全文获取类型
收费全文 | 16723篇 |
免费 | 1166篇 |
国内免费 | 112篇 |
专业分类
耳鼻咽喉 | 99篇 |
儿科学 | 363篇 |
妇产科学 | 309篇 |
基础医学 | 2510篇 |
口腔科学 | 370篇 |
临床医学 | 1692篇 |
内科学 | 3874篇 |
皮肤病学 | 451篇 |
神经病学 | 1698篇 |
特种医学 | 586篇 |
外科学 | 2124篇 |
综合类 | 40篇 |
一般理论 | 8篇 |
预防医学 | 1226篇 |
眼科学 | 182篇 |
药学 | 1188篇 |
中国医学 | 51篇 |
肿瘤学 | 1230篇 |
出版年
2024年 | 24篇 |
2023年 | 169篇 |
2022年 | 310篇 |
2021年 | 569篇 |
2020年 | 380篇 |
2019年 | 529篇 |
2018年 | 568篇 |
2017年 | 407篇 |
2016年 | 468篇 |
2015年 | 491篇 |
2014年 | 729篇 |
2013年 | 919篇 |
2012年 | 1348篇 |
2011年 | 1333篇 |
2010年 | 757篇 |
2009年 | 702篇 |
2008年 | 1102篇 |
2007年 | 1151篇 |
2006年 | 1075篇 |
2005年 | 1043篇 |
2004年 | 970篇 |
2003年 | 865篇 |
2002年 | 776篇 |
2001年 | 133篇 |
2000年 | 103篇 |
1999年 | 132篇 |
1998年 | 154篇 |
1997年 | 122篇 |
1996年 | 95篇 |
1995年 | 88篇 |
1994年 | 65篇 |
1993年 | 58篇 |
1992年 | 40篇 |
1991年 | 52篇 |
1990年 | 28篇 |
1989年 | 27篇 |
1988年 | 29篇 |
1987年 | 20篇 |
1986年 | 27篇 |
1985年 | 30篇 |
1984年 | 15篇 |
1983年 | 12篇 |
1982年 | 12篇 |
1981年 | 11篇 |
1980年 | 7篇 |
1979年 | 7篇 |
1977年 | 8篇 |
1976年 | 4篇 |
1905年 | 3篇 |
1903年 | 4篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
61.
Deckert M Lütjen S Leuker CE Kwok LY Strack A Müller W Wagner N Schlüter D 《European journal of immunology》2003,33(5):1418-1428
Under various inflammatory conditions, cell adhesion molecules are up-regulated in the central nervous system (CNS) and may contribute to the recruitment of leukocytes to the brain. In the present study, the functional role of vascular cell adhesion molecule (VCAM)-1 in Toxoplasma encephalitis (TE) was addressed using VCAM(flox/flox MxCre) mice. Neonatal inactivation of the VCAM-1 gene resulted in a lack of induction of VCAM-1 on cerebral blood vessel endothelial cells, whereas the constitutive expression of VCAM-1 on choroid plexus epithelial cells and the ependyma was unaffected; in these animals, resistance to T. gondii was abolished, and VCAM(flox/flox MxCre) mice died of chronic TE caused by a failure to control parasites in the CNS. Although leukocyte recruitment to the CNS was unimpaired, the B cell response was significantly reduced as evidenced by reduced serum levels of anti-T. gondii-specific IgM and IgG antibodies. Furthermore, the frequency and activation state of intracerebral T. gondii-specific T cells were decreased, and microglial activation was markedly reduced. Taken together, these data demonstrate the crucial requirement of VCAM-1-mediated immune reactions for the control of an intracerebral infectious pathogen, whereas other cell adhesion molecules can efficiently compensate for VCAM-1-mediated homing across cerebral blood vessels. 相似文献
62.
