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D H Russell N E Zorn A R Buckley P D Crowe M D Sauro E M Hadden R V Farese H E Laird 《European journal of pharmacology》1990,188(2-3):139-152
Prolactin (PRL) and other trophic factors rapidly activate a nuclear pool(s) of protein kinase C (nPKC) in purified splenocyte nuclei. The PRL also enhanced [2-3H]glycerol incorporation into nuclear mono- and triacylglycerol. An assay was devised which not only probed the ability of the hormone to activate protein kinase C (PKC) but also demonstrated the presence of nuclear substrates. Using this methodology, a biphasic concentration-response curve to PRL was observed. Heterologous species of PRL and various growth factors also activated nPKC. The PRL-induced nPKC stimulation was antagonized by various immunomodulators, G protein-coupling inhibitors, PKC inhibitors, a calmodulin inhibitor, and a peripheral benzodiazepine agonist and antagonist. A monoclonal antibody to PKC, anti-rat PRL antiserum and a monoclonal anti-rat PRL receptor antibody antagonized PRL-induced PKC-dependent nuclear phosphorylation, further implicating nPKC and a PRL receptor-mediated activation process. Nuclear PKC may be a major target for trophic regulation in response to both positive and negative growth signals. 相似文献
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As knowledge of the human genome continues to grow, more progress is being made towards not only identifying the genes involved in disease susceptibility but also in defining the synergistic role genes play with environmental exposures. The detection of gene‐environment interactions is important as it can offer clinicians a potential means of intervention. The discovery of interactions relies heavily on powerful statistical methods. We present a test, FBAT‐I, that can be used to investigate gene‐environment interaction. The test uses the case‐parent triad design and protects the statistical inference from potential spurious results due to population admixture. 相似文献
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C. Laird Birmingham 《Canadian Medical Association journal》1994,150(8):1276-1277
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Gerald L DeNardo Arutselvan Natarajan Saphon Hok Julie Perkins Monique Cosman Sally J DeNardo Felice C Lightstone Gary R Mirick Laird A Miers Rodney L Balhorn 《Journal of nuclear medicine》2007,48(8):1338-1347
Despite their large size, antibodies (Abs) are suitable carriers to deliver systemic radiotherapy, often molecular image-based, for lymphoma and leukemia. Lym-1 Ab has proven to be an effective radioisotope carrier, even in small amounts, for targeting human leukocyte antigen DR (HLA-DR), a surface membrane protein overexpressed on B-cell lymphoma. Pairs of molecules (referred to as ligands), shown by computational and experimental methods to bind to each of 2 sites within the Lym-1 epitopic region, have been linked to generate small (<2 kDa) molecules (referred to as selective high-affinity ligands [SHALs]) to mimic the targeting properties of Lym-1 Ab. METHODS: A lysine-polyethylene glycol (PEG) backbone was used to synthetically link 2 of the following ligands: deoxycholate, 5-leuenkephalin, triiodothyronine, thyronine, dabsyl-L-valine, and N-benzoyl-L-arginyl-4-amino-benzoic acid to generate a series of 13 bidentate SHALs with a biotin or 1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid (DOTA) chelate attached to the linker. These SHALs have been assessed for their selectivity in binding to HLA-DR10-expressing cells and for their pharmacokinetics and tissue biodistribution in mice. Biotinylated versions of these SHALs discriminated cell lines positive for HLA-DR10 expression with near-nanomolar affinity. The DOTA versions of 4 SHALs were labeled with (111)In for pharmacokinetic studies in mice with HLA-DR10-expressing malignant Raji xenografts. RESULTS: The bidentate, biotinylated, and DOTA-SHALs were synthesized in high-purity, multimilligram amounts. Mean radiochemical and product yields and purities were 90%, 75%, and 90% at mean specific activities of 3.9 MBq/microg (105 microCi/microg) for the (111)In-labeled SHALs. As expected, rapid blood clearance and tumor targeting were observed. The pharmacokinetics of the SHALs was influenced by the component ligands. Biliary clearance, kidney localization, and serum receptor binding contributed to less favorable tumor targeting. CONCLUSION: A series of SHALs was readily synthesized in multimilligram amounts and showed the expected selective binding in vitro. Better selection of the SHAL components should provide second-generation SHALs with improved properties to fulfill the substantial potential of these novel molecular carriers for targeting. 相似文献
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AR Jones BSC AJP Sandison FRCS WJ Owen MS FRCS 《International journal of clinical practice》1997,51(5):294-295
Pre-clerking of all patients undergoing elective general surgical operations was introduced at our hospital in an attempt to reduce an unacceptably high operation cancellation rate. A prospective audit has been performed on the effect of this policy on the cancellation rate. Before the introduction of pre-clerking there was a marked seasonal variation in the number of patients who failed to attend for surgery, which could be explained by absence on holiday. This seasonal variation disappeared after the start of pre-clerking clinics, but there has been no reduction in the number of cancellations for medical reasons. 相似文献
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In this study, we have examined the effects of metamizol (dipyrone), a non-opioid analgesic which is effective in relieving renal colic pain, on nociceptive responses evoked by stimulation of the ureter, on pyeloureteral motility and on intraureter pressure after ureter obstruction in anaesthetised rats. Metamizol (5–50 mg/kg i.v.) dose-dependently inhibited reflex pressor responses evoked by distensions of the ureter to pressures of 30, 55 and 75 mmHg for 30 s (ID50=8±1 mg/kg). Metamizol also dose-dependently reduced intraureter pressure during total ureter occlusion (25 mg/kg produced a reduction of 25% in 10 min). However, metamizol at doses up to 50 mg/kg had no effect on pyleoureteric motility (contraction amplitude, rate or intraureter pressure) under normal pressure conditions. We conclude that metamizol has a direct antinociceptive action on pain of ureteric origin, and spasmolytic effects after ureter obstruction (but not under normal conditions) which may also contribute to pain relief.accepted by K. Brune 相似文献