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Ad F Roffel Joost H Davids Carolina R S Elzinga Doris Wolf Johan Zaagsma Heinz Kilbinger 《British journal of pharmacology》1997,122(1):133-141
- The muscarinic receptor subtypes mediating contraction of the guinea-pig lung strip and inhibition of the release of acetylcholine from cholinergic vagus nerve endings in the guinea-pig trachea in vitro have previously been characterized as M2-like, i.e. having antagonist affinity profiles that are qualitatively similar but quantitatively dissimilar compared to cardiac M2 receptors. The present study sought to establish definitely the identity of these receptor subtypes by using the selective muscarinic receptor antagonist, tripitramine. Guinea-pig atria and guinea-pig trachea (postjunctional contractile response) were included for reference.
- It was found that tripitramine antagonized methacholine-induced contractions of the guinea-pig lung strip with a pKB value of 8.76±0.05. Both the parallel shifts of the concentration-response curves and the slope of the Schild plot being not significantly different from unity (when antagonist preincubation was for 2 h) indicated the involvement of a single population of receptors in the contractile response. From the pKB values obtained with tripitramine and a range of other selective muscarinic receptor antagonists (cf. Roffel et al., 1993), this single population of receptors can only be classified as M2-like.
- Tripitramine antagonized methacholine-induced negative chronotropic and inotropic responses in guinea-pig right and left atria with apparent pKB values of 9.4–9.6. However, such values were only obtained when antagonist preincubation was relatively long and/or antagonist concentration relatively high (e.g. with 1 h at 100 or 300 nM but 3 h at 30 nM). It thus appears that low concentrations of tripitramine do not readily equilibrate with M2 receptors in guinea-pig atria nor with M2-like receptors in the guinea-pig lung strip.
- Tripitramine increased electrical field stimulation-induced cholinergic twitch contractions in guinea-pig trachea in concentrations of 0.3–100 nM, by blocking prejunctional muscarinic inhibitory autoreceptors; with higher concentrations, twitch contractions were progressively diminished, as a result of blocking postjunctional M3 receptors (apparent pKB value 6.07±0.15). The pEC20 value (−log concentration that increases twitch by 20% of maximum) was 8.29±0.08, which would suggest that M4 receptors are involved in this response.
- Oxotremorine-induced inhibition of the release of prelabelled [3H]-acetylcholine from guinea-pig trachea, under conditions where there is no auto-feedback, was blocked by tripitramine (2 h preincubation) with a pKB value of 8.56±0.06. The slope of the corresponding Schild plot was not significantly different from unity, which together with the parallel shifts of the concentration-response curves indicated the involvement of a single muscarinic receptor subtype.
- Since the pKB value for tripitramine at prejunctional receptors in guinea-pig trachea is in between the affinities towards M2 and M4 receptors, correlation plots were constructed to compare the pKB values obtained with tripitramine and a range of other selective muscarinic receptor antagonists (cf. Kilbinger et al., 1995) to reported affinities at M1–M4 receptors. This showed rather similar distribution patterns of the data points around the line of equality in the case of M2 and M4 receptor subtypes. However, the correlation coefficient was markedly better for M2 (0.9667) than for M4 (0.5976). Since recent evidence suggests that M4 receptors are not expressed in cholinergic nerves from guinea-pig trachea, it is concluded that prejunctional muscarinic autoinhibitory receptors in this tissue exhibit an atypical M2 type character, with a pharmacological profile distinct from cardiac M2 receptors.
