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81.
Sheng Yu Katherine P Liao Stanley Y Shaw Vivian S Gainer Susanne E Churchill Peter Szolovits Shawn N Murphy Isaac S. Kohane Tianxi Cai 《J Am Med Inform Assoc》2015,22(5):993-1000
Objective Analysis of narrative (text) data from electronic health records (EHRs) can improve population-scale phenotyping for clinical and genetic research. Currently, selection of text features for phenotyping algorithms is slow and laborious, requiring extensive and iterative involvement by domain experts. This paper introduces a method to develop phenotyping algorithms in an unbiased manner by automatically extracting and selecting informative features, which can be comparable to expert-curated ones in classification accuracy.Materials and methods Comprehensive medical concepts were collected from publicly available knowledge sources in an automated, unbiased fashion. Natural language processing (NLP) revealed the occurrence patterns of these concepts in EHR narrative notes, which enabled selection of informative features for phenotype classification. When combined with additional codified features, a penalized logistic regression model was trained to classify the target phenotype.Results The authors applied our method to develop algorithms to identify patients with rheumatoid arthritis and coronary artery disease cases among those with rheumatoid arthritis from a large multi-institutional EHR. The area under the receiver operating characteristic curves (AUC) for classifying RA and CAD using models trained with automated features were 0.951 and 0.929, respectively, compared to the AUCs of 0.938 and 0.929 by models trained with expert-curated features.Discussion Models trained with NLP text features selected through an unbiased, automated procedure achieved comparable or slightly higher accuracy than those trained with expert-curated features. The majority of the selected model features were interpretable.Conclusion The proposed automated feature extraction method, generating highly accurate phenotyping algorithms with improved efficiency, is a significant step toward high-throughput phenotyping. 相似文献
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84.
Diabetic retinopathy is associated with a switch in splicing from anti- to pro-angiogenic isoforms of vascular endothelial growth factor 总被引:10,自引:0,他引:10
Aims/hypothesis Proliferative diabetic retinopathy results from excess blood vessel growth into the vitreous fluid of the eye. Retinal angiogenesis is regulated by expression of vascular endothelial growth factor (VEGF), and many studies have shown that VEGF is critically involved in proliferative diabetic retinopathy. VEGF is alternatively spliced to form the angiogenic (VEGFxxx) and potentially anti-angiogenic (VEGFxxxb) family of isoforms. The VEGFxxxb family is found in normal tissues, but down-regulated in renal and prostate cancer. Previous studies on endogenous expression of VEGF in the eye have not distinguished between the two families of isoforms.Methods We measured VEGFxxxb isoform expression in normal human eye tissue (lens, sclera, retina and iris) and vitreous fluid using enzyme-linked immunosorbent assay and Western blotting with a VEGFxxxb-specific antibody.Results VEGFxxxb protein was expressed in lens, sclera, retina, iris and vitreous fluid. Multiple isoforms were seen, including VEGF165b, VEGF121b, VEGF145b, VEGF183b and VEGF189b. In non-diabetic patients, 64±7% of the VEGF in the vitreous was VEGFxxxb (n=18), whereas in diabetic patients only 12.5±3.6% of total VEGF was VEGFxxxb.Conclusions/interpretation Since VEGFxxxb inhibits VEGFxxx-induced angiogenesis in a one-to-one stoichiometric manner, these results show that in the eye of diabetic patients VEGF splicing was switched from an anti-angiogenic to a pro-angiogenic environment. This occurred through changes to the ratio of VEGFxxx : VEGFxxxb. Alterations to splicing, and through that to the balance of VEGF isoforms, could therefore be a potential therapeutic strategy for diabetic retinopathy.Konopatskaya and Perrin are joint first authors. 相似文献
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Dr. Töres Theorell M.D. Dr. Richard H. Rahe MC USNR 《Behavioral medicine (Washington, D.C.)》2013,39(3):18-24
Abstract Thirty-six men and women who experienced a documented myocardial infarction, half of whom ultimately died from their disease and half of whom survived over a six-year period, provided longitudinal recent life changes and ballistocardiographic data. The 18 patients who died from their coronary disease indicated a significant buildup in life changes which peaked approximately one year prior to death; their serial ballistocardiograms indicated a significant buildup in average force of contraction which was seen to peak approximately six months prior to death. The 18 post-infarction patients who survived the six-year follow-up showed neither a buildup in life change nor a buildup in the ballistocardiographic index of cardiac contraction force. These findings of a life change peak preceding ballistocardiographic evidence of an “overworked” heart are discussed in terms of their possible medical and psychophysiological significances. 相似文献
87.
