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排序方式: 共有1509条查询结果,搜索用时 46 毫秒
21.
Matthias Szabolcs Megan Keniry Laura Simpson Latarsha J. Reid Susan Koujak Sarah C. Schiff Giselle Davidian Scott Licata Sofia Gruvberger-Saal Vundavalli V.V.S. Murty Subhadra Nandula Argiris Efstratiadis Jake A. Kushner Morris F. White Ramon Parsons 《The American journal of pathology》2009,174(1):276-286
Mutations in the phosphatase and tensin homologue (PTEN)/phosphatidylinositol-3 kinase-α (PI3K) signaling pathway are frequently found in human cancer. In addition, Pten+/− mice develop tumors in multiple organs because of the activation of the PI3K signaling cascade. Because activation of PI3K signaling leads to feedback inhibition of insulin receptor substrate-2 (IRS2) expression, an upstream activator of PI3K, we therefore anticipated that IRS2 expression would be low in tumors that lack PTEN. Surprisingly, however, an elevation of IRS2 was often detected in tumor samples in which PTEN levels were compromised. To determine the potential contribution of Irs2 to tumor progression, Pten+/− mice were crossed with Irs2+/− mice. Deletion of Irs2 did not affect the initiation of neoplasia found in Pten+/− mice but suppressed cancer cell growth, proliferation, and invasion through the basement membrane. Deletion of Irs2 also attenuated the expression of Myc in prostatic intraepithelial neoplasia in Pten+/− mice. In addition, the expression levels of IRS2 and MYC were highly correlated in human prostate cancer, and IRS2 could stimulate MYC expression in cultured cells. Our findings provide evidence that the PI3K-activating adaptor Irs2 contributes to tumor progression in Pten+/− mice by stimulating both Myc and DNA synthesis. 相似文献
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Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C 总被引:21,自引:0,他引:21
Promrat K McDermott DH Gonzalez CM Kleiner DE Koziol DE Lessie M Merrell M Soza A Heller T Ghany M Park Y Alter HJ Hoofnagle JH Murphy PM Liang TJ 《Gastroenterology》2003,124(2):352-360
BACKGROUND & AIMS: CCR5Delta32, a 32-base pair deletion of the CC chemokine receptor (CCR) 5 gene, is associated with slowed human immunodeficiency virus disease progression in heterozygotes and protection against infection in homozygotes. A recent study found a higher than expected frequency of CCR5Delta32/Delta32 in patients with hepatitis C virus infection. The roles of other disease-associated chemokine system polymorphisms have not been evaluated in hepatitis C virus infection. METHODS: Six chemokine system polymorphisms (CCR5Delta32, CCR5 promoter 59029-G/A, CCR2 -64I, RANTES [regulated upon activation, normal T cells expressed and secreted] -403 -G/A, and -28 -C/G and stromal derived factor 1 -3'A) were studied in 417 patients with liver diseases (339 with hepatitis C) and 2380 blood donors. The clinical parameters of hepatitis C virus infection were compared between carriers and noncarriers of each genetic variant. RESULTS: The frequency of CCR5Delta32 homozygosity was 0.8% in whites with hepatitis C virus and 1.1% in controls (P = 0.75). The CCR5Delta32 allele was not associated with any of the clinical parameters of hepatitis C virus infection. Hepatitis C virus-seropositive whites with the RANTES -403-A allele were less likely to have severe hepatic inflammation compared with those without (odds ratio, 0.34; P = 0.03). In multivariate analysis, the CCR5 promoter 59029 -A allele was marginally associated with a sustained response to interferon therapy (odds ratio, 3.07; P = 0.048). CONCLUSIONS: In this cohort, the frequency of CCR5Delta32 homozygosity in patients with hepatitis C was similar to controls. The high prevalence of CCR5Delta32 homozygosity in the hepatitis C virus patients of the earlier study likely reflects resistance to human immunodeficiency virus infection in hemophiliacs rather than a susceptibility to hepatitis C virus infection. Expression of CCR5 and RANTES may be important in the modulation of hepatic inflammation and response to interferon therapy in chronic hepatitis C. 相似文献
24.
Soza A Heller T Ghany M Lutchman G Jake Liang T Germain J Hsu HH Park Y Hoofnagle JH 《Journal of hepatology》2005,43(1):67-71
BACKGROUND/AIMS: Currently, there are no effective therapies available for patients with chronic hepatitis C who have failed to respond to optimal interferon alfa-based regimens. The aims of this pilot study were to assess the antiviral activity and safety of interferon gamma in chronic hepatitis C. METHODS: Patients with chronic hepatitis C, genotype 1, who had not responded to or who had relapsed after therapy with interferon alfa and ribavirin were enrolled in a trial of interferon gamma 1b given in doses of 100, 200 or 400 microg subcutaneously three times weekly for 4 weeks. Frequent blood samples were obtained for HCV RNA levels. RESULTS: Fourteen patients were enrolled. Geometric mean HCV RNA levels remained unchanged. Serum aminotransferase levels also did not change, while there were significant decreases in neutrophil counts (-41% from baseline) and hematocrit (-5%). Low grade fever and malaise were common with the first injection of interferon gamma, but no serious side effects were encountered. CONCLUSIONS: Although relatively well tolerated, interferon gamma in doses of 100-400 microg thrice weekly had no effect on HCV RNA levels in patients with chronic hepatitis C who had failed to achieve a sustained response to interferon alfa-based therapies. 相似文献
25.
