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71.
Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine 总被引:1,自引:0,他引:1
L. C. Kirkwood R. L. Nation & A. A. Somogyi 《British journal of clinical pharmacology》1997,44(6):549-555
Aims Using human liver microsomes from donors of the CYP2D6 poor and extensive metabolizer genotypes, the role of individual cytochromes P-450 in the oxidative metabolism of dihydrocodeine was investigated.
Methods The kinetics of formation of N- and O -demethylated metabolites, nordihydrocodeine and dihydromorphine, were determined using microsomes from six extensive and one poor metabolizer and the effects of chemical inhibitors selective for individual P-450 enzymes of the 1A, 2A, 2C, 2D, 2E and 3A families and of LKM1 (anti-CYP2D6) antibodies were studied.
Results Nordihydrocodeine was the major metabolite in both poor and extensive metabolizers. Kinetic constants for N -demethylation derived from the single enzyme Michaelis-Menten model did not differ between the two groups. Troleandomycin and erythromycin selectively inhibited N -demethylation in both extensive and poor metabolizers. The CYP3A inducer, α-naphthoflavone, increased N -demethylation rates. The kinetics of formation of dihydromorphine in both groups were best described by a single enzyme Michaelis-Menten model although inhibition studies in extensive metabolizers suggested involvement of two enzymes with similar K m values. The kinetic constants for O -demethylation were significantly different in extensive and poor metabolizers. The extensive metabolizers had a mean intrinsic clearance to dihydromorphine more than ten times greater than the poor metabolizer. The CYP2D6 chemical inhibitors, quinidine and quinine, and LKM1 antibodies inhibited O -demethylation in extensive metabolizers; no effect was observed in microsomes from a poor metabolizer.
Conclusions CYP2D6 is the major enzyme mediating O -demethylation of dihydrocodeine to dihydromorphine. In contrast, nordihydrocodeine formation is predominantly catalysed by CYP3A. 相似文献
Methods The kinetics of formation of N- and O -demethylated metabolites, nordihydrocodeine and dihydromorphine, were determined using microsomes from six extensive and one poor metabolizer and the effects of chemical inhibitors selective for individual P-450 enzymes of the 1A, 2A, 2C, 2D, 2E and 3A families and of LKM1 (anti-CYP2D6) antibodies were studied.
Results Nordihydrocodeine was the major metabolite in both poor and extensive metabolizers. Kinetic constants for N -demethylation derived from the single enzyme Michaelis-Menten model did not differ between the two groups. Troleandomycin and erythromycin selectively inhibited N -demethylation in both extensive and poor metabolizers. The CYP3A inducer, α-naphthoflavone, increased N -demethylation rates. The kinetics of formation of dihydromorphine in both groups were best described by a single enzyme Michaelis-Menten model although inhibition studies in extensive metabolizers suggested involvement of two enzymes with similar K
Conclusions CYP2D6 is the major enzyme mediating O -demethylation of dihydrocodeine to dihydromorphine. In contrast, nordihydrocodeine formation is predominantly catalysed by CYP3A. 相似文献
72.
KARL-ANTON KREUZER JU¨RGEN KURT ROCKSTROH WOLFGANG JELKMANN ALBERT THEISEN ULRICH SPENGLER & TILMANN SAUERBRUCH 《British journal of haematology》1997,96(2):235-239
Severe anaemia is a frequent complication in advanced HIV infection. In our study we investigated the interaction between cytokine network, HIV infection and erythropoietin (Epo) response with increasing anaemia levels. No correlations could be established between circulating tumour necrosis factor (TNF)-alpha and any of the examined parameters. However, a negative correlation was found between haemoglobin values and soluble TNF receptor levels (sTNF-R-I: r = −0.54; P < 0.001; sTNF-R II: r = −0.47; P < 0.001) as well as interleukin-6 levels ( r = −0.29; P < 0.001). In contrast, no significant increase in log[Epo], counterbalancing haemoglobin decline and paralleling the rise in sTNF receptors, was found. In patients classified as stage III, according to the Centers for Disease Control (CDC) classification, the erythropoietin response was significantly more impaired than in patients from CDC groups I and II ( P < 0.001). The results of this study suggest that similar to its action in vitro , activation of the TNF/TNF-R system may impair erythropoietin production in HIV-associated anaemia. Due to the brief half-life of TNF-α, this activation is particularly reflected by elevations of soluble TNF receptor levels. 相似文献
73.
Hiroki Hamanaka Nobuaki Maeda Masaharu Noda 《The European journal of neuroscience》1997,9(11):2297-2308
Protein tyrosine phosphatase ζ (PTPζRPTPβ) is a proteoglycan-type receptor-like protein tyrosine phosphatase specifically expressed in the brain. In addition to the transmembrane form (PTPζ-A), the extracellular splice variant (PTPζ-S) occurs as a major soluble chondroitin sulphate proteoglycan in the brain. We prepared antibodies which specifically recognize PTPζ-A and -S, and analysed the carbohydrate structures on the two PTPζ isoforms in the developing chick brain. lmmunoprecipitation experiments using these antibodies revealed that almost all of the keratan sulphate recognized by a monoclonal antibody (5D4) was exclusively bound to PTPζ-A and PTPζ-S. Addition of keratan sulphate to these proteoglycans markedly increased from embryonic day (E) 11, in contrast to the addition of LeX and HNK-1 carbohydrates, which gradually increased during development in accordance with expression of the core proteins, suggesting that keratan sulphate modification plays some specific roles. Moreover, at the early embryonic stage keratan sulphate was observed only in several restricted regions, especially at boundary regions such as the roof plate of the tectum, the zona limitans intrathalamica in the diencephalon, and the mesencephalon-metencephalon boundary. At the mesencephalon-metencephalon boundary, keratan sulphate modification of PTPζ isoforms was specifically observed from E3 to E6 on a ring of cells encircling the neural tube and their radially oriented processes, which were identified as radial glial fibres. This expression pattern of keratan sulphate spatiotemporally corresponded well to the formation of the fovea isthmi, a groove separating the mesencephalon from the metencephalon. These results suggest that carbohydrates including keratan sulphate on PTPζ isoforms play important roles in brain development by modulating the cell-cell and/or cell-substrate interactions mediated by these molecules. 相似文献
74.
