全文获取类型
收费全文 | 1287篇 |
免费 | 92篇 |
国内免费 | 4篇 |
专业分类
耳鼻咽喉 | 4篇 |
儿科学 | 46篇 |
妇产科学 | 18篇 |
基础医学 | 245篇 |
口腔科学 | 10篇 |
临床医学 | 125篇 |
内科学 | 294篇 |
皮肤病学 | 33篇 |
神经病学 | 143篇 |
特种医学 | 68篇 |
外科学 | 93篇 |
综合类 | 3篇 |
预防医学 | 88篇 |
眼科学 | 14篇 |
药学 | 104篇 |
中国医学 | 3篇 |
肿瘤学 | 92篇 |
出版年
2024年 | 5篇 |
2023年 | 23篇 |
2022年 | 30篇 |
2021年 | 71篇 |
2020年 | 40篇 |
2019年 | 68篇 |
2018年 | 62篇 |
2017年 | 39篇 |
2016年 | 47篇 |
2015年 | 60篇 |
2014年 | 67篇 |
2013年 | 70篇 |
2012年 | 129篇 |
2011年 | 134篇 |
2010年 | 76篇 |
2009年 | 47篇 |
2008年 | 74篇 |
2007年 | 56篇 |
2006年 | 41篇 |
2005年 | 46篇 |
2004年 | 32篇 |
2003年 | 28篇 |
2002年 | 33篇 |
2001年 | 6篇 |
2000年 | 6篇 |
1999年 | 4篇 |
1998年 | 2篇 |
1996年 | 4篇 |
1994年 | 3篇 |
1992年 | 2篇 |
1990年 | 5篇 |
1989年 | 8篇 |
1988年 | 5篇 |
1987年 | 11篇 |
1986年 | 6篇 |
1983年 | 3篇 |
1979年 | 2篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1974年 | 2篇 |
1971年 | 3篇 |
1967年 | 2篇 |
1965年 | 2篇 |
1964年 | 2篇 |
1961年 | 1篇 |
1960年 | 2篇 |
1956年 | 1篇 |
1955年 | 2篇 |
1954年 | 1篇 |
排序方式: 共有1383条查询结果,搜索用时 15 毫秒
71.
Bartolomucci A Palanza P Parmigiani S Pederzani T Merlot E Neveu PJ Dantzer R 《Brain research bulletin》2003,62(3):173-178
Brain cytokines have been implicated in brain plasticity and mood alterations. We present here the first evidence of a chronic stress-induced modulation of central cytokines, in absence of experimentally induced inflammatory processes. Several brain areas were extracted from stressed and control mice and cytokines mRNA analyzed with semi-quantitative RT-PCR. Mice subjected to chronic psychosocial stress showed decreased interleukin (IL)-1beta mRNA levels in the hippocampus, decreased IL-1Receptor antagonist in the striatum and pituitary, decreased tumor necrosis factor (TNF)-alpha in the striatum and hippocampus, and decreased glucocorticoid receptor (GR) in the striatum and hippocampus compared to group housed sibling mice. An independent group of mice subjected to chronic psychosocial stress also showed increased plasma corticosterone. These findings may open new perspectives for understanding the pathophysiological basis of chronic stress-induced disorders. 相似文献
72.
Peyron-Caso E Quignard-Boulangé A Laromiguière M Feing-Kwong-Chan S Véronèse A Ardouin B Slama G Rizkalla SW 《The Journal of nutrition》2003,133(7):2239-2243
Fish oil feeding has been shown to limit visceral fat accumulation in insulin-resistant rats. Our goal was to determine whether this finding is due to increased fat mobilization or decreased lipid storage. Adipocytes were isolated from rats fed for 3 wk a diet containing 57.5 g/100 g sucrose and 14 g/100 g lipids as either fish oil (SF) or a mixture of standard oils (SC); there was also a reference group (R). Substituting fish oil for standard oils protected rats from visceral fat hypertrophy, hypertriglyceridemia and hyperglycemia. The stimulation of lipolysis was greater in adipocytes isolated from SF-fed rats than in those from SC-fed rats. Fatty acid synthase (FAS) activity was markedly lower in the liver but not in the adipose tissues of rats fed SF. Lipoprotein lipase (LPL) activity was 2.2-fold higher in the adipose tissues but not in the muscle in rats fed the SF diet than in those fed the SC diet. The decrease in visceral fat in rats fed fish oil could be attributed to decreased plasma triacylglycerol concentration and/or increased lipid mobilization rather than to reduced lipid storage. 相似文献
73.
