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1.
D J Thomas A Sadler V V Subrahmanyam D Siegel M J Reasor D Wierda D Ross 《Molecular pharmacology》1990,37(2):255-262
Bone marrow stroma consists predominately of two cell types, macrophages and fibroblastoid stromal cells, which regulate the growth and differentiation of myelopoietic cells via the production of growth factors. We have previously shown that macrophages are more sensitive than fibroblastoid stromal cells (LTF cells) to the toxic effects of the benzene metabolite hydroquinone. In this study, the role of selective bioactivation and/or deactivation in the macrophage-selective effects of hydroquinone was examined. LTF and macrophage cultures were incubated with 10 microM [14C]hydroquinone to examine differential bioactivation. After 24 hr, the amount of 14C covalently bound to acid-insoluble macromolecules was determined. Macrophages had 16-fold higher levels of macromolecule-associated 14C than did LTF cells. Additional experiments revealed that hydroquinone bioactivation to covalent-binding species was hydrogen peroxide dependent in macrophage homogenates. Covalent binding in companion LTF homogenates was minimal, even in the presence of excess hydrogen peroxide. These data suggest that a peroxidative event was responsible for bioactivation in macrophages and, in agreement with this, macrophages contained detectable peroxidase activity whereas LTF cells did not. Bioactivation of [14C]hydroquinone to protein-binding species by peroxidase was confirmed utilizing purified human myeloperoxidase in the presence of hydrogen peroxide and ovalbumin as a protein source. High performance liquid chromatographic analysis of incubations containing purified myeloperoxidase, hydroquinone, and hydrogen peroxide showed that greater than 90% of hydroquinone was removed and could be detected stoichometrically as 1,4-benzoquinone. 1,4-Benzoquinone was confirmed as a reactive metabolite formed from hydroquinone in macrophage incubations using excess GSH and trapping the reactive quinone as its GSH conjugate, which was measured by high performance liquid chromatography with electrochemical detection. The activity of DT-diaphorase, a quinone reductase that has been invoked as a protective mechanism in quinone-induced toxicity, was 4-fold higher in LTF cells than macrophages. These data suggest that the macrophage-selective toxicity of hydroquinone results from higher levels of peroxidase-mediated bioactivation and/or lower levels of DT-diaphorase-mediated detoxification. 相似文献
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3.
D Subrahmanyam K Mehta D S Nelson Y V Rao C K Rao 《Journal of clinical microbiology》1978,8(2):228-232
Sera from cases of elephantiasis due to Wuchereria bancrofti infection promoted an intense adhesion of peripheral blood leukocytes to W. bancrofti microfilariae in vitro. A similar adhesion was also seen using sera from some normal persons living for several years in areas where filariasis is endemic. No such adhesion was evident with sera from microfilaria carriers or from normal subjects from nonendemic areas. The adhesion was complement independent and was associated with the immunoglobulin G fraction of serum. 51Cr release studies suggested the occurrence of cell-mediated cytotoxicity to W. bancrofti microfilariae in the presence of elephantiasis serum. Microfilariae of Litomosoides carinii could be isolated free of blood cells, from the blood of infected rats. In the presence of serum, or its immunoglobulin G fraction, from patients with elephantiasis, L. carinii microfilariae adhered to human peripheral blood leukocytes or rat spleen cells. 相似文献
4.
Kailash Prasad M.D. Ph.D. F.I.C.A. Subrahmanyam V. Mantha Ph.D. Jawahar Kalra M.D. Ph.D. F.I.C.A. Paul Lee M.Sc. 《The International journal of angiology》1997,6(1):13-17
Oxygen-free radicals have been implicated in hypercholesteolemic atherosclerosis. It is possible that hypercholesterolemia produces oxidative stress in myocardium. We therefore investigated the effects of a high cholesterol diet in the absence or presence of vitamin E on serum cholesterol and lipid peroxidation product malondialdehyde (MDA), chemiluminescence (M-CL), a measure of antioxidant reserve, and activity of antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px)] in cardiac muscles of rabbits. Rabbits were divided into four groups: Group I, regular rabbit chow diet; Group II, same as Group I + vitamin E; Group III, high cholesterol diet; Group IV, high cholesterol + vitamin E. The heart was removed under anesthesia at the end of 4 months on their respective diets for various biochemical measurements. Serum cholesterol in Groups III and IV increased to a similar extent. There was an increase in the levels of MDA, M-CL, GSH-Px activity and a decrease in SOD activity in hypercholesterolemic rabbits in the absence of vitamin E. Vitamin E prevented the hypercholesterolemia-induced changes in cardiac MDA, M-CL, and GSH-Px. These results suggest that hypercholesterolemia produces oxidative stress in the myocardium which may be due to a decrease in the antioxidant reserve, and that vitamin E is effective in preventing hypercholesterolemia-induced oxidative stress on the myocardium. 相似文献
5.
