全文获取类型
收费全文 | 369篇 |
免费 | 15篇 |
国内免费 | 3篇 |
专业分类
儿科学 | 25篇 |
妇产科学 | 3篇 |
基础医学 | 41篇 |
口腔科学 | 4篇 |
临床医学 | 14篇 |
内科学 | 93篇 |
皮肤病学 | 4篇 |
神经病学 | 15篇 |
特种医学 | 5篇 |
外科学 | 15篇 |
综合类 | 32篇 |
预防医学 | 40篇 |
眼科学 | 5篇 |
药学 | 51篇 |
中国医学 | 22篇 |
肿瘤学 | 18篇 |
出版年
2022年 | 2篇 |
2021年 | 4篇 |
2020年 | 5篇 |
2019年 | 14篇 |
2018年 | 15篇 |
2017年 | 16篇 |
2016年 | 7篇 |
2015年 | 7篇 |
2014年 | 34篇 |
2013年 | 38篇 |
2012年 | 25篇 |
2011年 | 25篇 |
2010年 | 23篇 |
2009年 | 19篇 |
2008年 | 24篇 |
2007年 | 25篇 |
2006年 | 11篇 |
2005年 | 16篇 |
2004年 | 14篇 |
2003年 | 13篇 |
2002年 | 5篇 |
2001年 | 9篇 |
2000年 | 1篇 |
1999年 | 1篇 |
1998年 | 9篇 |
1997年 | 4篇 |
1996年 | 6篇 |
1995年 | 7篇 |
1994年 | 2篇 |
1991年 | 1篇 |
1985年 | 1篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1979年 | 1篇 |
排序方式: 共有387条查询结果,搜索用时 46 毫秒
1.
Victoria A. Statler Frank R. Albano Jolanta Airey Daphne C. Sawlwin Alison Graves Jones Vince Matassa Esther Heijnen Jonathan Edelman Gary S. Marshall 《Vaccine》2019,37(2):343-351
Background
In the Southern Hemisphere 2010 influenza season, Seqirus’ split-virion, trivalent inactivated influenza vaccine was associated with increased reports of fevers and febrile reactions in young children. A staged clinical development program of a quadrivalent vaccine (Seqirus IIV4 [S-IIV4]; Afluria® Quadrivalent/Afluria Quad?/Afluria Tetra?), wherein each vaccine strain is split using a higher detergent concentration to reduce lipid content (considered the cause of the increased fevers and febrile reactions), is now complete.Methods
Children aged 6–59?months were randomized 3:1 and stratified by age (6–35?months/36–59?months) to receive S-IIV4 (n?=?1684) or a United States (US)-licensed comparator IIV4 (C-IIV4; Fluzone® Quadrivalent; n?=?563) during the Northern Hemisphere 2016–2017 influenza season. The primary objective was to demonstrate noninferior immunogenicity of S-IIV4 versus C-IIV4. Immunogenicity was assessed by hemagglutination inhibition (baseline, 28?days postvaccination). Solicited, unsolicited, and serious adverse events were assessed for 7, 28, and 180?days postvaccination, respectively.Results
S-IIV4 met the immunogenicity criteria for noninferiority. Adjusted geometric mean titer ratios (C-IIV4/S-IIV4) for the A/H1N1, A/H3N2, B/Yamagata, and B/Victoria strains were 0.79 (95% CI: 0.72, 0.88), 1.27 (1.15, 1.42), 1.12 (1.01, 1.24), and 0.97 (0.86, 1.09), respectively. Corresponding values for differences in seroconversion rates (C-IIV4 minus S-IIV4) were ?10.3 (?15.4, ?5.1), 2.6 (?2.5, 7.8), 3.1 (?2.1, 8.2), and 0.9 (?4.2, 6.1). Solicited, unsolicited, and serious adverse events were similar between vaccines in both age cohorts, apart from fever. Fever rates were lower with S-IIV4 (5.8%) than C-IIV4 (8.4%), with no febrile convulsions reported with either vaccine during the 7?days postvaccination.Conclusion
S-IIV4, manufactured with a higher detergent concentration, demonstrated noninferior immunogenicity to the US-licensed C-IIV4, with similar postvaccination safety and tolerability, in children aged 6–59?months. This completes the program demonstrating the immunogenicity and safety of S-IIV4 in participants aged 6?months and older.2.