Marion S Kara E Crepieux P Piketty V Martinat N Guillou F Reiter E 《The Journal of endocrinology》2006,190(2):341-350
FSH-receptor (FSH-R) signaling is regulated by agonist-induced desensitization and internalization. It has been shown, in a variety of overexpression systems, that G protein-coupled receptor kinases (GRKs) phosphorylate the activated FSH-R, promote beta-arrestin recruitment and ultimately lead to internalization. The accuracy of this mechanism has not yet been demonstrated in cells expressing these different molecules at physiological levels. Using sucrose gradient fractionation, we show that FSH induces the recruitment of the endogenous GRK 2 and beta-arrestin 1/2 from the cytoplasm to the plasma membrane of rat primary Sertoli cells. As assessed by ligand binding, the FSH-R was found expressed in the fractions where GRK 2 and beta-arrestins were recruited upon FSH treatment. In addition, the endogenous beta-arrestin 1 was found dephosphorylated in an agonist-dependent manner. Finally, a significant FSH-binding activity was co-immunoprecipitated with the endogenous beta-arrestins from agonist-stimulated but not from untreated Sertoli cell extracts. This FSH-R interaction with beta-arrestins was sustained for up to 30 min. In conclusion, our data strongly suggest that the GRK/beta-arrestin machinery plays a physiologically relevant role in the regulation of the FSH signaling. 相似文献
74.
Vincent Degos MD PhD Stéphane Peineau PhD Cora Nijboer PhD Angela M. Kaindl MD PhD Stéphanie Sigaut MD Géraldine Favrais MD PhD Frank Plaisant MD PhD Natacha Teissier MD PhD Elodie Gouadon PhD Alain Lombet PhD Elie Saliba MD PhD Graham L. Collingridge PhD Mervyn Maze MB ChB Ferdinando Nicoletti Cobi Heijnen PhD Jean Mantz MD PhD Annemieke Kavelaars PhD Pierre Gressens MD PhD 《Annals of neurology》2013,73(5):667-678
75.
Vincent Esteyrie Caroline Dehais Elodie Martin Catherine Carpentier Emmanuelle Uro-Coste Dominique Figarella-Branger Charlotte Bronniman Damien Pouessel Delphine Larrieu Ciron François Ducray Elizabeth Cohen-Jonathan Moyal Pola Network 《The oncologist》2021,26(5):e838-e846
Background IDH‐mutant anaplastic astrocytomas (AAs) are chemosensitive tumors for which the best choice of adjuvant chemotherapy between procarbazine, lomustine, and vincristine (PCV) or temozolomide (TMZ) after radiotherapy (RT) remains unclear.MethodsIn a large cohort of patients with histologically proven 2016 World Health Organization classification AA with IDH1/2 mutations included in the French national POLA cohort (n = 355), the primary objective was to compare progression‐free survival (PFS) between the two treatment regimens (n = 311). Secondary endpoints were overall survival (OS), progression type, pseudoprogression rate, and toxicity.ResultsThe 4‐year PFS in the RT + PCV arm was 70.8% versus 53.5% in the RT + TMZ arm, with a hazard ratio (HR) of 0.58 (95% confidence interval [CI], 0.38–0.87; p = .0074) in univariable analysis and 0.63 (95% CI, 0.41–0.97; p = .0348) in multivariable analysis. The 4‐year OS in the RT + PCV arm was 84.3% versus 76.6% in the RT + TMZ arm, with an HR of 0.57 (95% CI, 0.30–1.05; p = .0675) in univariable analysis. Toxicity was significantly higher in the RT + PCV arm with more grade ≥3 toxicity (46.7% vs. 8.6%, p < .0001).ConclusionRT + PCV significantly improved PFS compared with RT + TMZ for IDH‐mutant AA. However, RT + TMZ was better tolerated.Implications for PracticeIn the absence of fully conducted randomized trials comparing procarbazine, lomustine, and vincristine (PCV) with temozolomide (TMZ) in adjuvant treatment after radiotherapy (RT) for the management of IDH‐mutant anaplastic astrocytoma (AA) and a similar level of evidence, these two chemotherapies are both equally recommended in international guidelines. This study in a national cohort of IDH‐mutant AA defined according the 2016 World Health Organization (WHO) classification shows for the first time that the RT + PCV regimen significantly improves progression‐free survival in comparison with the RT + TMZ regimen. Even if at the time of analysis the difference in overall survival was not significant, this result provides new evidence for the debate about the chemotherapy regimen to prescribe in adjuvant treatment to RT for WHO 2016 IDH‐mutant AA. 相似文献
76.
