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1.
We report on generation of dopamine neurons from long-term cultures of human fetal mesencephalic precursor cells. These CNS precursor cells were successfully expanded in vitro using the mitogens epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2). Incubation of these cultures in 3% atmospheric oxygen resulted in higher cellular yields than room air. Following incubation in differentiation media containing interleukin (IL)-1b (IL-1b), IL-11, leukemia inhibitory factor (LIF), and glial cell line-derived neurotrophic factor (GDNF), up to 1% of the precursor cells converted into cells immunoreactive for tyrosine hydroxylase (TH), a marker for dopamine neurons. The TH immunoreactive cells exhibited morphological and functional properties characteristic of dopamine neurons in culture. These precursor cells might serve as a useful source of human dopamine neurons for studying the development and degeneration of human dopamine neurons and may further serve as a continuous, on-demand source of cells for therapeutic transplantation in patients with Parkinson's disease.  相似文献
2.
Previous studies demonstrated that chronic systemic exposure to the pesticide and mitochondrial toxin rotenone through jugular vein cannulation reproduced many features of Parkinson's disease (PD) in rats, including nigrostriatal dopaminergic degeneration and formation of alpha-synuclein-positive cytoplasmic inclusions in nigral neurons (R. Betarbet et al., 2000, Nat. Neurosci. 3, 1301-1306). Although novel and conceptually important, the rotenone model of PD suffered from being extremely labor-intensive. The current paper demonstrates that these same features of PD can be reproduced by chronic, systemic exposure to rotenone following implantation of subcutaneous osmotic pumps. Chronic subcutaneous exposure to low doses of rotenone (2.0-3.0 mg/kg/day) caused highly selective nigrostriatal dopaminergic lesions. Striatal neurons containing DARPP-32 (dopamine and cAMP-regulated phosphoprotein) remained intact with normal morphology, and NeuN staining revealed normal neuronal nuclear morphology. Neurons of the globus pallidus and subthalamic nucleus were spared. Subcutaneous rotenone exposure caused alpha-synuclein-positive cytoplasmic aggregates in nigral neurons. This new protocol for chronic rotenone administration is a substantial improvement in terms of simplicity and throughput.  相似文献
3.
Altered proteasomal function in sporadic Parkinson's disease   总被引:35,自引:0,他引:35  
Parkinson's disease (PD) is characterized pathologically by preferential degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNc). Nigral cell death is accompanied by the accumulation of a wide range of poorly degraded proteins and the formation of proteinaceous inclusions (Lewy bodies) in dopaminergic neurons. Mutations in the genes encoding alpha-synuclein and two enzymes of the ubiquitin-proteasome system, parkin and ubiquitin C-terminal hydrolase L1, are associated with neurodegeneration in some familial forms of PD. We now show that, in comparison to age-matched controls, alpha-subunits (but not beta-subunits) of 26/20S proteasomes are lost within dopaminergic neurons and 20S proteasomal enzymatic activities are impaired in the SNc in sporadic PD. In addition, while the levels of the PA700 proteasome activator are reduced in the SNc in PD, PA700 expression is increased in other brain regions such as the frontal cortex and striatum. We also found that levels of the PA28 proteasome activator are very low to almost undetectable in the SNc compared to other brain areas in both normal and PD subjects. These findings suggest that failure of the ubiquitin-proteasome system to adequately clear unwanted proteins may underlie vulnerability and degeneration of the SNc in both sporadic and familial PD.  相似文献
4.
Interleukin 1 in the brain: biology, pathology and therapeutic target   总被引:32,自引:0,他引:32  
The cytokine interleukin 1 (IL-1) has diverse actions in the brain. In normal brain the IL-1 system is expressed at low levels and is upregulated rapidly in response to local or peripheral insults. IL-1 mediates host defence responses to local and systemic disease and injury (e.g. fever, slow-wave sleep, appetite suppression and neuroendocrine responses) and to neuroinflammation and cell death in neurodegenerative conditions, such as stroke and head injury. It has also been implicated in chronic degenerative diseases, in particular, multiple sclerosis, Parkinson's and Alzheimer's diseases. The mechanisms regulating the expression and action of IL-1 are poorly understood, but involve multiple effects on neuronal, glial and endothelial cell function. Thus, the IL-1 system provides an attractive and intensely competitive target for therapeutic intervention.  相似文献
5.
微电极记录技术在手术治疗帕金森病中的作用   总被引:31,自引:3,他引:28  
目的:介绍微电极记录技术在治疗帕金森病中的作用。方法:采用微电极细胞电生理记录技术进行术中靶点监测,对100例帕金森病患者行苍白球腹后部(96例)和丘脑腹外侧核(4例)毁损术,患者术前及术后评估采用UPDRS积分,术中靶点更换率为87%。结果:手术效果优良,有效率100%,原有症状术后显著改善率平均达89.4%,无永久并发症。结论:微电极的应用能显著减少手术并发症的发生,提高手术效果。  相似文献
6.
