全文获取类型
收费全文 | 19086篇 |
免费 | 1274篇 |
国内免费 | 198篇 |
专业分类
耳鼻咽喉 | 240篇 |
儿科学 | 643篇 |
妇产科学 | 457篇 |
基础医学 | 2574篇 |
口腔科学 | 221篇 |
临床医学 | 1493篇 |
内科学 | 3541篇 |
皮肤病学 | 335篇 |
神经病学 | 1395篇 |
特种医学 | 623篇 |
外国民族医学 | 1篇 |
外科学 | 2429篇 |
综合类 | 480篇 |
一般理论 | 23篇 |
预防医学 | 2960篇 |
眼科学 | 606篇 |
药学 | 1121篇 |
2篇 | |
中国医学 | 135篇 |
肿瘤学 | 1279篇 |
出版年
2024年 | 23篇 |
2023年 | 169篇 |
2022年 | 285篇 |
2021年 | 618篇 |
2020年 | 284篇 |
2019年 | 517篇 |
2018年 | 626篇 |
2017年 | 441篇 |
2016年 | 469篇 |
2015年 | 546篇 |
2014年 | 737篇 |
2013年 | 1030篇 |
2012年 | 1494篇 |
2011年 | 1536篇 |
2010年 | 916篇 |
2009年 | 720篇 |
2008年 | 1118篇 |
2007年 | 1204篇 |
2006年 | 1133篇 |
2005年 | 962篇 |
2004年 | 895篇 |
2003年 | 846篇 |
2002年 | 723篇 |
2001年 | 372篇 |
2000年 | 324篇 |
1999年 | 270篇 |
1998年 | 105篇 |
1997年 | 104篇 |
1996年 | 78篇 |
1995年 | 74篇 |
1994年 | 72篇 |
1993年 | 49篇 |
1992年 | 163篇 |
1991年 | 146篇 |
1990年 | 167篇 |
1989年 | 180篇 |
1988年 | 146篇 |
1987年 | 150篇 |
1986年 | 119篇 |
1985年 | 110篇 |
1984年 | 77篇 |
1983年 | 62篇 |
1982年 | 26篇 |
1981年 | 31篇 |
1980年 | 28篇 |
1979年 | 46篇 |
1978年 | 23篇 |
1975年 | 35篇 |
1973年 | 25篇 |
1972年 | 27篇 |
排序方式: 共有10000条查询结果,搜索用时 765 毫秒
991.
Characterization of the anti-HIV effects of native lactoferrin and other milk proteins and protein-derived peptides 总被引:8,自引:0,他引:8
Berkhout B van Wamel JL Beljaars L Meijer DK Visser S Floris R 《Antiviral research》2002,55(2):341-355
In a search for natural proteins with anti-HIV activity, we screened a large set of purified proteins from bovine milk and peptide fragments thereof. Because several charged proteins and peptides are known to inhibit the process of virus entry, we selected proteins with an unusual charge composition or hydrophobicity profile. In contrast with some chemically modified (strongly negative) milk proteins, unmodified alpha(s2)-, beta- and kappa-casein, as well as several negatively and positively charged fragments thereof, did not show significant inhibition of virus replication. In fact, HIV-1 replication was elevated in the presence of beta-casein or amphiphilic fragments thereof. Bovine lactoferrin (bLF), a milk protein of 80 kDa, showed considerable inhibitory activity against HIV-1 with an IC50 of 0.4 microM. Modest inhibition was obtained with lactoferricin, a highly positively charged loop domain of bLF, indicating that other domains within the native bLF protein may also be required for inhibition. bLF blocked HIV-1 variants that use either the CXCR4 or the CCR5 coreceptor. In order to obtain further insight into the mechanism of action of this antiviral protein, we selected a bLF-resistant HIV-1 variant. The bLF-resistance phenotype is mediated by the viral envelope protein, which contains two interesting mutations that have previously been associated with an altered virus-host interaction and a modified receptor-coreceptor interaction. These results demonstrate that bLF targets the HIV-1 entry process. 相似文献
992.