The volume-activated chloride current in endothelial cells from bovine pulmonary artery is not modulated by phosphorylation 总被引:8,自引:0,他引:8
Géza Szücs Stephan Heinke Christine De Greef Luc Raeymaekers Jan Eggermont Guy Droogmans Bernd Nilius 《Pflügers Archiv : European journal of physiology》1996,431(4):540-548
We employed the patch-clamp technique to investigate the effects of various phosphorylation pathways on activation and modulation of volume-activated Cl- currents (I
Cl,vol) in cultured endothelial cells from bovine pulmonary arteries (CPAE cells). Half-maximal activation ofI
Cl,vol occurred at a hypotonicity of 27.5 ± 1.2%. Run-down of the current upon repetitive activation was less than 15% within 60 min. Stimulation of protein kinase C (PKC) by phorbol-12-myristate-13-acetate (PMA) or by (–)-indolactam did not affectI
Cl,vol. Down regulation of PKC activity by a 24-h preincubation of the cells with 0.2 mol/l PMA, or its inhibition by loading the cells with the specific inhibitory 19–31 pseudosubstrate peptide, did not influenceI
Cl,vol. Trifluoperazine and tamoxifen fully blockedI
cCl,vol with concentrations required for half-maximal inhibition of 3.0 and 2.4 mol/1 respectively. This inhibitory effect is probably not mediated by the calmodulin-antagonistic action of these compounds, because it occurs at free intracellular [Ca2+] of 50 nmol/l, which are below the threshold for calmodulin activation. The tyrosine kinase inhibitor herbimycin A (1 ol/1) and genistein (100 ol/1) did not affectI
Cl,vol Exposing CPAE cells to lysophosphatidic acid (1mol/1), an activator of p42 MAPkinase and the focal adhesion kinase p125FAK in endothelial cells, neither evoked a Cl– current nor affectedI
Cl,vol Neither wortmannin (10 mol/1), an inhibitor of MAP kinases and of PI-3 kinase, nor rapamycin (0.1 mmol/1), which interferes with the p70S6 kinase pathway, affectedI
Cl,vol Exposure of CPAE cells to heat or Na-arsenite, both activators of a recently discovered stress-activated tyrosine phosphorylation pathway, neither activated a current nor affected the hypotonic solution-induced Cl– current. We conclude that none of the studied phosphorylation pathways is essential for the activation of the Cl– current induced by hypotonicity. 相似文献
63.
Ping Wang Martina Anton Frank L. Graham Silvia Bacchetti 《Somatic Cell and Molecular Genetics》1995,21(6):429-441
An adenovirus vector (AdCre1) expressing Cre recombinase has been used to induce recombination betweenloxP sites in human chromosomes. G418 resistant cells with oneloxP site, generated by transfection with a plasmid containingloxP between the SV40 promoter and the G418 resistance (neo) gene, were infected with AdCre1 and transfected with a plasmid containingloxP adjacent to a promoterless hisD gene. This resulted in integration of hisD downstream of the SV40 promoter with gain of
histidinol and loss of G418 resistance. Since AdCre1 is non-replicating and Cre expression transient, histidinol resistant
cells containing the hisD gene flanked byloxP sites were stable. Reinfection of these cells with AdCre1 induced excision of hisD in over 90% of infected cells. This high
efficiency of site-specific recombination suggests that AdCre1 may be exploited for temporal and tissue-specific regulation
of gene expression and for chromosome engineering in vitro and in animals. 相似文献
64.
Jelley MJ Wortmann R 《BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy》2000,14(2):99-107
One of the earliest described conditions, gout continues to plague humanity. It is characterised by the deposition of monosodium urate crystals in the joints and soft tissue. The main clinical features of gout are hyperuricaemia, acute monoarticular arthritis, tophi and chronic arthritis, along with nephrolithiasis. Gout typically occurs in middle age and more commonly in men. Asymptomatic hyperuricaemia does not require treatment. The initial attack of acute gout usually affects a single joint, often the first metatarsal phalangeal joint. Definitive diagnosis requires demonstration of urate crystals in the joint fluid. Treatment of acute gout includes nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine and corticosteroids. The most important factor in success of treatment is how quickly therapy is begun after onset of symptoms. Drug treatment of hyperuricaemia includes allopurinol, sulfinpyrazone, probenecid and benzbromarone and should be used in patients with frequent gout attacks, tophi or urate nephropathy. 相似文献
65.
