全文获取类型
收费全文 | 197篇 |
免费 | 12篇 |
专业分类
基础医学 | 25篇 |
临床医学 | 22篇 |
内科学 | 108篇 |
皮肤病学 | 5篇 |
神经病学 | 13篇 |
特种医学 | 2篇 |
外科学 | 12篇 |
预防医学 | 10篇 |
药学 | 9篇 |
中国医学 | 1篇 |
肿瘤学 | 2篇 |
出版年
2022年 | 1篇 |
2021年 | 1篇 |
2020年 | 4篇 |
2019年 | 1篇 |
2017年 | 1篇 |
2016年 | 1篇 |
2015年 | 3篇 |
2014年 | 4篇 |
2013年 | 4篇 |
2012年 | 6篇 |
2011年 | 2篇 |
2010年 | 7篇 |
2009年 | 6篇 |
2008年 | 15篇 |
2007年 | 11篇 |
2006年 | 12篇 |
2005年 | 13篇 |
2004年 | 10篇 |
2003年 | 9篇 |
2002年 | 12篇 |
2001年 | 14篇 |
2000年 | 16篇 |
1999年 | 11篇 |
1998年 | 1篇 |
1997年 | 4篇 |
1996年 | 5篇 |
1995年 | 2篇 |
1994年 | 4篇 |
1991年 | 5篇 |
1990年 | 2篇 |
1987年 | 2篇 |
1986年 | 5篇 |
1985年 | 5篇 |
1984年 | 5篇 |
1983年 | 1篇 |
1981年 | 4篇 |
排序方式: 共有209条查询结果,搜索用时 15 毫秒
1.
B. Guigas J. E. de Leeuw van Weenen N. van Leeuwen A. M. Simonis‐Bik T. W. van Haeften G. Nijpels J. J. Houwing‐Duistermaat M. Beekman J. Deelen L. M. Havekes B. W. J. H. Penninx N. Vogelzangs E. van ‘t Riet A. Dehghan A. Hofman J. C. Witteman A. G. Uitterlinden N. Grarup T. Jørgensen D. R. Witte T. Lauritzen T. Hansen O. Pedersen J. Hottenga J. A. Romijn M. Diamant M. H. H. Kramer R. J. Heine G. Willemsen J. M. Dekker E. M. Eekhoff H. Pijl E. J. de Geus P. E. Slagboom L. M. ‘t Hart 《Diabetic medicine》2014,31(8):1001-1008
2.
The general consensus is that sleep promotes neuronal recovery and plasticity, whereas sleep deprivation (SD) impairs brain function, including cognitive processes. Indeed, a wealth of data has shown a negative impact of SD on learning and memory processes, particularly those that involve the hippocampus. The mechanisms underlying these negative effects of sleep loss are only partly understood, but a reoccurring question is whether they are in part caused by stress hormones that may be released during SD. The purpose of the present study is therefore to examine the role of glucocorticoid stress hormones in SD‐induced memory impairment. Male C57BL/6J mice were trained in an object‐location memory paradigm, followed by 6 hr of SD by mild stimulation. At the beginning of the SD mice were injected with the corticosterone synthesis inhibitor metyrapone. Memory was tested 24 hr after training. Blood samples taken in a separate group of mice showed that SD resulted in a mild but significant increase in plasma corticosterone levels, which was prevented by metyrapone. However, the SD‐induced impairment in object‐location memory was not prevented by metyrapone treatment. This indicates that glucocorticoids play no role in causing the memory impairments seen after a short period of SD. 相似文献
3.
van De Poll SW Römer TJ Volger OL Delsing DJ Bakker Schut TC Princen HM Havekes LM Jukema JW van Der Laarse A Puppels GJ 《Arteriosclerosis, thrombosis, and vascular biology》2001,21(10):1630-1635
Quantitative characterization of atherosclerotic plaque composition with standard histopathological methods remains limited to sectioned plaques. Raman spectroscopy enables nondestructive quantification of atherosclerotic plaque composition. We used Raman spectroscopy to study the effects of diet and lipid-lowering therapy on plaque development in apolipoprotein (APO) E*3-Leiden transgenic mice. Raman spectra were obtained over the full width and entire length of the ascending aorta and aortic arch. Spectra were modeled to calculate the relative dry weights of cholesterol and calcium salts, and quantitative maps of their distribution were created. In male mice (n=20) that received a high-fat/high-cholesterol (HFC) diet for 0, 2, 4, or 6 months, Raman spectroscopy showed good correlation between cholesterol accumulation and total serum cholesterol exposure (r approximately 0.87, P<0.001). In female mice (n=10) that were assigned to an HFC diet, with or without 0.01% atorvastatin, a strong reduction in cholesterol accumulation (57%) and calcium salts (97%) (P<0.01) was demonstrated in the atorvastatin-treated group. In conclusion, Raman spectroscopy can be used to quantitatively study the size and distribution of depositions of cholesterol and calcification in APOE*3-Leiden transgenic mice. This study encourages Raman spectroscopy for the quantitative investigation of atherosclerosis and lipid-lowering therapy in larger animals or humans in vivo. 相似文献
4.
