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991.
Fröhlich M Albermann N Sauer A Walter-Sack I Haefeli WE Weiss J 《Biochemical pharmacology》2004,68(12):2409-2416
The well known gender-related differences in drug action may partly be explained by changes in activity and expression of drug metabolising enzymes, but also by modulation of active drug transport systems (e.g. P-glycoprotein, Pgp) by sexual steroids, which is yet not well investigated. Because many women are using hormones (e.g. as oral contraceptives) we investigated the influence of different synthetic progestins on Pgp activity. Pgp inhibition of progesterone, medroxyprogesterone, chlormadinone, cyproterone, levonorgestrel, norethisterone, desogestrel, and norgestimate was measured in vitro in two Pgp over-expressing cell lines (L-MDR1, P388/dx cells) and the corresponding parental cell lines by means of calcein assay, and ex vivo in human peripheral blood mononuclear cells (PBMCs) by rhodamine123 efflux. For most progestins tested, concentrations needed to double baseline fluorescence (f2) in L-MDR1 cells were similar to that of the potent Pgp inhibitor quinidine, whereas levonorgestrel and norethisterone did not reach f2. The results in P388/dx cells essentially confirmed our findings in L-MDR1 cells. Additionally, Pgp inhibitory activity of all progestins tested was also shown ex vivo in PBMCs. The potent Pgp inhibition by several synthetic progestins in vitro and ex vivo suggests that such an interaction might be clinically relevant despite generally low plasma concentrations of progestins. The results may be of particular importance for Pgp substrates, such as protease inhibitors and chemotherapeutic agents, for which intracellular concentrations are critical. 相似文献
992.
Determination of certain drugs in binary mixtures formulations by second derivative ratio spectrophotometry and LC 总被引:1,自引:0,他引:1
Spectrophotometric and high-performance liquid chromatographic (HPLC) methods are developed for simultaneous determination of three binary mixtures with overlapping spectra. The spectrophotometric method is based on the use of second derivative of the ratio spectra (2DD) for resolution of three binary mixtures of indapamide with captopril (mixture 1), cinnarizine with heptaminol acefylline (mixture 2) and amoxycillin trihydrate with flucloxacillin sodium (mixture 3). The HPLC method depends on the separation of components of binary mixtures using ODS column with mobile phase consisting of acetonitrile and 5 mM aqueous heptane sulphonic acid sodium salt in ratios of (60:40, v/v, pH 5.5) for mixture 1, (50:50, v/v, pH 3.0) for mixture 2 and (35:65, v/v, pH 4.2) for mixture 3. The proposed methods are accurate, non-destructive and successfully applied for the determination of the three binary combinations in synthetic mixtures and commercial pharmaceutical products. 相似文献
993.
Zheng W Olivo M Soo KC 《International journal of cancer. Journal international du cancer》2004,110(2):295-300
5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PPIX) fluorescence has shown an outstanding sensitivity for the assessment of oral lesions, but its application was hampered by low specificity due to the high false-positive rates. The purpose of our study was to explore the feasibility of quantifying PPIX fluorescence images to improve the diagnostic specificity for detecting early oral lesions in vivo. A digitized 5-ALA-mediated endoscopic imaging system was utilized to acquire PPIX fluorescence images from in vivo oral tissues. Forty-nine patients (118 biopsies) with known or suspected premalignant or malignant oral lesions were recruited for ALA-PPIX fluorescence endoscopic imaging. The red and blue channels of PPIX fluorescence images were digitized and stored for fluorescence quantification. The red-to-blue intensity ratios were calculated from the fluorescence images to correlate with histologic findings of the biopsies. The results showed that normal oral mucosa exhibited blue color of the back-scattered excitation light in the fluorescence images, whereas the suspicious lesions displayed bright reddish fluorescence. Applying the red-to-blue intensity ratio (I(R)/I(B)) as a diagnostic algorithm yielded a sensitivity of 92% and 98%, and specificity of 96% and 96%, for separating benign tissue from dysplasia, and cancer tissue, respectively, and a sensitivity and specificity of 98% and 92%, respectively, for differentiating cancer tissue from dysplasia in the oral cavity. Our study demonstrates that quantifying ALA-PPIX fluorescence endoscopic images associated with the red-to-blue intensity ratio as a diagnostic algorithm can provide good differentiation between the different stages of oral premalignancy and malignancy (p<0.0001, unpaired 2-sided Student's t-test), and thus has a potential to significantly improve the noninvasive diagnosis and evaluation of early oral neoplasia in vivo. 相似文献
994.
