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991.
992.
Yoshinobu Takakura Makiya Nishikawa Fumiyoshi Yamashita Mitsuru Hashida 《Journal of drug targeting》2013,21(2):99-104
The influence of physicochemical properties on the in vivo pharmacokinetics of gene delivery vectors after systemic administration is reviewed based on our studies. We have been studying the development of DNA delivery systems, such as plasmid DNA complexed with cationic polymers (polyplexes) and cationic liposomes (lipoplexes). Even if target-recognizable ligand is incorporated into the system, the overall physicochemical properties, notably size and charge, are predominant factors influencing in vivo disposition characteristics of the vector. Based on this consideration, liver cell-specific carrier systems via receptor-mediated endocytosis were successfully developed by optimizing physicochemical characteristics. In conclusion, rational design of gene delivery vectors requires an understanding of their pharmacokinetics in relation to the physicochemical properties. Optimization of the physicochemical properties is important for successful in vivo gene delivery by non-viral vectors. 相似文献
993.
Ram I. Mahato Kenji Kawabata Yoshinobu Takakura Mitsuru Hashida 《Journal of drug targeting》2013,21(5):287-294
To control disposition and hence gene expression, we investigated the disposition characteristics of plasmid DNA complexed with the cationic liposomes Lipofectin® and LipofectACE® after intravenous injection in mice via the tail vein. The optimum ratios of DNA and liposome complexes were selected through in vitro cytotoxicity and transfection studies. The highest transfection was found at the DNA:liposome ratio of 1:5 w/w. Hence, this ratio was used for in vivo disposition studies, and the distribution patterns were compared with that of naked pCAT. Following intravenous injection of [32P] pCAT, radioactivity was rapidly eliminated from plasma and approximately 60% of the dose was taken up by the liver within 1.5 min. In the case of LipofectACE® samples, radioactivity elimination from plasma was equally rapid, but its accumulation was observed in both the liver (35%) and the lung (45%). For Lipofectin® samples, radioactivity was initially accumulated in both the liver (55%) and the lung (25%), but lung accumulation was not sustained beyond 5 min after administration. Both liposomal samples showed in vivo gene expression in the lung, heart, kidney and spleen, but not in the liver. Thus, the present study demonstrated the disposition and gene expression of pCAT can be controlled by complex formation with liposomes. 相似文献
994.
Wassana Yeeprae Shigeru Kawakami Yuriko Higuchi Fumiyoshi Yamashita Mitsuru Hashida 《Journal of drug targeting》2013,21(8-9):479-487
Cell-specific drug delivery is one of the most promising strategies for improving therapeutic efficiency and minimizing systemic toxicity. Carrier systems devoted to receptor-mediated targeting need to be developed. In the case of liver-non-parenchymal cell-specific targeting systems, glycosylated emulsions have been developed as carriers for lipophilic drugs and/or peptides. This present study demonstrates the in vivo disposition behaviour and pharmacokinetic characteristics of mannosylated (Man-) and fucosylated (Fuc-) emulsions incorporated with cholesten-5-yloxy-N-(4-((1-imino-2-d-thiomannosylethyl)amino)alkyl)formamide (Man-C4-Chol) and its fucosylated derivatives (Fuc-C4-Chol), respectively. Man- (or Fuc-) emulsions are composed of soybean oil, EggPC and Man-C4-Chol (or Fuc-C4-Chol) in a weight ratio of 70:25:5. After intravenous administration to mice, these two types of [3H]cholesteryl hexadecyl ether (CHE)-labelled glycosylated emulsions were rapidly eliminated from the blood circulation and preferentially recovered in the liver. In contrast, bare (Bare-) emulsions composed of soybean oil:EggPC:cholesterol (Chol) in a weight ratio of 70:25:5 were more retained in the blood circulation. The hepatic uptake clearances of Man- and Fuc-emulsions were 3.3- and 4.0-times greater than that of Bare-emulsions. Interestingly, the hepatic uptake clearance of Fuc-emulsions was significantly higher that that of Man-emulsions. The uptake ratios by non-parenchymal cells (NPC) and parenchymal cells (PC) (NPC/PC ratio) for Bare-, Man- and Fuc-emulsions were found to be 0.4, 2.0 and 2.9, respectively. The hepatic uptakes of [3H]CHE-labelled Man- and Fuc-emulsions were reduced by pre-dosing with glycosylated proteins and liposomes. These results clearly support the conclusion that Man- and Fuc-emulsions are promising carrier systems for liver NPC-specific targeting via receptor-mediated mechanism. 相似文献
995.
996.
997.
