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The locus coeruleus (LC) contains the majority of central noradrenergic neurons sending wide projections throughout the entire CNS. The LC is considered to be essential for multiple key brain functions including arousal, attention and adaptive stress responses as well as higher cognitive functions and memory. Electrophysiological studies of LC neurons have identified several characteristic functional features such as low‐frequency pacemaker activity with broad action potentials, transient high‐frequency burst discharges in response to salient stimuli and an apparently homogeneous inhibition of firing by activation of somatodendritic α2 autoreceptors (α2AR). While stress‐mediated plasticity of the α2AR response has been described, it is currently unclear whether different LC neurons projecting to distinct axonal targets display differences in α2AR function. Using fluorescent beads‐mediated retrograde tracing in adult C57Bl6/N mice, we compared the anatomical distributions and functional in vitro properties of identified LC neurons projecting either to medial prefrontal cortex, hippocampus or cerebellum. The functional in vitro analysis of LC neurons confirmed their mostly uniform functional properties regarding action potential generation and pacemaker firing. However, we identified significant differences in tonic and evoked α2AR‐mediated responses. While hippocampal‐projecting LC neurons were partially inhibited by endogenous levels of norepinephrine and almost completely silenced by application of saturating concentrations of the α2 agonist clonidine, prefrontal‐projecting LC neurons were not affected by endogenous levels of norepinephrine and only partially inhibited by saturating concentrations of clonidine. Thus, we identified a limited α2AR control of electrical activity for prefrontal‐projecting LC neurons indicative of functional heterogeneity in the LC‐noradrenergic system.  相似文献   
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The ability of mothers to sensitively attune their maternal responses to the needs of their developing young is fundamental to a healthy mother‐young relationship. The biological mechanisms that govern how mothers adjust caregiving to the dynamic changes in the demands of the young remain an open question. In the present study, we examined whether changes in monoamine levels, within discrete mesocorticolimbic structures involved in cognitive and motivational processes key to parenting, modulate this flexibility in caregiving across the postpartum period. The present study used a Wistar‐Kyoto (WKY) animal model of depression and control Sprague‐Dawley (SD) rats, which differ dramatically in their cognitive, motivational, and parenting performance. Levels of the monoamine neurotransmitters, dopamine, noradrenaline and serotonin, as well as their major metabolites, were measured within the medial prefrontal cortex, striatum, nucleus accumbens and medial preoptic area of SD and WKY mothers at early (postpartum day [PPD]7‐8), late (PPD15‐16) and weaning (PPD25) postpartum stages using high‐performance liquid chromatography with electrochemical detection. Consistent with our prior work, we find that caregiving of SD mothers declined as the postpartum period progressed. Relative to nulliparous females, early postpartum mothers had lower intracellular concentrations of monoamines, as well as lower noradrenaline turnover, and an elevated serotonin turnover within most structures. Postpartum behavioural trajectories subsequently corresponded to a progressive increase in all three monoamine levels within multiple structures. Compared to SD mothers, WKY mothers were inconsistent and disorganised in caring for their offspring and exhibit profound deficits in maternal behaviour. Additionally, WKY mothers had generally lower levels of all three monoamines, as well as different patterns of change across the postpartum period, compared to SD mothers, suggesting dysfunctional central monoamine pathways in WKY mothers as they transition and experience motherhood. Taken together, the results of the present study suggest a role for monoamines at multiple mesocorticolimbic structures with repect to modulating caregiving behaviours attuned to the changing needs of the young.  相似文献   
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Background: Attention-deficit/hyperactivity disorder (ADHD) is a CNS disorder that has its onset in childhood, but often persists into adulthood. There is growing recognition that adult ADHD can result in multiple negative consequences for individuals. ADHD is also often associated with a number of comorbid psychiatric disorders. Atomoxetine (ATX), a nonstimulant, selective noradrenergic reuptake inhibitor, was approved in the United States in 2002 for the treatment of ADHD in children and adolescents, as well as adults. We review here the safety and efficacy of ATX in adults with ADHD, including data in special populations, functional outcomes, as well as provider and patient real-world perceptions. Methods: We