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Keith J Murphy Andrew G Foley Alan W O'connell Ciaran M Regan 《Neuropsychopharmacology》2006,31(1):90-100
Recent data suggest that Alzheimer's patients who discontinue treatment with cholinesterase inhibitors have a significantly delayed cognitive decline as compared to patients receiving placebo. Such observations suggest cholinesterase inhibitors to provide a disease-modifying effect as well as symptomatic relief and, moreover, that this benefit remains after drug withdrawal. Consistent with this suggestion, we now demonstrate that chronic administration of tacrine, nefiracetam, and deprenyl, drugs that augment cholinergic function, increases the basal frequency of dentate polysialylated neurons in a manner similar to the enhanced neuroplasticity achieved through complex environment rearing. While both drug-treated and complex environment reared animals continue to exhibit memory-associated activation of hippocampal polysialylated neurons, the magnitude is significantly reduced suggesting that such interventions induce a more robust memory pathway that can acquire and consolidate new information more efficiently. This hypothesis is supported by our findings of improved learning behavior and enhanced resistance to cholinergic deficits seen following either intervention. Furthermore, the level of enhancement of basal neuroplastic status achieved by either drug or environmental intervention correlates directly with improved spatial learning ability. As a combination of both interventions failed to further increase basal polysialylated cell frequency, complex environment rearing and chronic drug regimens most likely enhanced cognitive performance by the same mechanism(s). These findings suggest that improved memory-associated synaptic plasticity may be the fundamental mechanism underlying the disease modifying action of drugs such as cholinesterase inhibitors. Moreover, the molecular and cellular events underpinning neuroplastic responses are identified as novel targets in the search for interventive drug strategies for the treatment of neurodegenerative and neuropsychiatric disorders. 相似文献
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Brian T. Foley Joan M. Moehring Thomas J. Moehring 《Somatic Cell and Molecular Genetics》1992,18(3):227-231
The histidine residue at position 715 of elongation factor 2 (EF-2) is posttranslationally modified in a series of enzymatic reactions to 2-[3-carboxyamido-3-(trimethylammonio)-propyl]histidine, which has been given the trivial name diphthamide. The diphthamide residue of EF-2 is the target site for ADP ribosylation by diphtheria toxin and Pseudomonas exotoxin A. ADP-ribosylated EF-2 does not function in protein synthesis. EF-2 that has not been posttranslationally modified at histidine 715 is resistant to ADP ribosylation by these toxins. In this report we show that a G-to-A transition in the first position of codon 717 of the EF-2 gene results in substitution of arginine for glycine and prevents addition of the side chain of diphthamide to histidine 715 of EF-2. EF-2 produced by the mutant gene is fully functional in protein synthesis.This work was supported by Public Health Service grant AI-09100 from the National Institute of Allergy and Infectious Diseases and by Biomedical Research Support Grant PHS07RR05429-27. Brian Foley is supported by a Cancer Biology Training Grant T32Ca-09286 from the National Cancer Institute. 相似文献
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I H Cox S J Erickson W D Foley D M Dewire 《AJR. American journal of roentgenology》1992,158(5):1051-1055
This study was designed to investigate a variety of sonographic features of ureteric jets in order to define patterns of flow and ranges of flow values in an asymptomatic population. The following features of ureteric jets were measured during a period of up to 30 min in a group of 15 asymptomatic volunteers after oral hydration (the mean value was calculated on each side): peak velocity (mean, 57 cm/sec); jet duration (mean, 4.6 sec); and number of peaks and subpeaks (mean, 2.2). Several flow patterns were observed, including discrete jets, ureteric streaming, and rest periods. For each patient the ratios of values obtained on the left and right sides were calculated for peak velocity (1.00-1.74; mean, 1.26); jet duration (1.00-4.69; mean, 1.83); and jet frequency (1.00-1.21; mean, 1.11). The interjet interval (period between jets) ranged from 2 to 150 sec. Bolus volume and jet frequency showed simultaneous moment-to-moment variation. The frequency and velocity rather than the duration ratios may be of greatest value in identifying patients with normal ureterodynamics. Our findings challenge two current concepts of renal pelvic and ureteral response to changes in urine output: (1) ureters have a fixed maximal discharge rate and (2) bolus volumes do not change until this rate is achieved. Asymmetric moment-to-moment fluctuations observed in jet frequency suggest that prolonged examination may be necessary to confirm normal symmetry of jet frequency in some patients with suspected ureteric obstruction. 相似文献
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K. L. Womer H.-U. Meier-Kriesche P. R. Patton K. Dibadj C. M. Bucci D. Foley S. Fujita B. P. Croker R. J. Howard T. R. Srinivas B. Kaplan 《American journal of transplantation》2006,6(1):209-213
BK virus nephropathy (BKVN) is now recognized as a major cause of renal allograft loss. Recent reports suggest that retransplantation in patients with graft loss due to BKVN is safe after return to dialysis. Since early transplantation is associated with improved outcomes, it would be advantageous if this procedure could be performed prior to ultimate graft loss. However, little data are available regarding the safety of this approach during active viremia. In this report, we describe successful preemptive retransplantation with simultaneous allograft nephrectomy in two patients with active BKVN and viremia at the time of surgery. With 21- and 12-month follow-up, respectively, both patients have stable allograft function and no evidence for active viral replication. We conclude that preemptive retransplantation can be considered in patients with failing allografts due to BKVN. 相似文献
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H C Wilkes T W Meade S Barzegar A J Foley L O Hughes K A Bauer R D Rosenberg G J Miller 《Thrombosis and haemostasis》1992,67(5):503-506
The effects of gemfibrozil on several indices of haemostatic activity were explored in male patients with coronary heart disease (CHD). Sixty-three of 71 patients completed a crossover study in which gemfibrozil 1,200 mg/day and matching placebo were each taken in randomised order for 2 months in a double-blind manner, separated by a 2-month washout period. Serum cholesterol decreased by an average (95% confidence interval) of 12 (9 to 15)% and non-fasting triglyceride concentration by 43 (34 to 51)% during active treatment. Plasma prothrombin fragment F1 + 2 concentration, a marker of the in vivo rate of generation of thrombin, was 25 (12 to 37)% lower on average while on gemfibrozil than during the placebo phase. Factor VII coagulant activity (VIIc) and antigen concentration, and fibrinopeptide A concentration were not influenced by gemfibrozil in the group overall. However, the VIIc response appeared to be dependent upon the untreated cholesterol level. Hypercholesterolaemic men (cholesterol greater than 6.5 mmol/l) experienced a significant reduction in VIIc averaging 6% of standard during active therapy. Other effects of gemfibrozil were a 5 (2 to 9)% increase in plasma fibrinogen by a gravimetric method, an 11 (8 to 13)% increase in platelet count, and a 6 (2 to 10)% reduction in white cell count. The reduced incidence of CHD following gemfibrozil therapy in hyperlipidaemic patients may arise in part through a reduction in procoagulant activity and thus the risk of an occlusive coronary thrombosis. 相似文献