Satoshi Takahashi Ryoichi Hamasuna Mitsuru Yasuda Shin Ito Kenji Ito Shuichi Kawai Takamasa Yamaguchi Takashi Satoh Kenichi Sunaoshi Koichi Takeda Nobukazu Suzuki Shinichi Maeda Hirofumi Nishimura Souichirou Fukuda Tetsuro Matsumoto 《Journal of infection and chemotherapy》2013,19(5):941-945
To clarify the clinical efficacy of STFX for patients with non-gonococcal urethritis (NGU), including chlamydial urethritis and Mycoplasma genitalium-positive urethritis, this study included male patients with NGU who were 20 years old or older. The pathogens, including Chlamydia trachomatis, M. genitalium and Ureaplasma urealyticum, were detected by nucleic acid amplification tests and the patients were treated with sitafloxacin 100 mg twice daily for 7 days. Microbiological and clinical efficacies were assessed for the patients with NGU posttreatment. Among the 208 patients enrolled in this study, data for a total of 118 patients could be analyzed. The median age was 32 (20–61) years. The median duration from the completion of treatment to the second visit was 21 (14–42) days. There were 68 pathogen-positive NGU cases and 50 with NGU without any microbial detection. Microbiological cure was achieved in 95.6 % of the pathogen-positive NGU patients. Total clinical cure was achieved in 91.3 % (105/115). In this study, STFX was able to eradicate 95.7 % of C. trachomatis, 93.8 % of M. genitalium and 100 % of U. urealyticum. The results of our clinical research indicate that the STFX treatment regimen should become a standard regimen recommended for patients with NGU. In addition, this regimen is recommended for patients with M. genitalium-positive NGU. 相似文献
998.
Polyelectrolyte multilayers were formed on a quartz crystal microbalance (QCM) substrate by using polyelectrolyte droplets. In this study, poly(diallyldimethylammonium chloride) (PDDA) and poly(sodium 4-styrene sulfonate) (PSS) were used. The formation of the multilayers was evaluated in terms of changes in the frequency of the QCM. The polymer droplet could be used to fabricate a polyelectrolyte multilayer. Model protein adsorption such as that in bovine serum albumin and its release behavior were compared with the ionic strength in the media. Moreover, the secondary structure of the adsorbed protein was evaluated by analyzing its circular dichroism spectrum. The adsorbed protein maintained its secondary structure on the layer-by-layer (LbL) membrane. This result strongly supports the fact that the multilayers fabricated by the polyelectrolyte droplet were similar in quality to those fabricated via an alternating adsorption process. In summary, the polyelectrolyte droplet method is a good candidate for the preparation of LbL assemblies in the biomedical field. 相似文献
999.
Ohashi M Ide S Sawaguchi A Suganuma T Kimitsuki T Komune S 《Medical molecular morphology》2008,41(1):28-33
The annular ligament across the stapediovestibular joint connects the stapes footplate and the vestibular window and plays
an important role in the sound conductive system of the ear. In this study, we investigated the distribution of extracellular
matrix components in the ligament by histochemical methods at light and electron microscopic levels. As results, light microscopic
immunohistochemistry of fibrillin and 36-kDa microfibril-associated glycoprotein (MAGP-36) showed intense immunoreactivities
in the annular ligament between the stapes footplate and vestibular window. In addition, the histochemical localization of
hyaluronic acid by using biotinylated hyaluronic acid-binding protein (HABP) clarifi ed the presence of hyaluronic acid in
the annular ligament. At the electron microscopic level, the immunogold labeling of fibrillin showed intense labeling on the
periphery of the electron-dense mantle. Furthermore, the labeling of fibrillin was preferentially seen on the fibrous components
among the electronlucent amorphous substance. The immunogold labeling of MAGP-36 was seen on the electron-dense mantle and
scattered on the electron-lucent amorphous substance. The gold labeling with biotinylated HABP clearly showed a distribution
of hyaluronic acid throughout the amorphous space in the ligament. The present results provide a histochemical profile of
the annular ligament of the rat stapediovestibular joint that may provide clues to elucidation of pathological changes in
the ligaments and conductive hearing loss in humans. 相似文献
1000.
Nagaike K Kawaguchi M Takeda N Fukushima T Sawaguchi A Kohama K Setoyama M Kataoka H 《The American journal of pathology》2008,173(5):1464-1475
Hepatocyte growth factor activator inhibitor type 1 (HAI-1)/serine protease inhibitor, Kunitz type 1 (SPINT1) is a membrane-bound, serine proteinase inhibitor initially identified as an inhibitor of hepatocyte growth factor activator. It also inhibits matriptase and prostasin, both of which are membrane-bound serine proteinases that have critical roles in epidermal differentiation and function. In this study, skin and hair phenotypes of mice lacking the Hai-1/Spint1 gene were characterized. Previously, we reported that the homozygous deletion of Hai-1/Spint1 in mice resulted in embryonic lethality attributable to impaired placental development. To test the role of Hai-1/Spint1 in mice, the placental function of Hai-1/Spint1-mutant mice was rescued. Injection of Hai-1/Spint1+/+ blastocysts with Hai-1/Spint1−/− embryonic stem cells successfully generated high-chimeric Hai-1/Spint1−/− embryos (B6Hai-1−/−High) with normal placentas. These embryos were delivered without apparent developmental abnormalities, confirming that embryonic lethality of Hai-1/Spint1−/− mice was caused by placental dysfunction. However, newborn B6Hai-1−/−High mice showed growth retardation and died by 16 days. These mice developed scaly skin because of hyperkeratinization, reminiscent of ichthyosis, and abnormal hair shafts that showed loss of regular cuticular septation. The interfollicular epidermis showed acanthosis with enhanced Akt phosphorylation. Immunoblot analysis revealed altered proteolytic processing of profilaggrin in Hai-1/Spint1-deleted skin with impaired generation of filaggrin monomers. These findings indicate that Hai-1/Spint1 has critical roles in the regulated keratinization of the epidermis and hair development. 相似文献