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Carolina Battellino Roxane Piazza Ana M M da Silva Yara Cury Sandra H P Farsky 《Toxicon》2003,41(5):583-593
Intravenous administration of antibothropic antivenom (BAv) neutralises the systemic effects, but does not efficiently reverse the local symptoms elicited by the Bothrops jararaca venom (BjV). The mechanisms involved in this poor protection have not been clarified. In this work, intravital microscopy studies were carried out to determine the efficacy of different schedules of BAv treatment on local effects evoked by topical application of BjV in the microcirculatory network of the internal spermatic fascia of Wistar rats. Results demonstrated that BAv administration 15 min before, simultaneously with, or 15 min after BjV application did not totally reverse the local symptoms, represented by disturbances of coagulation, development of haemorrhage lesions, vascular permeability increase and increment on leukocyte-endothelium interactions. This lack of effectiveness neither reflects an inadequate amount of specific antibodies in the antivenom against toxins responsible for local effects nor an insufficient dose of circulating BAv during the assays. Administration of fluorescein isothiocyanate (FITC) labelled-BAv showed the dynamics of distribution of the antivenom in the microcirculatory network. Images obtained from prior and simultaneously treated animals showed that the antivenom remains at luminal side of vessels before venom application, and the latency time to antivenom leakage is coincidental to that for local effects evoked by the venom. In addition, images from posterior treatment demonstrated that the intense alterations in the microcirculatory network impair antivenom distribution at the site of injection. Together, our data show that the lack of effectiveness of antivenom therapy is due to impaired and delayed venom and antivenom interaction at the site of injury. 相似文献
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Carolina Armengol Gemma Tarafa Loreto Boix Manel Solé Rosa Queralt Dolors Costa Oriol Bachs Jordi Bruix Gabriel Capellá 《Clinical cancer research》2004,10(6):2150-2157
PURPOSE: To allow the longitudinal investigation of molecular events associated with the progression of human hepatocellular carcinoma (HCC), we sought to develop a murine model by orthotopic implantation of tumor fragments obtained from patients diagnosed at early stage. EXPERIMENTAL DESIGN: Tumor pieces (2 x 2 mm) were implanted on the liver surface of nu/nu mice. After xenograft growing, subsequent passages were performed to achieve long-term implant viability. Isolation of tumoral hepatocytes was done to establish new cell lines. HCC characteristics, proliferation rate, apoptotic index (terminal deoxynucleotidyl transferase-mediated nick end labeling), and expression of cell-cycle regulators (cyclins E and A, p21(Cip1), p27(Kip1), p16(INK4a), pRb, and p53) were assessed by Western Blot and immunohistochemistry, to correlate them with tumor progression. RESULTS: Five (50%) of the 10 primary HCCs resulted in small slow-growing liver implants. Three of them are viable after 48 months, whereas the remaining two survived for 15 and 13 months. Xenografts throughout passages exhibited a more aggressive phenotype with a poorer degree of differentiation, intense proliferation, moderate apoptosis, cell-cycle deregulation, p53 alterations, microvascular invasion, and dissemination. In one single passage, we observed critical growth delay, which was associated with significant p27(kip1) overexpression. We established the anchor-free growing BCLC-9 cell line from one xenograft. This has gains of chromosomes 7, 5p, 6q, and 9q, is hepatitis B virus-DNA positive, does not secrete alpha-fetoprotein, and has TP53 missense mutations in codons 192 and 242. CONCLUSIONS: The orthotopic implantation of early HCC fragments in nude mice provides a useful model to investigate the mechanisms of human HCC evolution and to establish new cell lines. 相似文献
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Patterns of resistance and incomplete response to docetaxel by gene expression profiling in breast cancer patients. 总被引:8,自引:0,他引:8
Jenny C Chang Eric C Wooten Anna Tsimelzon Susan G Hilsenbeck M Carolina Gutierrez Yee-Lu Tham Mamta Kalidas Richard Elledge Syed Mohsin C Kent Osborne Gary C Chamness D Craig Allred Michael T Lewis Helen Wong Peter O'Connell 《Journal of clinical oncology》2005,23(6):1169-1177
PURPOSE: Chemotherapy for operable breast cancer decreases the risk of death. Docetaxel is one of the most active agents in breast cancer, but resistance or incomplete response is frequent. PATIENTS AND METHODS: Core biopsies from 24 patients were obtained before treatment with neoadjuvant docetaxel (four cycles, 100 mg/m(2) every 3 weeks), and response was assessed after chemotherapy. After 3 months of neoadjuvant chemotherapy, surgical specimens (n = 13) were obtained, and laser capture microdissection (LCM; n = 8) was performed to enrich for tumor cells. From each core, surgical, and LCM specimen, sufficient total RNA (3 to 6 microg) was extracted for cDNA array analysis using the Affymetrix HgU95-Av2 GeneChip (Affymetrix, Santa Clara, CA). RESULTS: From the initial core biopsies, differential patterns of expression of 92 genes correlated with