全文获取类型
收费全文 | 374篇 |
免费 | 39篇 |
国内免费 | 1篇 |
专业分类
耳鼻咽喉 | 2篇 |
儿科学 | 30篇 |
妇产科学 | 14篇 |
基础医学 | 65篇 |
口腔科学 | 3篇 |
临床医学 | 14篇 |
内科学 | 63篇 |
皮肤病学 | 4篇 |
神经病学 | 87篇 |
特种医学 | 6篇 |
外科学 | 49篇 |
综合类 | 4篇 |
预防医学 | 6篇 |
眼科学 | 2篇 |
药学 | 28篇 |
肿瘤学 | 37篇 |
出版年
2022年 | 3篇 |
2021年 | 2篇 |
2020年 | 3篇 |
2019年 | 4篇 |
2018年 | 7篇 |
2017年 | 5篇 |
2016年 | 11篇 |
2015年 | 11篇 |
2014年 | 11篇 |
2012年 | 4篇 |
2011年 | 5篇 |
2010年 | 4篇 |
2009年 | 8篇 |
2008年 | 19篇 |
2007年 | 18篇 |
2006年 | 25篇 |
2005年 | 25篇 |
2004年 | 21篇 |
2003年 | 23篇 |
2002年 | 29篇 |
2001年 | 23篇 |
2000年 | 13篇 |
1999年 | 16篇 |
1998年 | 6篇 |
1997年 | 7篇 |
1996年 | 3篇 |
1995年 | 5篇 |
1994年 | 3篇 |
1993年 | 2篇 |
1992年 | 9篇 |
1991年 | 9篇 |
1990年 | 4篇 |
1989年 | 7篇 |
1988年 | 6篇 |
1987年 | 4篇 |
1986年 | 5篇 |
1985年 | 3篇 |
1984年 | 3篇 |
1983年 | 5篇 |
1981年 | 2篇 |
1978年 | 2篇 |
1976年 | 5篇 |
1975年 | 3篇 |
1970年 | 2篇 |
1969年 | 4篇 |
1932年 | 2篇 |
1925年 | 2篇 |
1920年 | 2篇 |
1912年 | 1篇 |
1906年 | 1篇 |
排序方式: 共有414条查询结果,搜索用时 0 毫秒
131.
Goker-Alpan O Schiffmann R Park JK Stubblefield BK Tayebi N Sidransky E 《The Journal of pediatrics》2003,143(2):273-276
Neuronopathic Gaucher disease, classically divided into two types, can have a continuum of phenotypes, often defying categorization. Nine children had an intermediate phenotype characterized by a delayed age of onset but rapidly progressive neurological disease, including refractory seizures and oculomotor abnormalities. There was genotypic heterogeneity among these patients. 相似文献
132.
The exo-enzyme autotaxin/NPP2 (ATX/NPP2) is a potent stimulator of cell migration, invasion, metastasis, and angiogenesis. Recently, ATX/NPP2 was found to possess lysophospholipase D (lyso-LPD) activity, generating the bioactive mediator lysophosphatidic acid from precursors. In the present study, we used site-directed mutagenesis to delineate the active domain of lysophospholipid catalytic activity and to examine potential overlap with the nucleotide phosphodiesterase domain. We found four amino acid residues obligatory for the phosphodiesterase, lyso-PLD, and migration-stimulating activities of ATX/NPP2, suggesting that 5'-nucleotide phosphodiesterase (PDE) and lyso-PLD share a common reaction mechanism and inviting design of enzymatic inhibitors as therapeutic agents for neoplastic disease. 相似文献
133.
New prospects for the treatment of lysosomal storage diseases 总被引:12,自引:0,他引:12
Although individually rare, lysosomal storage disorders constitute a significant burden on society. To date, enzyme replacement therapy (ERT) has been the most successful therapeutic approach for lysosomal storage disorders. ERT reverses systemic manifestations of Gaucher disease but does not effectively treat the neurological complications. Recently, ERT produced a reduction of severe neuropathic pain, stabilisation of renal disease, and improved vascular function and structure in short-term, placebo-controlled trials in patients with Fabry's disease. Long-term studies are necessary to evaluate the full potential of ERT in this disease. In patients with Pompe disease, a fatal cardiac and skeletal muscle disorder, ERT improved cardiac function and structure, and increased overall muscle strength. It has already increased survival in a small number of affected infants. ERT also decreased liver and spleen size, joint mobility and quality of life in patients with mucopolysaccharidosis type I, but when the therapeutic protein is administered intravenously, it is unlikely to modify the neurological outcome in this or in other similar disorders. Bone marrow transplantation continues to be effective in Gaucher disease, in some forms of mucopolysaccharidosis and in mild forms of Krabbé disease, but it has high morbidity and mortality that limits its use in lysosomal storage disorders. Drugs that slow the rate of formation of accumulating glycolipids are being developed and one of them, OGT-918 (N-butyldeoxynojirimycin), is showing promise in patients with Gaucher disease. Gene therapy for lysosomal storage disorders holds promise as a replacement for the other therapies described here but requires much more development before clinical efficacy trials. 相似文献
134.
