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71.
Walker NJ Yoshizawa K Miller RA Brix AE Sells DM Jokinen MP Wyde ME Easterling M Nyska A 《Toxicologic pathology》2007,35(7):880-889
Dioxin and dioxin-related compounds have been associated with high incidences of pulmonary dysfunctions and/or cancers in humans. To evaluate the relative potencies of effects of these compounds, the National Toxicology Program completed a series of two-year bioassays which were conducted using female Harlan Sprague-Dawley rats. The rats were treated orally for up to 2 years with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB126), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and a ternary mixture of TCDD, PCB126 and PeCDF. In addition to treatment-related effects reported in other organs, a variety of pulmonary lesions were observed that were related to exposure. Pulmonary CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity was increased in all dosed groups. The most common non-neoplastic lesions, which occurred in all studies, were bronchiolar metaplasia and squamous metaplasia of the alveolar epithelium. Cystic keratinizing epithelioma was the most commonly observed neoplasm which occurred in all studies. A low incidence of squamous cell carcinoma was associated only with PCB126 treatment. Potential mechanisms leading to altered differentiation and/or proliferation of bronchiolar and alveolar epithelia may be through CYP1A1 induction or disruption of retinoid metabolism. 相似文献
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74.
S Ashworth A Berges E A Rabiner A A Wilson R A Comley R Y K Lai R Boardley G Searle R N Gunn M Laruelle V J Cunningham 《British journal of pharmacology》2014,171(5):1241-1249
BACKGROUND AND PURPOSE
This study aimed to investigate the relationship between the plasma concentration (PK) of the novel histamine H3 receptor antagonist, GSK239512, and the brain occupancy of H3 receptors (RO) in healthy human volunteers.EXPERIMENTAL APPROACH
PET scans were obtained after i.v. administration of the H3-specific radioligand [11C]GSK189254. Each subject was scanned before and after single oral doses of GSK239512, at 4 and 24 h after dose. PET data were analysed by compartmental analysis, and regional RO estimates were obtained by graphical analysis of changes in the total volumes of distribution of the radioligand, followed by a correction for occupancy by the high affinity radioligand. The PK/RO relationship was analysed by a population-modelling approach, using the average PK of GSK239512 during each scan.KEY RESULTS
Following administration of GSK239512, there was a reduction in the brain uptake of [11C]GSK189254 in all regions, including cerebellum. RO at 4 h was higher than at 24 h, and the PK/RO model estimated a PK associated with 50% of RO of 0.0068 ng·mL−1. This corresponds to a free concentration of 4.50 × 10−12 M (pK = 11.3).CONCLUSIONS AND IMPLICATIONS
The affinity of GSK239512 for brain H3 receptors in humans in vivo is much higher than that expected from studies in vitro, and higher than that observed in PET studies in pigs. The study illustrates the utility of carrying out PET studies in humans early in drug development, providing accurate quantification of GSK239512 RO in vivo as a function of time and dose. 相似文献75.
Shah Virali Mignucci Alexandra Turshudzhyan Alla Yodice Michael Tadros Micheal 《Esophagus》2022,19(3):493-499
Esophagus - High-Resolution Manometry (HRM) with provocative maneuvers, such as Multiple Rapid Swallows (MRS) and Apple Viscous Swallows (AVS), is commonly utilized to diagnose esophageal... 相似文献
76.
Safi H Gormus BJ Didier PJ Blanchard JL Lakey DL Martin LN Murphey-Corb M Vankayalapati R Barnes PF 《AIDS research and human retroviruses》2003,19(7):585-595
To characterize the manifestations of coinfection with M. tuberculosis and SIV infection, we studied 12 SIV-infected rhesus monkeys, six of which were infected intrabronchially with a low dose of Mycobacterium tuberculosis H37Rv. In the six coinfected animals, M. tuberculosis antigen-stimulated lung and blood cells produced high concentrations of IFN-gamma but not IL-4 8-16 weeks after infection. Of the three coinfected animals with high levels of plasma viremia, two developed disseminated tuberculosis and the other died of bacterial peritonitis. Of three coinfected animals with moderate levels of plasma viremia, two had no clinical or radiographic evidence of tuberculosis or progressive SIV infection for 6 months after infection. At neuropsy, pulmonary granulomata were observed and acid-fast organisms or M. tuberculosis were present. These clinical, immunologic and pathologic findings are consistent with those in humans with latent tuberculosis infection (LTBI), and suggest that a model of LTBI in SIV-infected primates can be developed. Such a model will permit delineation of the immunologic and microbial factors that characterize LTBI in HIV-infected persons. 相似文献
77.
