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21.
Cytokine responses during mycobacterial and schistosomal antigen-induced pulmonary granuloma formation. Production of Th1 and Th2 cytokines and relative contribution of tumor necrosis factor. 总被引:6,自引:4,他引:6 下载免费PDF全文
S. W. Chensue K. Warmington J. Ruth P. Lincoln M. C. Kuo S. L. Kunkel 《The American journal of pathology》1994,145(5):1105-1113
Synchronized pulmonary granulomas (GRs) were induced in presensitized mice by intravenous embolization of polymer beads bound with purified protein derivative (PPD) of Mycobacteria tuberculosis or soluble antigens derived from Schistosoma mansoni eggs (SEA). Uncoated beads served as a foreign body control (CON). Antigen-coated beads elicited GRs with characteristic epithelioid macrophages and multinucleate giant cells by 4 days after embolization. Unlike PPD GR, SEA bead lesions contained eosinophils, whereas CON beads elicited only a limited mononuclear infiltrate. GRs and draining lymph nodes (LN) were assessed on days 2, 4, and 8 for Th1-(interleukin-2 [IL-2], interferon-gamma[IFN] and Th2-type (IL-4, IL-5, and IL-10) cytokines. CON GR produced only a small amount of IFN-gamma on day 2 and failed to induce a significant response in draining LN. In contrast, both PPD and SEA antigen-coated beads induced reactive lymphoid hyperplasia but differed greatly in local and regional cytokine profiles. PPD GR produced IFN-gamma on day 2 and the draining LN produced predominantly Th1 cytokines on days 2 and 4. In contrast, SEA beads GRs were dominated by Th2 cytokines. The corresponding LN produced IL-2 and IL-4 on day 2; IL-2, IL-4, IFN-gamma, and IL-10 on day 4; then IL-2, IFN-gamma, and IL-4 on day 8, probably reflecting maturational changes of T cells. Macrophages (MP) from bead GR also showed different patterns of IL-6 and tumor necrosis factor (TNF) production. Compared with CON GR, MPs from PPD GR were weak sources of IL-6, whereas those of SEA GR showed enhanced and accelerated production. In contrast, MP of PPD GR had augmented TNF-producing capacity, whereas those of SEA GR showed delayed TNF production. In vivo depletion of TNF, respectively, caused 40 and 10% decreases in PPD GR and SEA GR but had no effect on CON GR area, indicating that TNF contributed to a greater degree to the PPD response. These data show that depending on the inciting agent, GR can be mediated by different cytokines. Characterization of inflammatory lesions by cytokine profiles should allow design of more rational therapeutic interventions. 相似文献
22.
Oligoclonal immunoglobulins in subacute sclerosing panencephalitis and multiple sclerosis: a study of idiotypic determinants. 下载免费PDF全文
Studies have been made of the idiotypic determinants of subacute sclerosing panencephalitis (SSPE) antibodies using rabbit antisera to serum and spinal fluid fractions.Evidence is presented indicating that serum and cerebrospinal fluid (CSF) anti-measles antibodies, as judged by their idiotypes, differ in their relative concentrations in the two compartments. The results indicate that some of these antibody subpopulations originate within the CNS, while others are made largely or entirely outside. In addition to strong idiotypic specificity, a limited cross-idiotypic specificity relating antibodies from three out of fourteen SSPE patients has been identified. In the course of these studies, measles virus was found to agglutinate red cells coated with antibody fraction to high titres. This system has proved useful in demonstrating the competition between anti-idiotypic antibody and antigen for the combining sites of the measles antibody. Two anti-idiotypic antisera have also been obtained against the spinal fluid IgG of multiple sclerosis (MS) patients. The possible use of these marker reagnets as well as related methodologies in the search for the antigens involved in MS bands is discussed. 相似文献
23.
Regulatory effects of interleukin-6 in immunoglobulin G immune-complex-induced lung injury. 总被引:2,自引:0,他引:2 下载免费PDF全文
T. P. Shanley J. L. Foreback D. G. Remick T. R. Ulich S. L. Kunkel P. A. Ward 《The American journal of pathology》1997,151(1):193-203
Interleukin-6 (IL-6) is a cytokine produced in response to a variety of inflammatory stimuli. Although IL-6 is often observed in increased amounts in acute respiratory distress syndrome, its role in the development of lung injury is unclear. The role of IL-6 was studied in the rat model of lung injury induced by the intra-alveolar deposition of IgG immune complexes. IL-6 induction, as determined by Northern blot analysis and bioactivity, was found as a function of time during the course of development of injury. Recombinant IL-6 instilled intratracheally at commencement of injury led to substantial reductions in lung vascular permeability, neutrophil accumulation, and levels of tumor necrosis factor (TNF)-alpha and macrophage inflammatory protein (MIP)-2 in bronchoalveolar lavage fluids. Conversely, blocking of intrinsic IL-6 by a neutralizing antibody resulted in increases in lung vascular permeability, neutrophil content, and TNF-alpha levels in bronchoalveolar lavage fluids. Rat alveolar macrophages stimulated in vitro with lipopolysaccharide in the presence of IL-6 showed a significant reduction in TNF-alpha expression. Together, these findings suggest that IL-6 acts as an intrinsic regulator of lung inflammatory injury after deposition of IgG immune complexes and that the protective effects of exogenously administered IL-6 may be in part linked to suppressed TNF-alpha production. 相似文献
24.
