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131.
Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages 总被引:7,自引:4,他引:7
The bone marrow microenvironment supports and regulates the proliferation and differentiation of hematopoietic cells. Dysregulated hematopoiesis in chronic myelogenous leukemia (CML) is caused, at least in part, by abnormalities in CML hematopoietic progenitors leading to altered interactions with the marrow microenvironment. The role of the microenvironment itself in CML has not been well characterized. We examined the capacity of CML stroma to support the growth of long-term culture-initiating cells (LTC-IC) obtained from normal and CML marrow. The growth of normal LTC-IC on CML stroma was significantly reduced compared with normal stroma. This did not appear to be related to abnormal production of soluble factors by CML stroma because normal LTC- IC grew equally well in Transwells above CML stroma as in Transwells above normal stroma. In addition, CML and normal stromal supernatants contained similar quantities of both growth-stimulatory (granulocyte colony-stimulating factor (CSF), interleukin-6, stem cell factor, granulocyte-macrophage CSF, and interleukin-1 beta) and growth- inhibitory cytokines (transforming growth factor-beta, macrophage inflammatory protein-1 alpha, and tumor necrosis factor-alpha). The relative proportion of different cell types in CML and normal stroma was similar. However, polymerase chain reaction and fluorescence in situ hybridization studies showed the presence of bcr-abl-positivo cells in CML stroma, which were CD14+ stromal macrophages. To assess the effect of these malignant macrophages on stromal function, CML and normal stromal cells were separated by fluorescence-activated cell sorting into stromal mesenchymal cell (CD14-) and macrophage (CD14+) populations. CML and normal CD14- cells supported the growth of normal LTC-IC equally well. However, the addition of CML macrophages to normal or CML CD14- mesenchymal cells resulted in impaired progenitor support. This finding indicates that the abnormal function of CML bone marrow stroma is related to the presence of malignant macrophages. In contrast to normal LTC-IC, the growth of CML LTC-IC on allogeneic CML stromal layers was not impaired and was significantly better than that of normal LTC-IC cocultured with the same CML stromal layers. These studies demonstrate that, in addition to abnormalities in CML progenitors themselves, abnormalities in the CML marrow microenvironment related to the presence of malignant stromal macrophages may contribute to the selective expansion of leukemic progenitors and suppression of normal hematopoiesis in CML. 相似文献
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Andrew D Boyd Young Min Yang Jianrong Li Colleen Kenost Mike D Burton Bryan Becker Yves A Lussier 《J Am Med Inform Assoc》2015,22(1):19-28
Reporting of hospital adverse events relies on Patient Safety Indicators (PSIs) using International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) codes. The US transition to ICD-10-CM in 2015 could result in erroneous comparisons of PSIs. Using the General Equivalent Mappings (GEMs), we compared the accuracy of ICD-9-CM coded PSIs against recommended ICD-10-CM codes from the Centers for Medicaid/Medicare Services (CMS). We further predict their impact in a cohort of 38 644 patients (1 446 581 visits and 399 hospitals). We compared the predicted results to the published PSI related ICD-10-CM diagnosis codes. We provide the first report of substantial hospital safety reporting errors with five direct comparisons from the 23 types of PSIs (transfusion and anesthesia related PSIs). One PSI was excluded from the comparison between code sets due to reorganization, while 15 additional PSIs were inaccurate to a lesser degree due to the complexity of the coding translation. The ICD-10-CM translations proposed by CMS pose impending risks for (1) comparing safety incidents, (2) inflating the number of PSIs, and (3) increasing the variability of calculations attributable to the abundance of coding system translations. Ethical organizations addressing ‘data-, process-, and system-focused’ improvements could be penalized using the new ICD-10-CM Agency for Healthcare Research and Quality PSIs because of apparent increases in PSIs bearing the same PSI identifier and label, yet calculated differently. Here we investigate which PSIs would reliably transition between ICD-9-CM and ICD-10-CM, and those at risk of under-reporting and over-reporting adverse events while the frequency of these adverse events remain unchanged. 相似文献
135.