No association between apolipoprotein E or N‐Acetyltransferase 2 gene polymorphisms and age‐related hearing loss 下载免费PDF全文
78.
I R Phillips E A Shephard A Ashworth B R Rabin 《Proceedings of the National Academy of Sciences of the United States of America》1985,82(4):983-987
A previously reported cDNA clone [pP450(1)] coding for a phenobarbital-inducible cytochrome P-450 variant of rat liver microsomal membranes, designated P-450e(U.C.), was used as a specific hybridization probe to screen a human liver cDNA library. Restriction mapping showed that two of the colonies isolated contained plasmids coding for overlapping regions of the same cDNA sequence. The clone [pHP450(1)] having the longer cDNA insert (1.25 kilobase pairs) was sequenced. The homology between the rat and human cDNAs is 62% in their coding regions but is only random (24%) in the 3'-noncoding nucleotides. The amino acid sequence deduced from the human cDNA is 50% identical to that of P-450e(U.C.). The homology increases to 72% if conservative changes in amino acid residues are permitted. The hydropathy profile of the polypeptide encoded by pHP450(1) is almost identical to that of P-450e(U.C.). Regions known to be highly conserved in cytochrome P-450 isozymes isolated from rat, rabbit, and mouse were found to be conserved in the amino acid sequence derived from pHP450(1). Analysis by Southern blotting indicated that the human cytochrome P-450 encoded by pHP450(1) is part of a multigene family. 相似文献
79.
Duylinh Nguyen Severin Gose Lina Castro Kathleen Chung Kyle Bernstein Micheal Samuel Heidi Bauer Mark Pandori 《Emerging infectious diseases》2014,20(7):1211-1213
The spread of Neisseria gonorrhoeae strains with reduced susceptibility to extended-spectrum cephalosporins is an increasing public health threat. Using Etest and multiantigen sequence typing, we detected sequence type 1407, which is associated with reduced susceptibilities to extended-spectrum cephalosporins, in 4 major populated regions in California, USA, in 2012. 相似文献
80.
S Natesan S Ashworth J Nielsen S-P Tang C Salinas S Kealey J B Lauridsen T B Stensb?l R N Gunn E A Rabiner S Kapur 《Translational psychiatry》2014,4(4):e376
A number of phosphodiesterase 10A (PDE10) inhibitors are about to undergo clinical evaluation for their efficacy in treating schizophrenia. As phosphodiesterases are in the same signalling pathway as dopamine D2 receptors, it is possible that prior antipsychotic treatment could influence these enzyme systems in patients. Chronic, in contrast to acute, antipsychotic treatment has been reported to increase brain PDE10A levels in rodents. The aim of this study was to confirm these findings in a manner that can be translated to human imaging studies to understand its consequences. Positron emission tomography (PET) scanning was used to evaluate PDE10A enzyme availability, after chronic haloperidol administration, using a specific PDE10A ligand ([11C]MP-10). The binding of [11C]MP-10 in the striatum and the cerebellum was measured in rodents and a simplified reference tissue model (SRTM) with cerebellum as the reference region was used to determine the binding potential (BPND). In rats treated chronically with haloperidol (2 mg kg−1 per day), there was no significant difference in PDE10A levels compared with the vehicle-treated group (BPND±s.d.: 3.57±0.64 versus 2.86±0.71). Following PET scans, ex vivo analysis of striatal brain tissue for PDE10A mRNA (Pde10a) and PDE10A enzyme activity showed no significant difference. Similarly, the PDE10A protein content determined by western blot analysis was similar between the two groups, contrary to an earlier finding. The results of the study indicate that prior exposure to antipsychotic medication in rodents does not alter PDE10A levels. 相似文献