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91.
92.
The goal of these studies was to develop a suramin dosing schedule that would maintain suramin plasma concentrations in mice in the 150-250 mu g/ml range. A high pressure liquid chromatography method was used to determine suramin plasma concentrations in mice. For pharmacokinetic studies CD2F(1) mice were treated intraperitoneally with 140 mg/kg of suramin. These pharmacokinetic data were used to develop a clinically relevant dosing regimen. To test the efficacy of this dosing regimen, athymic nude mice were implanted orthotopically with PC-3 prostate carcinoma cells, randomized, and treated intraperitoneally. The pharmacokinetically derived dosing regimen resulted in no antitumor effect against PC-3 prostate tumors. Suramin plasma concentrations ranged from 155 to 258 mu g/ml over the 14-day therapy period with tumor concentrations in the 53-241 mu g/g wet weight range. 相似文献
93.
Calcification of the human thoracic aorta during aging 总被引:3,自引:0,他引:3
The rate of calcification within the human thoracic aorta from completion of body growth to advanced old age was examined. Fifty-eight aortae, obtained at necropsy, were dissected into four layers: the complete intima and the separated media, which was subdivided into three tissue samples of equal thickness, defined as the media-inner,-middle, and-outer layers. The sampling sites selected for analysis were from regions of the aortic surface that were free of atherosclerotic plaques. The calcium content within each tissue layer of the aorta was determined. Arterial wall thickness and the cholesterol content of the four layers were also measured. Intimal calcification increased progressively during aging: from 1.6 g Ca/mg tissue at 20 years of age to 5.2 g Ca/mg tissue by 90 years of age. When intima calcium concentration was expressed by tissue volume (w/v), no significant change during aging was found. Medical calcification, as w/v and by w/w, increased throughout aging. Calcium accumulation was most marked in the middle, elastin-rich layer of the media, increasing from 1.4 g Ca/mg tissue at 20 years of age to 49.50 g Ca/mg tissue by 90 years of age. Calcium levels also increased in the other media layers, but at a slower rate then that found within the middle media. 相似文献
94.
Using radioligand binding assays and postmortem normal human brain tissue, we obtained equilibrium dissociation constants (Kds) for 17 antidepressants and two of their metabolites at histamine H1, muscarinic, 1-adrenergic, 2-adrenergic, dopamine D2, serotonin 5-HT1A, and serotonin 5-HT2 receptors. Several newer antidepressants were compared with older drugs. In addition, we studied some antimuscarinic, antiparkinson, antihistamine, and neuroleptic compounds at some of these receptors. For the antidepressants, classical tricyclic antidepressants were the most potent drugs at five of the seven receptors (all but 2-adrenergic and 5-HT1A receptors). The chlorophenylpiperazine derivative antidepressants (etoperidone, nefazodone, trazodone) were the most potent antidepressants at 2-adrenergic and 5-HT1A receptors. Of ten antihistamines tested, none was more potent than doxepin at histamine H1 receptors. At muscarinic receptors antidepressants and antihistamines had a range of potencies, which were mostly weaker than those for antimuscarinics. From the in vitro data, we expect adinazolam, bupropion, fluoxetine, sertraline, tomoxetine, and venlafaxine not to block any of these five receptors in vivo. An antidepressant's potency for blocking a specific receptor is predictive of certain side effects and drug-drug interactions. These studies can provide guidelines for the clinician in the choice of antidepressant. 相似文献
95.
Mark W. Kunkel Kenneth E. Hook Curtis T. Howard Sally Przybranowski Billy J. Roberts William L. Elliott Wilbur R. Leopold 《Investigational new drugs》1995,13(4):295-302
Summary PD153035 is a potent (Ki=6 pm) and specific inhibitor of the epidermal growth factor (EOF) receptor tyrosine kinase that suppresses tyrosine phosphorylation of the EGF receptor in A431 cells at nanomolar concentrations in cell culture. We have examined the pharmacokinetics of this compound and its ability to rapidly suppress phosphorylation of the EGF receptor in A431 human epidermoid tumors grown as xenografts in immunodeficient nude mice. Following a single i.p. dose of 80 mg/kg, the drug levels in the plasma and tumor rose to 50 and 22 M within 15 minutes. While the plasma levels of PD153035 fell below 1 M by 3 hours, in the tumors it remained at micromolar concentrations for at least 12 hours. The tyrosine phosphorylation of the EGF receptor was rapidly suppressed by 80–90% in the tumors. However receptor phosphorylation returned to control levels after 3 hours despite the continued presence of the drug at concentrations which, based on previousin vitro results, were predicted to maintain inhibition. EGF-stimulated tyrosine kinase activity in tumor extracts was decreased and recovered in parallel with the effects of PD153035 on receptor phosphorylation though the activity had reached only about half of the control activity after three hours. These results demonstrate the potential for using small molecule inhibitors to inhibit the EGF receptor tyrosine kinasein vivo, though a fair evaluation of their potential anti-cancer activity will have to wait for solutions to problems with sustained delivery which may allow us to maintain suppression of EGF receptor phosphorylation. 相似文献
96.