Tineke van de Weijer Esther Phielix Lena Bilet Evan G. Williams Eduardo R. Ropelle Alessandra Bierwagen Roshan Livingstone Peter Nowotny Lauren M. Sparks Sabina Paglialunga Julia Szendroedi Bas Havekes Norman Moullan Eija Pirinen Jong-Hee Hwang Vera B. Schrauwen-Hinderling Matthijs K.C. Hesselink Johan Auwerx Michael Roden Patrick Schrauwen 《Diabetes》2015,64(4):1193-1201
Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide (NAD+) precursors to increase oxidative phosphorylation and improve metabolic health, but human data are lacking. We hypothesize that the nicotinic acid derivative acipimox, an NAD+ precursor, would directly affect mitochondrial function independent of reductions in nonesterified fatty acid (NEFA) concentrations. In a multicenter randomized crossover trial, 21 patients with type 2 diabetes (age 57.7 ± 1.1 years, BMI 33.4 ± 0.8 kg/m2) received either placebo or acipimox 250 mg three times daily dosage for 2 weeks. Acipimox treatment increased plasma NEFA levels (759 ± 44 vs. 1,135 ± 97 μmol/L for placebo vs. acipimox, P < 0.01) owing to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene sets and a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response. Further studies in C2C12 myotubes confirmed a direct effect of acipimox on NAD+ levels, mitonuclear protein imbalance, and mitochondrial oxidative capacity. To the best of our knowledge, this study is the first to demonstrate that NAD+ boosters can also directly affect skeletal muscle mitochondrial function in humans. 相似文献
5.
6.
LDL receptor cooperates with LDL receptor-related protein in regulating plasma levels of coagulation factor VIII in vivo 总被引:5,自引:1,他引:5
下载免费PDF全文
![点击此处可从《Blood》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Low-density lipoprotein (LDL) receptor (LDLR) and LDLR-related protein (LRP) are members of the LDLR family of endocytic receptors. LRP recognizes a wide spectrum of structurally and functionally unrelated ligands, including coagulation factor VIII (FVIII). In contrast, the ligand specificity of LDLR is restricted to apolipoproteins E and B-100. Ligand binding to the LDLR family is inhibited by receptor-associated protein (RAP). We have previously reported that, apart from LRP, other RAP-sensitive mechanisms contribute to the regulation of FVIII in vivo. In the present study, we showed that the extracellular ligand-binding domain of LDLR interacts with FVIII in vitro and that binding was inhibited by RAP. The physiologic relevance of the FVIII-LDLR interaction was addressed using mouse models of LDLR or hepatic LRP deficiency. In the absence of hepatic LRP, LDLR played a dominant role in the regulation and clearance of FVIII in vivo. Furthermore, FVIII clearance was accelerated after adenovirus-mediated gene transfer of LDLR. The role of LDLR in FVIII catabolism was not secondary to increased plasma lipoproteins or to changes in lipoprotein profiles. We propose that LDLR acts in concert with LRP in regulating plasma levels of FVIII in vivo. This represents a previously unrecognized link between LDLR and hemostasis. 相似文献
7.
Scavenger receptor deficiency leads to more complex atherosclerotic lesions in APOE3Leiden transgenic mice. 总被引:9,自引:0,他引:9
M P de Winther M J Gijbels K W van Dijk P J van Gorp H suzuki T Kodama R R Frants L M Havekes M H Hofker 《Atherosclerosis》1999,144(2):315-321
Apolipoprotein (apo) E3Leiden is a dysfunctional apo E variant associated with familial dysbetalipoproteinemia in humans. Transgenic mice carrying the APOE3Leiden gene develop hyperlipidemia and are highly susceptible to diet-induced atherosclerosis. An early step in atherosclerosis is foam cell formation, which is thought to result from the unrestricted uptake of modified lipoproteins by macrophages. To investigate the role of the macrophage scavenger receptor type I and II (MSR-A) in this process, APOE3Leiden transgenic mice were crossed onto a MSR-A deficient background and the development of atherosclerosis was examined. In view of recent results with apo E deficient mice (Suzuki H et al., A role for the macrophage scavenger receptors in atherosclerosis. Nature 1997; 386(6622):292-296), absence of the MSR-A in APOE3Leiden mice was expected to lead to a reduction of atherosclerosis. In our study we compared APOE3Leiden/MSR-A deficient mice (E3L MSR-A -/-) to APOE3Leiden/MSR-A wild-type mice (E3L MSR-A +/+). These animals were fed an atherogenic diet for 10 weeks. Quantification of the lesion area showed no significant difference between E3L MSR-A -/- and E3L MSR-A +/+ mice although there was a trend towards the development of larger lesions in the E3L MSR-A -/- mice. All lesions were typed according to their cellular composition. In both male and female E3L MSR-A -/- mice, significantly more severe lesions developed as compared to E3L MSR-A +/+ mice. These results indicate that the effect of MSR-A deficiency on atherogenesis may depend on the presence or absence of apo E. 相似文献
8.
