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991.
Matsumoto K Aizawa H Shigyo M Inoue H Takata S Hara N 《Environmental toxicology and pharmacology》1996,1(4):227-233
To investigate the mechanism of the airway narrowing induced by cigarette smoke, anaesthetized guinea pigs were exposed to 200 puffs of smoke for 10 min. Airway narrowing was assessed by monitoring the total pulmonary resistance (RL). Plasma extravasation was determined by measuring the amount of Evans blue dye extravasated into the trachea and main bronchi. Exposure to cigarette smoke caused a marked airway narrowing and plasma extravasation. Pretreatment with the dual NK1 and NK2 receptor antagonist, FK224, abolished such airway narrowing and significantly inhibited the extravasation. While the NK1 receptor antagonist, FK888, inhibited the extravasation, it had no effect on airway narrowing. Atropine partially inhibited airway narrowing without affecting extravasation. Results suggest that the airway narrowing induced by cigarette smoke is caused by tachykinins, and that a cholinergic pathway is involved. Thickening of the airway walls induced by NK1 receptor-mediated extravasation may not be involved in such airway narrowing. 相似文献
992.
Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines 总被引:2,自引:0,他引:2
A. E. Wakeling A. J. Barker D. H. Davies D. S. Brown L. R. Green S. A. Cartlidge J. R. Woodburn 《Breast cancer research and treatment》1996,38(1):67-73
Summary Since the mitogenic action of EGF is mediated by ligand-induced autophosphorylation of the EGF receptor (EGFR), and EGFR is commonly overexpressed in solid human tumours, inhibitors of receptor tyrosine kinase activity (RTK) could prove to be effective antitumour agents. Screening of a compound library using an EGF-RTK enzyme prepared from human tumour derived A431 cells identified a series of potent (IC50<1µM) enzyme inhibitors. These inhibitors are quinazolines bearing a variety of substituted anilines at the 4-position. The most potent 4-anilinoquinazolines (IC50 20nM) have small non-polar meta substituents on the aniline ring, and are competitive with ATP and non-competitive with substrate. The growth inhibitory activity of these agents was assessed in vitro using KB cells (human oral squamous tumour) grown in the absence or presence of EGF. A selected compound, 4-(3-chloroanilino)quinazoline (CAQ), inhibited EGF-stimulated growth in a concentration dependent manner and complete blockade was observed at concentrations (1–10 µM) which had no effect on basal growth. Selectivity of growth inhibition by CAQ was further exemplified in IGF1-stimulated KB cells where no effect was detected at concentrations which completely blocked EGF-stimulated growth. Similarly, CAQ blocked TGF-stimulated growth in MCF-7 human breast cancer cells without affecting insulin-stimulated growth. These studies define a novel class of EGF-RTK inhibitors which are also potent and selective inhibitors of EGF-stimulated human tumour cell growthin vitro.
Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb. 相似文献
993.