Nicholas Beazley-Long Jing Hua Thomas Jehle Richard P. Hulse Rick Dersch Christina Lehrling Heather Bevan Yan Qiu Wolf A. Lagrèze David Wynick Amanda J. Churchill Patrick Kehoe Steven J. Harper David O. Bates Lucy F. Donaldson 《The American journal of pathology》2013,183(3):918-929
Vascular endothelial growth factor (VEGF) A is generated as two isoform families by alternative RNA splicing, represented by VEGF-A165a and VEGF-A165b. These isoforms have opposing actions on vascular permeability, angiogenesis, and vasodilatation. The proangiogenic VEGF-A165a isoform is neuroprotective in hippocampal, dorsal root ganglia, and retinal neurons, but its propermeability, vasodilatatory, and angiogenic properties limit its therapeutic usefulness. In contrast, a neuroprotective effect of endogenous VEGF-A165b on neurons would be advantageous for neurodegenerative pathologies. Endogenous expression of human and rat VEGF-A165b was detected in hippocampal and cortical neurons. VEGF-A165b formed a significant proportion of total VEGF-A in rat brain. Recombinant human VEGF-A165b exerted neuroprotective effects in response to multiple insults, including glutamatergic excitotoxicity in hippocampal neurons, chemotherapy-induced cytotoxicity of dorsal root ganglion neurons, and retinal ganglion cells (RGCs) in rat retinal ischemia-reperfusion injury in vivo. Neuroprotection was dependent on VEGFR2 and MEK1/2 activation but not on p38 or phosphatidylinositol 3–kinase activation. Recombinant human VEGF-A165b is a neuroprotective agent that effectively protects both peripheral and central neurons in vivo and in vitro through VEGFR2, MEK1/2, and inhibition of caspase-3 induction. VEGF-A165b may be therapeutically useful for pathologies that involve neuronal damage, including hippocampal neurodegeneration, glaucoma diabetic retinopathy, and peripheral neuropathy. The endogenous nature of VEGF-A165b expression suggests that non–isoform-specific inhibition of VEGF-A (for antiangiogenic reasons) may be damaging to retinal and sensory neurons.Vascular endothelial growth factor (VEGF) A, originally described as a potent vascular permeability and growth factor for endothelial cells, is up-regulated in the brain during stroke and ischemic episodes1 and has been linked with many neuronal diseases. The most widely studied isoform of VEGF-A, VEGF-A165a, is up-regulated in hypoxia, induces increased vascular permeability in neuronal vasculature, and can stimulate angiogenesis after ischemic episodes. The resulting edema and hyperemia can be damaging, but VEGF-A165a has also been found to have direct anticytotoxic effects on neurons, raising the possibility that it may act as an endogenous neuroprotective agent in neurodegenerative pathologies. VEGF-A exerts neurotrophic (survival) and neurotropic (neurogenesis and axon outgrowth) actions, which, although initially thought to be a function of increased angiogenesis and perfusion after neuronal injury,2 are now appreciated as direct effects of VEGF-A on neurons.The vegfa gene encodes numerous products by differential splicing, but not all isoforms exert the same effects.3 Alternative splicing of exon 8 leads to two functionally distinct families: the proangiogenic VEGF-Axxxa family and the counteracting VEGF-Axxxb family.4,5 VEGF-A165b prevents the VEGF-A165a effects on increased vascular permeability, blood vessel growth, and vasodilatation.4–7The therapeutic potential of VEGF-A and anti–VEGF-A treatments are now widely recognized, and effective anti–VEGF-A treatments are available in ophthalmology8 and oncology.9 The finding that VEGF-A is implicated in neuronal disorders (eg, Alzheimer disease, Parkinson disease, Huntington disease, diabetic neuropathy, and amyotrophic lateral sclerosis10) provides a rationale for the use of VEGF-A as a therapeutic agent in neurodegenerative conditions. Although this rationale is supported by preclinical evidence,11 the identification of the VEGF-Axxxb family requires reexamination of VEGF-A isoforms in these contexts to allow for the clear evidence that VEGF-A splicing variants are not functionally equivalent3 and to determine whether augmentation of the proangiogenic isoform family (VEGF-Axxxa) alone may have deleterious effects (eg, in occult malignancy and carcinoma in situ).The neuroprotective profile of the exon 8 alternatively spliced isoforms VEGF-Axxxb remains unexplored. Interestingly, VEGF-Axxxb isoforms do not exhibit the vascular effects seen with VEGF-Axxxa isoforms, such as a sustained increase in capillary permeability or hypotension.5,12 The lack of these potential adverse effects may make VEGF-Axxxb isoforms more amenable as therapeutic agents in neurodegenerative diseases.We therefore tested the hypothesis that VEGF-A165b is neuroprotective for central and peripheral neurons. We found that VEGF-A165b is expressed in central neurons and is neuroprotective in vitro and in vivo. This finding indicates that VEGF-A165b may prove to be a suitable therapeutic agent in neurodegenerative disorders, exhibiting fewer adverse effects than VEGF-A165a. 相似文献
88.
