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991.
992.
Several hydrazine derivatives (HD) tested so far have pharmacological
activities, but many also have toxic side effects, including
carcinogenesis. Their toxicity has been ascribed to carbocations (via
formation of azoxy intermediates), alkyl radicals or reactive oxygen
species. Cytotoxicity and transformation by carbocations is widely
accepted, but the role of alkyl radicals is still questioned. We have
investigated the cytotoxicity of HD to mouse fibroblasts in three
activation systems in which enhanced alkyl radical formation is
demonstrated by electron spin resonance/spin-trapping. Cytotoxicity was
assayed by inhibition of [3H-methyl]thymidine uptake into DNA of Balb/c 3T3
and/or Myc 9E fibroblasts (normal Balb/c 3T3 cells over-expressing the
c-myc proto-oncogene). Based on the results obtained in the cytotoxicity
assays we also investigated the transforming potential of procarbazine
(PCZ) and methylhydrazine (MeH) activated by horseradish peroxidase (HRP)
using the Myc 9E cell line, which aims at the activation of a second
cooperating oncogene. Our results show that: (i) cytotoxicity of HD to
mouse fibroblasts is increased by HRP activation of MeH, phenelzine and
PCZ, which displayed enhanced alkyl radical formation, but not of
1,2-dimethylhydrazine (DMH), which did not produce increased alkyl radical
formation under these conditions; (ii) cytotoxicity of neutrophil-activated
MeH (producing a 10-fold higher concentration of methyl radicals), is more
pronounced than DMH; (iii) MeH and DMH activated by prolonged
auto-oxidation in 24-h incubations have comparable cytotoxicity and alkyl
radical formation; and (iv) PCZ and MeH activation by HRP to alkyl radicals
increased the transformation induced in Myc 9E cells. Taken together, our
results strongly support a role for hydrazine-derived alkyl radicals in HD-
induced cytotoxicity and cell transformation.
相似文献
993.
994.
Modulation of human epidermal cell response to 2,3,7,8- tetrachlorodibenzo-p-dioxin by epidermal growth factor 总被引:2,自引:0,他引:2
Cultured human epidermal cells were treated with 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD) in the presence or absence of epidermal
growth factor (EGF). In both normal keratinocytes and a spontaneously
immortalized keratinocyte (SIK) line, TCDD treatment in the absence of EGF
induced a marked reduction in colony size and cell number, and it perturbed
colony morphology. These effects were largely prevented by EGF, indicating
that growth factor action in the cellular microenvironment may considerably
modify TCDD action in target cells. Both TCDD and EGF substantially reduced
expression of the differentiation markers keratin 1 and keratin 10 in the
normal and immortalized cells, and did so in an additive fashion. The cells
did not display a general loss of differentiated function, since several
other markers, including involucrin, were little affected. EGF dramatically
stimulated telomerase activity in SIK cultures, and TCDD prevented this
action but not by reducing cell growth. However, EGF did not stimulate
telomerase activity in normal human epidermal cells despite an evident
increase in their growth. The growth factor stimulation of telomerase in
the minimally deviated SIK line suggests that derepression of enzyme
activity in normal cells may occur in a stepwise fashion during neoplastic
progression. TCDD could act as a late stage tumor promoter by selecting for
variants in which telomerase is constitutively active.
相似文献
995.
FABIO CAPASSO ANNA GIUNTA† GIUSEPPE STABILE PIETRO TURCO VINCENZO LA ROCCA GABRIELLA GRIMALDI ANTONIO DE SIMONE 《Pacing and clinical electrophysiology : PACE》2005,28(S1):S1-S4
Cardiac resynchronization therapy (CRT) improves myocardial performance in patients with heart failure (HF) and left bundle-branch block (LBBB). Tissue Doppler echocardiography (TDE) has already been used to guide the selection of candidates for CRT. The objective of this study is to correlate the effects of CRT on left ventricular (LV) systolic function with wall motion synchrony assessed by TDE. High frame TDE data were obtained in 15 patients (mean age = 68.9 years, 11 men) with LBBB (QRS = 163 ± 13 ms) to derive temporal intraventricular horizontal asynchrony indexes, expressed as the time difference at the onset of shortening between the septum and the lateral (S-L) and antero-inferior (A-I) walls, and measure the amount of delayed longitudinal contraction (DLC) within the LV. All measurements were made at baseline, 24 hours after implantation, and at 1 year of follow-up. The results show that LV ejection fraction (EF) increased from 25 ± 6.2% at baseline to 36.9 ± 7.9% at 1 year, and was strongly related to DLC, expressed either by time duration (DLCd, r =−0.51; P < 0.0001) or percent of the basal segments (%DLC, r =−0.50; P < 0.001). New York Heart Association functional class, which decreased from 3.6 ± 0.5 to 2.3 ± 0.8, was correlated with %DLC (r = 0.50) and DLCd (r = 0.48, P < 0.001). Weaker correlations were found between LVEF and S-Li (r =−0.40) and between NYHA and S-Li (r = 0.40). It is concluded that DLC was the best among intraventricular asynchrony indexes in predicting increases in LVEF after CRT. DLC may be useful to identify responders to CRT. 相似文献
996.