R. Lupu M. Cardillo C. Cho L. Harris M. Hijazi C. Perez K. Rosenberg D. Yang C. Tang 《Breast cancer research and treatment》1996,38(1):57-66
Summary TheerbB-2 receptor plays an important role in the prognosis of breast cancer and is expressed at high levels in nearly 30% of tumors in breast cancer patients. While evidence accumulates to support the relationship betweenerbB-2 overexpression and poor overall survival in human breast cancer, understanding of the biological consequence(s) oferbB-2 overexpression remains elusive. The discovery ofheregulin has allowed us to identify a number of related but distinct biological endpoints which appear responsive to signal transduction through theerbB-2/4 receptor. These endpoints of growth, invasiveness, and differentiation have clear implications for the emergence, maintenance, and/or control of malignancy, and represent established endpoints in the assessment of malignant progression in human breast cancer. Preliminary studiesin vitro have shown thatheregulin induces a biphasic growth effect on cells witherbB-2 overexpression. Interestingly, we observed that expression ofheregulin correlates with a more aggressive/invasive, vimentin-positive phenotype in breast cancer cells lines. Therefore, we have postulated thatheregulin is involved in breast cancer tumor progression. We have shown thatheregulin inducesin vitro chemoinvasion and chemotaxis of breast cancer cells as well as growth in an anchorage dependent and independent manner. Interestingly, aheregulin neutralizing antibody inhibits chemotaxis and results in cell growth inhibition and blockade of the invasive phenotype. Strikingly, genetically engineered cells which constitutively expressheregulin demonstrate critical phenotypic changes that are associated with a more aggressive phenotype. Specifically, these cells are no longer dependent on estrogen for growth and are resistant to tamoxifenin vitro andin vivo, and moreover these cells metastasize to lymph nodes in athymic nude mice. These tumors appear to have lostbcl-2 expression as compared with the control tumors. In addition, presumably by activation/regulation of topoisomerase II, theheregulin-transfected cells become exquisitely sensitive to doxorubicin and VP-16. Clearly, mechanistic aspects of theerbB-2/4 andheregulin interaction need to be understood from a therapeutic standpoint which could provide additional insights into synergistic treatments for certain patients, or improve treatment regimens for a large number of women. The study ofheregulin and its co-expression witherbB-2/4 receptor and the assessment of its involvement in the progression from the in situ stage of breast tumors to the invasive one will additionally increase the relevance ofheregulin as a prognostic/diagnostic factor. We believe that our studies provide new insights into breast cancer diagnosis, prognosis, and treatment.Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb. 相似文献
994.
Inhibition of signaling from Type 1 receptor tyrosine kinases via intracellular expression of single-chain antibodies 总被引:3,自引:0,他引:3
Summary Members of the Type I / epidermal growth factor receptor (EGFR)-related family of receptor tyrosine kinases have been implicated in the development of human cancer. We have taken a novel approach using the intracellular expression of single chain antibodies (scFv) to specifically inhibit thein vivo action of these receptors. A scFv is a recombinant protein analogous to an Fv domain which is the smallest high affinity binding portion of an antibody. We report here on the expression in mammalian cells of cDNAs encoding scFv-225 and scFv-FRP5 directed against the extracellular domain of, respectively, human EGFR and human ErbB-2. The scFvs were provided with a signal peptide which directs them to the secretory pathway of the cell. scFv-225, which competes with EGF for binding, functions in an autocrine fashion to inhibit EGF-dependent cell growth. scFv-FRP5 was also provided with an endoplasmic reticulum (ER) retention signal and inactivates ErbB-2 in an intracrine fashion, by preventing its appearance on the cell surface.Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb. 相似文献
995.
Leonie J. M. Rijks Gerard J. Boer Erik Endert Kora de Bruin Jan C. van den Bos Peter A. P. M. van Doremalen Willem G. E. J. Schoonen Anton G. M. Janssen Eric A. van Royen 《European journal of nuclear medicine and molecular imaging》1996,23(3):295-307
We studied the potential of both stereoisomers of 17-[123I]iodovinyloestradiol (E- andZ-[123I]IVE) and of 11-methoxy-17-[123I]iodovinyloestradiol (E-andZ-[123I]MIVE) as suitable radioligands for the imaging of oestrogen receptor(ER)-positive human breast tumours. The 17-[123I]iodovinyloestradiols were prepared stereospecifically by oxidative radio-iododestannylation of the corresponding 17-tri-n-butylstannylvi-nyloestradiol precursors. Competitive binding studies were performed in order to determine the relative binding affinity (RBA) of the unlabelled 17-iodovinyloes-tradiols for the ER in both human MCF-7 breast tumour cells and rat uterine tissue, compared with that of diethylstilboestrol (DES). Target tissue uptake, retention and uptake selectivity of their123I-labelled analogues were studied in immature female rats. All four 17-iodovi-nyloestradiols showed high affinity for the ER in human MCF-7 cells, as well as rat uterus. Their RBA for the ER showed the following order of decreasing potency: RBA of DES >Z-IVE >Z-MIVE >E-MIVE E-IVE. Neither of these 17-iodovinyloestradiols showed any significant binding to the sex hormone binding globulin in human plasma. The biodistribution studies showed ER-mediated uptake in the uterus, ovaries and pituitary, that ofE- andZ-[123I]MIVE being higher than that ofE- andZ-[123I]IVE. High target-to-non-target tissue uptake ratios, especially at longer periods after injection (up to 24 h), were exhibited by both isomers of [123I]MIVE. The uterus-to-blood uptake ratio was higher forE-[123I]MIVE. However, the uterus-to-fat uptake ratio appeared to be higher for theZ-isomer of [123I]MIVE, especially at 24 h after injection. Metabolic properties and temperature effects, which play a more important role in vivo, probably cause the discrepancies seen between in vitro and in vivo binding results. On the basis of their in vitro binding properties and in vivo distribution characteristics we conclude thatE- andZ-[123I]MIVE could be suitable radioligands for the diagnostic imaging of ER in human breast cancer. Therefore, further studies with these radioligands in mature normal and tumour-bearing rats are warranted. 相似文献
996.
