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51.
Lp(a) lipoprotein is a major risk factor for cardiovascular disease: pathogenic mechanisms and clinical significance 总被引:8,自引:0,他引:8
The results of two previous and two recent studies of middle-aged males and females are presented to exemplify the clinical importance of lipoprotein (a) (Lp(a)) as a risk factor for atherosclerosis and coronary heart disease. In these studies various conventional and recently suggested risk factors were included and different methods for Lp(a) quantification were used. Lp(a) was a significant risk factor in all four studies. In the recent prospective case-control study, Lp(a) and cholesterol were found to act synergistically and predict primary acute myocardial infarction in Swedish males. A cholesterol level above 6.5 mmol/1 increased the risk of acute myocardial infarction if the Lp(a) level was above 200 mg/1. The plasma apo A-I level was a protective factor. In the other recent case-control study, an Lp(a) level above 500 mg/1 was a highly significant risk factor in Black and White US women with myocardial infarction or advanced coronary artery disease in addition to low density lipoprotein cholesterol levels above 130 mg/dl. A high apo A-I level was a protective factor. In these studies no other factors tested reached significance in multivariate logistic regression analysis. A hypothetical association between high Lp(a) levels and intracellular infection with Chlamydia pneumoniae is discussed. The results suggest that the Lp(a) level is useful in identifying high-risk individuals. Lowering low density lipoprotein cholesterol below 100 mg/dl (7lt;2.6 mmol/1) seems to be most important in both males and females with high-risk Lp(a) levels. 相似文献
52.
Analysis of the mechanism of lipoprotein(a) assembly 总被引:2,自引:0,他引:2
Marlys L. Koschinsky Santica M. Marcovina Lorraine F. May Brent R. Gabel 《Clinical genetics》1997,52(5):338-346
We have assessed the ability of a battery of purified recombinant apolipoprotein(a) (r-apo(a)) derivatives to bind to immobilized low-density lipoprotein (LDL) by ELISA. Removal of the apo(a) kringle IV type 8 and type 9 sequences dramatically reduced apo(a) binding to LDL. The binding of apo(a) to LDL was effectively inhibited by arginine, lysine, the lysine analogue ε-aminocaproic acid and proline; comparable inhibition was observed using the 17K and KIV5–8 r-apo(a) derivatives, suggesting a direct role for sequences contained in the latter species in mediating the initial non-covalent interactions which precede specific disulfide bond formation. We also determined that r-apo(a) binds directly to a synthetic apoB peptide spanning amino acid residues 3732–3745; this interaction appeared to be mediated by sequences present in apo(a) kringle IV types 8 and 9, and could be inhibited by arginine, lysine and proline. The results of this study indicate that the efficiency of Lp(a) assembly is a direct function of the initial non-covalent interactions between apo(a) and LDL; in addition, these studies suggest that Cys3734 in apoB mediates covalent linkage with apo(a) by virtue of the ability of the apoB sequences surrounding this residue to directly interact with apo(a) KIV type 9. 相似文献
53.
Restriction site polymorphism at the LPA (Lp(a) apoliprotein; apoliprotein(a)) locus 总被引:1,自引:0,他引:1
A restriction site polymorphism in the Lp(a) apolipoprotein gene (the LPA gene) is reported. The basis for the polymorphism is presence or absence of an MspI restriction site that appears to be 3' to the last kringle IV structure of the gene. The "1" gene (presence of the restriction site) has a frequency of 0.316 and the "2" gene (absence of the restriction site) has a frequency of 0.684. Both members of each of 67 monozygotic (MZ) twin pairs had the same genotype and there was Mendelian segregation of the DNA variants in 40 families with a total of 75 children. There was a lower proportion of people with genotype 1-1 in the top quartile than in the 3 bottom quartiles of the population distribution of Lp(a) lipoprotein levels but the difference did not reach statistical significance. 相似文献
54.