It has been suggested that proton magnetic resonance spectroscopy (MRS) of the striatum can differentiate between parkinsonian syndromes. The present study aims to examine this claim by performing a systematic review of the existing literature. A MEDLINE search was performed between 1966 and October 1999, along with searches of conference abstracts and reference lists of papers identified. Eleven groups have used MRS to examine metabolite ratios in the striatum in Parkinsonian syndromes. A number of these have shown reduced N-acetylaspartate/choline (NAA/Cho) and/or N-acetylaspartate/creatine (NAA/Cr) ratios in either idiopathic Parkinson's disease (IPD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP) or corticobasal degeneration. However, the heterogeneity in the results precludes the use of any of these findings in differential diagnosis at the present time. The only group to use absolute metabolite concentrations rather than ratios showed that the decreased NAA/Cho ratio in IPD was because of an increase in choline which is of uncertain biological significance. Further large multicentre trials are required using absolute quantitation of tissue metabolite concentrations and a standardized technique. The patients entering such studies must be rigorously assessed to establish the diagnosis of the type of parkinsonism as accurately as possible. Any discriminatory abnormality must be tested in a large prospective study of newly presenting parkinsonian patients with long-term clinical follow up and ultimate pathological confirmation of the diagnosis as far as possible.  相似文献
7.
葛根素对帕金森病保护作用的实验研究   总被引:26,自引:0,他引:26  
目的 :探讨葛根素能否对雌激素水平降低的帕金森小鼠提供保护作用 ,为开发具有雌激素替代作用的药物预防和治疗 PD提供新的线索。方法 :采用免疫组化染色 (ABC法 )计数酪氨酸羟化酶 (TH)的阳性细胞数 ,TUNEL法观察每视野下凋亡细胞数目 ,比较各组的差异。结果 :正常雌性小鼠 MPTP造模组 (A组 )比去势后 MPTP造模组 (B组 )中给予生理盐水组 (B1组 )、 MPTP造模后去势组 (C组 )给予生理盐水组 (C1组 )的 TH阳性细胞数目明显增多 ,凋亡细胞数目减少 (P<0 .0 5 ) ;B组中给雌激素组 (B2组 )与给葛根素组 (B3组 )相比无显著性差异 (P>0 .0 5 ) ;B2组、 B3组与 B1组相比有显著性差异 (P<0 .0 5 ) ;B1组与 C1组相比无显著性差异 (P>0 .0 5 ) ;在 C组中 ,给雌激素组 (C2组 )和给葛根素组 (C3组 )比对照组 (C1组 ) TH阳性细胞数目增多 ,凋亡细胞数目减少 (P<0 .0 5 ) ,C2组与 C3组相比无显著性差异 (P>0 .0 5 )。结论 :葛根素对帕金森病具有保护作用 ,并与凋亡有关  相似文献
8.
The ability to differentiate neural stem cells (NSCs) into dopamine neurons is fundamental to their role in cell replacement therapies for neurodegenerative disorders such as Parkinson's disease. We show here that when a clonal line (C17.2) of undifferentiated NSCs is transplanted into the intact or 6-hydroxydopamine-lesioned striatum, cells withdraw from the cell cycle (BrdU(-)), migrate extensively in the host striatum, and express markers associated with neuronal (beta-tubulin III(+), NSE(+), NeuN(+)) but not glial (GFAP(-), MBP(-), A2B5(-)) differentiation. Importantly, by 2-5 weeks postgrafting, in the majority of these transplants, nearly all engrafted cells express the dopamine-synthesizing enzymes tyrosine hydroxylase and aromatic L-amino decarboxylase, sometimes resulting in changes in motor behavior. In contrast, no NSCs stain for dopamine-beta-hydroxylase, choline acetyltransferase, glutamic acid decarboxylase, or serotonin. We conclude that, following transplantation into the intact or 6-hydroxydopamine-lesioned rat, the adult brain contains intrinsic cues sufficient to direct the specific expression of dopaminergic traits in immature multipotential neural stem cells.  相似文献
9.
运动障碍病1135例手术治疗报告   总被引:22,自引:2,他引:20  
目的 探讨手术治疗运动障碍病(MDs)的疗效、适应证、靶点选择和风险。方法 967名8个病种的MDs患者接受了1135例次的微电极导向立体定向神经外科手术。靶点选择苍白球腹后部(PVP)、丘脑腹外侧核和丘脑底核(STN)。通过毁损或脑深部电刺激(DBS)靶点达到症状学治疗的 目的。采用国际通用的疗效评估方法,对特定本组之间进行比较。结果 帕金森病(PD)是MDs手术治疗中主要的病种(88.3%),PVP是目前主要的治疗靶点(64.8%),手术明显改善了患者的生存质量。初步结果显示STN和DBS对PD的改善程度高于PVP。手术风险为1.8%。结论 手术对MDs有肯定和持久的疗效。STN可能是最具潜力的PD治疗性核团。  相似文献
10.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopaminergic neurons in the substantia nigra (SN). Among the many pathogenic mechanisms thought to contribute to the demise of these cells, dopamine-dependent oxidative stress has classically taken center stage due to extensive experimental evidence showing that dopamine-derived reactive oxygen species and oxidized dopamine metabolites are toxic to nigral neurons. In recent years, however, the involvement of neuro-inflammatory processes in nigral degeneration has gained increasing attention. Not only have activated microglia and increased levels of inflammatory mediators been detected in the striatum of deceased PD patients, but a large body of animal studies points to a contributory role of inflammation in dopaminergic cell loss. Recently, postmortem examination of human subjects exposed to the parkinsonism-inducing toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), revealed the presence of activated microglia decades after drug exposure, suggesting that even a brief pathogenic insult can induce an ongoing inflammatory response. Perhaps not surprisingly, non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the risk of developing PD. In the past few years, various pathways have come to light that could link dopamine-dependent oxidative stress and microglial activation, finally ascribing a pathogenic trigger to the chronic inflammatory response characteristic of PD.  相似文献
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