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71.
The pharmacological properties of the imidazobenzodiazepine, FG 8205, a novel partial agonist at the benzodiazepine receptor 总被引:2,自引:1,他引:1
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M D Tricklebank T Honoré S D Iversen J A Kemp A R Knight G R Marshall N M Rupniak L Singh S Tye F Watjen 《British journal of pharmacology》1990,101(3):753-761
1. The pharmacological properties of the benzodiazepine receptor ligand, FG 8205 (7-chloro-5,6-dihydro-5-methyl-6-oxo-3-(5-isopropyl-1,2,4-oxadiazol++ +-3-yl)-4H- imidazol[1,5a][1,4]benzodiazepine) have been examined. 2. FG 8205 potently displaced [3H]-flumazenil binding in rat cortical membranes with a Ki of 3.3 nM, but was inactive at 13 neurotransmitter recognition sites. 3. Consistent with a partial agonist profile, the affinity of FG 8205 for the benzodiazepine recognition site was increased in the presence of gamma-aminobutyric acid (GABA, 300 microM) by a degree (-log [IC50 in the presence of GABA/IC50 alone] = 0.34) significantly less than found for diazepam (0.46). FG 8205 also potentiated the inhibitory potency of the GABAA-receptor agonist, isoguvacine, on the hippocampal CA1 population spike and, again, the maximum shift (-log dose-ratio = 0.2) was significantly less than that seen with diazepam (0.4). 4. In anticonvulsant studies, the ED50 doses of FG 8205 and diazepam needed to antagonize seizures induced by pentylenetetrazol (PTZ) or by sound in audiogenic seizure prone mice were similar with values of 0.2-0.3 mg kg-1, i.p. However, even high doses of FG 8205 (50 mg kg-1) did not protect against seizures induced by electroshock. 5. FG 8205 released responding suppressed by footshock in a rat operant conditioned emotional response task over the dose range 0.5-50 mg kg-1 (i.p.). Similar doses of FG 8205 had a marked taming effect in cynomolgus monkeys.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
72.
G. Singh J. F. Hussain A. MacKinnon C. M. Brown D. A. Kendall V. G. Wilson 《Naunyn-Schmiedeberg's archives of pharmacology》1994,351(1):17-26
In the present study we have prepared crude, methanolic extracts of bovine lung and bovine brain and, using radioligand binding assays in conjunction with a number of simple chromatographic techniques, provided evidence for the presence of a non-catecholamine ’clonidine-displacing substance‘ (CDS). The level of CDS in lung extracts (9?units/g wet weight n=11) is approximately 3 times that in the brain extracts. Furthermore, the effect of the crude, methanolic extracts are selective for non-adrenoceptor, imidazoline (labelled by [ 3H]-idazoxan) and a 2-adrenoceptor binding sites (labelled by [ 3H]-clonidine); both extracts are 5–10-fold more potent displacers of ligand binding to a 2-adrenoceptors compared with binding to opiate receptors (labelled by [ 3H]-etorphine) and practically inactive against a 1-adrenoceptor and muscarinic binding sites (labelled by [ 3H]- prazosin and [ 3H]-quinuclidinyl benzilate, respectively). With the exception of the non-adrenoceptor, imidazoline binding assay, which used rat kidney membranes labelled by [ 3H]-idazoxan in the presence of the a 2-adrenoceptor antagonist RS-15385-197, all radioreceptor assays involved bovine cerebral cortex membranes. Although the extracts contain catecholamines (brain only), histamine (lung only) and monovalent cations (both), which have the potential to interfere with the radioligand binding assays, their concentrations were too low to account for the effects observed. Preliminary attempts at purification of the extracts revealed that CDS activities from the two tissues are similar, i.e., practically insoluble in organic solvents at room temperature, not affected by either Sep-Pak C 18 column or anion exchange resins but retained (along with the monovalent cations) by cation exchange resin. However, following chromatographic separation on a Biogel P2 column, the CDS-containing eluates are cation-free and exhibit qualitatively similar elution profiles. Future experiments will involve further purification of ’clonidine-displacing substance‘ to characterize its interaction with a 2-adrenoceptor binding sites in greater detail and establish whether it has biological activity consistent with the properties implied by its effects in radioligand binding assays. 相似文献
73.