Subrahmanyam YV Yamaga S Prashar Y Lee HH Hoe NP Kluger Y Gerstein M Goguen JD Newburger PE Weissman SM 《Blood》2001,97(8):2457-2468
A comprehensive study of changes in messenger RNA (mRNA) levels in human neutrophils following exposure to bacteria is described. Within 2 hours there are dramatic changes in the levels of several hundred mRNAs including those for a variety of cytokines, receptors, apoptosis-regulating products, and membrane trafficking regulators. In addition, there are a large number of up-regulated mRNAs that appear to represent a common core of activation response genes that have been identified as early-response products to a variety of stimuli in a number of other cell types. The activation response of neutrophils to nonpathogenic bacteria is greatly altered by exposure to Yersinia pestis, which may be a major factor contributing to the virulence and rapid progression of plague. Several gene clusters were created based on the patterns of gene induction caused by different bacteria. These clusters were consistent with those found by a principal components analysis. A number of the changes could be interpreted in terms of neutrophil physiology and the known functions of the genes. These findings indicate that active regulation of gene expression plays a major role in the neutrophil contribution to the cellular inflammatory response. Interruption of these changes by pathogens, such as Y pestis, could be responsible, at least in part, for the failure to contain infections by highly virulent organisms. 相似文献
6.
Glucose and fat metabolism in adipose tissue of acetyl-CoA carboxylase 2 knockout mice 总被引:3,自引:0,他引:3 下载免费PDF全文
Oh W Abu-Elheiga L Kordari P Gu Z Shaikenov T Chirala SS Wakil SJ 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(5):1384-1389
Acc2-/- mutant mice, when fed a high-fat/high-carbohydrate (HF/HC) diet, were protected against diet-induced obesity and diabetes. To investigate the role of acetyl-CoA carboxylase 2 (ACC2) in the regulation of energy metabolism in adipose tissues, we studied fatty acid and glucose oxidation in primary cultures of adipocytes isolated from wild-type and Acc2-/- mutant mice fed either normal chow or a HF/HC diet. When fed normal chow, oxidation of [14C]palmitate in adipocytes of Acc2-/- mutant mice was approximately 80% higher than in adipocytes of WT mice, and it remained significantly higher in the presence of insulin. Interestingly, in addition to increased fatty acid oxidation, we also observed increased glucose oxidation in adipocytes of Acc2-/- mutant mice compared with that of WT mice. When fed a HF/HC diet for 4-5 months, adipocytes of Acc2-/- mutant mice maintained a 25% higher palmitate oxidation and a 2-fold higher glucose oxidation than WT mice. The mRNA level of glucose transporter 4 (GLUT4) decreased several fold in the adipose tissue of WT mice fed a HF/HC diet; however, in the adipose tissue of Acc2-/- mutant mice, it was 7-fold higher. Moreover, lipolysis activity was higher in adipocytes of Acc2-/- mutant mice compared with that in WT mice. These findings suggest that continuous fatty acid oxidation in the adipocytes of Acc2-/- mutant mice, combined with a higher level of glucose oxidation and a higher rate of lipolysis, are major factors leading to efficient maintenance of insulin sensitivity and leaner Acc2-/- mutant mice. 相似文献
7.
Either a single oral dose of 1,1,1-trichloro-2,2-bis-(p-chlorophenyl) ethane (DDT), 150 mg/kg body weight or a long-term chronic dose of the pesticide, 10 mg/kg body weight daily for 100 days was administered to rhesus monkeys and the level of various lipid classes was studied in the brain. A significant decrease was observed in total lipid, unesterified cholesterol and phospholipid (PL) level. Individual PL fractions showed a generalized pattern of reduction, so also did the cholesterol (chol)/PL ratio. Sphingomyelin (SM) registered a significant increase, while no significant alteration was observed in the brain galactolipid and ganglioside level. Lipid lowering effect of DDT was more pronounced in the chronic group. Lipids associated with the myelin sheath were found to be more resistant to pesticide injury, while cholesterol and PL metabolism were more affected. 相似文献
8.