Correlation between midazolam and lignocaine pharmacokinetics and MEGX formation in healthy volunteers
下载免费PDF全文
![点击此处可从《British journal of clinical pharmacology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Swart EL van der Hoven B Groeneveld AB Touw DJ Danhof M 《British journal of clinical pharmacology》2002,53(2):133-139
AIMS: The objectives of the present investigation were: (a) to determine the correlation between lignocaine and midazolam pharmacokinetics following intravenous administration in healthy volunteers, (b) to determine the effects of treatment with an inhibitor of CYP3A4 (erythromycin) on this correlation and (c) to assess the precision of the MEGX-test as a sole predictor of lignocaine and midazolam pharmacokinetics. METHODS: The study was conducted in four male and four female healthy volunteers, aged between 21 and 26 years, who received 1 mg kg-1 lignocaine HCl i.v. on days 1, 3, 5, 9 and 10 of the investigation. On days 5 and 10 they also received midazolam, 0.075 mg kg-1 i.v. and from days 6-10 they took erythromycin 500 mg orally, four times daily. Following administration of lignocaine and midazolam, frequent venous blood samples were obtained for determination of the concentrations of lignocaine, MEGX and midazolam. RESULTS: In the absence of erythromycin a statistically significant linear correlation was observed between the clearance of lignocaine and midazolam (CL(midazolam)= 0.41 x CL(lignocaine)+ 1.2; r(2) = 0.857; P < 0.001). Erythromycin cotreatment resulted in a loss of the correlation between the two clearances (r(2) = 0.39; P = 0.1). Erythromycin caused a statistically significant reduction in midazolam clearance from the original value of 3.8 to 2.5 (95% CI for the difference -2.27, -0.35) ml kg-1 min-1. Interestingly there was no significant change in the clearance of lignocaine (6.4 vs 5.8 (95% CI for the difference -2.74, -1.51) ml kg-1 min-1). Furthermore no correlation at all was observed between the MEGX-test and lignocaine or midazolam clearances. Considering the data on day 1, 3 and 5 the intra-individual coefficient of variation in the MEGX-test was 45.3% at 15 min and 23.5% at 30 min, respectively. CONCLUSIONS: It is concluded that there is a significant correlation between lignocaine and midazolam clearances but this correlation is lost after CYP3A4 inhibition by erythromycin. The MEGX-test is of no value in assessing intra- and inter-individual variability in midazolam clearance. 相似文献
993.
We surveyed a randomized group of 1050 adult patients stratified for age and sex, from a general practice in Oxfordshire, to find out their attitudes to electronic health records (EHRs). Eighty-six per cent thought that patients should have the right to see their records. While 72% knew that they had the right to see their records, only 4% had done so. Private EHR viewing booths with a computer and fingerprint identification system were installed in the primary care centre. Patients were randomly selected from those who responded to the questionnaire and wished to view their EHR. Of the 100 patients who saw their online EHR, 99 found the session useful and 84 found their records easy to understand. Three focus groups were held with 14 patients who said that they did not want to access their EHRs. The reasons patients gave during the focus groups included that they trusted their general practitioner and thought it would imply a lack of confidence. After the focus groups, 11 patients changed their minds and accessed their records. We believe that patient-accessed EHRs will offer substantial benefits to patients, health professionals and the National Health Service as a whole. 相似文献
994.
Liu JR Chen BQ Yang YM Han XH Xue YB Wang XL Zheng YM Liu RH 《Environmental health and preventive medicine》2002,7(5):205-210
Objectives To determine the effect of cis-9, trans-11-conjugated linoleic acid on the cell cycle of mammary cancer cells (MCF-7) and
its possible mechanism of inhibition cancer growth.
Methods Using cell culture and immunocytochemical techniques, we examined the cell growth, DNA synthesis, expression of PCNA, cyclin
A, B1, D1, p16ink4a and p21cip/wafl of MCF-7 cells which were treated with various c9, t11-CLA concentrations (25 mM, 50 mM, 100 mM and 200 mM) of c9, t11-CLA
for 24 and 48 h, with negative controls (0.1% ethanol).
Results The cell growth and DNA synthesis of MCF-7 cells were inhibited by c9, t11-CLA. MCF-7 cells, after treatment with various
c9, t11-CLA doses mentioned above for 8 days, the inhibition frequency was 27.18%, 35.43%, 91.05%, and 92.86%, respectively
and the inhibitory effect of c9, t11-CLA on DNA synthesis (except for 25 mM, 24 h) incorporated significantly less3H-TdR than did the negative control (P<0.05 andP<0.01). To further investigate the influence on the cell cycle progression, we found that c9, t11-CLA may arrest the cell
cycle of MCF-7 cells. Immunocytochemical staining demonstrated that MCF-7 cells preincubated in media supplemented with different
c9, t11-CLA concentrations at various times significantly decreased the expressions of PCNA, and Cyclin, A, B1, D1 compared with the negative controls (P<0.01), whereas the expressions of p16ink4a and p21cip/wafl, cyclin-dependent kinases inhibitors (CDKI), were increased.
Conclusions The cell growth and proliferation of MCF-7 cells is inhibited by c9, t11-CLA by blocking the cell cycle, which reduces expressions
of cyclin A, B1, D1 and enhances expressions of CDKI (p16ink4a and p21cip/wafl). 相似文献
995.
