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111.
Bouzamondo-Bernstein E Hopkins SD Spilman P Uyehara-Lock J Deering C Safar J Prusiner SB Ralston HJ DeArmond SJ 《Journal of neuropathology and experimental neurology》2004,63(8):882-899
Loss of the GABAergic system of neurons has been reported to be the first detectable neuropathological change in prion diseases, which features the accumulation of an aberrant isoform of the prion protein (PrP(Sc)). To determine the timing of GABAergic system dysfunction and degeneration and its relationship to PrP(Sc) accumulation during the course of prion disease in Syrian hamsters, we applied 3 approaches: i) quantifying GABA-immunopositive neurons and their processes by light and electron microscopy to test for selective loss; ii) measuring evoked [3H]-GABA release from synaptosomes to test for functional abnormalities; and iii) determining the kinetics of PrP(Sc) accumulation in subcellular fractions to correlate it with GABAergic dysfunction. At the terminal stages of disease, we found a significant increase in the number of GABA-positive and -negative presynaptic boutons with abnormally aggregated synaptic vesicles. At the same stage, we also found an equal degree of GABA-immunopositive and -immunonegative presynaptic bouton loss. In contrast, GABA-positive neocortical cell bodies increased, based on stereologic estimates in the terminal stage of scrapie. In the context of these abnormalities, evoked release of [3H]-GABA from cortical and thalamic synaptosomes was significantly decreased, which correlated well with the accumulation of PrP(Sc) in synaptosomes and cell membrane fractions. 相似文献
112.
Bouillier H Samain E Rücker-Martin C Renaud JF Marty J Safar M Dagher G 《Archives des maladies du coeur et des vaisseaux》2002,95(7-8):641-646
Angiotensin II (Ang II) is involved in hypertension-related arterial wall hypertrophy [1]. Regulation of AT II transduction pathway in vascular smooth muscle cells (VSMC) may involve cytoskeleton and extracellular matrix (ECM) [2]. We assessed the role of components of ECM on Cai2+ increase induced by Ang II in Wistar-Kyoto (WKY) and Spontaneously Hypertensive Rats (SHR) aortic VSMC. The effect of Ang II (1 mumol) on Ca2+ mobilization was studied in cultured VSMC isolated from the aorta of 6-wk old WKY (MAP (m +/- SE) = 98 +/- 4 mmHg) and SHR (136 +/- 5 mmHg; p < 0.05), using fluorescent imaging microscopy (Fura-2 AM). Cai2+ release from internal stores and Ca2+ influx were assessed in the absence and upon reintroduction of external Ca2+ respectively. Cells were cultured on uncoated glass coverslips (control) or coated with either collagen I (10 micrograms/mL), collagen IV (7 micrograms/mL), vitronectin (0.1 microgram/mL), fibronectin (3 micrograms/mL) and extracellular matrix extract (matrigel, 1/10) and studied at confluence. Paxillin was located in cells by indirect immunofluorescence micrography. Results are expressed in % of Control. Statistical significance (p < 0.05) was assessed with Student's t-test for unpaired data. The effects on Ang II-induced Ca2+ mobilization of growing cells on ECM are in Table. Paxillin in Control cells appeared as dots at the cell boundaries. Density increased in cells grown on collagen I with a diffuse distribution in the WKY cells. On matrigel, paxillin was located in a belt-like fashion at the periphery of the cell. These effects were not linked to differences in cell cycle (flux cytometry). 相似文献
113.
Safar H Mourad JJ Safar M Blacher J 《Archives des maladies du coeur et des vaisseaux》2002,95(12):1215-1218
Aortic pulse wave velocity (PWV), a classical index of aortic stiffness, may be easily measured in humans using non invasive ultrasound methods of high reproducibility. Recent epidemiological studies have shown that, independently of confounding factors as age, blood pressure and cardiac mass, aortic PWV is a predictor of cardiovascular (CV) mortality in populations of hypertensive subjects, whether they have or not end-stage renal disease. Since aortic PWV is dominantly influenced by age, this finding may be of major importance for the evaluation of CV risk in geriatric populations. 相似文献
114.
115.
The blood pressure pattern in spontaneously hypertensive rats (SHRs) involves three main characteristics: increase in mean blood pressure (MBP); increase in thoracic aorta (proximal) and iliac (distal) pulse pressure (PP); disappearance of the normal PP amplification between the proximal and the distal arteries. Whether pharmacologic agents may reduce MBP with different or even opposite effects regarding PP and PP amplification has been poorly investigated. In SHRs and Wistar-Kyoto (WKY) anesthetized rats, the NO inhibitor l-nitro-arginine methyl ester (l-NAME) was infused at the dosage of 1 mg/kg for 30 min. Before and after infusion, 7 microg/kg/min acetylcholine (Ach) and 200 mg/kg adenosine (Ado) were perfused for 4 min. Proximal and distal intra-arterial BP was monitored throughout the procedure. In both WKYs and SHRs, l-NAME increased proximal and distal systolic (SBP), diastolic (DBP), and MBP but not PP. Before l-NAME, SBP, DBP, and MBP were significantly reduced by Ado and Ach. After l-NAME, such blood pressure reductions were abolished with Ach but not Ado. In both strains, the proximal and distal PP, when expressed in percent reduction of MBP, were significantly higher under Ado than under Ach. The Ado but not Ach changed PP amplification, causing a reduction in WKYs and an increase in SHRs independent of l-NAME. Vasodilating agents may reduce MBP with significantly different effects on PP. The Ado alters PP amplification, an effect not obtained with the nitric oxide endothelium-dependent vasorelaxing agent Ach. Tail SBP measurements cannot predict such dissociated changes. 相似文献
116.