Communication on end-of-life decisions with patients wishing to die at home: the making of a guideline for GPs in Flanders, Belgium
下载免费PDF全文
![点击此处可从《The British journal of general practice》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Reginald Deschepper Robert Vander Stichele Jan L Bernheim Els De Keyser Greta Van Der Kelen Freddy Mortier Luc Deliens 《The British journal of general practice》2006,56(522):14-19
BACKGROUND: Communication with patients on end-of-life decisions is a delicate topic for which there is little guidance.AIM: To describe the development of a guideline for GPs on end-of-life communication with patients who wish to die at home, in a context where patient autonomy and euthanasia are legally regulated. DESIGN OF STUDY: A three-phase process (generation, elaboration and validation). In the generation phase, literature findings were structured and then prioritised in a focus group with GPs of a palliative care consultation network. In the elaboration phase, qualitative data on patients' and caregivers' perspectives were gathered through a focus group with next-of-kin, in-depth interviews with terminal patients, and four quality circle sessions with representatives of all constituencies. In the validation phase, the acceptability of the draft guideline was reviewed in bipolar focus groups (GPs-nurses and GPs-specialists). Finally, comments were solicited from experts by mail. SETTING: Primary home care in Belgium. SUBJECTS: Participants in this study were terminal patients (n = 17), next-of-kin of terminal patients (n = 17), GPs (n = 25), specialists (n = 3), nurses (n = 8), other caregivers (n = 2) and experts (n = 41). RESULTS: Caregivers and patients expressed a need for a comprehensive guideline on communication in end-of-life decisions. Four major communication themes were prioritised: truth telling; exploration of the patient's wishes regarding the end of life; dealing with disproportionate interventions; and dealing with requests for euthanasia in the terminal phase of life. Additional themes required special attention in the guideline: continuity of care by the GP; communication on foregoing food and fluid; and technical aspects of euthanasia. CONCLUSION: It was feasible to develop a guideline by combining the three cornerstones of evidence-based medicine: literature search, patient values and professional experience. 相似文献
66.
Phosphatidylcholine-Specific Phospholipase C from Listeria monocytogenes Is an Important Virulence Factor in Murine Cerebral Listeriosis 总被引:1,自引:0,他引:1
下载免费PDF全文
![点击此处可从《Infection and immunity》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Dirk Schlüter Eugen Domann Christine Buck Torsten Hain Herbert Hof Trinad Chakraborty Martina Deckert-Schlüter 《Infection and immunity》1998,66(12):5930-5938
Meningoencephalitis is a serious and often fatal complication of Listeria monocytogenes infection. The aim of the present study was to analyze the role of internalin A (InlA) and B, which are involved in the invasion of L. monocytogenes into cultivated host tissue cells, and that of phosphatidylcholine-specific phospholipase C (PlcB), which mainly promotes the direct cell-to-cell spread of L. monocytogenes, in murine cerebral listeriosis by use of an InlA/B (ΔinlAB2)- and a PlcB (ΔplcB2)-deficient isogenic deletion mutant strain and the wild-type (WT) L. monocytogenes EGD. Listeria strains were directly applied to the brain, a technique which has been employed previously to study the pathogenesis of cerebral listeriosis (D. Schlüter, S. B. Oprisiu, S. Chahoud, D. Weiner, O. D. Wiestler, H. Hof, and M. Deckert-Schlüter, Eur. J. Immunol. 25:2384–2391, 1995). We demonstrated that PlcB, but not InlA or InlB, is an important virulence factor in cerebral listeriosis. Nonimmunized mice infected intracerebrally with the ΔplcB2 strain survived significantly longer and had a reduced intracerebral bacterial load compared to mice infected with the ΔinlAB2 strain or WT bacteria. In addition, immunization with the WT prior to intracerebral infection significantly increased the survival rate of mice challenged intracerebrally with the ΔplcB2 strain compared to that of mice infected with the WT or ΔinlAB2 strain. Histopathology revealed that the major difference between the various experimental groups was a significantly delayed intracerebral spread of the ΔplcB2 mutant strain, indicating that cell-to-cell spread is an important pathogenic feature of cerebral listeriosis. Interestingly, irrespective of the Listeria mutant used, the apoptosis of hippocampal and cerebellar neurons and an internal hydrocephalus developed in surviving mice, indicating that these complications are not dependent on the virulence factors InlA/B and PlcB. In conclusion, this study points to PlcB as a virulence factor important for the intracerebral pathogenesis of murine L. monocytogenes meningoencephalitis. 相似文献
67.