Alejandro J Garcia Colton Tom Miriam Guemes Gloria Polanco Maria E Mayorga Korinna Wend Gustavo A Miranda‐Carboni Susan A Krum 《Journal of bone and mineral research》2013,28(2):283-290
The benefits of estrogens on bone health are well established; how estrogens signal to regulate bone formation and resorption is less well understood. We show here that 17β‐estradiol (E2)‐induced apoptosis of bone‐resorbing osteoclasts is mediated by cleavage and solubilization of osteoblast‐expressed Fas ligand (FasL). U2OS‐ERα osteoblast‐like cells expressing an EGFP‐tagged FasL at the C‐terminus showed decreased fluorescence after E2 treatment, indicative of a cleavage event. Treatment of U2OS‐ERα cultures with a specific MMP3 inhibitor in the presence of E2 blocked FasL cleavage and showed an increase in the number of EGFP‐FasL+ cells. siRNA experiments successfully knocked down MMP3 expression and restored full‐length FasL to basal levels. E2 treatment of both human and murine primary osteoblasts showed upregulation of MMP3 mRNA expression, and calvarial organ cultures showed increased expression of MMP3 protein and colocalization with the osteoblast‐specific RUNX2 after E2 treatment. In addition, osteoblast cell cultures derived from ERαKO mice showed decreased expression of MMP3 but not MMP7 and ADAM10, two known FasL proteases, demonstrating that ERα signaling regulates MMP3. Also, conditioned media of E2‐treated calvarial osteoblasts showed an approximate sixfold increase in the concentration of soluble FasL, indicating extensive cleavage, and soluble FasL concentrations were reduced in the presence of a specific MMP3 inhibitor. Finally, to show the role of soluble FasL in osteoclast apoptosis, human osteoclasts were cocultured with MC3T3 osteoblasts. Both a specific MMP3 inhibitor and an MMP inhibitor cocktail preserved osteoclast differentiation and survival in the presence of E2 and demonstrate the necessity of MMP3 for E2‐induced osteoclast apoptosis. These experiments further define the molecular mechanism of estrogen's bone‐protective effects by inducing osteoclast apoptosis through upregulation of MMP3 and FasL cleavage. © 2013 American Society for Bone and Mineral Research 相似文献
3.
目的探讨FAS-670A/G多态性与宫颈癌易感性之间的关系。方法全面检索相关文献,收集2012年1月前有关FAS-670A/G多态性与宫颈癌易感性的病例对照研究,使用Stata 10.0进行Meta分析。结果最终纳入病例对照研究10项,累计病例2174例,对照2514例。在显性模型、隐性模型、加性模型中,Meta分析的OR值及95%CI分别为1.08(0.83-1.41)、0.99(0.76-1.30)、1.03(0.91-1.17),且按种族所进行的分层分析中各OR值均未达到显著性水平。结论 FAS-670A/G多态性与宫颈癌易感性之间无显著关联。 相似文献
4.
Amy Perkins Claudia Lehmann R. Charles Lawrence Sandra J. Kelly 《International journal of developmental neuroscience》2013
Fetal alcohol spectrum disorders represent a wide range of symptoms associated with in utero alcohol exposure. Animal models of FASD have been useful in determining the specific neurological consequences of developmental alcohol exposure, but the mechanisms of those consequences are unclear. Long-lasting changes to the epigenome are proposed as a mechanism of alcohol-induced teratogenesis in the hippocampus. The current study utilized a three-trimester rodent model of FASD to examine changes to some of the enzymatic regulators of the epigenome in adolescence. Combined pre- and post-natal alcohol exposureresulted in a significant increase in DNA methyltransferase activity (DNMT), without affecting histone deacetylase activity (HDAC). Developmental alcohol exposure also caused a change in gene expression of regulators of the epigenome, in particular, DNMT1, DNMT3a, and methyl CpG binding protein 2 (MeCP2). The modifications of the activity and expression of epigenetic regulators in the hippocampus of rodents perinatally exposed to alcohol suggest that alcohol's impact on the epigenome and its regulators may be one of the underlying mechanisms of alcohol teratogenesis. 相似文献
5.
