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91.
Huang Z Dias R Jones T Liu S Styhler A Claveau D Otu F Ng K Laliberte F Zhang L Goetghebeur P Abraham WM Macdonald D Dubé D Gallant M Lacombe P Girard Y Young RN Turner MJ Nicholson DW Mancini JA 《Biochemical pharmacology》2007,73(12):1971-1981
Type 4 phosphodiesterases (PDE4) inhibitors are emerging therapeutics in the treatment of a number of chronic disorders including asthma, chronic obstructive pulmonary disease (COPD) and cognitive disorders. This study delineates the preclinical profile of L-454,560, which is a potent, competitive and preferential inhibitor of PDE4A, 4B, and 4D with IC50 values of 1.6, 0.5 and 1.2 nM, respectively. In contrast to the exclusive binding of cilomilast and the preferential binding of roflumilast to the PDE4 holoenzyme state (Mg2+-bound form), L-454,560 binds to both the apo-(Mg2+-free) and holoenzyme states of PDE4. The intrinsic enzyme potency for PDE4 inhibition by L-454,560 also results in an effective blockade of LPS-induced TNFalpha formation in whole blood (IC50 = 161 nM) and is comparable to the human whole blood potency of roflumilast. The cytokine profile of inhibition of L-454,560 is mainly a Th1 profile with significant inhibition of IFNgamma and no detectable inhibition of IL-13 formation up to 1 microM. L-454,560 was also found to be efficacious in two models of airway hyper-reactivity, the ovalbumin (OVA) sensitized and challenged guinea pig and the ascaris sensitized sheep model. Furthermore, L-454560 was also effective in improving performance in the delayed matching to position (DMTP) version of the Morris watermaze, at a dose removed from that associated with potential emesis. Therefore, L-454,560 is a novel PDE4 inhibitor with an overall in vivo efficacy profile at least comparable to roflumilast and clearly superior to cilomilast. 相似文献
93.
Luke Nicholson Clara Vazquez-Alfageme Piyali Sen Namritha V. Patrao Tunde Peto Yit Yang Sobha Sivaprasad Philip G. Hykin 《Eye (London, England)》2022,36(5):1086
AimsTo report, using ultra-widefield angiography (UWFA) the area, distribution, and change in retinal capillary nonperfusion (RCNP) at baseline and 100 weeks in eyes with central retinal vein occlusion (CRVO) receiving anti-VEGF for macula oedema.MethodsProspective longitudinal multi-centre cohort study. Adults with CRVO treated with anti-VEGF therapy for macular oedema underwent UWFA at baseline and week-100. The area, distribution, and change in total, peripheral and posterior pole RCNP were determined.ResultsOf 153 eyes at baseline, mean area of RCNP was 34.3DA and 12 (7.8%) had ≥75DA RCNP. More than 10DA RCNP was present in the temporal periphery in 75.8% of eyes vs. 10.5% in the nasal periphery. At week-100, mean RCNP was 42.1DA with a median change from baseline of 3.3DA 95% CI [0.4, 7.3]; p < 0.01. Of 146 eyes with ≤10DA of posterior pole RCNP at baseline, 16/146 (11.0%) progressed to >10DA at week-100. These eyes had a median increase in total RCNP of 69.7DA [95% CI 27.2–85.4] vs 0DA [0.0–1.4]; p < 0.001 for those who did not, and two developed neovascular glaucoma. Larger baseline area of RCNP and history of glaucoma were risk factors for posterior pole RCNP developing.ConclusionsWith UWFA, significant baseline RCNP was identified in the majority of CRVO patients, notably in the temporal periphery, but large increases over 100 weeks were uncommon. Development of >10DA posterior pole RCNP is a marker for widespread RCNP and in such cases the risk of anterior segment neovascularisation is not abolished by concomitant anti-VEGF therapy.Subject terms: Retinal diseases, Vision disorders 相似文献
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E. M. Lenz J. C. Lindon J. K. Nicholson J. M. Weeks D. Osborn 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(6):535-546
1. The metabolic fate of the model ecotoxin 3-trifluoromethylaniline (3-TFMA) in earthworm was studied by 19 F- and directly coupled 19 F/ 1 H-HPLC-NMR spectroscopy. Earthworms of Eisenia veneta spp. were subjected to the ecotoxin during a filter papercontact toxicity test at exposure levels of 1000, 100, 10, 1 and 0.1 µg cm -2. A metabolic profile was obtained previously by 19 F-NMR spectroscopy and metabolites were observed at all the exposure levels. 2. Identification of metabolites in individual worm extracts at the (lethal) exposure levels of 1000 and 100 µg cm -2 could be achieved on-line without sample preparation by 19 F/ 1 H-HPLC-NMR spectroscopy. 19 F-HPLC-NMR spectroscopy was used in the continuous-flow mode, which enabled the HPLC chromatographic retention times (t R) of the metabolites to be established in a single analytical step. 3. In total, three 19 F-NMR signals could be detected, of which one was identified as the parent compound. Two earlier eluting metabolites were identified to be α - and β -glucoside conjugates of 3-TFMA. 4. Metabolites at the lower (sublethal) exposure levels of 10, 1 and 0.1 µg cm -2 escaped identification by 19 F/ 1 H-HPLC-NMR spectroscopy as outlined here and will require concentration prior to analysis. 相似文献
99.
H. Major J. Castro-Perez J. K. Nicholson I. D. Wilson 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(8):855-869
1. The metabolic fate of 4-bromoaniline (4-BrA) was investigated in rat following intraperitoneal administration at 50?mg kg ? 1 using HPLC-TOF-MS/MS. 2. The sensitivity provided by the use of TOF-MS/MS, aided by the distinctive isotope pattern resulting from the presence of the bromine substituent in the molecule, enabled the detection of many previously uncharacterized metabolites in the samples. 3. Several groups of minor metabolites were detected in the urine that corresponded to a number of isomeric hexose and di-hexose-containing conjugates (possibly glucosides and diglucosides) of 4-BrA. 4. As well as hexose and di-hexose conjugates of 4-BrA, several further groups of metabolites that also contained either a sulphamate or sulphate group in addition to the sugar moieties were also detected. 相似文献
100.
Travis WD Hunninghake G King TE Lynch DA Colby TV Galvin JR Brown KK Chung MP Cordier JF du Bois RM Flaherty KR Franks TJ Hansell DM Hartman TE Kazerooni EA Kim DS Kitaichi M Koyama T Martinez FJ Nagai S Midthun DE Müller NL Nicholson AG Raghu G Selman M Wells A 《American journal of respiratory and critical care medicine》2008,177(12):1338-1347