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991.
Amyloid plaques associated with Alzheimer's disease (AD) induce inflammatory responses associated with activated microglia and reactive astrocytes, which exacerbate neurodegeneration through release of inflammatory cytokines, reactive oxygen species, and other factors. Inflammation contributes to neurodegeneration at later stages of AD, but it may also play a role in early disease pathogenesis. We found that before plaque deposition, amyloid precursor protein (APP)/presenilin 1 (PSEN1) transgenic mice (PSAPP mice), a well-characterized model of AD, exhibit evidence of cerebrovascular inflammation. Expression of the endothelial cell-specific antigen MECA-32 (mouse endothelial cell antigen-32) was upregulated in the cerebrovasculature of young PSAPP mice (3 months old) and was similar to that observed in mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis characterized by neuroinflammation. MECA-32 is normally expressed in central and peripheral vasculature throughout development, but expression in the cerebrovasculature is downregulated on establishment of the blood-brain barrier (BBB). However, CNS inflammation triggers re-expression of MECA-32 in compromised cerebrovasculature. Our study indicates that MECA-32 may be a robust marker of cerebrovascular inflammation and compromised BBB integrity, triggered by soluble amyloid-β early in disease pathogenesis. 相似文献
992.
Alzheimer's disease (AD) is one of the major neurodegenerative diseases that deteriorates cognitive functions and primarily affects associated brain regions involved in learning and memory, such as the neocortex and the hippocampus. Following the discovery and establishment of its role as a neurotransmitter, serotonin (5-HT), was found to be involved in a multitude of neurophysiological processes including mnesic function, through its dedicated pathways and interaction with cholinergic, glutamatergic, GABAergic and dopaminergic transmission systems. Abnormal 5-HT neurotransmission contributes to the deterioration of cognitive processes in ageing, AD and other neuropathologies, including schizophrenia, stress, mood disorders and depression. Numerous studies have confirmed the pathophysiological role of the 5-HT system in AD and that several drugs enhancing 5-HT neurotransmission are effective in treating the AD-related cognitive and behavioural deficits. Here we present a comprehensive overview of the role of serotonergic neurotransmission in brain development, maturation and ageing, discuss its role in higher brain function and provide an in depth account of pathological modifications of serotonergic transmission in neurological diseases and AD. 相似文献
993.
Doorn KJ Lucassen PJ Boddeke HW Prins M Berendse HW Drukarch B van Dam AM 《Progress in neurobiology》2012,98(2):222-238
Recent data has indicated that the traditional view of Parkinson's disease (PD) as an isolated disorder of the nigrostriatal dopaminergic system alone is an oversimplification of its complex symptomatology. Aside from classical motor deficits, various non-motor symptoms including autonomic dysfunction, sensory and cognitive impairments as well as neuropsychiatric alterations and sleep disturbances are common in PD. Some of these non-motor symptoms can even antedate the motor problems. Many of them are associated with extranigral neuropathological changes, such as extensive α-synuclein pathology and also neuroinflammatory responses in specific brain regions, i.e. microglial activation, which has been implicated in several aspects of PD pathogenesis and progression. However, microglia do not represent a uniform population, but comprise a diverse group of cells with brain region-specific phenotypes that can exert beneficial or detrimental effects, depending on the local phenotype and context. Understanding how microglia can be neuroprotective in one brain region, while promoting neurotoxicity in another, will improve our understanding of the role of microglia in neurodegeneration in general, and of their role in PD pathology in particular. Since neuroinflammatory responses are in principle modifiable, such approaches could help to identify new targets or adjunctive therapies for the full spectrum of PD-related symptoms. 相似文献
994.
Knöchel C Oertel-Knöchel V O'Dwyer L Prvulovic D Alves G Kollmann B Hampel H 《Progress in neurobiology》2012,96(1):46-68
The current review outlines the under-appreciated effects of physical exercise on the course of psychiatric disorders, focussing on recent findings from animal and human research. Several studies have shown that regular physical exercise is significantly beneficial for psychiatric patients both on a biological and a psychological level. Positive effects of controlled exercise include improved metabolic responses, neuro-protection, increased quality of life, and reduced psychopathological symptoms.Studies investigating the effectiveness of various physical training interventions in alleviating severe mental diseases, such as Alzheimer's dementia (AD), schizophrenia (SZ) or major depressive disorder (MDD) indicate that physical exercise can relieve symptoms of depression, psychosis and dementia and more importantly can curtail further progression of these diseases. This review assesses the most effective methods of physical training for specific psychiatric symptoms.Introducing physical exercise in therapeutic regimes would be an innovative approach that could significantly reduce the severity of psychopathological and cognitive symptoms in patients. The positive biological and molecular outcomes associated with physical exercise render it a concrete therapeutic strategy for improving the quality of live and reducing physical illness in psychiatric patients. Therefore, integrating physical activity into a patient's social life may be an effective treatment strategy. Furthermore, exercise might have the potential to be a preventative treatment within the context of multi-modal therapeutic programs. 相似文献
995.