Verónica Balaszczuk Crhistian Bender Germán Pereno Carlos A. Beltramino 《International journal of developmental neuroscience》2013
Mothers who consume alcohol during pregnancy may cause a neurotoxic syndrome termed fetal alcohol spectrum disorder (FASD) in the offspring, which includes cognitive deficits and emotional/social disturbances. These alterations are thought to be caused, at least in part, by alcohol-induced imbalance in neurotrophic factor levels, which are critically involved in normal neurodevelopment. Our goal was to study whether brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) expression were affected by alcohol in central extended amygdala (CEXA) and pyriform cortex (Pyr), structures strongly involved in emotional/social behaviors. Further, we evaluated how these changes could be related to blood and brain alcohol concentrations. Postnatal day (PND) pups at 7, 15 and 20-days old were administered alcohol (2.5 g/kg s.c. at 0 and 2 h) or saline. Immunohistochemistry was used to detect the expression of BDNF and GDNF at 2, 12 and 24 h after drug administration. Also, gas chromatography was bused to measure blood alcohol levels (BALs) and brain alcohol levels (BrALs) at each hour, from 2 to 8 h after the second alcohol administration. Results showed: (1) alcohol-induced enhancement of BDNF positive cells on PND 7 and 20, a decrease on PND 15 in the CEXA, and no changes in the Pyr on PND 7 and 20, but a diminished on PND 15; (2) GDNF positive cells rise after alcohol administration for the three ages in the CEXA and Pyr except on PND 15, where there was a decline; and (3) pharmacokinetics analysis demonstrated age-related differences showing equal BALs on PND 7 and 20 but higher BALs on PND 15. In contrast, BrALs were higher on PND 7 than 15 and 20. Hence, BALs may not be predictive of BrALs in postnatal rats. Furthermore, we did not find a relationship between age in pharmacokinetic differences and neurotrophins response. In conclusion, the CEXA and Pyr are brain structures sensitive to alcohol-induced imbalance in neurotrophic factors expression; and BALs are not a mirror of BrALs. 相似文献
6.
Chun‐Liang Tung Da‐Tong Ju Bharath Kumar Velmurugan Bo Ban Tran D. Dung Dennis J.‐Y. Hsieh Vijaya P. Viswanadha Cecilia H. Day Yueh‐Min Lin Chih‐Yang Huang 《Environmental toxicology》2019,34(12):1320-1328
Carthamus tinctorius L. (Compositae) is used in Chinese medicine to treat heart disease and inflammation. In our previous study, we found that C. tinctorius L. inhibited lipopolysaccharides (LPS)‐induced tumor necrosis factor‐alpha (TNF‐α) activation, JNK expression, and apoptosis in H9c2 cardiomyoblast cells. The present study was performed to investigate the protective effect of C. tinctorius extract (CTF) on LPS‐challenged H9c2 myocardioblast cell and to explore the possible underlying mechanism. Cell viability assay showed that LPS treatment decreased the cell viability of H9c2 cell, whereas CTF treatment reversed LPS cytotoxicity in a dose‐dependent manner, especially in the LPS + CTF 25 (μg/mL) group. LPS treatment‐induced apoptosis was determined by transferase‐mediated dUTP nick end labeling assay, and by Western blot. LPS‐induced apoptotic bodies were decreased following CTF treatment. Expression of TNF‐α, FAS‐L, FAS, FADD, caspase‐8, BID, and t‐BID was significantly increased in LPS‐treated H9c2 cells. In contrast, it was significantly suppressed by the administration of CTF extract. In addition, CTF treatment activates antiapoptotic proteins, Bcl‐2 and p‐Bad, and downregulates Bax, cytochrome‐c, caspase‐9, caspase‐3, and apoptosis‐inducing factor expression. Furthermore, CTF exerted cytoprotective effects by activating insulin‐like growth factor‐I (IGF‐I) signaling pathway leading to downregulation of the apoptotic proteins involved in FAS death receptor pathway. In addition, AG1024 and IGF‐I receptor (IGF‐IR) inhibitor and siRNA silencing reverses the effect of CTF implying that CTF functions through the IGF‐IR pathway to inhibit LPS‐induced H9c2 apoptosis. These results suggest that treatment with CTF extract prevented the LPS‐induced apoptotic response through IGF‐I pathway. 相似文献
7.