Primary structure and biological activity of human brain-derived neurotrophic factor 总被引:13,自引:0,他引:13
A Rosenthal D V Goeddel T Nguyen E Martin L E Burton A Shih G R Laramee F Wurm A Mason K Nikolics 《Endocrinology》1991,129(3):1289-1294
Brain-derived neurotrophic factor (BDNF) is a 27-kDa basic protein of noncovalently linked 13.5-kD subunits related to nerve growth factor and is produced by the central nervous system (CNS). BDNF has been shown to promote the survival of neurons located in or directly connected with the CNS and is likely to function in adjusting the cell number within neuronal populations to the need of this projection field. Here we describe the primary structure of a human BDNF cDNA, the biological activities of pure recombinant human BDNF, and the tissue distribution of rat BDNF. BDNF mRNA can be found in some peripheral tissues as well as in the CNS, and recombinant human BDNF is a potent neurotrophic factor for primary peripheral sensory neurons. 相似文献
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Free radicals alter ionic calcium levels and membrane phospholipids in cultured rat ventricular myocytes 总被引:1,自引:0,他引:1
K P Burton A C Morris K D Massey L M Buja H K Hagler 《Journal of molecular and cellular cardiology》1990,22(9):1035-1047
Oxygen-derived free radicals have been implicated in damage to membrane phospholipids leading to alterations in membrane function. The purpose of this study was to investigate alterations in intracellular ionic calcium (Ca2+) levels and Ca2+ transients, cellular morphology, conjugated diene levels, arachidonate release, and lactate dehydrogenase release resulting from the exposure of cultured neonatal rat ventricular myocytes to a xanthine oxidase catalyzed free radical generating system capable of producing superoxide and hydroxyl radicals. The ability of alpha-tocopherol to prevent alterations due to free radical exposure was investigated. For measurements of Ca2+, myocytes grown on coverslips for 3-4 days were loaded with fura-2/AM and studied by microspectrofluorometry. Control myocytes superfused with a physiological buffer or buffer containing purine and iron-loaded transferrin exhibited Ca2+ transients associated with spontaneous contractions. For control, buffer perfused myocytes (n = 4), the fura-2 340/380 ratios were 0.5 +/- 0.1 (mean +/- S.E.) and 1.6 +/- 0.03 at the minimum and maximum, respectively, of the Ca2+ transient, after 1 h of perfusion. Exposure to the free radical generating solution (n = 14) altered intracellular Ca2+. The 340/380 minimum ratio was 639% of the control value after approximately 30-70 mins with cessation of normal Ca2+ transients. Bleb development was associated with increased Ca2+. Myocytes reperfused with control medium continued to exhibit an elevated minimum fura-2 ratio at 687% of control. Myocytes pretreated with 10 microM alpha-tocopherol (n = 13) for 18-24 h and exposed to free radicals did not exhibit increases in intracellular Ca2+, having a minimum 340/380 ratio of 0.5 +/- 0.1 after 60-90 mins, and although myocytes often ceased contracting, they resumed spontaneous Ca2+ transients with control medium reperfusion and also maintained normal structure. Exposure of myocyte cultures to free radical generating solutions resulted in increased levels of conjugated dienes and increased release of [3H]arachidonate and lactate dehydrogenase compared to control values after 1 h. alpha-Tocopherol treatment attenuated the increase in conjugated diene levels, and the release of [3H]arachidonate and lactate dehydrogenase. Thus, free radicals alter intracellular Ca2+, conjugated dienes and membrane structure indicating their ability to induce altered ionic homeostasis in association with myocardial membrane damage. alpha-Tocopherol decreased free radical mediated injury. 相似文献
138.
Concepts of rehabilitation for the management of low back pain 总被引:4,自引:0,他引:4
This chapter develops rehabilitation principles for the clinical and occupational management of non-specific low back pain (LBP). Rehabilitation has traditionally been a secondary intervention, which focused on permanent impairment, but this is inappropriate for LBP. Most patients with LBP do not have any irremediable impairment and long-term incapacity is not inevitable: given the right care, support and opportunity, most should be able to return to work. Rehabilitation should then address obstacles to recovery and barriers to (return to) work. Rehabilitation should not be a separate, second stage after 'treatment' is complete: rehabilitation principles should be integral to clinical and occupational management. It should be possible to reduce sickness absence and long-term incapacity due to LBP by at least 30-50%, but this will require a fundamental shift in management culture. 相似文献
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OBJECTIVES: Generalized pruritus is a common complication of cholestatic liver diseases, although its pathogenesis remains elusive. Current treatments are often inadequate and may be poorly tolerated, so the clinician is sometimes faced with a patient in misery and no good therapeutic options. Because, in our experience, several patients with primary biliary cirrhosis (PBC) claimed that sertraline had improved their pruritus, we sought to determine whether sertraline use was associated with changes in pruritus medications or self-reported severity of pruritus in a large cohort of patients with PBC. METHODS: The self-reported severity of pruritus was followed prospectively in 40 patients with PBC for a mean of 7.5 +/- 1.3 yr. These data were then retrospectively examined to determine the effect of sertraline on pruritus in all subjects who had received sertraline at some time during the study. RESULTS: For 28 of 32 patients with pruritus, itching was stable or fluctuated slightly over the follow-up period. No patient experienced rapid progression of pruritus, and four patients experienced a sustained resolution of their pruritus. Ten subjects started sertraline and continued it long enough (>6 months) to determine its lasting effect on pruritus. Three of these individuals did not have significant pruritus before or after sertraline. Of the seven patients with pruritus, six (86%) recorded a significant reduction or resolution of pruritus in their weekly diaries and also decreased or completely stopped other medications for pruritus. CONCLUSIONS: Sertraline use is associated with an improvement in cholestatic pruritus. This novel observation implies that serotonergic fibers are important in regulating the perception of itch. 相似文献