全文获取类型
收费全文 | 15444篇 |
免费 | 918篇 |
国内免费 | 101篇 |
专业分类
耳鼻咽喉 | 164篇 |
儿科学 | 323篇 |
妇产科学 | 166篇 |
基础医学 | 2203篇 |
口腔科学 | 222篇 |
临床医学 | 1597篇 |
内科学 | 3820篇 |
皮肤病学 | 334篇 |
神经病学 | 1858篇 |
特种医学 | 985篇 |
外科学 | 2331篇 |
综合类 | 75篇 |
一般理论 | 7篇 |
预防医学 | 620篇 |
眼科学 | 226篇 |
药学 | 772篇 |
中国医学 | 8篇 |
肿瘤学 | 752篇 |
出版年
2023年 | 131篇 |
2022年 | 149篇 |
2021年 | 411篇 |
2020年 | 245篇 |
2019年 | 327篇 |
2018年 | 376篇 |
2017年 | 269篇 |
2016年 | 392篇 |
2015年 | 394篇 |
2014年 | 564篇 |
2013年 | 771篇 |
2012年 | 1225篇 |
2011年 | 1212篇 |
2010年 | 749篇 |
2009年 | 706篇 |
2008年 | 1088篇 |
2007年 | 1073篇 |
2006年 | 1030篇 |
2005年 | 1014篇 |
2004年 | 907篇 |
2003年 | 807篇 |
2002年 | 728篇 |
2001年 | 167篇 |
2000年 | 131篇 |
1999年 | 160篇 |
1998年 | 157篇 |
1997年 | 132篇 |
1996年 | 84篇 |
1995年 | 78篇 |
1994年 | 59篇 |
1993年 | 49篇 |
1992年 | 58篇 |
1991年 | 49篇 |
1990年 | 66篇 |
1989年 | 40篇 |
1988年 | 29篇 |
1987年 | 33篇 |
1986年 | 28篇 |
1985年 | 23篇 |
1984年 | 35篇 |
1983年 | 23篇 |
1982年 | 24篇 |
1980年 | 19篇 |
1979年 | 24篇 |
1978年 | 18篇 |
1977年 | 26篇 |
1975年 | 21篇 |
1974年 | 22篇 |
1968年 | 18篇 |
1930年 | 22篇 |
排序方式: 共有10000条查询结果,搜索用时 359 毫秒
91.
van den Engel NK an Haack M Martin S Kolb H 《Journal of molecular medicine (Berlin, Germany)》2002,80(5):301-308
Adhesion molecules are important for leukocyte extravasation and for the delivery of costimulatory signals in T cell activation. We therefore interfered in the immune process leading to islet inflammation in diabetes prone NOD mice by oral vaccination with plasmid DNA encoding soluble ICAM-1. Female NOD mice were treated orally with ICAM-1, TGF-beta, or control plasmid DNA and received a single injection of cyclophosphamide for synchronization and acceleration of the disease process in the pancreas. Quantitative RT-PCR analysis of pancreatic mRNA showed that cyclophosphamide induced the expression of Th1 cytokines (IFN-gamma and IL-12p40) in vehicle- or control plasmid-treated mice. Treatment with ICAM-1 and TGF-beta DNA resulted in increased levels of IL-10 mRNA in the pancreas, indicating an anti-inflammatory regulatory immune response. Histological analysis of pancreatic islets showed that the DNA treatment did not alter islet infiltration in response to cyclophosphamide. Hence vaccination with the ICAM-1 plasmid had not suppressed leukocyte migration but rather modulated lymphocyte activity, similarly as seen for the TGF-beta-encoding plasmid. Neither of the three plasmids caused recognizable changes in cytokine expression in the small intestine, Peyer's patches, or mesenteric lymph nodes. We conclude that oral vaccination with DNA encoding immunoregulatory molecules such as ICAM-1 and TGF-beta represents an approach for modulating the ongoing inflammatory process in the pancreas of diabetes prone NOD mice. 相似文献
92.