26.
Jake L. Nowicki Daniel Mullany Amy Spooner Tracy A. Nowicki Peta M. Mckay Amanda Corley Paul Fulbrook John F. Fraser 《Australian critical care》2018,31(5):257-263
Background
Pressure injuries contribute significantly to patient morbidity and healthcare costs. Critically ill patients are a high risk group for pressure injury development and may suffer from skin failure secondary to hypoperfusion. The aim of this study was to report hospital acquired pressure injury incidence in intensive care and non-intensive care patients; and assess the clinical characteristics and outcomes of ICU patients reported as having a hospital acquired pressure injury to better understand patient factors associated with their development in comparison to ward patients.Methods
The setting for this study was a 630 bed, government funded, tertiary referral teaching hospital. A secondary data analysis was undertaken on all patients with a recorded PI on the hospital’s critical incident reporting systems and admitted patient data collection between July 2006 to March 2015.Results
There were a total of 5280 reports in 3860 patients; 726 reports were intensive care patients and 4554 were non-intensive care patients, with severe hospital acquired PI reported in 22 intensive care patients and 54 non-intensive care patients. Pressure injury incidence increased in intensive care patients and decreased in non-intensive care patients over the study period. There were statistically significant differences in the anatomical location of severe hospital acquired pressure injuries between these groups (p = 0.008).Conclusion
Intensive care patients have greater than 10-fold higher hospital acquired pressure injury incidence rates compared to other hospitalised patients. The predisposition of critically ill patients leaves them susceptible to pressure injury development despite implementation of pressure injury prevention strategies. Skin failure appears to be a significant phenomenon in critically ill patients and is associated with the use of vasoactive agents and support systems such as extra corporeal membrane oxygenation and mechanical ventilation. 相似文献27.
28.
T. Jake Samuel Rhys Beaudry Satyam Sarma Vlad Zaha Mark J. Haykowsky Michael D. Nelson 《Current heart failure reports》2018,15(6):332-339
Purpose of Review
This review summarizes recent developments highlighting the clinical utility of diastolic stress testing along the heart failure continuum.Recent Findings
Invasive hemodynamic assessment of cardiac filling pressures during physiological stress is the gold-standard technique for unmasking diastolic dysfunction. Non-invasive surrogate techniques, such as Doppler ultrasound, have shown excellent agreement with invasive approaches and are now recommended by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. While cycle exercise is often advocated, recent evidence supports the use of isometric handgrip as a viable alternative stressor.Summary
Diastolic stress testing is a powerful tool to enhance detection of diastolic dysfunction, is able to differentiate between cardiac and non-cardiac pathology, and should be incorporated into routine clinical assessment.29.
Kathrin Witmer Farah A. Dahalan Michael J. Delves Sabrina Yahiya Oliver J. Watson Ursula Straschil Darunee Chiwcharoen Boodtee Sornboon Sasithon Pukrittayakamee Richard D. Pearson Virginia M. Howick Mara K. N. Lawniczak Nicholas J. White Arjen M. Dondorp Lucy C. Okell Kesinee Chotivanich Andrea Ruecker Jake Baum 《Antimicrobial agents and chemotherapy》2021,65(1)
30.
Patrick J. Cimino Yue Yang Xianwu Li Jake F. Hemingway Makenzie K. Cherne Shawn B. Khademi Yoshinori Fukui Kathleen S. Montine Thomas J. Montine C. Dirk Keene 《Experimental and molecular pathology》2013
Alzheimer's disease (AD) neuropathology is characterized by innate immune activation primarily through prostaglandin E2 (PGE2) signaling. Dedicator of cytokinesis 2 (DOCK2) is a guanyl nucleotide exchange factor expressed exclusively in microglia in the brain and is regulated by PGE2 receptor EP2. DOCK2 modulates microglia cytokine secretion, phagocytosis, and paracrine neurotoxicity. EP2 ablation in experimental AD results in reduced oxidative damage and amyloid beta (Aβ) burden. This discovery led us to hypothesize that genetic ablation of DOCK2 would replicate the anti-Aβ effects of loss of EP2 in experimental AD. To test this hypothesis, we crossed mice that lacked DOCK2 (DOCK2 −/−), were hemizygous for DOCK2 (DOCK2 +/−), or that expressed two DOCK2 genes (DOCK2 +/+) with APPswe-PS1Δe9 mice (a model of AD). While we found no DOCK2-dependent differences in cortex or in hippocampal microglia density or morphology in APPswe-PS1Δe9 mice, cerebral cortical and hippocampal Aβ plaque area and size were significantly reduced in 10-month-old APPswe-PS1Δe9/DOCK2 −/− mice compared with APPswe-PS1Δe9/DOCK2 +/+ controls. DOCK2 hemizygous APPswe-PS1Δe9 mice had intermediate Aβ plaque levels. Interestingly, soluble Aβ42 was not significantly different among the three genotypes, suggesting the effects were mediated specifically in fibrillar Aβ. In combination with earlier cell culture results, our in vivo results presented here suggest DOCK2 contributes to Aβ plaque burden via regulation of microglial innate immune function and may represent a novel therapeutic target for AD. 相似文献