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A 7-deaza-adenosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties 下载免费PDF全文
Olsen DB Eldrup AB Bartholomew L Bhat B Bosserman MR Ceccacci A Colwell LF Fay JF Flores OA Getty KL Grobler JA LaFemina RL Markel EJ Migliaccio G Prhavc M Stahlhut MW Tomassini JE MacCoss M Hazuda DJ Carroll SS 《Antimicrobial agents and chemotherapy》2004,48(10):3944-3953
Improved treatments for chronic hepatitis C virus (HCV) infection are needed due to the suboptimal response rates and deleterious side effects associated with current treatment options. The triphosphates of 2'-C-methyl-adenosine and 2'-C-methyl-guanosine were previously shown to be potent inhibitors of the HCV RNA-dependent RNA polymerase (RdRp) that is responsible for the replication of viral RNA in cells. Here we demonstrate that the inclusion of a 7-deaza modification in a series of purine nucleoside triphosphates results in an increase in inhibitory potency against the HCV RdRp and improved pharmacokinetic properties. Notably, incorporation of the 7-deaza modification into 2'-C-methyl-adenosine results in an inhibitor with a 20-fold-increased potency as the 5'-triphosphate in HCV RdRp assays while maintaining the inhibitory potency of the nucleoside in the bicistronic HCV replicon and with reduced cellular toxicity. In contrast, while 7-deaza-2'-C-methyl-GTP also displays enhanced inhibitory potency in enzyme assays, due to poor cellular penetration and/or metabolism, the nucleoside does not inhibit replication of a bicistronic HCV replicon in cell culture. 7-Deaza-2'-C-methyl-adenosine displays promising in vivo pharmacokinetics in three animal species, as well as an acute oral lethal dose in excess of 2,000 mg/kg of body weight in mice. Taken together, these data demonstrate that 7-deaza-2'-C-methyl-adenosine is an attractive candidate for further investigation as a potential treatment for HCV infection. 相似文献
114.
Vasiliadis HM Collet JP Shapiro S Venturini A Trojan DA 《Archives of physical medicine and rehabilitation》2002,83(8):1109-1115
OBJECTIVE: To identify predictive and associated factors for muscle and joint pain in postpoliomyelitis syndrome (PPS). DESIGN: Cross-sectional study design. SETTING: Postpolio clinics. PARTICIPANTS: Baseline data on 126 PPS patients entered into a multicentered clinical trial. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Adjusted odds ratios were computed by using logistic regression modeling. Patients with or without muscle or joint pain were compared with regard to predictors and associated factors. RESULTS: In multivariate analyses for muscle pain, significant predictive and associated factors were female gender (P=.0006), longer duration of general fatigue (P=.019), and a lower score on the general health scale (P=.009) of the Medical Outcomes Study 36-Item Short-From Health Survey (SF-36). In multivariate analyses for joint pain, significant predictive and associated factors were female gender (P<.003), longer latency (duration of stability after polio; P=.008), younger age at interview (P<.002), greater weakness at acute polio (P<.07), weaker lower-extremity muscle strength (P<.04), and a lower SF-36 general health scale score (P<.02). CONCLUSIONS: Women are more likely to report muscle and joint pain in PPS. Greater initial motor unit involvement and lower-extremity weakness may be additional important factors for determining joint pain. Both muscle and joint pain are associated with reductions in quality of life. 相似文献
115.
Replication fitness and NS5B drug sensitivity of diverse hepatitis C virus isolates characterized by using a transient replication assay 总被引:4,自引:0,他引:4
Ludmerer SW Graham DJ Boots E Murray EM Simcoe A Markel EJ Grobler JA Flores OA Olsen DB Hazuda DJ LaFemina RL 《Antimicrobial agents and chemotherapy》2005,49(5):2059-2069
The innate genetic variability characteristic of chronic hepatitis C virus (HCV) infection makes drug resistance a concern in the clinical development of HCV inhibitors. To address this, a transient replication assay was developed to evaluate the replication fitness and the drug sensitivity of NS5B sequences isolated from the sera of patients with chronic HCV infection. This novel assay directly compares replication between NS5B isolates, thus bypassing the potential sequence and metabolic differences which may arise with independent replicon cell lines. Patient-derived NS5B sequences were similar to those of the established HCV genotypes, but isolates from each patient shared genetic variability specific to that patient, with additional genetic variability observed across the individual isolates. Every sample provided functional NS5B isolates which supported subgenomic replication, frequently to levels comparable to that of laboratory-optimized replicons. All isolates were equivalently sensitive to an active-site nucleoside inhibitor, but the sensitivities to a panel of nonnucleoside inhibitors which targeted three distinct sites on NS5B varied among the isolates. In con1, the original laboratory-optimized replicon, the NS5B S282T substitution confers resistance to the nucleoside inhibitor but impairs replication. This substitution was engineered into both genotype 1a and genotype 1b isolates. Replication was severely debilitated, demonstrating that no compensatory residues were encoded within these genetically diverse sequences to increase the replication fitness of the mutated replicons. This work describes a transient replicon-based assay that can support the clinical development of compounds which target NS5B and demonstrates its utility by examining several patient-derived NS5B isolates for replication fitness and differential sensitivity to NS5B inhibitors. 相似文献
116.