Glutathione redox system in oxidative lung injury 总被引:15,自引:0,他引:15
Rahman Q Abidi P Afaq F Schiffmann D Mossman BT Kamp DW Athar M 《Critical reviews in toxicology》1999,29(6):543-568
Glutathione (GSH) is a ubiquitous intracellular thiol present in all tissues, including lung. Besides maintaining cellular integrity by creating a reduced environment, GSH has multiple functions, including detoxification of xenobiotics, synthesis of proteins, nucleic acids, and leukotrienes. Present in high concentrations in bronchoalveolar lavage fluid (BALF), GSH provides protection to the lung from oxidative injury induced by different endogenous or exogenous pulmonary toxicants. Its depletion in the lung has been associated with the increased risk of lung damage and disease. The redox system of GSH consists of primary and secondary antioxidants, including glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), and glucose 6-phosphate dehydrogenase (G6PD). Alterations in the activities of these enzymes may reflect reduced cellular defense and may serve as surrogate markers of many lung diseases. As GSH is also involved in the regulation of expression of protooncogenes and apoptosis (programmed cell death), the development of diseases such as cancer and human immune deficiency may be affected by depleting or elevating cellular GSH levels. Exogenous delivery of GSH or its precursor N-acetyl cysteine (NAC) is being used as chemotherapeutic approach. 相似文献
135.
I Gery Z Schiffmann I Weiss L Mugraby 《International archives of allergy and applied immunology》1976,52(1-4):188-195
Intraperitoneal treatment of mice with adjuvants affects the in vitro response of their lymphocytes toward class-specific mitogen. Spleen cells from animals injected with Corynebacterium parvum organisms showed in some cases an increase in their response to all mitogens, while in other experiments, a moderate decrease in the reaction to T-specific mitogens (concanavalin A and phytohemagglutinin) was found. Injection of lipopolysaccharide (LPS) and in particular Bordetella pertussis bacteria, brought about a marked reduction in the response of spleen cells to B mitogens (LPS and PPD) but had little or no effect on the reaction to the T mitogens. Intraperitoneal administration of B. pertussis caused a marked depletion of lymph nodes and a high level of lymphocytosis. Blood cells of the treated mice showed an increased response to T mitogens, whereas mesenterial lymph node cultures reacted higher than the controls to LPS and without stimulation. No change was noted in the responses of cells from the axillary lymph nodes of these pertussis-treated mice. 相似文献
136.
Laurent P Becker JA Valverde O Ledent C de Kerchove d'Exaerde A Schiffmann SN Maldonado R Vassart G Parmentier M 《Nature neuroscience》2005,8(12):1735-1741
Prolactin-releasing peptide (PrRP) and its receptor G protein-coupled receptor 10 (GPR10) are expressed in brain areas involved in the processing of nociceptive signals. We investigated the role of this new neuropeptidergic system in GPR10-knockout mice. These mice had higher nociceptive thresholds and stronger stress-induced analgesia than wild-type mice, differences that were suppressed by naloxone treatment. In addition, potentiation of morphine-induced antinociception and reduction of morphine tolerance were observed in mutants. Intracerebroventricular administration of PrRP in wild-type mice promoted hyperalgesia and reversed morphine-induced antinociception. PrRP administration had no effect on GPR10-mutant mice, showing that its effects are mediated by GPR10. Anti-opioid effects of neuropeptide FF were found to require a functional PrRP-GPR10 system. Finally, GPR10 deficiency enhanced the acquisition of morphine-induced conditioned place preference and decreased the severity of naloxone-precipitated morphine withdrawal syndrome. Altogether, our data identify the PrRP-GPR10 system as a new and potent negative modulator of the opioid system. 相似文献
137.
Germline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors 总被引:12,自引:0,他引:12 下载免费PDF全文
Isozaki K Terris B Belghiti J Schiffmann S Hirota S Vanderwinden JM 《The American journal of pathology》2000,157(5):1581-1585
The proto-oncogene KIT encodes the receptor tyrosine kinase KIT. Gain-of-function mutations in the juxtamembrane domain of KIT have been reported in human gastrointestinal stromal tumors. In a family with multiple gastrointestinal stromal tumors and diffuse hyperplasia of myenteric plexus layer, we have identified another mutation of KIT, a single base mutation, resulting in the substitution of Glu for Lys(642) in the kinase I domain, and studied its biological effect in a cellular system. The mouse homologue of the human KIT mutant was generated by site-directed mutagenesis and stably transfected into the interleukin-3-dependent Ba/F3 murine cell line. The oncogenic potential of the mutated KIT was assessed in vitro by a proliferation assay and in vivo by transplantation into nude mice. Transfected Ba/F3 cells grew autonomously in absence of growth factors and formed tumors in nude mice. Substitution of Glu for Lys(642) is an oncogenic mutation in the tyrosine kinase domain of KIT. As germline heterozygous mutation, it causes a diffuse hyperplasia of myenteric interstitial cells of Cajal during embryonic development and occurrence of multiple gastrointestinal stromal tumors at adulthood. 相似文献
138.
