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41.
In vitro evidence for both the nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington's disease 总被引:6,自引:1,他引:6
A unifying feature of the CAG expansion diseases is the formation of
intracellular aggregates composed of the mutant polyglutamine-expanded
protein. Despite the presence of aggregates in affected patients, the
precise relationship between aggregates and disease pathogenesis is
unresolved. Results from in vivo and in vitro studies of mutant huntingtin
have lead to the hypothesis that nuclear localization of aggregates is
critical for the pathology of Huntington's disease (HD). We tested this
hypothesis using a 293T cell culture model system that compared the
frequency and toxicity of cytoplasmic and nuclear huntingtin aggregates. We
first assessed the mode of nuclear transport of N-terminal fragments of
huntingtin, and show that the predicted endogenous NLS is not functional,
providing data in support of passive nuclear transport. This result
suggests that proteolysis is a necessary step for nuclear entry of
huntingtin. Additionally, insertion of nuclear import or export sequences
into huntingtin fragments containing 548 or 151 amino acids was used to
reverse the normal localization of these proteins. Changing the subcellular
localization of the fragments did not influence their total aggregate
frequency. There were also no significant differences in toxicity
associated with the presence of nuclear compared with cytoplasmic
aggregates. The findings of nuclear and cytoplasmic aggregates in affected
brains, together with these in vitro data, support the nucleus and cytosol
as subcellular sites for pathogenesis in HD.
相似文献
42.
José María Mateos reas Lüthi Natasa Savic Beat Stierli Peter Streit Beat H. Gähwiler R. Anne McKinney 《The Journal of physiology》2007,581(1):129-138
Maintenance of dendritic spines, the postsynaptic elements of most glutamatergic synapses in the central nervous system, requires continued activation of AMPA receptors. In organotypic hippocampal slice cultures, chronic blockade of AMPA receptors for 14 days induces a substantial loss of dendritic spines on CA1 pyramidal neurons. Here, using serial section electron microscopy, we show that loss of dendritic spines is paralleled by a significant reduction in synapse density. In contrast, we observed an increased number of asymmetric synapses onto the dendritic shaft, suggesting that spine retraction does not inevitably lead to synapse elimination. Functional analysis of the remaining synapses revealed that hippocampal circuitry compensates for the anatomical loss of synapses by increasing synaptic efficacy. Moreover, we found that the observed morphological and functional changes were associated with altered bidirectional synaptic plasticity. We conclude that continued activation of AMPA receptors is necessary for maintaining structure and function of central glutamatergic synapses. 相似文献
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Schiffenbauer J Streit WJ Butfiloski E LaBow M Edwards C Moldawer LL 《Clinical immunology (Orlando, Fla.)》2000,95(2):117-123
Experimental autoimmune encephalomyelitis develops in mice immunized with CNS antigens. To elucidate the role that specific proinflammatory cytokines play in the induction of this process we examined the development of EAE in mice with targeted disruptions of the TNF p55 or p75 or the IL-1 p80 receptors. EAE developed in mice with either one or both TNF receptors deleted although the onset of disease in mice with the p55 receptor deleted was delayed. However, mice with a deletion of the IL-1 p80 receptor failed to develop any inflammatory lesions in the CNS or evidence of clinical EAE. Thus we conclude that TNF or its receptors contribute to, but are not necessary for, the induction of EAE while the IL-1 p80 receptor is absolutely required. The p55 TNF receptor plays a role in determining the onset of disease and its severity. 相似文献
45.
Expression of vascular endothelial growth factor induces an invasive phenotype in human squamous cell carcinomas 总被引:11,自引:0,他引:11 下载免费PDF全文
Detmar M Velasco P Richard L Claffey KP Streit M Riccardi L Skobe M Brown LF 《The American journal of pathology》2000,156(1):159-167
Inhibition of the vascular endothelial growth factor (VEGF) receptor Flk-1 has been shown to prevent invasion of experimental squamous cell carcinomas (SCC). To directly investigate the role of VEGF in tumor invasion, we stably transfected human SCC-13 cells, which are characterized by a noninvasive phenotype in vivo, with expression vectors containing murine VEGF(164) in sense (SCC/VEGF+) or antisense (SCC/VEGF-) orientation or with vector alone (SCC/vec). SCC/vec cells formed slowly growing, well-differentiated tumors with well-defined borders between tumor and stroma, after intradermal or subcutaneous injection. In contrast, SCC/VEGF+ tumors were characterized by rapid tumor growth, with small cell groups and single cells invading into the surrounding tissue, and by admixture of blood vessels and tumor cells in areas of tumor invasion. We detected an increase in tumor vessel density and size in VEGF-overexpressing tumors, resulting in a more than fourfold increase in total vascular areas. In contrast, SCC/VEGF- clones formed noninvasive, sharply circumscribed tumors with reduced vascular density. These findings demonstrate that selective VEGF overexpression was sufficient to induce tumor invasiveness, and they provide further evidence for an active role of the tumor stroma in cancer progression. 相似文献
46.