Kinetics of viremia and acute liver injury in relation to outcome of neonatal woodchuck hepatitis virus infection 总被引:4,自引:0,他引:4
Wang Y Menne S Baldwin BH Tennant BC Gerin JL Cote PJ 《Journal of medical virology》2004,72(3):406-415
The kinetics of serum viral responses and acute liver injury were studied during neonatal woodchuck hepatitis virus (WHV) infection in relation to the chronic or resolved outcome. The mean concentrations of serum WHV DNA and surface antigen were significantly higher by week 10 post infection in chronic infections compared to resolving infections, and diverged even further by the time of peak viral load development in serum (week 12). After week 12, these viral markers were detected less frequently with time and at lower concentrations in the resolved outcome. In both outcomes, mean serum activities of hepatic enzymes became increased significantly above baseline by weeks 10-12, peaked at week 14, and normalized by weeks 20-22, thus indicating transient acute liver injury. The increasing liver injury responses were comparable between outcomes at week 12, when serum viral load was markedly higher in the developing chronic infections. This suggested a deficiency in early non-cytolytic control of infection in the chronic outcome. At week 14, liver injury was significantly greater in the resolved outcome and associated with higher mean Fas ligand (FasL) and perforin messenger RNAs (mRNAs) in liver compared to the chronic outcome. This indicated greater immune-mediated killing of infected hepatocytes during resolution. Thus, chronicity as an outcome of neonatal WHV infection develops relatively early during the acute phase of infection due to reduced immune-mediated clearance of infected hepatocytes by both cytolytic and non-cytolytic processes. 相似文献
93.
Chromosome aberrations in B-cell chronic lymphocytic leukemia: reassessment based on molecular cytogenetic analysis 总被引:13,自引:0,他引:13
Döhner H Stilgenbauer S Döhner K Bentz M Lichter P 《Journal of molecular medicine (Berlin, Germany)》1999,77(2):266-281
In B-cell chronic lymphocytic leukemia (B-CLL) clonal chromosome aberrations are detected in approximately 40–50% of tumors
when using conventional chromosome banding analysis. Most studies find trisomy 12 to be the most frequent chromosome aberration,
followed by structural aberrations of the long arm of chromosomes 13 and 14. Trisomy 12 and the ”14q+” marker are associated
with shorter survival times, while the patients with 13q abnormalities have a favorable outcome, similar to those with a normal
karyotype. The development of molecular cytogenetic techniques has greatly improved our ability to detect chromosome aberrations
in tumor cells. Using fluorescence in situ hybridization, chromosome aberrations can be detected not only in dividing cells
but also in interphase nuclei, an approach referred to as interphase cytogenetics. The prevalence of specific aberrations in B-CLL is currently being reassessed by interphase cytogenetics. By far the most
frequent abnormality are deletions involving chromosome band 13q14, followed by deletions of the genomic region 11q22.3-q23.1,
trisomy 12, deletions of 6q21-q23, and deletions/mutations of the TP53 tumor suppressor gene at 17p13. The evaluation of the true incidence of these aberrations now provides the basis for more
accurate correlations with clinical characteristics and outcome. Deletions/mutations of the TP53 gene have been shown to be associated with resistance to treatment and to be an independent marker for poor survival. 11q
deletions have been associated with extensive nodal involvement, rapid disease progression, and short survival times. Whether
trisomy 12, 13q14, and 6q deletions have a prognostic impact awaits further study. The application of these molecular cytogenetic
techniques will also contribute to the identification of the pathogenetically relevant genes that are affected by the chromosome
aberrations in B-CLL.
Received: 2 February 1998 / Accepted: 31 March 1998 相似文献
94.
Valeria Casavola Stephan J. Reshkin Heini Murer Corinna Helmle Kolb 《Pflügers Archiv : European journal of physiology》1992,420(3-4):282-289
LLC-PK1/PKE20 cells (a continuous epithelial cell line) has two different Na/H exchange activities: Na/H-1 located in the basolateral membrane and Na/H-2 located in the apical membrane [Casavola et al. (1989) Biochem Biophys Res Commun 165:833–837; Haggerty et al. (1988) Proc Natl Acad Sci USA 86:6797–6801]. In the present report we have studied hormone regulation of these exchange activities by measuring Na-dependent recovery of pHi from an acid load (by using microspectrofluorometry and 2,7-bis(carboxyethyl)-5,6-carboxyfluorescein) in response to activation of regulatory cascades by either pharmacological agents or by vasopressin or calcitonin. Agents leading to activation of protein kinase A (cAMP-dependent), such as forskolin (10 M), 8-Br-cAMP (0.25 mM), and isobutylmethylxanthine (0.5 mM), inhibited Na/H-2 and Na/H-1 by an average of 49%. Stimulation of protein kinase C by a phorbol ester (phorbol 12-myristate 13-acetate, TPA, 100 nM) inhibited Na/H-2 (by an average of 48%) and stimulated Na/H-1 (by an average of 38%); these effects of TPA were also observed in the presence of forskolin (100 M). Addition of either vasopressin (2 M) or calcitonin (0.3 M) onto both sides of the monolayer decreased the activity of Na/H-2 by an average of 26.3% and 27.7% respectively, and stimulated the activity of Na/H-1 by an average of 17.4% and 38.7% respectively; exposure of cells to either hormone stimulated production of cAMP and inositol trisphosphate, respectively. Separate hormone additions to either the apical or basolateral cell surface led to effects similar to those produced by simultaneous hormone additions onto both cell surfaces, although the relative response of Na/H exchangers to either agonist is variable. In summary, these results suggest that in LLC-PK 1/PKE20 cells, vasopressin and calcitonin can act via receptor systems coupled either to adenylate cyclase or to phospholipase C. Activation of these receptor systems can lead to inhibition of Na/H-2 and stimulation of Na/H-1. 相似文献
95.