Estimation methods for nonlinear mixed-effects modelling have considerably improved over the last decades. Nowadays, several algorithms implemented in different software are used. The present study aimed at comparing their performance for dose-response models. Eight scenarios were considered using a sigmoid E(max) model, with varying sigmoidicity and residual error models. One hundred simulated datasets for each scenario were generated. One hundred individuals with observations at four doses constituted the rich design and at two doses, the sparse design. Nine parametric approaches for maximum likelihood estimation were studied: first-order conditional estimation (FOCE) in NONMEM and R, LAPLACE in NONMEM and SAS, adaptive Gaussian quadrature (AGQ) in SAS, and stochastic approximation expectation maximization (SAEM) in NONMEM and MONOLIX (both SAEM approaches with default and modified settings). All approaches started first from initial estimates set to the true values and second, using altered values. Results were examined through relative root mean squared error (RRMSE) of the estimates. With true initial conditions, full completion rate was obtained with all approaches except FOCE in R. Runtimes were shortest with FOCE and LAPLACE and longest with AGQ. Under the rich design, all approaches performed well except FOCE in R. When starting from altered initial conditions, AGQ, and then FOCE in NONMEM, LAPLACE in SAS, and SAEM in NONMEM and MONOLIX with tuned settings, consistently displayed lower RRMSE than the other approaches. For standard dose-response models analyzed through mixed-effects models, differences were identified in the performance of estimation methods available in current software, giving material to modellers to identify suitable approaches based on an accuracy-versus-runtime trade-off. 相似文献
77.
Marion Imbert-Bouteille Frédéric Tran Mau Them Julien Thevenon Thomas Guignard Vincent Gatinois Jean-Baptiste Riviere Anne Boland Vincent Meyer Jean-François Deleuze Elodie Sanchez Florence Apparailly David Geneviève Marjolaine Willems 《European journal of medical genetics》2019,62(3):161-166
Alazami syndrome (AS) (MIM# 615071) is an autosomal recessive microcephalic primordial dwarfism (PD) with recognizable facial features and severe intellectual disability due to depletion or loss of function variants in LARP7. To date, 15 patients with AS have been reported. Here we describe two consanguineous Algerian sisters with Alazami PD due to LARP7 homozygous pathogenic variants detected by whole exome sequencing. By comparing these two additional cases with those previously reported, we strengthen the key features of AS: severe growth restriction, severe intellectual disability and some distinguishing facial features such as broad nose, malar hypoplasia, wide mouth, full lips and abnormally set teeth. We also report significant new findings enabling further delineation of this syndrome: disproportionately mild microcephaly, stereotypic hand wringing and severe anxiety, thickened skin over the hands and feet, and skeletal, eye and heart malformations. From previous reviews, we summarize the main etiologies of PD according to the involved mechanisms and cellular pathways, highlighting their clinical core features. 相似文献
78.