Delayed image of iodine-123 iomazenil as a relative map of benzodiazepine receptor binding: The optimal scan time 总被引:2,自引:0,他引:2
Yoshihiro Onishi Yoshiharu Yonekura Fumiko Tanaka Sadahiko Nishizawa Hidehiko Okazawa Koichi Ishizu Toru Fujita Junji Konishi Takao Mukai 《European journal of nuclear medicine and molecular imaging》1996,23(11):1491-1497
Delayed single-photon emission tomograpic (SPET) images after an intravenous bolus injection of iodine-123 iomazenil have been used as a relative map of benzodiazepine receptor binding. We determined the optimal scan time for obtaining such a map and assessed the errors of the map. SPET and blood data from six healthy volunteers and five patients were used. A three-compartment kinetic model was employed in simulation studies and analyses of actual data. The simulation studies suggested that, in the normal brain, the scan time at which a single SPET image best represented the relative receptor binding was 3.0–3.5 h post-injection. This finding was supported by actual data from the volunteers. The simulation studies also suggested that the optimal scan time was not greatly changed by the variability of the input functions, and that the error in the SPET image contrast in the vicinity of the optimal scan time was not increased by changes in the tracer kinetics in the entire brain. The SPET image contrast in the patients at 3.0 h post-injection agreed well with the reference receptor binding estimated by kinetic analysis, with a mean error of 3.6%. These findings support the use of a single SPET image after bolus injection of [123I]iomazenil as a relative map of benzodiazepine receptor binding. For this purpose, a SPET scan time of 3.0-3.5 h post-injection is recommended. 相似文献
997.
Conny J. van der Laken Otto C. Boerman Wim J. G. Oyen Marjo T. P. van de Vent Roland A. M. J. Claessens Jos W. M. van der Meere Frans H. M. Corstens 《European journal of nuclear medicine and molecular imaging》1996,23(11):1531-1535
Recently, we demonstrated that radiolabelled interleukin-l (IL-1) specifically accumulates in focal infection in mice through interaction with its receptor. Unfortunately, systemic side-effects of IL-1 limit its clinical application. We investigated whether this problem could be circumvented by using the interleukin-1 receptor antagonist (IL-Ira), an equally sized protein that binds to the same receptors as IL-1 without induction of biological effects. Biodistribution of125I-IL-1 and125I-IL-Ira was determined in Swiss mice withStaphylococcus aureus-induced abscesses in the left calf muscle at 4, 12, 24 and 48 h after injection of either 0.4 MBq125I-IL1 or 0.4 MBq125I-IL-Ira. In vitro, the proteins displayed similar binding characteristics. High-performance liquid chromatographic analysis revealed a tendency for IL-Ira to associate with serum proteins. Both proteins rapidly cleared from most organs. However, the abscess uptake of125I-IL-Ira was significantly lower than that of125I-IL-1 at all time points (48 h p.i.: 0.06±0.01%ID/g vs 0.60±0.04%ID/g;P<0.02). The abscess-to-contralateral muscle ratios did not exceed 15.5±2.9 for125I-IL-lra, while the ratios for125I-IL-1 reached 46.9±5.7 at 48 h p.i. Despite similar in vitro receptor binding, the abscess uptake of IL-Ira was much lower than that of IL-1. The interaction of IL-Ira with serum proteins in vivo may reduce its availability for receptor binding in the infection. Although on theoretical grounds IL-Ira is very interesting, these characteristics will prevent its development as a clinically useful radiopharmaceutical to image infection. 相似文献
998.