Gert Baumann Stephan B. Felix Claus D. Heidecke Gotthard Rieß Ursula Loher Liesel Ludwig Prof. Dr Hans Blömer 《Inflammation research》1984,15(3-4):216-228
Left ventricular infarction (AMI) was produced in experimental animals and the contractile response to -adrenergic and H2-histaminergic stimulation by isoproterenol and impromidine tested in the isolated perfused heart preparation. Adenylate cyclase activity as well as binding characteristics of [3H]-dihydroalprenolol ([3H]-DHA), [3H]-methyl-tiotidine ([3H]-TIOT) and [3H]-quinuclidinyl benzilate ([3H]-QNB) to cardiac
1-, H2- and cholinergic muscarinic receptors were determined in sarcolemmal membrane preparations of the right ventricle of the same hearts. In addition, an attempt was made to elucidate the therapeutic value of post-AMI treatment with impromidine in the presence and absence of-sympathomimetic, in contrast to administration of prenalterol and the conventional therapy with -sympathomimetic drugs, e.g. dobutamine. Three days post-AMI the dose-response curve for isoproterenol of right ventriculardP/dt
max was significantly depressed, while the inotropic effect of impromidine was not impaired. Stimulation of adenylate cyclase activity by isoproterenol was reduced by 80% whereas impromidine and NaF stimulation rates were unaltered. Receptor-binding studies indicated a 90% loss and 10-times lowered affinity (K
D) of the remaining -receptors while specific [3H]-TIOT- and [3H]-QNB-binding was unchanged.Administration of dobutamine increased mortality rates and extension of infarct size, led to a further decrease in contractile response to isoproterenol, induced complete insensitivity of adenylate cyclase to isoproterenol stimulation and caused pronounced additional reduction of number and affinity of [3H]-DHA-binding sites. In contrast, all above alterations were prevented by treatment with either prenalterol or combined administration of impromidine plus metoprolol. It is concluded, that these alterations in the non-ischemic, uninvolved myocardium post-AMI are the result of catecholamine-induced specific damage of sarcolemmal -receptors. Furthermore, treatment with H2-agonists in combination with -blocking agents may have beneficial effects, whereas conventional therapy with -sympathomimetic drugs tends to worsen the already depressed function of the -adrenergic stimulation mechanism.Supported by grants Ba 666/1 and Ba 666/2-2 from the Deutsche Forschungsgemeinschaft (DFG).Data presented in this paper are part of a doctoral thesis by Dr S.B. Felix. 相似文献
96.
Accumulation of very long-chain fatty acids does not affect mitochondrial function in adrenoleukodystrophy protein deficiency 总被引:2,自引:0,他引:2
Oezen I Rossmanith W Forss-Petter S Kemp S Voigtländer T Moser-Thier K Wanders RJ Bittner RE Berger J 《Human molecular genetics》2005,14(9):1127-1137
X-linked adrenoleukodystrophy (X-ALD, OMIM 300100) is a severe inherited neurodegenerative disease, associated with the accumulation of very long-chain fatty acids (VLCFA). The recent unexpected observation that the accumulation of VLCFA in tissues of the Abcd1-deficient mouse model for X-ALD is not due to a deficiency in VLCFA degradation, led to the hypothesis that mitochondrial abnormalities might contribute to X-ALD pathology. Here, we report that in spite of substantial accumulation of VLCFA in whole muscle homogenates, normal VLCFA levels were detected in mitochondria obtained by organellar fractionation. Polarographic analyses of the respiratory chain as well as enzymatic assays of isolated muscle mitochondria revealed no differences between X-ALD and control mice. Moreover, analysis by electron microscopy, revealed normal size, structure and localization of mitochondria in muscle of both groups. Similar to the results obtained in skeletal muscle, the mitochondrial enzyme activities in brain homogenates of Abcd1-deficient and wild-type animals also did not differ. Finally, studies on mitochondrial oxidative phosphorylation in permeabilized human skin fibroblasts of X-ALD patients and controls revealed no abnormalities. Thus, we conclude that the accumulation of VLCFA per se does not cause mitochondrial abnormalities and vice versa-mitochondrial abnormalities are not responsible for the accumulation of VLCFA in X-ALD mice. 相似文献
97.
