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71.
Theodore A Slotkin Frederic J Seidler Dan Qiao Justin E Aldridge Charlotte A Tate Mandy M Cousins Becky J Proskocil Harmanjatinder S Sekhon Jennifer A Clark Stacie L Lupo Eliot R Spindel 《Neuropsychopharmacology》2005,30(1):129-144
Studies in developing rodents indicate that nicotine is a neuroteratogen that disrupts brain development by stimulating nicotinic acetylcholine receptors (nAChRs) that control neural cell replication and differentiation. We administered nicotine to pregnant Rhesus monkeys from gestational day 30 through 160 by continuous infusion, achieving maternal plasma levels comparable to those in smokers (30 ng/ml). Fetal brain regions and peripheral tissues were examined for nAChR subtypes, other neurotransmitter receptors, and indices of cell signaling and cell damage. Nicotine evoked nAChR upregulation, but with distinct regional disparities indicative of selective stimulatory responses. Similarly, indices of cell loss (reduced DNA), cell size and neuritic outgrowth (protein/DNA and membrane/total protein ratios) were distinct for each region and did not necessarily follow the rank order of nAChR upregulation, suggesting the involvement of additional mechanisms such as oxidative stress. We then attempted to offset the adverse effects of nicotine with standard dietary supplements known to interact with nicotine. By itself, choline elicited nicotine-like actions commensurate with its promotion of cholinergic neurotransmission. When given in combination with nicotine, choline protected some regions from damage but worsened nicotine's effects in other regions. Similarly, Vitamin C supplementation had mixed effects, increasing nAChR responses while providing protection from cell damage in the caudate, the brain region most susceptible to oxidative stress. Our results indicate that nicotine elicits neurodevelopmental damage that is highly selective for different brain regions, and that dietary supplements ordinarily thought to be neuroprotectant may actually worsen some of the adverse effects of nicotine on the fetal brain. 相似文献
72.
In-depth studies on the intra-organismal distribution of toxin may yield valuable clues about potential ecological functions. The distribution of tetrodotoxin (TTX) in previously unexamined tissues of two species of blue-ringed octopuses, wild-caught Hapalochlaena fasciata and Hapalochlaena lunulata from the aquarium industry, was surveyed. Tissues from each individual were examined separately. Tetrodotoxin was detected in posterior salivary gland (PSG), arm, mantle, anterior salivary glands, digestive gland, testes contents, brachial heart, nephridia, gill, and oviducal gland of H. fasciata. By contrast TTX was found only in the PSG, mantle tissue, and ink of H. lunulata. The highest concentrations of TTX resided in the PSG of both species; however, the arms and mantle contained the greatest absolute amounts of TTX. Minimum total amounts of TTX per octopus ranged from 60 to 405 μg in H. fasciata and from 0 to 174 μg in H. lunulata and correlated well with the amounts in the PSG. Transport of TTX in the blood is loosely suggested by the presence of the toxin in blood-rich organs such as the gill and brachial hearts. The distributional data also suggest both offensive and defensive functions of TTX. 相似文献
73.
Alice N Neely Ronald T Plessinger Becky Stamper Richard J Kagan 《Journal of burn care & research》2008,29(1):73-76
Cultures of allograft sites on burn patients occasionally show microbes that were not previously cultured from that patient. Our purpose was to determine 1) if microbes on allograft sites could have been transferred to the burn patient from the allograft donor and 2) if microbial transfer is different if the allograft was fresh or frozen. All allografts were cultured by the skin bank after recovery (pre-antimicrobial) and after the skin had been in an antimicrobial solution (post-antimicrobial). These culture results were compared with the results of cultures taken at the hospital from the allograft sites of burn patients. All allograft recipients at the burn hospital during 2005 were included in this Institutional Review Board approved study. Sixty-one donors provided 143 allografts for 38 patients. From the 61 donors, 114 precultures were taken; 19.5% were positive for at least one organism. Only 6.8% of 118 post-antimicrobial cultures were positive. Of the 143 allografts on burn patients, 111 were used fresh and 32 had been cryopreserved. During dressing changes, 124 cultures were taken from sites that received fresh allograft and 27 from sites that received frozen; 54.8% of cultures from fresh allograft sites and 41.5% from frozen sites (not significant, chi) were positive for microbes, which were mostly the patient's own flora. None of the microbes isolated from the burn patient allograft sites matched organisms on the pre- or post-antimicrobial cultures from the donor allografts. Regardless of whether the allografts were fresh or frozen, no instances were identified in which donor microorganisms were transferred from a donor to a recipient. 相似文献
74.
75.