Elodie Ristorcelli Evelyne Beraud Sylvie Mathieu Dominique Lombardo Alain Verine 《International journal of cancer. Journal international du cancer》2009,125(5):1016-1026
We previously reported that exosomal nanoparticles secreted by human pancreatic tumoral cell lines decrease tumoral cell proliferation through the mitochondria‐dependent apoptotic pathway, because of activation of pro‐apoptotic phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and of glucose synthase kinase‐3β (GSK‐3β). Interactions between exosomal nanoparticles and cells are thought to involve membrane lipid rafts. However, the underlying mechanism is unknown. Here, we report that the interaction of exosomal nanoparticles with pancreatic cancer cells led to decreased expression of hairy and enhancer‐of‐split homolog‐1 (Hes‐1), the intranuclear target of Notch‐1 signaling pathway, and to activation of the apoptotic pathway after a cell cycle arrest in G0G1 phase. Strikingly, the expression level of Notch‐1 pathway components was critical, because exosomal nanoparticles decreased the proliferation of cells in which these partners are either weakly represented, in differentiated adenocarcinoma cells, or inhibited, in poorly differentiated carcinoma cells, by blocking presenilin in the γ‐secretase complex that regulates the Notch‐1 pathway. Overexpression of Notch‐1 intracellular domain resulted in the reversion of the cell proliferation inhibition promoted by exosomal nanoparticles. Blocking presenilin unexpectedly resulted in activation of PTEN and GSK‐3β. Conversely, inhibiting either PTEN or GSK‐3β increased Hes‐1 expression and partially counteracted the inhibition of proliferation promoted by exosomal nanoparticles, highlighting reciprocal regulations between Notch signaling and PTEN/GSK‐3β. We concluded that interactions of exosomal nanoparticles with target cells, at lipid rafts where Notch‐1 pathway partners are localized, hampered the functioning of the Notch‐1 survival pathway and activated the apoptotic pathway, which determines tumoral cell fate. © 2009 UICC 相似文献
79.
Amir Boukhris MD Imed Feki MD Elodie Denis BS Mohamed Imed Miladi MD Alexis Brice MD Chokri Mhiri MD Giovanni Stevanin PhD 《Movement disorders》2008,23(3):429-433
Hereditary spastic paraplegias (HSP) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower limbs. The locus designated spastic paraplegia 15 (SPG15), located in a 16‐Mb interval on chromosome 14q, is associated with a rare autosomal recessive complicated form of HSP known as Kjellin's syndrome. In this study, we describe three additional families, of Tunisian origin, linked to the SPG15 locus, one of which had a significant multipoint LOD score of 3.46. In accordance with previous reports, the phenotype of our patients consisted of early onset spastic paraparesis associated with mental impairment and severe progression. Retinal degeneration was not observed, however, but we extended the phenotype of this form to include peripheral neuropathy and white matter abnormalities on MRI. Interestingly, like retinal degeneration, thin corpus callosum is not a constant feature in this entity. © 2007 Movement Disorder Society 相似文献
80.
Christian Goetz Elodie Breton Philippe Choquet Vincent Israel-Jost André Constantinesco 《Journal of nuclear medicine》2008,49(1):88-93
Localization of regions with increased uptake of radiotracer in small-animal SPECT is greatly facilitated when using coregistration with anatomic images of the same animal. As MRI has several advantages compared with CT (soft-tissue contrast and lack of ionizing radiation) we developed a SPECT/low-field MRI hybrid device for small-animal imaging. METHODS: A small-animal single-pinhole gamma-camera (pinhole, 1.5 mm in diameter and 12 cm in focal length) adjacent to a dedicated low-field (0.1 T) small MR imager (imaging volume, 10 x 10 x 6 cm(3)) was used. The animal was placed in a warmed nonmagnetic polymethyl methacrylate imaging cell for MR acquisition, which was followed immediately by SPECT after translation of the imaging cell from one modality to the other. 3-Dimensional T1-weighted sequences were used for MRI. Phantom studies enabled verification of a low attenuation (10%) for (99m)Tc and (201)Tl and a very slight increase in Compton scattering due to the radiofrequency coil and polymethyl methacrylate imaging cell. RESULTS: SPECT/MRI data acquisition and image coregistration of selected examples using different radiotracers for lungs, kidneys, and brain were obtained in 3 nude mice with isotropic spatial resolutions of 0.5 x 0.5 x 0.5 mm(3) for MRI and 1 x 1 x 1 mm(3) for SPECT. The total acquisition time for combined SPECT and MRI lasted 1 h 45 min. CONCLUSION: A low-magnetic-field strength of 0.1 T is a simple and useful solution for a small-animal dual-imaging device combining pinhole SPECT with the adjacent MR imager. 相似文献