Brites P Motley AM Gressens P Mooyer PA Ploegaert I Everts V Evrard P Carmeliet P Dewerchin M Schoonjans L Duran M Waterham HR Wanders RJ Baes M 《Human molecular genetics》2003,12(18):2255-2267
Rhizomelic chondrodysplasia punctata is a human autosomal recessive disorder characterized by skeletal, eye and brain abnormalities. The disorder is caused by mutations in the PEX7 gene, which encodes the receptor for a class of peroxisomal matrix enzymes. We describe the generation and characterization of a Pex7 mouse knockout (Pex7(-/-)). Pex7(-/-) mice are born severely hypotonic and have a growth impairment. Mortality in Pex7(-/-) mice is highest in the perinatal period although some Pex7(-/-) mice survived beyond 18 months. Biochemically Pex7(-/-) mice display the abnormalities related to a Pex7 deficiency, i.e. a severe depletion of plasmalogens, impaired alpha-oxidation of phytanic acid and impaired beta-oxidation of very-long-chain fatty acids. In the intermediate zone of the developing cerebral cortex Pex7(-/-) mice have an increase in neuronal density. In vivo neuronal birthdating revealed that Pex7(-/-) mice have a delay in neuronal migration. Analysis of bone ossification in newborn Pex7(-/-) mice revealed a defect in ossification of distal bone elements of the limbs as well as parts of the skull and vertebrae. These findings demonstrate that Pex7 knockout mice provide an important model to study the role of peroxisomal functioning in the pathogenesis of the human disorder. 相似文献
68.
Licastro F Grimaldi LM Bonafè M Martina C Olivieri F Cavallone L Giovanietti S Masliah E Franceschi C 《Neurobiology of aging》2003,24(7):921-926
Two different polymorphic regions of the interleukin-6 (IL-6) gene were investigated in patients with Alzheimer's disease (AD) and non-demented controls. The -174 C allele in the promoter region of IL-6 gene was over-represented in AD patients compared to controls and significantly increased the risk of AD. Moreover, the -174 CC genotype was associated with a high risk of the disease in women. The D allele of a variable number of tandem repeat (VNTR) was in strong linkage disequilibrium with the -174 C allele and slightly increased AD risk. On the other hand, the frequency of the VNTR C allele was decreased in patients with AD and was negatively associated with the risk of developing AD. Both the -174 CC and VNTR DD genotypes were also associated with increased IL-6 levels in the blood and brain from AD. These findings suggest that IL-6 may play a multifaceted role in AD by affecting the turnover of the cytokine. 相似文献
69.
70.
Yang JQ Chun T Liu H Hong S Bui H Van Kaer L Wang CR Singh RR 《European journal of immunology》2004,34(6):1723-1732
Mechanisms responsible for the development of autoimmune skin disease in humans and animal models with lupus remain poorly understood. In this study, we have investigated the role of CD1d, an antigen-presenting molecule known to activate natural killer T cells, in the development of inflammatory dermatitis in lupus-susceptible MRL-lpr/lpr mice. In particular, we have established MRL-lpr/lpr mice carrying a germ-line deletion of the CD1d genes. We demonstrate that CD1d-deficient MRL-lpr/lpr mice, as compared with wild-type littermates, have more frequent and more severe skin disease, with increased local infiltration with mast cells, lymphocytes and dendritic cells, including Langerhans cells. CD1d-deficient MRL-lpr/lpr mice had increased prevalence of CD4(+) T cells in the spleen and liver and of TCR alpha beta (+)B220(+) cells in lymph nodes. Furthermore, CD1d deficiency was associated with decreased T cell production of type 2 cytokines and increased or unchanged type 1 cytokines. These findings indicate a regulatory role of CD1d in inflammatory dermatitis. Understanding the mechanisms by which CD1d deficiency results in splenic T cell expansion and cytokine alterations, with increased dermal infiltration of dendritic cells and lymphocytes in MRL-lpr/lpr mice, will have implications for the pathogenesis of inflammatory skin diseases. 相似文献