Preparation and antitubercular activities in vitro and in vivo of novel Schiff bases of isoniazid 总被引:1,自引:0,他引:1
Michael J. Hearn Michael H. Cynamon Michaeline F. Chen Rebecca Coppins Jessica Davis Helen Joo-On Kang Abigail Noble Becky Tu-Sekine Marianne S. Terrot Daniella Trombino Minh Thai Eleanor R. Webster Rebecca Wilson 《European journal of medicinal chemistry》2009,44(10):4169-4178
Structural modification of the frontline antitubercular isonicotinic acid hydrazide (INH) provides lipophilic adaptations (3–46) of the drug in which the hydrazine moiety of the parent compound has been chemically blocked from the deactivating process of N2-acetylation by N-arylaminoacetyl transferases. As a class, these compounds show high levels of activity against Mycobacterium tuberculosis in vitro and in tuberculosis-infected macrophages. They provide strong protection in tuberculosis-infected mice and have low toxicity. With some representatives of this class achieving early peak plasma concentrations approximately three orders of magnitude above minimum inhibitory concentration, they may serve as tools for improving our understanding of INH-based treatment modalities, particularly for those patients chronically underdosed in conventional INH therapy. 相似文献
76.
77.
Dorner B 《Director (Cincinnati, Ohio)》2002,10(3):107-110
Have you ever swallowed a food or liquid only to have it "go down the wrong way"? If you have, then you have an idea of what it might be like to have a swallowing problem. Now multiply that experience times the more than 600 times a day that we normally swallow! Imagine how difficult it would be to deal with that on a daily basis. Approximately 6-15 million Americans are affected by dysplagia (chewing and swallowing problems). About 53-74% of nursing home residents, 14% of hospital patients and 33% of rehabilitation center patients have some form of dysphagia, which can have a dramatic impact on nutritional status. 相似文献
78.
Hartkoorn RC Chandler B Owen A Ward SA Bertel Squire S Back DJ Khoo SH 《Tuberculosis (Edinburgh, Scotland)》2007,87(3):248-255
If tuberculosis therapy is to be shortened it is imperative that the sterilising activity of current and future anti-tuberculosis drugs is enhanced. Intracellular Mycobacterium tuberculosis (MTB) phagocytosed by macrophages may be a key subpopulation of bacteria that are less readily eliminated by therapy. Here we investigate whether macrophages provide MTB with a pharmacological sanctuary site, making them less susceptible to chemotherapy than extracellular bacilli. Intracellular drug activity was determined by a novel colorimetric method that measures the ability of a drug to protect A-THP1 cells from infection-mediated cell death by H37Rv. Extracellular bactericidal activity was determined by the microplate alamar blue assay (MABA). Further, the effect of P-glycoprotein (P-gp) expressed on macrophages on the intracellular kill of H37Rv was assessed. To screen the anti-tuberculosis drugs for P-gp substrate specificity, their toxicity and cellular accumulation were determined in CEM and CEM(VBL100) cells. Intracellular and extracellular anti-tuberculosis drug activity following 7-day treatment with isoniazid (mean EC(50)+/-SD: 36.7+/-2.2 and 57.2+/-2.5 ng/mL, respectively) and ethambutol (243+/-95 and 263+/-12 ng/mL, respectively) were similar. However, for rifampicin a higher concentration was required to kill intracellular (148+/-32 ng/mL) versus extracellular (1.27+/-0.02 ng/mL) bacilli. The P-gp inhibitor tariquidar, significantly increased intracellular kill of H37Rv by ethambutol and rifampicin and both of these drugs were shown to be substrates for P-gp using the P-gp overexpressing CEM(VBL100) cells. We observed a large discrepancy between intracellular and extracellular activity of rifampicin (but not with isoniazid or ethambutol). Several factors could have accounted for this including inoculum size, media and cell-mediated metabolism. These factors make the comparison of intracellular and extracellular drug activity complex. However, the intracellular assay described here has potential for studying the impact of host proteins (such as drug transporters) on the intracellular activity of drugs, and has been used successfully here to demonstrate that both rifampicin and ethambutol are substrates for P-gp. 相似文献
79.
Yang C Feng J Song W Wang J Tsai B Zhang Y Scaringe WA Hill KA Margaritis P High KA Sommer SS 《Proceedings of the National Academy of Sciences of the United States of America》2007,104(39):15394-15399
Aminoglycosides can bypass nonsense mutations and are the prototypic agents for translational bypass therapy (TBT). Initial results demonstrate the need for more potent drugs and an in vivo model system for quantitative assessment of TBT. Herein, we present an in vivo system for evaluating the efficacy of premature stop codon management therapies: in vivo quantitative stop codon management repli-sampling TBT efficacy assay (IQSCMaRTEA). Application of IQSCMaRTEA reveals that geneticin is much more efficacious in vivo than gentamicin. Treatment with geneticin elicits a multiday response, and residual F9 antigen can be detected after 3 weeks. These data demonstrate the utility of IQSCMaRTEA for evaluating drugs that bypass nonsense mutations. In addition, IQSCMaRTEA may be helpful for testing inhibitors of nonsense-mediated decay, as stop codon management therapy will sometimes require inhibition of nonsense-mediated decay and translational bypass of the nonsense mutation. Furthermore, geneticin, its metabolites, or better tolerated analogues should be evaluated as a general treatment with multiday response for severe genetic disease caused by nonsense mutation. 相似文献
80.