Howard A. Werman Subrahmanyam Darbha Michael Cudnik Jeffrey Caterino 《Prehospital emergency care》2017,21(4):461-465
Introduction: A recent analysis of the National Sample Project demonstrated that the mortality benefits of air medical transport do not extend to patients age 55 or older. The purpose of the current investigation was to evaluate mortality benefits of air transport in adult trauma patients ≥ 55 years of age. Methods: A retrospective analysis of all adult patients greater than age 55 years directly transported from a trauma scene to a Level I or II facility was conducted. The primary outcome variable was in-hospital mortality. Using the imputed dataset we then performed multivariable logistic regression with mortality as the dependent variable to determine if mode of transport had a significant impact on mortality for patients older than 55 years of age. Results: There were 7,739 (90.9%) patients transported by ground and 682 (9.1%) transported by air in our dataset. There were 3,556 between the ages of 55 to 69 years and an additional 4865 over the age of 69 years. In the multivariable model of all patients ≥ 55, air transport was associated with lower mortality (adjusted odds ratio [aOR] = 0.60; 95% confidence interval [CI] = 0.39--0.91; p = 0.017) when compared to those transported by ground. Conclusion: Our study was able to demonstrate a survival benefit for the cohort of patients age greater than 55 years of age. 相似文献
9.
Metabolism of a novel phosphodiesterase-IV inhibitor (V11294) by human hepatic cytochrome P450 forms
Subrahmanyam V Renwick AB Walters DG Price RJ Tonelli AP Lake BG 《Xenobiotica; the fate of foreign compounds in biological systems》2002,32(6):521-534
1. The metabolism of a novel phosphodiesterase-IV inhibitor (V11294) was studied in human liver microsomal and cytosol preparations and in cDNA-expressed human hepatic CYP forms. 2. Human liver microsomes, but not cytosol, catalysed the NADPH-dependent metabolism of V11294 to V10331 (formed by hydroxylation of the cyclopentyl ring), V10332 (N-desethyl V11294) and V11689 (formed by hydroxylation of the isopropyl side chain). In addition, smaller amounts of a secondary metabolite V11690 (which can be formed from either V10332 or V11689) were also produced. 3. Kinetic analysis of V11294 metabolism to V10331, V10332 and V11689 in two preparations of pooled human liver microsomes revealed average K(m) = 2.5, 8.1 and 3.9 micro M, respectively. 4. The metabolism of V11294 was determined with a characterized bank of 16 individual human liver microsomal preparations employing a V11294 substrate concentration of 8 micro M (i.e. approximately the K(m) for V10332 formation and around twice the K(m) for V10331 and V11689 formation). Good correlations (r(2) = 0.570-0.903) were observed between V10331, V10332 and V11689 formation and markers of CYP3A forms. In contrast, poorer correlations (r(2) = 0.0002-0.428) were observed with markers of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP4A9/11. 5. Using human B-lymphoblastoid cell microsomes containing cDNA-expressed CYP forms, V11294 (8 micro M) was metabolized by cDNA-expressed CYP3A4 to V10331, V10332 and V11689, with lower amounts of V11690 also being formed. Lower rates of V11294 metabolism to some V11294 metabolites were also observed with cDNA-expressed CYP2C9, CYP2C19 and CYP2D6, whereas only very low or undetectable rates of V11294 metabolism were observed with cDNA-expressed CYP1A2, CYP2A6, CYP2B6, CYP2C8 and CYP2E1. 6. The metabolism of V11294 (8 micro M) to V10331, V10332 and V11689 was markedly inhibited by the CYP3A mechanism-based inhibitor troleandomycin. In contrast, V11294 metabolism was not significantly affected by inhibitors of CYP1A2, CYP2C9, CYP2D6 and CYP2E1 or by the CYP2C19 substrate S-mephenytoin. 7. In summary, by correlation analysis, chemical inhibition studies and the use of cDNA-expressed CYPs, V11294 metabolism in human liver to V10331, V10332 and V11689 appears to be primarily catalysed by CYP3A forms. 相似文献
10.
Subrahmanyam K Kraut RE Greenfield PM Gross EF 《The Future of children / Center for the Future of Children, the David and Lucile Packard Foundation》2000,10(2):123-144
The increasing amount of time children are spending on computers at home and school has raised questions about how the use of computer technology may make a difference in their lives--from helping with homework to causing depression to encouraging violent behavior. This article provides an overview of the limited research on the effects of home computer use on children's physical, cognitive, and social development. Initial research suggests, for example, that access to computers increases the total amount of time children spend in front of a television or computer screen at the expense of other activities, thereby putting them at risk for obesity. At the same time, cognitive research suggests that playing computer games can be an important building block to computer literacy because it enhances children's ability to read and visualize images in three-dimensional space and track multiple images simultaneously. The limited evidence available also indicates that home computer use is linked to slightly better academic performance. The research findings are more mixed, however, regarding the effects on children's social development. Although little evidence indicates that the moderate use of computers to play games has a negative impact on children's friendships and family relationships, recent survey data show that increased use of the Internet may be linked to increases in loneliness and depression. Of most concern are the findings that playing violent computer games may increase aggressiveness and desensitize a child to suffering, and that the use of computers may blur a child's ability to distinguish real life from simulation. The authors conclude that more systematic research is needed in these areas to help parents and policymakers maximize the positive effects and to minimize the negative effects of home computers in children's lives. 相似文献