Franco Fiaccadori Florio Ghinelli Guido Pelosi Daria Sacchini Gian Luigi Vaona Maria Luisa Zeneroli Emilio Rocchi Vincenzo Santunione Paolo Gibertini Ezio Ventura 《International Journal of Clinical & Laboratory Research》1980,10(2):411-422
Summary Hepatic encephalopathy may complicate chronic liver diseases and portosystemic shunting. Recently it has been suggested that
a change in the blood amino acid pattern (with elevated phenylalanine, tyrosine, methionine and depressed branched chain amino
acids) and increased levels of octopamine and phenylethanolamine (a false neurotransmitter) are related causally to neurological
symptoms. Previous works have suggested that an amino acid mixture of special formulation (enriched in branched chain amino
acids and poor in aromatic amino acids) can normalize the plasma amino acid levels and consequently improve the neurological
state. In order to test the actual therapeutic effect of these specially formulated solutions, the following therapeutic protocols
were administered to 3 groups of cirrhotic patients: group 1 (15 cases): lactulose; group 2 (8 cases): special amino acid
solutions; group 3 (8 cases): special amino acid solutions and lactulose. Clinical, laboratory and EEG examinations in a preliminary
experiment, before and after treatment, showed that the best effect was obtained by the combined treatment with amino acid
solutions and lactulose. 相似文献
117.
Fabio Scarpa Daria Sanna Tiziana Lai Piero Cossu Marco Curini-Galletti Marco Casu 《Conservation Genetics Resources》2016,8(4):411-413
The order Proseriata (Platyhelminthes) represents one of the most abundant soft-bodied meiofaunal groups. These minute interstitial organisms are characterized by a very simple morphology, which often hides the occurrence of cryptic species. Accordingly, molecular analyses are often needed to provide reliable taxonomic assessment and/or species identification. For these purposes the 18S and 28S rDNA genes have been so far the markers of choice. Here, we present a set of new primers for the sequencing of the whole ribosomal region in Proseriata, which improves the size of the sequenced segment from the current 3100 bp (18S + 28S D1–D6) to about 6300 bp. A broader molecular dataset may be used to achieve deeper insights on the systematics of Proseriata. 相似文献
118.
Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure 总被引:24,自引:0,他引:24 下载免费PDF全文
Urbanek K Torella D Sheikh F De Angelis A Nurzynska D Silvestri F Beltrami CA Bussani R Beltrami AP Quaini F Bolli R Leri A Kajstura J Anversa P 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(24):8692-8697
In this study, we tested whether the human heart possesses a cardiac stem cell (CSC) pool that promotes regeneration after infarction. For this purpose, CSC growth and senescence were measured in 20 hearts with acute infarcts, 20 hearts with end-stage postinfarction cardiomyopathy, and 12 control hearts. CSC number increased markedly in acute and, to a lesser extent, in chronic infarcts. CSC growth correlated with the increase in telomerase-competent dividing CSCs from 1.5% in controls to 28% in acute infarcts and 14% in chronic infarcts. The CSC mitotic index increased 29-fold in acute and 14-fold in chronic infarcts. CSCs committed to the myocyte, smooth muscle, and endothelial cell lineages increased approximately 85-fold in acute infarcts and approximately 25-fold in chronic infarcts. However, p16(INK4a)-p53-positive senescent CSCs also increased and were 10%, 18%, and 40% in controls, acute infarcts, and chronic infarcts, respectively. Old CSCs had short telomeres and apoptosis involved 0.3%, 3.8%, and 9.6% of CSCs in controls, acute infarcts, and chronic infarcts, respectively. These variables reduced the number of functionally competent CSCs from approximately 26,000/cm3 of viable myocardium in acute to approximately 7,000/cm3 in chronic infarcts, respectively. In seven acute infarcts, foci of spontaneous myocardial regeneration that did not involve cell fusion were identified. In conclusion, the human heart possesses a CSC compartment, and CSC activation occurs in response to ischemic injury. The loss of functionally competent CSCs in chronic ischemic cardiomyopathy may underlie the progressive functional deterioration and the onset of terminal failure. 相似文献
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