Blum D Hemming FJ Galas MC Torch S Cuvelier L Schiffmann SN Sadoul R 《Neuroscience letters》2004,368(3):309-313
Chronic intoxication by 3-nitropropionic acid in the Lewis rat reproduces many features reminiscent of Huntington's disease including behavioural alterations and cortico-striatal degeneration. In particular, in this model, striatal degeneration is accompanied by calpain activation as found in the human disease. The present study was undertaken to determine whether the expression of Alix (apoptosis linked gene-2 interacting protein), a widespread protein involved in neuronal death, would be modified in the striatum and cortex of 3NP-treated rats. The results clearly show that Alix immunoreactivity is increased in the neuronal cell bodies of the lateral striatum, where degeneration is massive. The medial striatum and the cortex that lack neurodegeneration remain only weakly labelled. This is further evidence suggesting an involvement of Alix in the events driving neuronal death. 相似文献
139.
Donald Dassesse Jean-Marie Vanderwinden Ilan Goldberg Jean-Jacques Vanderhaeghen Serge N. Schiffmann 《The European journal of neuroscience》1999,11(9):3101-3114
Adenosine and the adenosine receptor antagonist, caffeine, modulate locomotor activity and striatal neuropeptide expression through interactions with the dopaminergic system by mechanisms which remain partially undetermined. We addressed this question by using quantitative immunocytochemistry and in situ hybridization, combined with retrograde tracing of striatal neurons, to characterize the mechanism(s) leading to the striatal increase in the immediate early genes (IEG), c-fos, zif-268 and arc, following a single injection of caffeine or the A1 antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). Caffeine and DPCPX induced c-fos, zif-268 and arc expression, both at mRNA and protein levels, in large proportions of striatonigral and striatopallidal neurons. The involvement of dopamine systems was evaluated by manipulations of the dopaminergic transmission. Quinpirole, a D2 agonist, almost completely blocked the caffeine-induced IEG increase in both striatopallidal and striatonigral neurons. Conversely, the lesion of the nigrostriatal pathway and the D1 antagonist SCH23390 abolished the caffeine effects in striatonigral neurons but had no or slight effect, respectively, on its action in striatopallidal neurons. These observations demonstrate that caffeine- and DPCPX-mediated IEG inductions involved different mechanisms in striatonigral and striatopallidal neurons through blockade of A1 receptors. Immediate early gene inductions result from a stimulation of dopamine release in striatonigral neurons and from activation of glutamate release and probably also acetylcholine release in striatopallidal neurons. These results also support the idea that, besides A2A receptors, adenosine acting at the A1 receptor plays pivotal functions in the basal ganglia physiology and that blockade of these receptors by specific or nonspecific antagonists, DPCPX and caffeine, may influence a broad range of neuronal functions in the striatum. 相似文献
140.
H. Schiffmann S. Singer D. Singer E. v. Richthofen J. Rathgeber K. Züchner 《Intensive care medicine》1999,25(9):997-1002
Objective: Thus far only few data are available on airway humidification during high-frequency oscillatory ventilation (HFOV). Therefore,
we studied the performance and efficiency of a heated humidifier (HH) and a heat and moisture exchanger (HME) in HFOV using
an artificial lung model. Methods: Experiments were performed with a pediatric high-frequency oscillatory ventilator. The artificial lung contained a sponge
saturated with water to simulate evaporation and was placed in an incubator heated to 37 °C to prevent condensation. The airway
humidity was measured using a capacitive humidity sensor. The water loss of the lung model was determined gravimetrically.
Results: The water loss of the lung model varied between 2.14 and 3.1 g/h during active humidification; it was 2.85 g/h with passive
humidification and 7.56 g/h without humidification. The humidity at the tube connector varied between 34.2 and 42.5 mg/l,
depending on the temperature of the HH and the ventilator setting during active humidification, and between 37 and 39.9 mg/l
with passive humidification. Conclusion: In general, HH and HME are suitable devices for airway humidification in HFOV. The performance of the ventilator was not
significantly influenced by the mode of humidification. However, the adequacy of humidification and safety of the HME remains
to be demonstrated in clinical practice.
Received: 22 September 1998 Final version received: 22 March 1999 Accepted: 23 April 1999 相似文献