Elliott EM 《American family physician》1999,59(8):2104, 2109; author reply 2112, 2115-2104, 2109; author reply 2112, 2116
97.
Measures to prevent cricket injuries: an overview 总被引:6,自引:0,他引:6
Cricket is a major international sport, generally played in British Common-wealth nations. Although strictly a non-contact sport, injuries in cricket can result in a number of ways. In high level cricket, overuse injuries are common and related to the physical demands of the sport, particularly in the delivery of the ball. The bowling action involves repetitive twisting, extension and rotation of the trunk at the same time as absorption of large ground reaction forces over a short period of time. These movements, if performed incorrectly or too frequently, can lead to overuse injuries of the back, particularly in elite and high level cricketers. Cross-sectional studies have demonstrated that spinal overuse injuries occur more frequently to cricketers adopting a mixed bowling action than to those who favour a front- or side-on bowling technique. Strategies to ensure that cricketers do not adopt the mixed action or bowl too fast for extended periods can prevent these back injuries. Injuries resulting from impacts, generally from the cricket ball, can also occur and are more common during low level competition or informal participation. Because of the potential severity of these impacts, a range of protective equipment ranging from body padding to gloves and face protectors are now common features of standard cricket equipment. Although a number of measures to prevent cricket injuries have been widely suggested in the literature, there have been very few studies that have formally assessed their effectiveness in preventing injury. Further research is needed to gain a greater understanding of the biomechanics of cricket actions, the mechanisms of resultant injuries and the role of various risk factors in injury causation. 相似文献
98.
This paper further characterizes the response to axotomy of mouse transcallosal cortical neurons, a population of neurons that seems to be particularly refractory to regeneration. Mouse transcallosal cortical neurons did not upregulate mRNA for the growth-associated protein alpha 1-tubulin following axotomy, even when the axonal distance from injury to cell body was only 100-300 microns. Previous experiments had found no upregulation of another growth-associated protein, GAP-43, by transcallosal neurons following axotomy 1-2 mm from the cell body. These latest results establish that this population of neurons fails to respond to axotomy even when it is extremely proximal and that this failure is not a peculiarity specific to one growth-associated protein but is indicative of a generally poor regenerative response. 相似文献
99.
J S Katz G I Wolfe P B Andersson D S Saperstein J L Elliott S P Nations W W Bryan R J Barohn 《Neurology》1999,53(5):1071-1076
OBJECTIVE: To describe a sporadic motor neuron disorder that remains largely restricted to the upper limbs over time. BACKGROUND: Progressive amyotrophy that is isolated to the upper limbs in an adult often suggests ALS. The fact that weakness can remain largely confined to the arms for long periods of time in individuals presenting with this phenotype has not been emphasized. METHODS: We reviewed the records of patients who had a neurogenic "man-in-the-barrel" phenotype documented by examination at least 18 months after onset. These patients had severe bilateral upper-extremity neurogenic atrophy that spared lower-extremity, respiratory, and bulbar musculature. RESULTS: Nine of 10 patients meeting these criteria had a purely lower motor neuron disorder. During follow-up periods ranging from 3 to 11 years from onset, only three patients developed lower-extremity weakness, and none developed respiratory or bulbar dysfunction or lost the ability to ambulate. CONCLUSION: Patients presenting with severe weakness that is fully isolated to the upper limbs, without pyramidal signs, may have a relatively stable variant of motor neuron disease. 相似文献
100.
Ventromedial prefrontal cortex mediates guessing 总被引:11,自引:0,他引:11
Guessing is an important component of everyday cognition. The present study examined the neural substrates of guessing using a simple card-playing task in conjunction with functional magnetic resonance imaging (fMRI). Subjects were scanned under four conditions. In two, they were shown images of the back of a playing card and had to guess either the colour or the suit of the card. In the other two they were shown the face of a card and had to report either the colour or the suit. Guessing compared to reporting was associated with significant activations in lateral prefrontal cortex (right more than left), right orbitofrontal cortex, anterior cingulate, bilateral inferior parietal cortex and right thalamus. Increasing the guessing demands by manipulating the number of alternative outcomes was associated with activation of the left lateral and medial orbitofrontal cortex. These data suggest that while simple two choice guessing depends on an extensive neural system including regions of the right lateral prefrontal cortex, activation of orbitofrontal cortex increases as the probabilistic contingencies become more complex. Guessing thus involves not only systems implicated in working memory processes but also depends upon orbitofrontal cortex. This region is not typically activated in working memory tasks and its activation may reflect additional requirements of dealing with uncertainty. 相似文献