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Human carboxylesterase 1 (hCES1), encoded by the CES1 gene, is the predominant hepatic hydrolase responsible for the metabolism of many therapeutic agents, toxins, and endogenous substances. Genetic variants of CES1 can affect hCES1 function and expression and ultimately influence clinical response to drugs serving as hCES1 substrates. The CES1 gene consists of three isoforms including the functional CES1A1 and CES1A2 genes and the nonfunctional pseudogene CES1A3. Natural variants of these isoforms exert differing impacts on hCES1 function. However, the existing CES1 genotyping methods are incapable of determining whether these variants belong to CES1A1, CES1A2, or CES1A3 because of the high similarity among these three genes, as a consequence they are unable to discriminate between heterozygotes and homozygotes. We report the development of a novel long-range PCR-based, discriminative genotyping assay capable of specifically detecting the variants among CES1A1, CES1A2, and CES1A3 genes. The comparison of the genotyping results between this novel assay and those previously reported methods highlighted the necessity of applying the discriminative genotyping assay in pharmacogenetic studies involving CES1 gene. 相似文献
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The objective of this paper is to describe the patterns and associated behaviours related to alcohol consumption among a selected sample of pregnant women seeking prenatal care in inner city Washington DC. Women receiving prenatal care at one of nine sites completed an anonymous alcohol-screening questionnaire. Questions concerned the amount, type and pattern of alcohol consumption. Women were categorised as at no, low, moderate or high risk for alcohol consumption during pregnancy. For comparisons of risk levels of drinking, bivariate associations were examined using Fisher's exact test. Odds ratios (ORs) and 95% confidence intervals (CIs) were also computed. Although 31% of current/recent drinkers stated that they continued to drink during pregnancy, responses to quantity/frequency questions revealed that 42% continued to do so. Women who were at high compared with moderate risk acknowledged that others were worried about their consumption [OR=4.0, 95% CI 1.5, 10.6], that they drank upon rising [OR=6.7, 95% CI 1.8, 26.9], had a need to reduce drinking [OR=3.2, 95% CI 1.3, 8.1] and in the past 5 years had had fractures [OR=4.2, 95% CI 1.0, 17.8] or a road traffic injury [OR=3.4, 95% CI 1.0, 12.2]. Women in the high/moderate compared with low-risk group were more likely to have been injured in a fight or assault [OR=2.7, 95% CI 1.3, 5.6]. This study validated the usefulness of our questionnaire in identifying women who were at risk for alcohol consumption during pregnancy across a range of consumption levels. Using our screening tool, women were willing to disclose their drinking habits. This low-cost method identifies women appropriate for targeting of interventions. 相似文献
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Brinda S. Desai Julie A. Schneider Jia-Liang Li Paul M. Carvey Bill Hendey 《Journal of neural transmission (Vienna, Austria : 1996)》2009,116(5):587-597
Alterations in the blood brain barrier and brain vasculature may be involved in neurodegeneration and neuroinflammation. We
sought to determine if vascular remodeling characterized by angiogenic vessels or increased vascular density, occurred in
pathologically confirmed Alzheimer’s disease (AD) postmortem human brain tissues. We examined brains of deceased, older catholic
clergy from the Religious Order Study, a longitudinal clinical–pathological study of aging and AD. The hippocampus, midfrontal
cortex, substantia nigra, globus pallidus and locus ceruleus were examined for integrin αvβ3 immunoreactivity, a marker of
angiogenesis, and vascular densities. Activated microglia cell counts were also performed. All areas except the globus pallidus
exhibited elevated αvβ3 immunoreactivity in AD cases compared with controls. Only in the hippocampus did the ongoing angiogenesis
result in increased vascular density compared with controls. Vascular density was correlated with Aβ load in the hippocampus
and αvβ3 reactivity was correlated with neurofibrillary tangles in the midfrontal cortex and in the substantia nigra. These
data indicate that ongoing angiogenesis is present in brain regions affected by AD pathology and may be related to tissue
injury. 相似文献
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Ravikumar B Sarkar S Davies JE Futter M Garcia-Arencibia M Green-Thompson ZW Jimenez-Sanchez M Korolchuk VI Lichtenberg M Luo S Massey DC Menzies FM Moreau K Narayanan U Renna M Siddiqi FH Underwood BR Winslow AR Rubinsztein DC 《Physiological reviews》2010,90(4):1383-1435
(Macro)autophagy is a bulk degradation process that mediates the clearance of long-lived proteins and organelles. Autophagy is initiated by double-membraned structures, which engulf portions of cytoplasm. The resulting autophagosomes ultimately fuse with lysosomes, where their contents are degraded. Although the term autophagy was first used in 1963, the field has witnessed dramatic growth in the last 5 years, partly as a consequence of the discovery of key components of its cellular machinery. In this review we focus on mammalian autophagy, and we give an overview of the understanding of its machinery and the signaling cascades that regulate it. As recent studies have also shown that autophagy is critical in a range of normal human physiological processes, and defective autophagy is associated with diverse diseases, including neurodegeneration, lysosomal storage diseases, cancers, and Crohn's disease, we discuss the roles of autophagy in health and disease, while trying to critically evaluate if the coincidence between autophagy and these conditions is causal or an epiphenomenon. Finally, we consider the possibility of autophagy upregulation as a therapeutic approach for various conditions. 相似文献
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B S Levy R E Fontaine C A Smith J Brinda G Hirman D B Nelson P M Johnson O Larson 《JAMA》1975,234(3):289-294
In Minneapolis, 107 cases of hepatitis A were identified and traced primarily to consumption of cold sandwiches served for lunch in a department store's popular basement restaurant. A sandwich-maker in the restaurant was the index patient. The date of onset of her illness and the dates of food consumption and onset of illness of infrequent restaurant patrons were consistent with accepted periods of infectivity and incubation for hepatitis A. Because the sandwich-maker frequently touched her hands to her mouth when she worked, and because we could not find evidence for fecal, airborne, or other modes of transmission, we believe that she may have contaminated food with infectious oropharyngeal secretions. The secondary attack rate was much lower among household contacts who received immune serum globulin than among those who had not. 相似文献