Samuels ME Forbey KC Reid JE Abkevich V Bulka K Wardell BR Bowen BR Hopkins PN Hunt SC Ballinger DG Skolnick MH Wagner S 《Clinical genetics》2001,59(2):88-98
Defects in the lipoprotein lipase (LPL) gene are associated with dyslipidemia in the general population. Several rare mutations in the gene, as well as two common coding region polymorphisms, D9N and N291S, exhibit deleterious effects on circulating lipid levels. Using a linkage-based approach, we have identified a large Utah kindred segregating the D9N variant in the LPL gene. The kindred was ascertained for premature coronary heart disease and was expanded based on familial dyslipidemia. A genomic scan identified a region of linkage including LPL, and mutation screening identified the segregating variant. In the kindred, the variant shows high penetrance for a hypoalphalipoproteinemia phenotype, but is also associated with hypertriglyceridemia and elevated insulin levels. The strength of linkage was dependent on the combination of phenotype definition and model parameters, favoring the use of a MOD score approach. Most other studies of LPL have proceeded by mutation screening of randomly chosen individuals or selected affected probands; this is the first example identifying a segregating LPL mutation using direct linkage. 相似文献
55.
本文观察了体外丙二醛(MDA),铜离子(Cu2+氧化修饰的脂蛋白(a)[Lp(a)]结构和生物学性质的变化。氧化修饰Lp(a)过氧化程度增高,负电荷增加,易被巨噬细胞—清道夫受体识别和摄取。MDA修饰Lp(a)出现新的MDA-LDL位点;同纤维蛋白溶酶原(Pg)竞争抑制试验显示氧化、修饰Lp(a)同Pg同源性增加。提示载脂蛋白(a)状态同动脉粥样硬化的病理过程有关。 相似文献
56.
S. A. Kurilovich E. V. Pozdeeva A. P. Serdyuk I. O. Svetlova Yu. A. Shakhov 《Bulletin of experimental biology and medicine》1990,110(6):1660-1663
Institute of Therapy, Siberian Branch, Academy of Medical Sciences of the USSR, Novosibirsk. All-Union Preventive Medicine Research Center, Ministry of Health of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR Yu. P. Nikitin.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 110, No. 12, pp. 611–613, December, 1990. 相似文献
57.
Predominance of a 6 bp deletion in exon 2 of the LDL receptor gene in Africans with familial hypercholesterolaemia 下载免费PDF全文
Thiart R Scholtz CL Vergotine J Hoogendijk CF de Villiers JN Nissen H Brusgaard K Gaffney D Hoffs MS Vermaak WJ Kotze MJ 《Journal of medical genetics》2000,37(7):514-519
In South Africa, the high prevalence of familial hypercholesterolaemia (FH) among Afrikaners, Jews, and Indians as a result of founder genes is in striking contrast to its reported virtual absence in the black population in general. In this study, the molecular basis of primary hypercholesterolaemia was studied in 16 Africans diagnosed with FH. DNA analysis using three screening methods resulted in the identification of seven different mutations in the coding region of the low density lipoprotein (LDLR) gene in 10 of the patients analysed. These included a 6 bp deletion (GCGATG) accounting for 28% of defective alleles, and six point mutations (D151H, R232W, R385Q, E387K, P678L, and R793Q) detected in single families. The Sotho patient with missense mutation R232W was also heterozygous for a de novo splicing defect 313+1G→A. Several silent mutations/polymorphisms were detected in the LDLR and apolipoprotein B genes, including a base change (g→t) at nucleotide position −175 in the FP2 LDLR regulatory element. This promoter variant was detected at a significantly higher (p<0.05) frequency in FH patients compared to controls and occurred in cis with mutation E387K in one family. Analysis of four intragenic LDLR gene polymorphisms showed that the same chromosomal background was identified at this locus in the four FH patients with the 6 bp deletion. Detection of the 6 bp deletion in Xhosa, Pedi, and Tswana FH patients suggests that it is an ancient mutation predating tribal separation approximately 3000 years ago.
Keywords: apolipoprotein B; hypercholesterolaemia; low density lipoprotein receptor; mutation 相似文献
Keywords: apolipoprotein B; hypercholesterolaemia; low density lipoprotein receptor; mutation 相似文献
58.