A consistent change in the distribution of single units as a function of several of their properties of response to clicks, noise and tone bursts was observed along the rostro-caudal axis in the ventral division of the medial geniculate body (vMGB). From posterior to anterior, the proportion of inhibitory response patterns and non-monotonic intensity functions progressively decreased; response latencies were progressively shorter and less dispersed from caudal to rostral. This functional heterogeneity is consistent with the segregation of the thalamocortical interconnections: the anterior part of vMGB projects to the anterior and primary auditory cortical fields, whereas the posterior part of vMGB projects mainly to the posterior auditory cortical field. Changes in the distribution of response properties from posterior to anterior in vMGB were found to be correlated with a progressive decrease of the density of GABA-immunoreactive neurons from caudal to rostral. Since GABAergic neurons in sensory thalamic nuclei are believed to be interneurons, these data suggest that interneurons might contribute to regional changes in the distribution of some response properties along the rostro-caudal axis in vMGB. In particular, the high proportion of inhibitory response patterns and non-monotonic intensity functions in the posterior vMGB might well be related to the high density of GABA-containing neurons caudally, where they exert a strong inhibitory influence on principal cells. Intrinsic neurons might contribute to the segregation of the acoustic information transferred from vMGB to the various auditory cortical fields. In contrast, no clear and systematic change in the distribution of response properties along the rostro-caudal axis was observed in the medial division of the MGB, in which the GABA-immunoreactive neurons were evenly distributed. 相似文献
47.
48.
CJT De Amorim e Silva A Mackenzie LM Hallowell SE Stewart MR Ditchfield 《Journal of Medical Imaging and Radiation Oncology》2006,50(4):319-323
The aim of this study was to evaluate the effectiveness of a practice magnetic resonance unit, in preparing children to undergo magnetic resonance procedures without general anaesthesia (GA) or sedation. The records of children who attended the practice MRI between February 2002 and April 2004 were retrospectively reviewed. Each record was assessed as to whether the child had passed or failed the practice MRI intervention. Those children who were considered to have passed and were proceeded to a clinical non‐GA MRI had the report of the clinical scan reviewed. If the scan had been reported as non‐diagnostic because of movement artefact it was classified as a failed scan, otherwise it was considered a pass. One hundred and thirty‐four children undertook a practice MRI (age range 4.1–16.1 years, median age 7.7 years, 47% boys) and 120/134 (90%) passed the practice session. In all, 117/120 (98%) subsequently had a clinical non‐GA MRI and 110/117 (94%) passed (median age 7.8 years, 47% boys). Preparation is a safe and effective method to reduce the need for sedation and GA in children undergoing a clinical MRI scan. It provides a positive medical experience for children, parents and staff, and results in cost savings for the hospital. 相似文献
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50.
L Armenio G Baldini M Bardare A Boner R Burgio G Cavagni M La Rosa F Marcucci M Miraglia del Giudice MR Pulejo 《Archives of disease in childhood》1993,68(2):193-197
After a two week baseline, 209 asthmatic children (mean age 10 years, range 6-17) were randomly allocated to receive 4 mg nedocromil sodium (n = 110) or placebo (n = 99) four times daily for 12 weeks in addition to their current treatment. The children completed daily diary cards and visited the clinic at four week intervals. Statistically significant differences in favour of nedocromil sodium were seen for clinician assessment of asthma severity and diary card symptom scores, pulmonary function and inhaled beta 2 bronchodilator use. Total symptom score decreased by 50% from baseline in the nedocromil sodium group and by 9% in the placebo group during the final four weeks. Nedocromil sodium was considered very or moderately effective by 78% of children/parents (placebo 59%) and 73% of clinicians (placebo 50%). Nausea, headache and sleepiness, and dyspnoea led to withdrawal of one child from nedocromil sodium and placebo treatments, respectively. Reports of sore throat and headache were marginally greater with the nedocromil sodium treatment. It is concluded that nedocromil sodium was both effective and safe in the treatment of asthma in children. 相似文献