Nina L. Fransen Jakob B. A. Crusius Joost Smolders Mark R. Mizee Corbert G. van Eden Sabina Luchetti Ester B. M. Remmerswaal Jrg Hamann Matthew R. J. Mason Inge Huitinga 《Brain pathology (Zurich, Switzerland)》2020,30(1):106-119
Over the last few decades, several common single nucleotide polymorphisms (SNPs) have been identified that correlate with clinical outcome in multiple sclerosis (MS), but the pathogenic mechanisms underlying the clinical effects of these SNPs are unknown. This is in part because of the difficulty in the functional translation of genotype into disease‐relevant mechanisms. Building on our recent work showing the association of clinical disease course with post‐mortem MS lesion characteristics, we hypothesized that SNPs that correlate with clinical disease course would also correlate with specific MS lesion characteristics in autopsy tissue. To test this hypothesis, 179 MS brain donors from the Netherlands Brain Bank MS autopsy cohort were genotyped for 102 SNPs, selected based on their reported associations with clinical outcome or their associations with genes that show differential gene expression in MS lesions. Three SNPs linked to MS clinical severity showed a significant association between the genotype and either the proportion of active lesions (rs2234978/FAS and rs11957313/KCNIP1) or the proportion of mixed active/inactive lesions (rs8056098/CLEC16A). Three SNPs linked to MS pathology‐associated genes showed a significant association with either proportion of active lesions (rs3130253/MOG), incidence of cortical gray matter lesions (rs1064395/NCAN) or the proportion of remyelinated lesions (rs5742909/CTLA4). In addition, rs2234978/FAS T‐allele carriers showed increased FAS gene expression levels in perivascular T cells and perilesional oligodendrocytes, cell types that have been implicated in MS lesion formation. Thus, by combining pathological characterization of MS brain autopsy tissue with genetics, we now start to translate genotypes linked to clinical outcomes in MS into mechanisms involved in MS lesion pathogenesis. 相似文献
8.
9.
The Interaction of Ethanol and Vitamin A as a Potential Mechanism for the Pathogenesis of Fetal Alcohol Syndrome 总被引:4,自引:0,他引:4
Richard D. Zachman Mary A. Grummer 《Alcoholism, clinical and experimental research》1998,22(7):1544-1556
The mechanism of the fetal embryopathology resulting from ethanol ingestion during pregnancy is not established. This review summarizes recent research on the interaction of ethanol and vitamin A in models that explore if an interaction between these two compounds might potentially be the mechanism for fetal alcohol syndrome. The rationale for this hypothesis includes the known facts that: (1) in adults, ethanol ingestion alters vitamin A metabolism and tissue distribution; (2) there are many phenotypic similarities between fetal alcohol syndrome and malformations of both vitamin A toxicity and deficiency; and (3) the vitamin A metabolite, retinoic acid (RA), is a potent mediator in embryogenesis and differentiation. One interaction that could possibly alter fetal development is that the synthesis of RA from retinol, catalyzed by alcohol dehydrogenase, might be competitively inhibited by ethanol leading to RA deficiency. Controversy over this hypothesis continues. Another model demonstrates in vivo effects of pregnant rat mother's ethanol consumption on retinol, retinyl ester, RA content, RA receptor (RAR) binding, and the levels of RAR expression in developing fetal organs. The variable responses in this model still need clarification, and specific defects resulting from specific RAR changes have not yet been identified. In a quail embryo model, ethanol treatment mimics vitamin A deficiency, and RA appears to prevent the adverse effects of ethanol. Finally, RA and ethanol reverse or block each other's effects in studies on isolated neuroblastoma cells. Taken together, these experiments show definite interactions between ethanol and vitamin A. Further studies are needed to determine if any of these mechanisms significantly contribute to prenatal ethanol consumption embryopathy; but, clearly this hypothesis is gaining experimental support. 相似文献
10.