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Shiro Akinaga Tadashi Ashizawa Katsushige Gomi Hiroe Ohno Makoto Morimoto Chikara Murakata Masami Okabe 《Cancer chemotherapy and pharmacology》1992,29(4):266-272
Summary Novel derivatives of K-252a, (8R*,9S*,11S*)-(–)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8, 11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo [a,g]-cycloocta[cde]trinden-1-one, an inhibitor of protein kinases and calmodulin-dependent phosphodiesterase, were synthesized and evaluated for their antitumor activity in vitro and in vivo. Of ten derivatives tested, four were active against the P388 murine leukemia i. p.-i. p. system, although K-252a was inactive. Among these derivatives, KT6124 was selected for further biological evaluation studies because its efficacy was the highest. KT6124 was also active against sarcoma 180 and B16 melanoma. It exerted a relatively broad spectrum of antiproliferative activity against 20 human tumor cell lines in vitro. To determine the mechanism(s) of action underlying the antitumor activity of KT6124, we tested the drug for inhibition of protein kinases, including Ca2+-and phospholipid-dependent protein kinase (PKC), in intact A431 human epidermoid carcinoma cells in comparison with the PKC-inhibitory activity of K-252a. KT6124 did not antagonize the action of phorbol 12-myristate 13-acetate (PMA) in A431 cells, whereas K-252a did, suggesting that KT6124 may not act on protein kinases in the cells. The interaction of KT6124 with DNA in living cells was examined by the alkaline elution method. KT6124 apparantly exhibited DNA scission both dose-and time-dependently in the target cells. The DNA breakage was dependent on proteinase K treatment, suggesting its possible interaction with DNA-related enzyme(s). These results indicate that KT6124 exerts antitumor activity by acting on DNA or on DNA-related enzyme(s) in tumor cells rather than via the inhibition of protein kinases. 相似文献
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László Prónai Hiroe Nakazawa Kohji Ichimori Yoshinori Saigusa Tomoichi Ohkubo Kazuko Hiramatsu Shigeru Arimori János Fehér 《Inflammation》1992,16(5):437-450
This study was performed to examine the pattern of Superoxide (O
2
–
·) generation from leukocytes using the O
2
–
· specific chemiluminescence (CL) method.Cypridina luciferin analog, 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo[1,2-alpha]pyrazin-3-one (MCLA) was used as a CL probe. The appropriate conditions of the MCLA method was first determined for the evaluation of the time course of O
2
–
· generation by leukocytes. The time course of O
2
–
· generation obtained by the MCLA-CL system was compared with that by the luminol-dependent CL, electron spin resonance (ESR)/spin trapping, and cytochromec systems. Following stimulation by three different stimulants (PMA, OZ, FMLP), leukocytes continuously generated O
2
–
· for up to 5 h in the MCLA-CL system, irrespective of the kind of stimulation. The curves obtained by generation ceased more rapidly in the luminol-CL, ESR/spin trapping, and cytochromec systems. A 50% activity of the initial value was observed at 70 min in the MCLA-CL system, but 30, 10 and 35 min in the other systems, respectively. The CL or O
2
–
· generation value decreased to less than 1% (possible termination) at 300, 90, 120 and 180 min, respectively. With the exception of ESR studies with OZ, the cell viability was not significantly affected in any of the trials. These results indicate that leukocytes can generate O
2
–
· much longer than previously estimated and that the MCLA-CL-system is the most suitable system for the measurement of the O
2
–
· generation by leukocytes. 相似文献
5.
S Niwano Y Aizawa K Ebe S Miyajima T Funazaki K Suzuki M Satoh A Shibata 《Journal of cardiology》1988,18(4):1155-1162
Therapeutic evaluation of sustained monomorphic ventricular tachycardia (VT) using electrophysiologic study (EPS) is presented in a case of refractory VT. A 54-year-old man with a history of recurring syncope underwent coronary angiography which revealed total occlusion of the posterior descending branch of the right coronary artery. Left ventriculography showed a left ventricular aneurysm at the cardiac apex. Ejection fraction of the left ventricle was 36%. He had four VTs of different QRS morphologies in 12 lead electrocardiograms. According to our programmed ventricular stimulations, single or double, and rarely triple, extra stimuli were administered after eight basic stimuli at two basic cycle lengths. Rapid ventricular pacing, up to 210 bpm, was then added. The stimuli were delivered to two different sites in the right ventricle and to at least one site in the left ventricle. When the entire protocol could not induce VT, isoproterenol was given intravenously, and the same protocol was repeated. No drug could prevent VT attacks, even after the surgical resection of two VT foci, VT was still inducible. Postoperative drug therapy could not prevent VT induction in EPS. However, changes in the mode required for VT induction were observed. Among 47 patients with sustained monomorphic VT treated in our hospital, 24 had EPS to evaluate the efficacies of therapeutic interventions, such as drugs and surgery. In 14 patients, no VT was induced by the entire VT induction protocol. Among the remaining 10 patients, four showed changes in the VT induction mode, but VT recurred in their clinical courses even after their treatments.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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Yoshinori Seko Shigeru Ishiyama Toshiro Nishikawa Takeshi Kasajima Michiaki Hiroe Shin Suzuki Sugao Ishiwata Sachio Kawai Yuetsu Tanaka Miyuki Azuma Tetsuji Kobata Hideo Yagita Ko Okumura Ryozo Nagai 《Cardiovascular pathology》2002,11(3):166-170
BACKGROUND: T-cell-mediated myocardial damage is known to be involved in acute myocarditis and dilated cardiomyopathy. Recently, we found that tumor necrosis factor (TNF) ligand superfamily costimulatory molecules, especially 4-1BBL, played an important role in the myocardial damage of murine acute viral myocarditis. METHODS AND RESULTS: To investigate the roles for CD27L, CD30L, OX40L and 4-1BBL, which belong to TNF ligand superfamily, in the development of acute myocarditis and dilated cardiomyopathy, we analyzed the expression of these antigens in the myocardial tissues of patients with acute myocarditis and dilated cardiomyopathy. We also examined expression of the receptors for these molecules, CD27, CD30, OX40 and 4-1BB, which belong to TNF receptor superfamily, on the infiltrating cells. Strong expression of CD27L, CD30L and 4-1BBL and weak to moderate expression of OX40L was found in the cardiac myocytes of patients with acute myocarditis. Moderate expression of CD27L, CD30L and 4-1BBL and weak expression of OX40L was found on the cardiac myocytes of patients with dilated cardiomyopathy. Most of the infiltrating cells expressed CD27, CD30 and 4-1BB and a part of the infiltrating cells expressed OX40. CONCLUSIONS: Our findings suggest that expression of TNF ligand superfamily costimulatory molecules on cardiac myocytes may play a role in the cell-mediated myocardial damage in patients with acute myocarditis and dilated cardiomyopathy as in murine viral myocarditis. 相似文献
8.