The pulmonary intravascular macrophages (PIMs) have been described in several species of animals. This study demonstrates for the first time that the equine lung has PIMs as resident phagocytes in its microvasculature. Their salient features such as globular surface coat, structures of the endocytic pathway, and related cell organelles closely resemble those of the calf, goat, and sheep. The exquisite organization of the coat globules in the form of a linear chain was structurally similar to the lipolytic lipase and the heparin-sensitive globular coat from PIMs of calf, goat, and sheep. Monastral blue (MB) when employed as a tracer to assess the phagocytic properties of equine PIMs induced similar modification of the globules of the coat into lipid droplets, reminiscent of neutral lipids. Lipids droplets (modified coat globules) were delivered into acid phosphatase-positive endosomes and lysosomes. Concurrently, the unaltered globules of the coat, probably internalized via fluid-phase constitutive pinocytoses, followed a different endocytic pathway. Large-scale platelet uptake by the PIMs was observed with thrombocytopenia in MB-treated ponies. The possible significance of hypothetical LDL-coat and the endocytic organelles as equivalents of synthetic apparatus of vasoactive lipids in the PIMs of horse needs to be assessed in future studies. 相似文献
74.
Search is under way to develop reliable tests for the prediction of stone risk. Several indices and ratios on the basis of
urinary excretions have been suggested. In the present study the applicability of some risk indices and ratios in slum dwellers
of Dharavi area of Bombay was examined. No significant difference was observed in IAP (ionic activity product) and CORI (calcium
oxalate risk index) between stone formers (SF) and normal subjects (NS).
We have suggested two more adjuncts, PIR (promoter/inhibitor ratio) and COQ (calcium oxalate quotient), and found them to
be quite useful in the detection of risk.
Pre-existence of risk factor(s) in the majority of the normal population suggests that triggering of stone formation should
be a transient phenomenon in this population.
No consistent pattern of relationship between various urinary parameters was observed. 相似文献
75.
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77.
Nina Singh Cheryl Wannstedt Lois Keyes Marilyn M Wagener Thomas V Cacciarelli 《Liver transplantation》2005,11(6):700-704
A vast majority of the transplant recipients are cytomegalovirus (CMV)-seropositive (R+). We sought to assess variables predictive of CMV infection, specifically in R+ liver transplant recipients. Study patients comprised 182 consecutive liver transplant recipients who survived at least 14 days after transplantation. Surveillance testing was used to detect CMV infection. Pre-emptive therapy was employed for the prevention of CMV disease, however, no antiviral prophylaxis was used for CMV infection. CMV infection developed in 32.5% (38 of 117) of R+ patients, 84.6% (33 of 39) of R-/D+, and 3.8% (1 of 26) of R-/D- patients. In R+ patients, Hispanic race (21.6% vs. 7.8%, P = 0.06), donor CMV seropositivity (73.7% vs. 45.6%, P = 0.005), and hepatocellular carcinoma (23.7% vs. 6.3%, P = 0.05) correlated with a higher risk of CMV infection. In a multivariate model, Hispanic race (OR: 3.5, 95% CI: 1.03-11.6, P = 0.045), donor CMV serostatus (OR: 4.0, 95% CI: 1.6-10.2, P = 0.003) and hepatocellular carcinoma (OR: 5.8, 95% CI: 1.6-20.5, P = 0.006) were all significant independent predictors of CMV infection. The aforementioned variables did not portend a higher risk of CMV infection in R-/D+ patients; donor CMV seropositivity overwhelmed all other risk factors in R- patients (P < 0.00001). In conclusion, CMV-seropositive liver transplant recipients at risk for CMV infection can be identified based on readily assessable variables. Preventive strategies may be selectively targeted toward these patients. 相似文献
78.
79.
Background: Tibialis posterior is a frequent cause of an acquired flatfoot deformity and the prevalence is not known. If tibialis posterior dysfunction was found to occur frequently, a greater awareness may result leading to earlier patient diagnosis, referral and treatment.Objectives: To validate a screening questionnaire for tibialis posterior dysfunction, and to investigate the prevalence of tibialis posterior dysfunction in a high-risk patient population.Methods: The screening questionnaire was given prospectively to 65 patients (44 females, 21 males; mean age 79.6 years) attending an unrelated care of the elderly appointment. A foot and ankle surgery fellow separately examined all feet for tibialis posterior dysfunction.Results: The survey was 100% sensitive and 98.3 % specific at detecting tibialis posterior dysfunction. Six of the 65 patients (5 females, 1 male) had tibialis posterior dysfunction, and two had bilateral involvement. All six of the patients had longstanding symptoms, all had consulted their doctor and three had seen an orthopaedic surgeon; only one of the six patients had been correctly diagnosed.Conclusions: This study suggests that tibialis posterior dysfunction occurs frequently, but is seldom diagnosed in elderly women. Further epidemiologic studies are needed to determine the true prevalence. 相似文献
80.