Epidemiological studies in the past decade have stressed the importance of pulse pressure (PP) as an independent risk factor for cardiovascular morbidity and mortality. We briefly review the epidemiological evidence and discuss the pathophysiological mechanisms which involve arterial stiffness and wave reflections in older patients. We discuss the therapeutic consequences of targeting PP rather than systolic (S) or diastolic (D) blood pressure (BP) when using antihypertensive agents. With this line of evidence it is important, first, to determine what minimal PP level indicates cardiovascular risk and, second, to note that an increasing number of clinical studies indicate that PP is poorly sensitive to placebo, while SBP and DBP are conversely highly sensitive. Finally, on the basis of large-scale intervention trials, PP seems to be an appropriate tool for studies of clinical pharmacology and therapeutics in the fields of hypertension, congestive heart failure and other cardiovascular diseases. 相似文献
117.
118.
Safar P 《Annals of emergency medicine》2003,41(6):887-8; author reply 888
119.
Cefalu WT; Wagner JD; Bell-Farrow AD; Edwards IJ; Terry JG; Weindruch R; Kemnitz JW 《Toxicological sciences》1999,52(2):49-55
Caloric restriction (CR) has been observed to retard aging processes and
extend the maximum life span in rodents. In an effort to evaluate the
effect of this nutritional intervention on physiologic variables in higher
species, several nonhuman primate trials are ongoing. In particular, a
study evaluating the independent effect of CR on the extent of
atherosclerosis was initiated in 1993 in 32 adult cynomolgus monkeys.
Therefore, the trial was designed to achieve identical cholesterol intake
after animals were randomized to a control group or a calorie-restricted
group (30% reduction from baseline caloric intake). The animals were
routinely evaluated for glycated proteins, plasma insulin and glucose
levels, insulin sensitivity, and specific measures for abdominal fat
distribution by CT scans over a 4-year interval. The results from 4 years
of intervention demonstrate that CR improves cardiovascular risk factors
(such as visceral fat accumulation) and improves insulin sensitivity. In
contrast to other primate studies with normolipidemic animals, CR had no
independent effects on plasma lipid levels and composition in the presence
of equivalent amounts of dietary cholesterol intake. Preliminary analysis
of atherosclerotic lesion extent in the abdominal aorta has failed to
demonstrate differences between control animals and CR animals. Follow- up
studies are being conducted to determine the effect of CR on
atherosclerosis extent in coronary and carotid arteries.
相似文献
120.
Chamiot-Clerc P Colle MH Legrand M Sassard J Safar ME Renaud JF 《Clinical and experimental pharmacology & physiology》1999,26(11):883-888
1. Thoracic aortas of normotensive (Wistar-Kyoto (WKY) and Lyon normotensive (LN)) and hypertensive (spontaneously hypertensive rats (SHR) and Lyon hypertensive (LH)) rats from two groups (Japanese (WKY rats and SHR) and Lyon (LN and LH rats)) were compared using organ chambers. Changes in endothelium and smooth muscle reactivity to noradrenaline (NA), carbamylcholine and N omega-nitro-L-arginine (L-NNA) were analysed to distinguish between changes in reactivity that are associated with the presence of hypertension and those that are dependent on group (Japanese vs Lyon). 2. Aortas of hypertensive rats had lower pD2 values for NA than aortas from normotensive rats. These differences were associated with hypertension (P < 0.005 and P < 0.01) and group (P < 0.005 and P < 0.005) in presence or absence of endothelium, respectively, whereas no difference was seen in the maximal developed tension in response to NA. 3. Aortas also differed by a reduced ability to relax in response to carbamylcholine in hypertensive rats; this effect is hypertension (P < 0.05) and group (P < 0.005) dependent, without any change in carbamylcholine pD2 values. 4. Changes in maximum developed tension in the presence of L-NNA were found to be endothelium dependent and pressure and group independent. Furthermore, the change in tension induced by L-NNA appears significantly more pronounced in SHR than in LH rats (P < 0.05). 5. These results indicate that the common defect associated with hypertension appears to be linked to the endothelium through alpha-adrenoceptors and muscarinic receptors in both the Japanese and Lyon groups. However, SHR differs markedly from LH rats by having a higher developed tension in response to NA, this increased tension being counterbalanced by the release of nitric oxide, as observed in the presence of L-NNA. 相似文献