Beljaars L Floris R Berkhout B Smit C Meijer DK Molema G 《Biochemical pharmacology》2002,63(9):1663-1673
The substitution of human serum albumin with negatively charged molecules, such as succinic acid (Suc-HSA) or aconitic acid (Aco-HSA), resulted in proteins with potent anti-HIV activities, by binding to viral gp120 (V3 loop). The aim of the present study was to investigate whether the distribution of negative charges on the albumin backbone influences the anti-HIV activity. Therefore, we prepared albumins with clusters of negatively charged groups by coupling of heparin. The effects of this substitution on anti-HIV activity, in vivo distribution and the protein structure as compared to random succinylation were assessed. In vitro studies indicated that HSA-modified with heparin 6 or 13 kD displayed anti-HIV activity (IC50=660 and 37 nM, respectively) and exhibited affinity for gp120-V3 loop, although the activity was lower than that of Suc-HSA. Combined derivatization of HSA with heparin 13 kD and aconitic acid groups resulted in significantly increased inhibitory actions (IC50=2.8 nM). Structural analysis showed that modification of HSA with heparin did not lead to extensive unfolding of the protein, meaning that these modified proteins were still globular in structure. In contrast, succinylation of HSA resulted in a highly randomly coiled conformation. Dynamic light scattering experiments revealed that, at neutral pH, the heparin fragments attached to the protein were wrapped around the molecule rather than sticking out into the solution. In conclusion, coupling of sufficient clustered negative charges, by coupling of Hep-fragments, on HSA resulted in a clear anti-HIV activity of the protein. Yet, random distribution of anionic groups in the albumin seemed more optimal for in vitro anti-HIV activity. The higher plasma and lymphatic concentrations of Hep-HSA compared to Suc-HSA seemed more favorable for an anti-HIV activity in vivo. 相似文献
996.
The interaction between the locus coeruleus and dorsal raphe nucleus was investigated by means of dual-probe microdialysis in conscious rats. The release of noradrenaline and 5-hydroxytryptamine (5-HT) after inhibition or stimulation of locus coeruleus and dorsal raphe activity was sampled in both nuclei and analysed by high-pressure liquid chromatography (HPLC). The inhibition of locus coeruleus activity by the infusion of the alpha(2)-adrenoceptor agonist clonidine (100 microM) decreased the release of noradrenaline to 20% in the locus coeruleus and 30% in the dorsal raphe, whilst the release of 5-HT decreased to 80% of control in the two brain areas. The excitation of locus coeruleus activity by the muscarinic receptor agonist carbachol (100 microM) led to an increase in the release of noradrenaline to 240% and 220% of control in the locus coeruleus and dorsal raphe, respectively. The release of 5-HT in both nuclei did not respond to the carbachol infusion into the locus coeruleus. Infusion of the 5-HT(1A) receptor agonist flesinoxan into the dorsal raphe (1 microM) significantly decreased the release of 5-HT in the dorsal raphe and locus coeruleus to 45% and 65% of control, respectively. The release of noradrenaline was decreased in the dorsal raphe to 45% by flesinoxan, whereas no changes were seen in the release of noradrenaline in the locus coeruleus. In conclusion, the innervation of the dorsal raphe by the locus coeruleus has a slight excitatory effect on the release of 5-HT in the dorsal raphe. The dorsal raphe does not exert a direct inhibitory influence on the release of noradrenaline in the locus coeruleus. Finally, the release of noradrenaline in the dorsal raphe may be locally regulated by 5-HT(1A) receptors. 相似文献
997.
Lin CW Nakane M Stashko M Falls D Kuk J Miller L Huang R Tyree C Miner JN Rosen J Kym PR Coghlan MJ Carter G Lane BC 《Molecular pharmacology》2002,62(2):297-303
Glucocorticoids are potent anti-inflammatory and immunosuppressant agents. However, they also produce serious side effects that limit their usage. It has been proposed that anti-inflammatory properties of glucocorticoids are caused mostly by repression of activator protein 1- and nuclear factor kappabeta-stimulated synthesis of inflammatory mediators, whereas most of their adverse effects are associated with trans-activation of genes involved with metabolic processes. Our laboratories have sought to discover novel glucocorticoid receptor (GR) ligands that have high repression but low trans-activation activities. We describe here cellular properties of 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(1-methylcyclohexen-3-y1)-1H-[1]benzopyrano[3,4-f]quinoline (A276575) and its four enantiomers. Similar to dexamethasone, A276575 exhibited high affinity for GR and potently repressed interleukin (IL) 1beta-stimulated IL-6 production in human skin fibroblasts, prostaglandin (PG) E(2) production in A549 human lung epithelial cells, and concanavalin A-induced monocyte proliferation. In contrast to dexamethasone, A276575 caused smaller induction of aromatase activity in human skin fibroblasts and antagonized dexamethasone-induced activation of an mouse mammary tumor virus-glucocorticoid-response element (GRE) reporter gene construct. Among the four enantiomers of A276575, the two (-)-enantiomers showed 10- to 30-fold higher affinities for GR than their respective (+)-enantiomers. Both (-)-Syn and (-)-Anti enantiomers of A276575 were potent inhibitors of IL-1beta-stimulated PGE2 production in A549 lung epithelial cells; unexpectedly, however, only the (-)-Anti enantiomer inhibited regulated on T-cell activation, normal T-cell expressed and secreted (RANTES) production in A549 cells. In summary, A276575 is a novel, nonsteroidal GR ligand that possesses high repression activities against inflammatory mediator production but has lower GRE trans-activation activities than traditional steroids. Differential repression of RANTES and PGE2 production in a cell by the two (-)-enantiomers of A276575 illustrates the complexity of repression by GR. 相似文献
998.