searched the databases Embase, MEDLINE and PsycINFO using the terms ‘ADHD’ and ‘adult’ and ‘ATX’ capturing publications from January 1, 1998, to March 27, 2014. Only publications in English were considered. Results: ATX demonstrated significantly greater improvement than placebo (PBO) on the Conners Adult ADHD Rating Scale-Investigator rated:Screening Version (CAARS-Inv:SV) in all trials (N = 6; total score difference ranged from ?3.5 to ?5.5). For long-term trials using the CAARS-Inv:SV, ATX demonstrated significantly greater improvement than PBO in three of four trials (total score differences ranged from ?0.1 to ?6.0). In short-term studies, ATX showed significantly greater improvement than PBO on the Adult ADHD Quality-of-Life scale total score in three of three studies, but results were mixed on the Sheehan Disability Scale. Three studies of ATX have reported statistically significant improvement (compared with PBO) on the Behavior Rating Inventory of Executive Function-Adult Version Self Report scale. The most common adverse events (occurring in ≥ 10% of patients taking ATX) were nausea, dry mouth, decreased appetite, insomnia and fatigue. Conclusions: ATX is an important treatment option for the right patient. ATX can provide long-term, consistent symptom relief and functional improvement for adults with ADHD.  相似文献   
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Reduced noradrenaline levels have been reported to occur in the motor cortices of PD patients postmortem. Imaging techniques have recently become available to specifically study noradrenergic terminal function in vivo using PET. The objective of this study was to evaluate cortical 11C‐MeNER binding in PD patients. Thirty PD patients and 12 healthy control subjects comparable in age, sex, and cognitive performance underwent PET imaging with 11C‐MeNER, a specific ligand of the noradrenaline transporter. Cortical noradrenaline transporter binding was compared at a voxel level using Statistical Parametric Mapping, whereas cortical thickness was assessed using FreeSurfer software with MRI. PD patients showed reduced 11C‐MeNER binding in the primary motor cortex unrelated to cortical thickness; other cortical regions did not differ between groups. In a subgroup analysis, patients with higher Hoehn & Yahr stage exhibited more pronounced 11C‐MeNER binding reductions. Loss of cortical noradrenergic projections to the primary motor cortex occurs in PD associated with disease stage. © 2018 International Parkinson and Movement Disorder Society  相似文献   
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In the second part we focus on two treatment strategies that may overcome the main limitations of current antidepressant drugs. First, we review the experimental and clinical evidence supporting the use of glutamatergic drugs as fast-acting antidepressants. Secondly, we review the involvement of microRNAs (miRNAs) in the pathophysiology of major depressive disorder (MDD) and the use of small RNAs (e.g.., small interfering RNAs or siRNAs) to knockdown genes in monoaminergic and non-monoaminergic neurons and induce antidepressant-like responses in experimental animals.The development of glutamatergic agents is a promising venue for antidepressant drug development, given the antidepressant properties of the non-competitive NMDA receptor antagonist ketamine. Its unique properties appear to result from the activation of AMPA receptors by a metabolite [(2 S,6 S;2 R,6 R)-hydroxynorketamine (HNK)] and mTOR signaling. These effects increase synaptogenesis in prefrontal cortical pyramidal neurons and enhance serotonergic neurotransmission via descending inputs to the raphe nuclei. This view is supported by the cancellation of ketamine's antidepressant-like effects by inhibition of serotonin synthesis.We also review existing evidence supporting the involvement of miRNAs in MDD and the preclinical use of RNA interference (RNAi) strategies to target genes involved in antidepressant response. Many miRNAs have been associated to MDD, some of which e.g., miR-135 targets genes involved in antidepressant actions. Likewise, SSRI-conjugated siRNA evokes faster and/or more effective antidepressant-like responses. Intranasal application of sertraline-conjugated siRNAs directed to 5-HT1A receptors and SERT evoked much faster changes of pre- and postsynaptic antidepressant markers than those produced by fluoxetine.  相似文献   
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目的 探讨玛咖提取物对运动耐力和血激素水平的影响。方法 采用循环水流自由游泳,给予Wistar大鼠2.0、4.0和8.0 g/(kg·bw)玛咖提取物,连续给药15 d。第16天,采用酶联免疫吸附法(ELISA)检测血去甲肾上腺素(NA)、雌二醇(E2)、睾酮(T)水平。结果 给予玛咖提取物2.0、4.0和8.0 g/(kg·bw)15 d,下沉前游泳时间和游泳总时间比单纯游泳组分别延长了32.51%、60.04%、106.52%和16.99%、56.50%、101.73%(P<0.01),下沉次数比单纯游泳组分别减少了18.89%、35.89%、58.06%(P<0.01)。大鼠血NA水平比对照组分别增加了3.30%、6.60%、16.50%,比单纯游泳组分别增加了42.49%、47.05%、60.70%;血E2水平比对照组增加了132.83%、102.72%、62.26%(P<0.01),比单纯游泳组降低了23.88%、33.72%、46.95%;血T水平比对照组分别增加了5.11%、37.65%、123.16%,比单纯游泳组分别增加了28.98%、68.92%、173.85%(P<0.01)。结论 玛咖提取物具有缓减疲劳、增强运动能力的作用。其机制与升高血NA和T水平,降低E2水平有关。  相似文献   
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