The mammary gland is a hormone-target organ derived from epidermis and develops as a result of reciprocal mesenchymal-epithelial interactions. The induction of mammary differentiation from indifferent epidermal cells by mammary mesenchyme implies induction of the complement of hormone receptors characteristic of normal mammary epithelium in cells of the epidermis. Considering the facts that mammary epithelial differentiation is induced by mammary mesenchyme and that certain aspects of hormone response (androgen-induced mammary regression) are inextricably linked to mesenchymal-epithelial interactions, it is evident that the biology of the mammary gland arises from and is maintained via cell-cell interactions. As a corollary, perturbation of stromal-epithelial interactions in adulthood may play a role in mammary carcinogenesis and in turn may provide opportunities for differentiation therapy. 相似文献
999.
Bernd Schröder R. Kaune Ch. Schlumbohm G. Breves J. Harmeyer 《Calcified tissue international》1993,52(4):305-309
Summary The role of 1,25-dihydroxycholecalciferol (calcitriol) for intestinal calcium (Ca2+) absorption was studied in newborn (<1 week old) and weaned piglets (>6 weeks old). In both groups, normal piglets and piglets
suffering from inherited pseudo vitamin D-deficiency rickets, type I (PVDRI) were used. In this inherited disorder, renal
production of calcitriol is absent. Plasma samples were assayed for calcitriol and total Ca, and dissociation constants (Kd) and maximum binding capacities (Bmax) of intestinal calcitriol receptors were determined under equilibrium conditions at 4°C. Unidirectional Ca2+-flux rates were measured across stripped duodenal mucosae in Ussing chambers in the absence of electrochemical gradients.
The plasma calcitriol concentrations of neonatal (26.5±7.1 pg/ml, n=11;
± SEM) and weaned PVDRI piglets (18.8±5.7 pg/ml, n=8)were unphysiologically low and differed significantly from control animals
(83.6±14.8 pg/ml, n=8, and 86.9±9.6 pg/ml, n=11, respectively). However, newborn PVDRI piglets had normal plasma Ca levels
at least during the first days of life. They became hypocalcemic and developed clinical symptoms of rickets during the following
weeks. In newborn PVDRI and control piglets, Bmax was significantly lower (84±28 fmol/mg protein and 127±55 fmol/mg protein, n=9, respectively) than in weaned piglets (741±82
fmol/mg protein, n=9, and 778±121 fmol/mg protein, n=8, respectively). Significant net Ca2+-fluxes were found in both newborn PVDRI and control piglets (88.8±25.1 nmol · cm-2 · h-1, n=6, and 86.5±10.5 nmol · cm−2 · h−1,n=9, respectively). However, active net Ca2+ absorption was completely absent in weaned PVDRI piglets. These results indicate the presence of vitamin D-independent mechanisms
for active intestinal Ca2+ absorption during early postnatal life in pigs. 相似文献
1000.
B. M. Conti-Tronconi M. Morgutti M. G. Albizzati F. Clementi 《Journal of neurology》1978,217(4):281-286
Summary Lymphocytes of twenty-seven patients with polymyositis were incubated in vitro with cholinergic receptor rich membranes obtained from the electric organs of Torpedo Marmorata.Lymphocytes of polymyositic patients were slightly stimulated; positive responses were present mainly in patients affected from more than a year. Sensitization against the nicotinic cholinergic receptor may explain the occurrence of the myasthenic syndrome with polymyositis.Fellow of the A. Villa Rusconi foundation 相似文献