Villavicencio-Lorini P Laabs S Danker K Reutter W Horstkorte R 《Journal of molecular medicine (Berlin, Germany)》2002,80(10):671-677
Sialylation of glycoproteins and glycolipids plays an important role during development, regeneration and pathogenesis of several diseases. The physiological precursor of all sialic acids is N-acetyl- D-mannosamine. The N-acyl side chain of sialic acid can be modified by exposure of cells to synthetic N-acyl-modified D-mannosamines. In a new experimental approach cells were cultivated in the presence of N-propanoyl- D-mannosamine. This unnatural precursor of sialic acid is taken up by cells and efficiently metabolized to the respective N-acyl-modified neuraminic acid in vitro and in vivo. Here we report on the biological consequences of the incorporation of the unnatural N-propanoylneuraminic acid into glycoconjugates of HL60 cells. Biochemical engineering of the acyl side chain of neuraminic acids activates beta(1)-integrins (VLA4 or VLA5), resulting in an increased adhesion of HL60 cells to fibronectin. 相似文献
98.
99.
Stephan G. M. Meuwissen Anne Bosma Evert van Donk Reinier Waalewijn Gerard Pals Jan C. Pronk Aldur W. Eriksson Hendrik Mullink Chris J. L. M. Meijer 《Virchows Archiv : an international journal of pathology》1988,413(1):11-16
Summary No data are available on the localization of Pepsinogen A (PGA=PG I) and Pepsinogen C (PGC=PG II) positive cells in Barrett's epithelium. Endoscopic biopsy specimens were taken from the columnar epithelium from 23 patients (n=93), and in addition from the cardia from eight healthy control subjects (n=38). The tissue was stained by the immunoperoxidase technique with specific anti-pepsinogen antisera, and double immunostained for PGA and PGC. In the Barrett's epithelium PGA was found in 28 out of 93 biopsy specimens (30.1%) and PGC in 55 out of 93 (59.1%). Chief cells always stained both for PGA and PGC, while clear mucous cells were often PGA– and PGC+. PGA+ and PGC+ cells were found each in 100% of the biopsy specimens with fundic type epithelium, in 21.7% and 70.7% of biopsy specimens with junctional type, in 0% and 26.1% of biopsy specimens with specialized epithelium and in 12.5% and 43.5% of biopsy specimens with mixed junctional/specialized features respectively. Dysplastic epithelium stained always negatively with both anti-pepsinogen antisera. In most control cardia biopsy specimens PGA as well as PGC were demonstrable; occasionally clear mucous glands were PGA– and PGC+.It is concluded that pepsinogen-containing cells can be accurately identified in the Barrett's epithelium; their presence seems related to the histological cell type. Identification of pepsinogen positive cells may contribute to a more accurate morphological classification of the Barrett's epithelium.Presented in part at the Annual Meeting of the American Gastroenterological Association, San Francisco, May 1986 相似文献
100.
Cation channels,cell volume and the death of an erythrocyte 总被引:8,自引:0,他引:8
Lang F Lang KS Wieder T Myssina S Birka C Lang PA Kaiser S Kempe D Duranton C Huber SM 《Pflügers Archiv : European journal of physiology》2003,447(2):121-125
Similar to a variety of nucleated cells, human erythrocytes activate a non-selective cation channel upon osmotic cell shrinkage. Further stimuli of channel activation include oxidative stress, energy depletion and extracellular removal of Cl–. The channel is permeable to Ca2+ and opening of the channel increases cytosolic [Ca2+]. Intriguing evidence points to a role of this channel in the elimination of erythrocytes by apoptosis. Ca2+ entering through the cation channel stimulates a scramblase, leading to breakdown of cell membrane phosphatidylserine asymmetry, and stimulates Ca2+-sensitive K+ channels, thus leading to KCl loss and (further) cell shrinkage. The breakdown of phosphatidylserine asymmetry is evidenced by annexin binding, a typical feature of apoptotic cells. The effects of osmotic shock, oxidative stress and energy depletion on annexin binding are mimicked by the Ca2+ ionophore ionomycin (1 µM) and blunted in the nominal absence of extracellular Ca2+. Nevertheless, the residual annexin binding points to additional mechanisms involved in the triggering of the scramblase. The exposure of phosphatidylserine at the extracellular face of the cell membrane stimulates phagocytes to engulf the apoptotic erythrocytes. Thus, sustained activation of the cation channels eventually leads to clearance of affected erythrocytes from peripheral blood. Susceptibility to annexin binding is enhanced in several genetic disorders affecting erythrocyte function, such as thalassaemia, sickle-cell disease and glucose-6-phosphate dehydrogenase deficiency. The enhanced vulnerability presumably contributes to the shortened life span of the affected erythrocytes. Beyond their role in the limitation of erythrocyte survival, cation channels may contribute to the triggering of apoptosis in nucleated cells exposed to osmotic shock and/or oxidative stress. 相似文献