Group-matching designs are commonly used to identify the diagnosis-specific characteristics of children with developmental disabilities. In this paper, we address three issues central to the use of this design. The first concerns the alpha level to be used for considering groups to be matched on the control variable(s). The second involves the measurement characteristics of the control and target variables. We discuss the properties of standard scores, raw scores, and age equivalents and argue against the use of age equivalents. In addition, we consider the appropriateness of the commonly made prediction that groups that are matched for a control variable such as language ability or nonverbal reasoning ability but are not matched for chronological age should perform at equivalent levels on the target variable. Finally, we discuss issues related to the interpretation of significant between-group differences on the target variable, assuming groups are well-matched on the control variables, and describe the benefits of a method that focuses on characterizing a disorder on a case-by-case basis and then aggregating the cases, using the measures of sensitivity and specificity from signal detection theory. 相似文献
995.
MacNeil MA Heussy JK Dacheux RF Raviola E Masland RH 《The Journal of comparative neurology》2004,472(1):73-86
The population of bipolar cells in the rabbit retina was studied using Golgi impregnation and photocatalyzed filling of single cells with dihydrorhodamine, a quantitative sampling technique. The Golgi method revealed the morphology and stratification of cells in detail. The photofilling method allowed us to estimate the frequency of the cell types. From a sample of 243 Golgi-impregnated bipolar cells and 107 photofilled cells, we identified 1 type of rod bipolar cell and 12 types of cone bipolar cells. An analysis based on retinal coverage indicates that this number of types could be contained within the number of bipolar cells known to exist. The dendrites of most cone bipolars contacted all the cones within the individual cone bipolar cell's dendritic field. Types of bipolar cell were encountered at roughly similar frequency, without any one type predominating. The rabbit retina thus contains about a dozen parallel and roughly equipotent through-pathways. 相似文献
996.
PURPOSE: To develop an assay to evaluate the bioequivalence of overcoated and marketed montelukast formulations, the former to be used for future blinded clinical studies. METHODS: The method used automated 96-well sample preparation and dual-column HPLC analysis for increased throughput. Regression analysis was performed using the total peak height of montelukast and its photodegradent, a cis-ethenyl geometric isomer. This approach successfully compensated for montelukast's light sensitivity, allowing both clinical specimen handling and bioanalytical laboratory analysis to be conducted without extensive precautions being taken to protect samples from UV light. To ensure a molar equivalent fluorescence response between the cis (Z) and trans (E) isomers, the emission wavelength and detector attenuation were both increased just prior to the elution of the montelukast peak (i.e., the trans isomer), effectively dampening the response of the stronger fluorophore. Plasma proteins were precipitated using acetonitrile, and 50 microl of supernatant was injected onto an HPLC system consisting of two C18 analytical columns connected to a 10-port switching valve. Injections were overlapped on alternating columns allowing twice as many samples to be processed during each analytical run. RESULTS: The calibration curve was linear from 5 to 2000 ng ml(-1). The inter-day and intra-day precision expressed as coefficient of variation (%CV), were 1.1-6.1% and 3.1-6.7%, respectively. The accuracy, reported as percentage bias, was less than or equal to +/-9.1%. The absolute recovery was determined to be 94.3% and 98.1% at 15 and 1500 ng ml(-1), respectively. CONCLUSIONS: This assay represents a rapid, accurate, and sensitive method for the determination of montelukast in human plasma. The method has been successfully used to demonstrate the bioequivalence of the overcoated montelukast formulations to their equivalent marketed tablets. 相似文献
997.