Raman spectroscopic investigation of atorvastatin,amlodipine, and both on atherosclerotic plaque development in APOE*3 Leiden transgenic mice 总被引:4,自引:0,他引:4
van de Poll SW Delsing DJ Jukema JW Princen HM Havekes LM Puppels GJ van der Laarse A 《Atherosclerosis》2002,164(1):65-71
Raman spectroscopy allows quantitative, non-destructive evaluation of entire, intact atherosclerotic plaques. We quantified the anti-atherosclerotic effects of atorvastatin and amlodipine on progression of atherosclerosis using post-mortem Raman spectroscopic plaque imaging in 28 APOE*3 Leiden transgenic mice who were fed a high fat/high cholesterol diet for 28 weeks. Mice were assigned to a control group receiving the diet alone or to groups that received the diet with either 0.01% w/w atorvastatin, 0.002% w/w amlodipine, or the combination. The entire excised aortic arch was scanned with Raman microspectroscopy for quantitation of the distribution of cholesterol and calcification content. When mice had been treated with atorvastatin, cholesterol accumulation and calcification in the aortic arch was reduced by 91 and 98%, respectively, (both P<0.001). Amlodipine did not reduce the cholesterol content but reduced calcification of the aorta by 69% (P<0.05). The combination of amlodipine and atorvastatin was as effective as atorvastatin alone. This study demonstrates the strong atheroprotective potential of atorvastatin. In addition it is demonstrated that amlodipine reduces mineralization of atherosclerotic plaque. No synergistic effect of the combination of amlodipine and atorvastatin on plaque development is demonstrated. This study encourages Raman spectroscopic evaluations of anti-atherosclerotic drugs in larger animals and humans in vivo. 相似文献
9.
Draijer R Volger OL Dahlmans VE de Wit EC Havekes LM Princen HM 《Biochemical pharmacology》2002,63(9):1755-1761
Previous rodent studies suggested that the potent hypolipidemic agent 4-amino-2-(4,4-dimethyl-2-oxo-1-imidazolidinyl)pyrimidine-5-N-(trifluoromethyl-phenyl) carboxamide monohydrochloride (HOE 402) is an inducer of the LDL receptor (LDLR). Using wild-type and heterozygous and homozygous LDLR-deficient (LDLR+/0 and LDLR0/0) mice, fed a low or high cholesterol diet, we investigated whether HOE 402 specifically induces the LDLR and whether other pathways are affected. Upon treatment with 0.05% (w/w) HOE 402, the serum cholesterol levels of wild-type, LDLR+/0 and LDLR0/0 mice, were maximally reduced by 53, 56, and 73%, respectively (P<0.05), by reducing levels in very low density-lipoprotein (VLDL), intermediate density-lipoprotein (IDL), and low density-lipoprotein (LDL) cholesterol, whereas high density-lipoprotein (HDL) cholesterol levels were increased. The observations that HOE 402 exhibited no effect on in vivo clearance of 125I-labeled LDL in wild-type mice, and clearly reduced serum cholesterol levels in LDLR0/0 mice, indicate that the LDLR is not the main target for the compound. In wild-type mice, production of VLDL-TG, and cholesterol were reduced by more than 50% by HOE 402 (P<0.05), whereas VLDL apolipoprotein B (ApoB) secretion was unaffected, indicating that HOE 402 treatment changes the size, rather than the number of the secreted VLDL particles. The reduced VLDL production was accompanied by a 22% decreased hepatic cholesterol ester concentration (P<0.05). Additionally, HOE 402 treatment strongly reduced the aortic content of atherosclerotic lesions by 90 and 72% in LDLR+/0 and LDLR0/0 mice, respectively (P<0.01). In conclusion, HOE 402 is a potent cholesterol-lowering compound, which inhibits VLDL production, and consequently attenuates atherosclerosis development. 相似文献
10.
Kleemann R Princen HM Emeis JJ Jukema JW Fontijn RD Horrevoets AJ Kooistra T Havekes LM 《Circulation》2003,108(11):1368-1374