Kinetic profiles of sequential gene expressions for chemokines in mice with contact hypersensitivity
Using cDNA microarray technology, the expression of chemokine genes in the elicitation site of 2,4,6-trinitrochlorobenzene-induced contact hypersensitivity (CHS) was examined in mice. Of the 33 genes analyzed, levels of 11 gene expressions changed, and these can be assigned to four groups based on their kinetic patterns; (1) LARC/CCL20 whose mRNA level increased rapidly at 3 h post-challenge and then gradually decreased, (2) JE/CCL2, MARC/CCL7, MIP-1gamma/CCL9, monocyte chemoattractant protein (MCP)-5/CCL12, ELC/CCL19 and BRAK/CXCL14 whose mRNA levels increased with time and reached the maximum at 6-9 h post-challenge, (3) LIX/CXCL5, Mig/CXCL9 and IP-10/CXCL10 whose mRNA levels increased gradually at least up to 12 h post challenge, and (4) SLC/CCL21 whose mRNA level decreased gradually with time after challenge. The findings suggest that sequential expression of chemokine genes is essential for orientating non-specific skin response to hapten-specific CHS response through the recruitment of inflammatory cells such as neutrophils, monocytes/macrophages and T-cells from the circulation into the tissue site. 相似文献
9.
John L. Johnson Hiroe Shiratsuchi Zahra Toossi Jerrold J. Ellner 《Journal of clinical immunology》1997,17(5):387-395
The pathophysiologic basis for the exuberant intracellular growth of Mycobacterium avium complex (MAC) in AIDS patients is unclear but may relate to altered expression of modulatory cytokines. Interleukin (IL)-1, IL-6, and TNF- expression by monocytes from AIDS patients and healthy subjects (HS) stimulated with isogeneic MAC strains (SmT, smooth-transparent, virulent; SmD, smooth-domed, avirulent) was examined. Spontaneous cytokine production was not observed in patients with AIDS. MAC strains induced less IL-1 and IL-1 release in AIDS patients than HS (P < 0.05). The ratio of cell-associated to supernatant IL-1 also was increased in AIDS patients (P = 0.03). IL-1 mRNA expression paralleled protein release in either group of subjects. In both HS and AIDS patients, stimulation with SmD induced more IL-1 and TNF- release by monocytes compared to SmT. In AIDS patients, SmD also induced greater IL-6 release than SmT (P < 0.01). Alterations in monocyte expression and compartmentalization of the regulatory cytokines IL-1 and IL-6 may enhance bacterial replication and contribute to the patho-genesis of MAC infection in AIDS. 相似文献
10.
Hiroe Ono Motoki Iwasaki Aya Kuchiba Yoshio Kasuga Shiro Yokoyama Hiroshi Onuma Hideki Nishimura Ritsu Kusama Sumiko Ohnami Hiromi Sakamoto Teruhiko Yoshida Shoichiro Tsugane 《Cancer science》2012,103(12):2159-2164
Global hypomethylation of leukocyte DNA has been associated with an increased risk of cancer. As dietary and genetic factors related to one‐carbon metabolism may influence both the methylation and synthesis of DNA, we investigated associations between these factors and the global methylation level of peripheral blood leukocyte DNA based on a cross‐sectional study of 384 Japanese women. Dietary intake of folate and vitamins B2, B6, and B12 was assessed with a validated semiquantitative food frequency questionnaire. Five polymorphisms in methylenetetrahydrofolate reductase (MTHFR) ( rs1801133 and rs1801131 ), methionine synthase (MTR) ( rs1805087 ), and methionine synthase reductase (MTRR) ( rs10380 and rs162049 ) were genotyped. Global DNA methylation of leukocyte DNA was quantified using Luminometric Methylation Assay. A linear trend of association between methylation and dietary and genetic factors was evaluated by regression coefficients in a multivariable linear regression model. Mean global methylation level (standard deviation) was 70.2% (3.4) and range was from 59.0% to 81.2%. Global methylation level significantly decreased by 0.36% (95% confidence interval, 0.03–0.69) per quartile category for folate level. Subgroup analysis suggested that alcohol drinking modified the association between folate intake and global methylation level (Pinteraction = 0.01). However, no statistically significant association was observed for intake of vitamins B2, B6, and B12, alcohol consumption, or five single nucleotide polymorphisms of MTHFR, MTR, and MTRR. We found that higher folate intake was significantly associated with a lower level of global methylation of leukocyte DNA in a group of healthy Japanese females. 相似文献