The production of chemotactic cytokines in an allogeneic response. The role of intercellular adhesion molecule-1 and lymphocyte function-associated antigen-3. 总被引:1,自引:0,他引:1 下载免费PDF全文
N. W. Lukacs S. L. Kunkel M. D. Burdick R. M. Strieter 《The American journal of pathology》1993,143(4):1179-1188
The in vitro mixed lymphocyte reaction (MLR) is regarded as a model of responsiveness to allogeneic major histocompatibility complex antigens and has historically been used to elucidate the pathway of T lymphocyte proliferation. In addition, the MLR response may reflect activation pathways relevant in acute allograft rejection. In the present study, we have applied the MLR to examine the role of adhesion molecules intercellular adhesion molecule-1 and lymphocyte function-associated antigen-3 in the induction of tumor necrosis factor-alpha (TNF-alpha) as well as chemotactic cytokines, interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1 alpha (MIP-1 alpha). Monoclonal antibodies to the adhesion molecules (5 micrograms/ml) were added to one-way human MLR cultures and supernatants collected at various time points. The monoclonal antibodies to the adhesion molecules significantly suppressed the proliferative response by 50 to 80%. Cytokine production, TNF-alpha (3.2 +/- 0.5 ng/ml), MIP-1 alpha (12.9 +/- 3.3 ng/ml), MCP-1 (18.8 +/- 3.4 ng/ml), and IL-8 (57 +/- 18 ng/ml) peaked on day 5 of the assay. The addition of anti-intercellular adhesion molecule-1 to the cultures suppressed TNF-alpha, MIP-1 alpha, MCP-1, and IL-8 production by 68% (1.05 +/- 0.29 ng/ml), 85% (2.0 +/- 1.2 ng/ml), 63% (6.8 +/- 2.9 ng/ml), and 47% (30.3 +/- 3.7 ng/ml), respectively. Likewise, the addition of anti-lymphocyte function-associated antigen-3 monoclonal antibody suppressed the cytokines by 78% (0.71 +/- 0.34 ng/ml), 66% (4.5 +/- 2.2 ng/ml), 52% (8.8 +/- 2.2 ng/ml), and 73% (15.7 +/- 4.4 ng/ml), respectively. Immunohistochemical staining indicated that monocytes were the primary source of the chemokines IL-8, MCP-1, and MIP-1 alpha. The addition of exogenous recombinant TNF-alpha (5 ng/ml) or recombinant IL-2 (5 units/ml) to the anti-intercellular adhesion molecule-1-treated cultures allowed the recovery of the proliferative response as well as restoration of IL-2, TNF-alpha, and IL-8, but not MCP-1 or MIP-1 alpha, indicating that both soluble and adhesion molecule signals are required for the production of the C-C family of chemokines in allogeneic responses. Thus, the events resulting in cellular proliferation and chemokine production were dependent on adhesion molecule interactions. 相似文献
25.
Cross idiotypic specificity among cold agglutinins in relation to combining activity for blood group-related antigens 总被引:8,自引:3,他引:8 下载免费PDF全文
The previous observations of cross idiotypic specificity of IgM cold agglutinins were further investigated in quantitative precipitin assays and attempts were made to relate shared idiotypic specificity to combining specificity for I, i and Pr antigens of red cells. Shared idiotypic determinants were observed among anti-I and anti-i antibodies which are now known to have combining specificity for determinants present on precursors of the ABH and Lewis blood group substances. There was evidence that one cold agglutinin, Ma, which had previously been shown to have an unusual kind of I specificity was deficient in the idiotypic determinants associated with the other anti-I proteins. 相似文献
26.