Beutels P Edmunds WJ Antoñanzas F De Wit GA Evans D Feilden R Fendrick AM Ginsberg GM Glick HA Mast E Péchevis M Van Doorslaer EK van Hout BA;Viral Hepatitis Prevention Board 《PharmacoEconomics》2002,20(1):1-7
The methods that have been used to estimate the clinical and economic impact of vaccination programmes are not always uniform, which makes it difficult to compare results between economic analyses. Furthermore, the relative efficiency of vaccination programmes can be sensitive to some of the more controversial aspects covered by general guidelines for the economic evaluation of healthcare programmes, such as discounting of health gains and the treatment of future unrelated costs. In view of this, we interpret some aspects of these guidelines with respect to vaccination and offer recommendations for future analyses. These recommendations include more transparency and validation, more careful choice of models (tailored to the infection and the target groups), more extensive sensitivity analyses, and for all economic evaluations (also nonvaccine related) to be in better accordance with general guidelines. We use these recommendations to interpret the evidence provided by economic evaluation applied to viral hepatitis vaccination. We conclude that universal hepatitis B vaccination (of neonates, infants or adolescents) seems to be the most optimal strategy worldwide, except in the few areas of very low endemicity, where the evidence to enable a choice between selective and universal vaccination remains inconclusive. While targeted hepatitis A vaccination seems economically unattractive, universal hepatitis A vaccination strategies have not yet been sufficiently investigated to draw general conclusions. 相似文献
999.
BACKGROUND: In the Balloon Angioplasty and Anticoagulation Study (BAAS), coumarins added to routine aspirin therapy before coronary angioplasty reduced cardiac events at the cost of a slightly higher risk of bleeding complications. OBJECTIVE: To determine the cost effectiveness of coumarin treatment, based on the occurrence of both cardiac and bleeding events. METHODS: Effectiveness was measured, applying two definitions, in terms of the number of events occurring at one year. In the first definition, the occurrence of death, myocardial infarction (MI), or stroke was assessed. The second definition also included revascularisations and major bleeding episodes as an event. Costs were limited to direct medical costs. Cost effectiveness was addressed by probability ellipses representing the point estimates and uncertainties surrounding both costs and effectiveness. RESULTS: At 1 year, death, MI or stroke occurred 1.1% less often when treating with aspirin plus coumarins rather than aspirin therapy alone. When revascularisations and major bleeding events were also included, the difference was 5.0%. Overall, the additional costs in relation to coumarin treatment were compensated by a reduction in repeat interventions. When including all costs, the savings associated with coumarin treatment were estimated at Euros 235 per patient after 1 year. The probability that coumarins are cost saving was estimated at 0.85. The probability that coumarins combine additional effectiveness with cost savings was estimated at 0.70 when survival free of MI or stroke as an effectiveness measure was considered, and at 0.83 when survival free of MI, stroke, revascularisation or major bleeding was considered. CONCLUSION: Coumarin therapy added to routine aspirin therapy before coronary angioplasty, and continued during follow-up, may not only be considered more effective but also cost saving relative to aspirin therapy alone. 相似文献
1000.
Organ perfusion techniques bridge the methodological gap between in vivo studies on the one hand and in vitro studies on the other. In drug candidate selection and subsequent development the differences between these systems should be considered carefully in study design, as one approach may be more suitable than the other depending on the question(s) being asked and, in particular, how the data will be used. This article is not concerned with the mechanics, the surgery or composition of perfusates as there are numerous reviews/books covering these aspects. Instead, using perfused gut, liver, lung, kidney and brain as examples, the emphasis is on the usefulness (or otherwise) of the data generated with respect to drug absorption, metabolism, pharmacokinetics (PK) and the factors which affect these parameters. Perfusion systems are not difficult to set up but do require 'high maintenance' for routine use. For this reason they have been used sparingly by the pharmaceutical industry mainly for problem solving or mechanistic studies. The latter part of this article shows how simultaneous dosing of numerous compounds followed by multiple--component analysis using LC/MS/MS has proved to be an effective way to improve the throughput of absorption, pharmacokinetics and metabolism screening ex vivo. 相似文献