雌、孕激素对IL-6基因在子宫内膜表达的影响 总被引:4,自引:1,他引:3
为了进一步了解白介素-6(IL-6)在生殖过程中的作用,应用斑点杂交和原位杂交方法,研究IL-6在小鼠子宫内膜的基因表达和雌、孕激素对这种表达的影响。实验证明,正常动情前期子宫内膜间质细胞有IL-6cRNA基因表达,切除动物卵巢,即可消除这种表达。如给去卵巢动物2mg孕激素加10ng雌激素或20mg孕激素加100ng雌激素,它们的光密度(IOD)值分别可达到2.3和2.5。结果证明,子宫内膜间质细胞是产生细胞因子IL-6的主要细胞之一,并受卵巢激素的调控。 相似文献
75.
Shinichiro Yasumoto Jun Tsujita Shuhei Imayama Yoshiaki Hori 《The Journal of dermatology》1996,23(7):499-501
We report a case of Gianotti-Crosti syndrome associated with human herpesvirus-6 (HHV-6) infection. An eight-month-old girl developed monomorphous papules on her cheeks, buttocks, and extremities after the subsidence of exanthema subitum. Viral antibody analysis confirmed primary HHV-6 infection. HHV-6 may be added to the list of causative agents of Gianotti-Crosti syndrome. 相似文献
76.
77.
The effects of bilateral nucleus accumbens microinjections ofd-ala-met-enkephalinamide (DALA) were assessed in behavioral activation and lateral hypothalamic self-stimulation (LHSS) rate-frequency curve-shift paradigms in normal and accumbens 6-OHDA (4.0 µg) treated rats. Microinjections of DALA (2.5 µg/µl) in the behavioral activation paradigm had little effect on normal activity; however, DALA administered to 6-OHDA treated rats produced a significant overall increase in locomotion. The 6-OHDA DALA-induced locomotion effect peaked at 2 weeks after 6-OHDA treatment and then returned to baseline levels by week 5 posttreatment. Using LHSS, DALA tested over a range of doses (2.5, 5, 10, 20 µg/µl) displayed a weak biphasic reward effect only at the highest dose, which was characterized by an initial suppression followed by an elevation. DALA significantly depressed initial operant motor/performance in LHSS in a dose dependent fashion. Micro-injections of the normally ineffective low dose of DALA (2.5 µg/µl) following accumbens 6-OHDA treatment produced a significant LHSS reward decrease 2 weeks posttreatment, while LHSS motor/performance was relatively unaffected. Results are discussed in terms of opiate-dopamine and limbic-motor interactions. 相似文献
78.
79.
应用脉冲多普勒超声心动图对30例使用1,6-二磷酸果糖的肺炎心衰患儿进行心室舒缩功能指标的观测,并以20例常规治疗的心衰患儿及20例正常儿为对照组,评价1,6-二磷酸果糖的疗效。结果表明,1,6-二磷酸果糖能明显改善PEP、PEP/ET、PEP/R-R、FVI和SV等心室收缩功能指标及PFVE、E/A、PFVA等心室舒张功能指标,使心功能恢复正常。1,6-二磷酸果糖对肺炎心衰引起的心肌缺血、缺氧有保护作用。 相似文献
80.
Sensory neuropeptides are not directly involved in bronchial hyperresponsiveness induced by interleukin-8 in guinea-pigs in vivo 总被引:1,自引:0,他引:1
M. FUJIMURA M. TSUJIURA M. NOMURA M. MIZUGUCHI T. MATSUDA K. MATSUSHIMA 《Clinical and experimental allergy》1996,26(3):357-362
Background Interleukin-8 (IL-8) hus been shown to be a chemotactic factor for netitrophils, T-lymphocytes and eosinophils. Repeated intranasal administration of IL-8 enhances bronchial responsiveness to inhaled histamine in guinea-pigs. Neuropeptides which arc released trotn C-fibre nerve-endings have been postulated to induce bronchial hyperresponsiveness through neurogenic inflammation. Objective This study was conducted to examine whether sensory neuropeptides are involved in the IL-8-induced bronchial hyperresponsiveness. Methods IL-8 at a dose of 5μg/kg was administered intranasally to guinea-pigs twice a week for 3 weeks. One day after the last administration, animals were anesthetized and artificially ventilaled through tracheal cannula, and lateral pressure at the tracheal cannula (Pao) was measured as an overall index of airway responses lo increasing concentrations of inhaled histamine (25, 50, 100, and 200 μg/mL). A NKI and NK2 dual antagonist FK224(10mg/kg), a selective NK1 antgonist FK888 (10mg/kg) or vehicle was intravenously administered 10min before measurement of bronchial responsiveness. Result The IL-8 treatment significantly enhanced bronchial responsiveness to histamine (ANOVA P < 0.01). FK224 or FK888 did not alter the IL-8-induced bronchial hyperresponsiveness. Conclusion We conclude that repeated intranasal administratioti of IL-8 causes bronchial hyperresponsiveness (BHR) and that neuropeptides such as neurokinin A and substance P do not directly contribute to the development of BHR induced by IL-8. 相似文献