Inactivation of Exonuclease 1 in mice results in DNA mismatch repair defects,increased cancer susceptibility,and male and female sterility 总被引:12,自引:0,他引:12 下载免费PDF全文
Wei K Clark AB Wong E Kane MF Mazur DJ Parris T Kolas NK Russell R Hou H Kneitz B Yang G Kunkel TA Kolodner RD Cohen PE Edelmann W 《Genes & development》2003,17(5):603-614
Exonuclease 1 (Exo1) is a 5'-3' exonuclease that interacts with MutS and MutL homologs and has been implicated in the excision step of DNA mismatch repair. To investigate the role of Exo1 in mammalian mismatch repair and assess its importance for tumorigenesis and meiosis, we generated an Exo1 mutant mouse line. Analysis of Exo1(-/-) cells for mismatch repair activity in vitro showed that Exo1 is required for the repair of base:base and single-base insertion/deletion mismatches in both 5' and 3' nick-directed repair. The repair defect in Exo1(-/-) cells also caused elevated microsatellite instability at a mononucleotide repeat marker and a significant increase in mutation rate at the Hprt locus. Exo1(-/-) animals displayed reduced survival and increased susceptibility to the development of lymphomas. In addition, Exo1(-/-) male and female mice were sterile because of a meiotic defect. Meiosis in Exo1(-/-) animals proceeded through prophase I; however, the chromosomes exhibited dynamic loss of chiasmata during metaphase I, resulting in meiotic failure and apoptosis. Our results show that mammalian Exo1 functions in mutation avoidance and is essential for male and female meiosis. 相似文献
27.
Precipitin reactions of the C1q component of complement with aggregated gamma-globulin and immune complexes in gel diffusion 总被引:56,自引:0,他引:56 下载免费PDF全文
A gel diffusion method for demonstrating precipitin reactions of C1q with aggregated γ-globulin and immune complexes is described. Optimal precipitin lines were found to occur with 0.6 per cent agarose in 0.01 M EDTA at pH 7.2 and ionic strength 0.1. Reduction and alkylation of γ-globulin aggregates destroyed the precipitability with C1q. Precipitation occurred only with aggregates greater than 19S and with soluble immune complexes formed in two to twenty times antigen excess. γ-Globulin complexes were detected by this procedure in hypocomplementaemic sera from patients with systemic lupus erythematosus and hypocomplementaemic joint fluids from patients with rheumatoid arthritis. The relevance of this in vitro system to in vivo complement consumption in various disease states is discussed. 相似文献
28.
Systemic lupus erythematosus with deficiency of the T4 epitope on T helper/inducer cells 总被引:2,自引:0,他引:2
Three black Jamaicans with systemic lupus erythematosus (SLE) were identified whose T helper/inducer cells lacked the T4 epitope (T4 epitope-deficient phenotype). All three patients had lymphadenopathy as part of their syndromes. The asymptomatic and otherwise healthy T4 epitope-deficient brother of one of these patients also had lymphadenopathy in a distribution identical to that of his sister with SLE. Family studies pointed to an autosomal codominant mode of inheritance not linked to the HLA locus for the T4 epitope phenotype. Cultures of peripheral-blood mononuclear cells revealed impaired B-cell differentiation upon stimulation with pokeweed mitogen in cells originating from the T4 epitope-deficient family members as compared with those originating from their T4 epitope-intermediate relatives. Ratios of T helper/inducer cells to T suppressor/cytotoxic cells, the presence of various autoantibodies, and proliferation in response to mitogens and in the mixed lymphocyte reactions did not correlate with T4 epitope phenotype. We suggest that SLE in association with the T4 epitope-deficient phenotype may represent a unique subset of patients with SLE that has distinct clinical and immunologic properties. 相似文献
29.
30.
Cytotoxicity of tumor necrosis factor-alpha for human umbilical vein endothelial cells 总被引:10,自引:0,他引:10
L Schuger J Varani R M Marks S L Kunkel K J Johnson P A Ward 《Laboratory investigation; a journal of technical methods and pathology》1989,61(1):62-68
Human umbilical vein endothelial cells were examined for sensitivity to killing by human recombinant tumor necrosis factor-alpha (TNF-alpha). Treatment of the cells with concentrations of TNF-alpha up to 50 ng/ml for 18 hours did not produce evidence of cytotoxicity. However, a marked cytotoxic effect was found when TNF-alpha pretreated cells were incubated in Hanks' balanced salt solution for a further 4 hours. Exposure of the cells to heat-inactivated or antibody-neutralized TNF-alpha did not result in cytotoxicity. Human recombinant interleukin-1 also lysed endothelial cells under the same conditions, whereas human recombinant macrophage-colony stimulating factor did not. Inclusion of superoxide dismutase, catalase, or soybean trypsin inhibitor in the culture medium during the time of endothelial cell exposure to TNF-alpha had no protective effects. Likewise, allopurinol (a xanthine oxidase inhibitor) and nordihydro-guaiaretic acid (a lipoxygenase inhibitor) were not protective under the same conditions. In contrast, the ferric iron chelator deferoxamine mesylate and three different cyclooxygenase inhibitors provided significant protection against TNF-alpha induced cytotoxicity. When human dermal fibroblasts and human squamous epithelial cells were used in place of the umbilical vein endothelial cells, these cells were resistant to TNF-alpha mediated killing. These findings demonstrate that under the experimental conditions employed, TNF-alpha is cytotoxic for human umbilical vein endothelial cells. This may have implications in a number of in vivo situations in which TNF-alpha is thought to play a role. 相似文献