No HeadingPurpose. To characterize complex coacervates/flocculates of lysozyme and heparin in terms of binding stoichiometry and to determine the effect of complexation on protein structure and stability.Methods. Insoluble lysozyme-heparin complexes were formed at pH 7.2 and the binding stoichiometry determined using a solution depletion method. Protein structure was determined by infrared spectroscopy and intrinsic fluorescence. Protein stability was evaluated using differential scanning calorimetry and followed in a 12-weeks storage stability study at 37C.Results. Binding stoichiometry between heparin and lysozyme was found to be dependent on ionic strength of the solution. At low ionic strength (I 0.01) about 11 lysozyme molecules could bind to a 17 kDa heparin chain, 3 to a 6 kDa chain, and less than 2 to a 3 kDa chain. At higher ionic strength (I 0.1), only 7 lysozyme molecules could bind to a 18 kDa heparin chain.. Above ionic strengths of approximately 0.32 M, no insoluble complexes were observed. Infrared spectroscopy and intrinsic fluorescence did not show any major changes in protein structure upon complexation to heparin. In contrast, differential scanning calorimetry showed a large decrease in the melting temperature of the protein, from 77C to 61C. Moreover, after 12-weeks storage at 37C, only 60% protein recovery was observed for the complexes, with no loss of protein for the uncomplexed protein.Conclusions. Heparin has multiple binding sites for lysozyme, amounting to at most one lysozyme molecule per 3 disaccharide units of heparin. Complexation decreased lysozyme stability, suggesting that heparin has a higher affinity for the unfolded state than the native state. Similar destabilization may occur for other proteins upon interaction with highly charged polymeric compounds or surfaces. 相似文献
998.
To study whether the patency to erythrocytes in retinal microvessels of diabetic rats is reduced or blocked before the vessels
lose their patency to plasma flow. Methods: We used recognized techniques to induce diabetic and galactose related microvascular retinal lesions in rats: (1) alloxan
induction (2) streptozotocin induction (3) galactose-containing diet. The rats were followed up to 17 months. We used our
vascular trichrome technique to observe the effects of the ongoing diabetes on the retinal microcirculation. Results: A focal leakage of a plasma-borne fluorescent dye was noted around the junction of the deep retinal capillaries and the ascending
venules to the superficial retinal circulation in the streptozotocin and alloxan diabetic rats by the 14th month, and, by
the 16th month, retinal capillary non-perfusion and retinal vascular malformations were present. The affected vessels showed
patency to microspheres (0.2 μm in diameter) but no perfusion of erythrocytes. No such changes were seen in the galactose-fed rats. Conclusions: (1) The location between the deep retinal capillary net and the ascending venules may be the site of early vascular leakage
in the diabetic rat model, (2) the erythrocytes’ passage in the affected retinal microcirculation was blocked before the development
of complete blockage to plasma in diabetic rats. The logical assumption that during the development stage of retinal capillary
occlusion there may be a transient stage of microvascular insufficiency was examined. The lathyrogen, imino-diproprionitrile
(IDPN), had previously been effective for creating a fast-developing model of retinal vasculopathy. Using that model, we demonstrated
a stage in which the retinal microvasculature was blocked to erythrocytes but not to plasma [1]. However, we questioned the
applicability of our findings to more slowly developing microvasculopathies, such as diabetic retinopathy. We designed the
current study to examine the presence of such stage in slowly developing microvasculopathy. Animal models that are known to
induce “diabetic retinopathy-like” changes used [2–4]. The diabetic animals were followed for a period of 17 months. Starting
at the 12th month, a few animals of each group were killed and the retains were examined with our trichrome method [1] for
relative capillary patency to erythrocytes and plasma, for functionality of endothelial cells, and for disturbances in the
blood–retinal barrier. The results of this study support the hypothesis that retinal microvascular insufficiency does exist
as a temporary stage that precedes the development of complete capillary blockage in long-term developing rat models of diabetic
retinopathy. 相似文献
999.