Alves LA; Coutinho-Silva R; Persechini PM; Spray DC; Savino W; Campos de Carvalho AC 《Blood》1996,88(1):328-334
The existence of functional gap junctions in migratory cells of the immune system is a controversial issue. In this report, we have focused on one particular cell type, namely the macrophages, because connexin- 43, a protein that forms gap junctions, has been described in peritoneal macrophages and a macrophage cell line (J774), by Northern and Western blot analysis. To test whether these cell types expressed functional gap junctions, we assayed dye coupling by intracellular injection of Lucifer Yellow. We observed that nonstimulated macrophages are not coupled among themselves and did not form functional gap junctions with an epithelial cell line, which expresses functional gap junctions formed by connexin-43. Dye coupling was also not detected between macrophages previously activated by lipopolysaccharide or interferon-gamma. We further examined the presence of functional coupling using the more sensitive technique of dual whole cell patch- clamp, and again, did not find electrical coupling between macrophages, consistent with the dye microinjection data. We also examined the possible presence of hemigap junction channels activated by extracellular adenosine triphosphate (ATP) using a dye uptake assay and the whole cell patch-clamp technique. Conditions expected to close gap junction hemichannels (exposure to octanol and low intracellular pH) did not decrease ATP-induced Lucifer Yellow uptake, whereas conditions expected to increase hemichannel opening either did not affect ATP permeabilization (dibutyryl adenosine monophosphate) or decreased it (zero extracellular CA+2). Finally, in experiments using resident macrophages derived from conexin-43 knockout mice, we observed ATP induced dye uptake. Our experimental data thus indicate that macrophages in vitro do not form functional gap junctions and that the permeability pathway activated by extracellular ATP is not formed by a hemigap junction channel. 相似文献
997.
998.
999.
Tissue inhibitor of metalloproteinases (TIMP)-1, -2 and -3 in human endometrium during the menstrual cycle 总被引:12,自引:5,他引:7
The extensive remodelling of the human endometrium throughout the menstrual
cycle is accompanied by changes in production of matrix metalloproteinases,
the activity of which can be inhibited by specific tissue inhibitors or by
tissue inhibitors of metalloproteinases (TIMP)s with a 1:1 stoichiometry.
This study immunolocalized TIMP-1, TIMP-2 and TIMP-3 in dated normal human
endometrium across the menstrual cycle and examined cultured endometrial
cells for their production. All three TIMPs were present in the major
cellular compartments, luminal epithelium, glands, stroma, endothelial
cells and vascular smooth muscle cells with the most intense
immunoreactivity in the luminal epithelium. TIMP-1 and -3 were lower in the
mid-to-late proliferative phase with a nadir of TIMP-3 particularly in the
late proliferative phase. Decidualized stromal cells stained strongly
positive for TIMP-1, -2 and -3. Cells of haematopoietic origin never
stained. Monensin treatment of tissue resulted in accumulation of TIMPs in
all cellular compartments but particularly of TIMP-1 in epithelium.
Cultured endometrial stromal cells released more TIMP-1 than TIMP-2 or
TIMP-3 into culture medium and all were increased following decidualization
in vitro. Epithelial cells in culture produced less TIMPs than stromal
cells, and only a few epithelial cells in each culture were immunopositive
for TIMP-1. The ubiquitous distribution of TIMPs implicates them in
maintenance of endometrial integrity, with changes in the matrix
metalloproteinases without concomitant changes in TIMPs determining
endometrial matrix degradation.
相似文献
1000.
A flow cytometric procedure was investigated for its ability to detect antibodies directed against blood group A, HLA, and PlA1 (HPA-1a) antigens. When type O sera were tested against platelets from blood group A donors, only 9 of 14 positive reactions were observed. Furthermore, the expression of blood group A varied more than 100-fold on platelets derived from individual donors. When anti-HLA-A2 and -B7 were evaluated, 11 of 11 individuals with HLA-A2 and -B7 antigens reacted. In contrast, when platelets from donors whose HLA antigens included HLA-B8 or -B12 were tested with anti-HLA-B8 or -HLA-B12, respectively, positive reactions were observed in only 3 of 7 instances, despite the fact that the lymphocytes reacted strongly. Platelets from 10 HLA-A2-positive donors, which had been stored for up to 20 months at -70 degrees C, were studied. In all cases, frozen-stored platelets reacted well with an anti-HLA-A2. Limited testing with an anti-PlA1 (anti-HPA-1a) showed equal reactivity with fresh and frozen platelets. Finally, the method was compared to a visual immunofluorescence assay using sera from patients who were refractory to platelet transfusions. The results agreed in 30 of 37 comparisons, and most discrepancies were resolved in favor of flow cytometry. It is concluded that flow cytometry is useful for detecting platelet alloantibodies and possibly for prospective platelet crossmatching, as HLA- and platelet-specific antibodies can be identified by using platelets stored frozen for several months. 相似文献