AMJ van Wegberg RAF Evers JGM Burgerhof E van Dam M.R. Heiner-Fokkema MCH Janssen MC de Vries FJ van Spronsen 《Molecular genetics and metabolism》2021,132(1):49-55
BackgroundIn patients with phenylketonuria, stability of blood phenylalanine and tyrosine concentrations might influence brain chemistry and therefore patient outcome. This study prospectively investigated the effects of tetrahydrobiopterin (BH4), as a chaperone of phenylalanine hydroxylase on diurnal and day-to-day variations of blood phenylalanine and tyrosine concentrations.MethodsBlood phenylalanine and tyrosine were measured in dried blood spots (DBS) four times daily for 2 days (fasting, before lunch, before dinner, evening) and once daily (fasting) for 6 days in a randomized cross-over design with a period with BH4 and a period without BH4. The sequence was randomized. Eleven proven BH4 responsive PKU patients participated, 5 of them used protein substitutes during BH4 treatment. Natural protein intake and protein substitute dosing was adjusted during the period without BH4 in order to keep DBS phenylalanine levels within target range. Patients filled out a 3-day food diary during both study periods. Variations of DBS phenylalanine and Tyr were expressed in standard deviations (SD) and coefficient of variation (CV).ResultsBH4 treatment did not significantly influence day-to-day phenylalanine and tyrosine variations nor diurnal phenylalanine variations, but decreased diurnal tyrosine variations (median SD 17.6 μmol/l, median CV 21.3%, p = 0.01) compared to diet only (median SD 34.2 μmol/l, median CV 43.2%). Consequently, during BH4 treatment diurnal phenylalanine/tyrosine ratio variation was smaller, while fasting tyrosine levels tended to be higher.ConclusionBH4 did not impact phenylalanine variation but decreased diurnal tyrosine and phenylalanine/tyrosine ratio variations, possibly explained by less use of protein substitute and increased tyrosine synthesis. 相似文献
89.
Randle C. Johnson M.D. Major USAF MC Michael H. Bleshman M.D. James W. DeFord M.D. 《Diseases of the colon and rectum》1978,21(7):510-513
Summary We have presented an unusual case of benign lymphoid hyperplasia, which manifested as a cecal deformity in a 15-year-old boy.
The clinical manifestation may have been related to partial occlusion of the appendiceal orifice. In future cases of benign
lymphoid hyperplasia, colonoscopy may be diagnostic, and if it is used for continuing observation, may avert unnecessary surgical
procedures in children and young adults. 相似文献
90.
LTC Lawrence F. Johnson MC USA LTC Tom R. Demeester MC USA MAJ Roger C. Haggitt MC USA 《Digestive diseases and sciences》1978,23(6):498-509
Exposure of the distal esophageal mucosa to acid gastric juice was quantitated by 24-hr pH monitoring in 100 individuals and was correlated with morphologic data derived from esophageal biopsies. The degree of acid exposure to the distal esophagus correlated directly with increases in both relative and absolute length of the subepithelial papillae and to relative basal zone hyperplasia. Both papillary length and basal zone hyperplasia decreased after antireflux surgery had reduced acid exposure to normal. Reflux in the recumbent position resulted in prolonged exposure of the mucosa to acid because of poor acid clearing from the esophagus. This caused longer papillae than did upright reflux, where there were more frequent reflux episodes, but with rapid acid clearance. The presence of a hiatal hernia was associated with longer papilae, lower DES pressure, increased reflux frequency, and prolonged recumbent acid clearance. Twenty-four hour pH monitoring correlated better with papillary length than did symptoms or other clinical measures of gastroesophageal reflux. 相似文献