Maul H Shi L Marx SG Garfield RE Saade GR 《American journal of obstetrics and gynecology》2003,189(4):963-967
OBJECTIVE: The purpose of this study was to determine whether the platelet-activating factor antagonist WEB-2170 inhibits preterm cervical ripening induced by lipopolysaccharide or by antiprogestin RU 486. STUDY DESIGN: Timed-pregnant rats were killed on day 16 after treatment with (1) WEB-2170, lipopolysaccharide, lipopolysaccharide plus WEB-2170, or vehicle control and (2) with WEB-2170, RU 486, RU 486 plus WEB-2170, or vehicle control. Cervical ripening was assessed by light-induced fluorescence and resistance to stretch. Statistics were assessed by 1-way analysis of variance followed by Tukey-test (P <.05). RESULTS: Light-induced fluorescence and resistance to stretch were significantly lower in the lipopolysaccharide-treated and in the RU486-treated animals compared with vehicle control (lipopolysaccharide:light-induced fluorescence, 7.0+/-0.6 vs 12.8+/-0.8 [P=.001]; resistance to stretch, 0.41+/-0.03 N/mm vs 0.54+/-0.04 N/mm [P <.05]; RU486:light-induced fluorescence, 9.6+/-0.6 vs 11.7+/-0.6 [P <.05]; resistance to stretch, 0.28+/-0.06 N/mm vs 0.61+/-0.02 N/mm [P <.001]). Compared with vehicle control, WEB-2170 alone did not alter cervical light-induced fluorescence or resistance to stretch. Although WEB-2170 significantly blocked cervical ripening after lipopolysaccharide administration (light-induced fluorescence, 11.3+/-1.3 [P <.05]; resistance to stretch, 0.61+/-0.04 [P <.01]), WEB-2170 did not inhibit the RU 486-induced cervical ripening. CONCLUSION: Although infection-related cervical ripening is inhibited by platelet-activating factor antagonists, the physiologic process of cervical ripening appears to be unaffected. Platelet-activating factor inhibition may be of clinical value in the infection-related pathologic processes that are responsible for premature cervical ripening. 相似文献
1000.
Chromosomal information derived from single blastomeres isolated from cleavage-stage embryos and cultured in vitro 总被引:1,自引:0,他引:1
OBJECTIVE: To evaluate the potential of proliferation of single blastomeres isolated from human cleavage-stage embryos for use in preimplantation genetic diagnosis of chromosomal abnormalities. DESIGN: A laboratory study of chromosomal content of blastomeres isolated from embryos of patients from an in vitro fertilization program. SETTING: University hospital laboratory. PATIENT(S): Couples undergoing IVF or ICSI. INTERVENTION(S): Blastomeres were isolated from normally fertilized cleavage-stage human embryos, cultured in vitro or fixed immediately, and analyzed by fluorescence in situ hybridization (FISH) probes. MAIN OUTCOME MEASURES: Chromosomal information yielded by blastomeres cultured in vitro compared with those obtained from blastomeres that were processed for chromosomal analysis directly after isolation. RESULT(S): The percentage of cultured blastomeres that produced FISH results was significantly lower than the percentage of blastomeres processed for FISH directly after isolation (72% vs. 90%). Lack of FISH results from cultured cells, which in most cases was related to nuclear anomalies, was significantly more frequent among nondivided than divided blastomeres (39% vs. 21%). Both cultured and noncultured cells showed diploid, aneuploid and polyploid chromosome complements on FISH. Compared with directly processed cells, cultured cells yielded a higher proportion of polyploid patterns (22.9% vs. 6.1%). Of the cultured blastomeres that divided, 18% produced progeny with mosaicism. CONCLUSION(S): Although blastomere culture may increase the number of cells available for chromosomal analysis, the high frequency of nuclear defects and the occurrence of polyploidy and mosaicism among cultured cells discourage the use of blastomere isolation and proliferation strategy for use in preimplantation genetic diagnosis. 相似文献