphoid cells may be responsible for this discrepancy. 相似文献
69.
Quantitative flow cytometric analysis of opsonophagocytosis and killing of nonencapsulated Haemophilus influenzae by human polymorphonuclear leukocytes. 总被引:3,自引:0,他引:3
下载免费PDF全文
![点击此处可从《Clinical and Vaccine Immunology : CVI》网站下载免费的PDF全文](/ch/ext_images/free.gif)
L Vogel L van Alphen F Geluk A Troelstra E Martin R Bredius P Eijk H Jansen J Dankert 《Clinical and Vaccine Immunology : CVI》1994,1(4):394-400
Since nonencapsulated Haemophilus influenzae persists in the lower respiratory tracts of patients with chronic bronchitis despite the presence of specific antibodies, complement, and polymorphonuclear leukocytes (PMNs), opsonophagocytosis of H. influenzae was analyzed. Nonencapsulated H. influenzae isolated from the sputa of chronic bronchitis patients was labeled with fluorescein isothiocyanate and incubated with human PMNs in the presence of complement and antibodies for 30 min at 37 degrees C. Candida albicans was added to each sample as an internal standard, and the reduction of the number of bacteria was determined by flow cytometry. Fluorescence quenching with ethidium bromide was used to discriminate between intracellular and extracellular bacteria. Opsonophagocytosis of viable H. influenzae d1 was 17% +/- 29% in the presence of complement and human pooled sera containing high titers of strain-specific antibodies. Opsonophagocytosis of six other H. influenzae strains was also poor. Under the same conditions, opsonophagocytosis of Staphylococcus aureus was 90% +/- 5%, and opsonophagocytosis of C. albicans was 55% +/- 23%. About half of the number of H. influenzae bacteria associated with PMNs was internalized. Opsonophagocytosis of heat-killed H. influenzae d1 (41% +/- 20%) was higher than that of viable bacteria of the same strain (P < 0.05). This result suggests that the accessibility of epitopes on H. influenzae for opsonizing antibodies is better on killed than on viable bacteria. We conclude that viable nonencapsulated H. influenzae is poorly opsonophagocytized in the presence of strain-specific antibodies and complement. 相似文献
70.
Flow Perfusion Culture of Marrow Stromal Cells Seeded on Porous Biphasic Calcium Phosphate Ceramics 总被引:2,自引:0,他引:2
Holtorf HL Sheffield TL Ambrose CG Jansen JA Mikos AG 《Annals of biomedical engineering》2005,33(9):1238-1248
Calcium phosphate ceramics have been widely used for filling bone defects to aid in the regeneration of new bone tissue. Addition of osteogenic cells to porous ceramic scaffolds may accelerate the bone repair process. This study demonstrates the feasibility of culturing marrow stromal cells (MSCs) on porous biphasic calcium phosphate ceramic scaffolds in a flow perfusion bioreactor. The flow of medium through the scaffold porosity benefits cell differentiation by enhancing nutrient transport to the scaffold interior and by providing mechanical stimulation to cells in the form of fluid shear. Primary rat MSCs were seeded onto porous ceramic (60% hydroxyapatite, 40% β-tricalcium phosphate) scaffolds, cultured for up to 16 days in static or flow perfusion conditions, and assessed for osteoblastic differentiation. Cells were distributed throughout the entire scaffold by 16 days of flow perfusion culture whereas they were located only along the scaffold perimeter in static culture. At all culture times, flow perfused constructs demonstrated greater osteoblastic differentiation than statically cultured constructs as evidenced by alkaline phosphatase activity, osteopontin secretion into the culture medium, and histological evaluation. These results demonstrate the feasibility and benefit of culturing cell/ceramic constructs in a flow perfusion bioreactor for bone tissue engineering applications. 相似文献