docetaxel response (P = .001). However, the molecular patterns of the residual cancers after 3 months of docetaxel treatment were strikingly similar, independent of initial sensitivity or resistance. This relative genetic homogeneity after treatment was observed in both LCM and non-LCM surgical specimens. The residual tumor after treatment in tumors that were initially sensitive indicates selection of a residual and resistant subpopulation of cells. The gene expression pattern was populated by genes involved in cell cycle arrest at G(2)M (eg, mitotic cyclins and cdc2) and survival pathways involving the mammalian target of rapamycin. CONCLUSION: A specific and consistent gene expression pattern was found in residual tumors after docetaxel treatment. These profiles provide therapeutic targets that could lead to improved treatment. 相似文献
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Carolina B. Wandscheer Jonny E. Duque Mario A.N. da Silva Yoshiyasu Fukuyama Jonathan L. Wohlke Juliana Adelmann Jos D. Fontana 《Toxicon》2004,44(8):829-835
Ethanolic extracts from the kernels of ripe fruits from the Indian Lilac Melia azedarach and from the well-known Neem tree, Azadirachta indica were assayed against larvae of Aedes aegypti, the mosquito vector of dengue fever. The lethality bioassays were carried out according to the recommendations of the World Health Organization. Extracts were tested at doses ranging from 0.0033 to 0.05 g% in an aqueous medium for 24 and 48 h, at 25 or 30 °C, with or without feeding of the larvae. LC50, LC95 and LC99 were determined. Both seed extracts proved lethal for third to fourth instar larvae. Non-fed A. aegypti larvae were more susceptible to Azadirachta extracts at both temperatures. Under a more realistic environmental situation, namely with fed larvae at 25 °C, the death rates caused by the Melia extract were higher, although at 30 °C the extract of Azadirachta had an even higher lethality. Inter allia, the LC50 values for the crude extracts of these two members of the Meliaceae ranged from 0.017 to 0.034 g% while the LC99 values ranged from 0.133 to 0.189 g%. Since no downstream processing was undertaken to purify the active agents in the extracts, our findings seem very promising, suggesting that it may be possible to increase the larvicidal activity further by improving the extraction and the fractionation of the crude limonoids, for instance removing the co-extracted natural fats. 相似文献
29.
Carolina de Mattos Duarte Hugo Verli Joo Xavier de Araújo-Júnior Isac Almeida de Medeiros Eliezer J. Barreiro Carlos Alberto Manssour Fraga 《European journal of pharmaceutical sciences》2004,23(4-5):363-369
We describe herein the structural optimization of new piperamide analogues, designed from two natural prototypes, piperine 1 and piperdardine 2, obtained from Piper tuberculatum Jacq. (Piperaceae). Molecular modeling studies using semiempirical AM1 method were made in order to establish rational modifications to optimize them by molecular simplification. The targeted compounds (10) and (11) were respectively obtained using benzaldehyde (12) and para-anisaldehyde (13) as starting materials. 1H NMR spectra showed that the target compounds were diastereoselectively obtained as the (E)-isomer, the same geometry of the natural prototypes. These new synthetic amides presented significant hypotensive effects in cardiovascular essays using in vivo methodologies. Compound 11 (N-[5-(4′-methoxyphenyl)-2(E)-pentenoyl]thiomorpholine) showed a potency 10,000 times greater than its prototype 5, evidencing an optimization of the molecular architecture for this class of hypotensive drug candidates. 相似文献
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Fran?oise V Botelho Luciana R Enéas Giovana C Cesar Carolina S Bizzotto Erico Tavares Fabrícia A Oliveira M Beatriz A Gloria Marialice P C Silvestre Rosa M E Arantes Jacqueline I Alvarez-Leite 《Food and chemical toxicology》2004,42(8):1259-1267
Eggplant (Solanum melongena) has been used as hypocholesterolemic agent in many countries. However, few controlled studies were addressed to this subject and atherogenesis. We have evaluated the effect of eggplant on cholesterol metabolism and atherogenesis in LDLR(-/-) mice. Animals were fed on chow (n=17) or atherogenic (n=21) diet during 12 weeks receiving water (control) or eggplant extract. Liver, serum and fecal lipids, together with serum lipoproteins were measured. Oxidative stress was evaluated through conjugate diene formation and ox-LDL antibodies by enzyme immunoassay. Atherosclerotic lesions were measured in different sites of aorta. Total cholesterol and atherogenic lipoproteins did not decrease after eggplant intake. Animals receiving eggplant and chow diet showed increased anti-ox-LDL antibodies and a decreased lag phase of conjugated diene formation, indicating a higher oxidative stress than controls. No differences were seen in lesion area of aortic valve. Eggplant extract had high histamine and other amine levels that could enhance LDL oxidation and its endocytosis. Eggplant did not decrease plasma cholesterol nor prevent the development of atherosclerosis in LDLR(-/-) mice. Surprisingly, eggplant increased oxidative stress, representing a risk factor for atherosclerosis. These results did not support the use of eggplant extract as hypocholesterolemic agent. 相似文献