目的:观察血凝素氧化低密度脂蛋白受体-1(LOX-1)对氧化LDL(ox-LDL)诱导的人脐静脉内皮细胞(human unbilical vein endothelial cells, HUVECs)表达单核细胞趋化蛋白(monocyte chemoattractant protein-1, MCP-1)基因及蛋白的影响。 方法: 用RT-PCR和Western blot的方法观察ox-LDL对培养的HUVECs表达LOX-1和MCP-1基因及蛋白的影响,然后用LOX-1的受体阻滞剂爱兰苔胶(carrageenan) 和聚肌苷酸[polyinosinic acid,poly(I)]与HUVECs预先作用后,再观察内皮细胞表达LOX-1和MCP-1基因和蛋白的变化。 结果: 用不同浓度的ox-LDL(0 mg/L、10 mg/L、20 mg/L 、50 mg/L、100 mg/L)与HUVECs培养24 h后,LOX-1和MCP-1的mRNA和蛋白的表达明显增加,呈浓度依赖性;用Carrageenan 和polyinosinic acid与HUVECs预先作用2 h后,再加入50 mg/L的ox-LDL培养24 h,与未加Carrageenan和polyinosinic acid相比,HUVECsLOX-1和MCP-1的mRNA和蛋白的表达明显减少。 结论: ox-LDL可以调节培养的HUVECsLOX-1和MCP-1基因和蛋白的表达,LOX-1作为ox-LDL的特异性受体,可能介导了ox-LDL诱导血管内皮细胞分泌MCP-1,从而在动脉粥样硬化的发生发展中起着重要的作用。 相似文献
59.
Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1 } is a type-Ⅱ membrane protein belonging to the C-type lectin family molecules, which acts as a cell surface endocytosis receptor for atherogenic oxidized LDL (Ox-LDL). LOX-1 supports the binding internalization and proteolytic degradation of oxidized LDL, but not of significant amounts of acetylated LDL. LOX-1 is initially synthesized as a 40 kD precursor protein with N-linked high mannose-type carbohydrate, which is further glycosylated and processed into a 48-kD mature form. In vivo, endothelial cells that cover early therosclerotic lesions, intimal macrophages and smooth muscle cells in advanced atherosclerotic plaques express LOX-1. LOX-1 is cleaved at membrane proximal extracellular domain and released from the cell surface. Measurement of soluble LOX-1 in vivo may provide novel diagnostic strategy for the evaluation and prediction of atherosclerosis and vascular diseases. 相似文献
60.
Antioxidant enzymes and paraoxonase show a co-activity in preserving low-density lipoprotein from oxidation 总被引:1,自引:0,他引:1
Sözmen EY Sözmen B Girgin FK Delen Y Azarsiz E Erdener D Ersöz B 《Clinical and experimental medicine》2001,1(4):195-199
Oxidative modification of low-density lipoprotein in the artery wall plays a crucial role in the development of atherosclerosis.
This physiopathological mechanism is clearly inhibited by high-density lipoprotein possibly via paraoxonase enzyme activity,
present in high-density lipoprotein. In this study we determined the in vitro susceptibility of low-density lipoprotein to
oxidation and the effect of various factors, such as paraoxonase phenotypes, on this process. Low-density lipoprotein from
healthy volunteers (n=66) was isolated using the precipitant reagent and the oxidation was evaluated by measuring the malonyl dialdehyde and diene
levels. Low-density lipoprotein cholesterol and phospholipid, vitamin E, serum cholesterol, high-density lipoprotein and low-density
lipoprotein cholesterol levels, and erythrocyte antioxidant enzymes were also determined. There was no difference among the
parameters with regard to gender. Low-density lipoprotein samples obtained from subjects with the AA allele were more prone
to oxidation, as observed by their higher stimulated conjugated diene (P=0.041) and thiobarbituric acid-related substance (P=0.042) levels, than samples from subjects with AB or BB alleles. The subjects with the BB allele had higher superoxide dismutase
(P=0.021) and catalase (insignificant increase) activities, while their conjugated diene (P=0.000) levels were lower. In conclusion, our results revealed that the high low-density lipoprotein oxidation is related
to the high low-density lipoprotein cholesterol content and low phospholipid content. The present study demonstrated an increase
in superoxide dismutase and catalase activities, asl well as PON1 activities, in subjects with the BB allele. Since these
enzymes all show activity against low-density lipoprotein oxidation, we propose that future investigations on atherosclerotic
processes should address PON1 polymorphism as well as PON1 and other antioxidant enzymes.
Received: 7 May 2001 / Accepted: 14 December 2001 相似文献