Morquette P Lavoie R Fhima MD Lamoureux X Verdier D Kolta A 《Progress in neurobiology》2012,96(3):340-355
The basic pattern of rhythmic jaw movements produced during mastication is generated by a neuronal network located in the brainstem and referred to as the masticatory central pattern generator (CPG). This network composed of neurons mostly associated to the trigeminal system is found between the rostral borders of the trigeminal motor nucleus and facial nucleus. This review summarizes current knowledge on the anatomical organization, the development, the connectivity and the cellular properties of these trigeminal circuits in relation to mastication. Emphasis is put on a population of rhythmogenic neurons in the dorsal part of the trigeminal sensory nucleus. These neurons have intrinsic bursting capabilities, supported by a persistent Na(+) current (I(NaP)), which are enhanced when the extracellular concentration of Ca(2+) diminishes. Presented evidence suggest that the Ca(2+) dependency of this current combined with its voltage-dependency could provide a mechanism for cortical and sensory afferent inputs to the nucleus to interact with the rhythmogenic properties of its neurons to adjust and adapt the rhythmic output. Astrocytes are postulated to contribute to this process by modulating the extracellular Ca(2+) concentration and a model is proposed to explain how functional microdomains defined by the boundaries of astrocytic syncitia may form under the influence of incoming inputs. 相似文献
996.
This study aimed to characterize the cortical deficits in processing auditory inputs in patients with Alzheimer's disease (AD). The magnetic counterparts of P50 (M50) and mismatch negativity (MMNm) during a passive oddball paradigm were analyzed with equivalent current dipole modeling. The results showed larger cortical activation of standard-evoked M50 in AD patients compared to young and elderly controls. In contrast, smaller amplitudes and longer peak latencies were found in the MMNm of the elderly and AD patients compared with young adults. The MMNm latency was longer in AD patients than in elderly controls. A Spearman correlation test showed an inverse correlation between the cortical strengths of M50 and MMNm in the right hemisphere. In conclusion, age-related changes in the M50 and MMNm components, which may reflect deficits in central auditory processing, are discussed, along with the possibility that increased M50 responses are related to decreased inhibition of redundant inputs in mild AD. 相似文献
997.
Neurodegenerative diseases affect the lives of millions of patients and their families. Due to the complexity of these diseases and our limited understanding of their pathogenesis, the design of therapeutic agents that can effectively treat these diseases has been challenging. Huntington disease (HD) is one of several neurological disorders with few therapeutic options. HD, like numerous other neurodegenerative diseases, involves extensive neuronal cell loss. One potential strategy to combat HD and other neurodegenerative disorders is to intervene in the execution of neuronal cell death. Inhibiting neuronal cell death pathways may slow the development of neurodegeneration. However, discovering small molecule inhibitors of neuronal cell death remains a significant challenge. Here, we review candidate therapeutic targets controlling cell death mechanisms that have been the focus of research in HD, as well as an emerging strategy that has been applied to developing small molecule inhibitors—fragment-based drug discovery (FBDD). FBDD has been successfully used in both industry and academia to identify selective and potent small molecule inhibitors, with a focus on challenging proteins that are not amenable to traditional high-throughput screening approaches. FBDD has been used to generate potent leads, pre-clinical candidates, and has led to the development of an FDA approved drug. This approach can be valuable for identifying modulators of cell-death-regulating proteins; such compounds may prove to be the key to halting the progression of HD and other neurodegenerative disorders. 相似文献
998.
《Annals of human biology》2012,39(5):388-392
AbstractBackground: Endemic fluorosis induced by high concentrations of fluoride in groundwater and soils is a major health problem in several countries, particularly in volcanic areas.Aim: To evaluate the occurrence of dental fluorosis resulting from exposure to high levels of environmental fluoride in 79 AD Herculaneum and close Vesuvius towns.Subjects and methods: The occurrence of dental fluorosis from teeth of the Herculaneum victims of the 79 AD eruption and some individuals from Pompeii (14–37 AD) and Nocera Inferiore (Salerno, IV sec. AD) was detected by means of Particle Induced Gamma-ray Emission technique (PIGE).Results: A clinical and analytical scenario of dental fluorosis resulted from the extreme high fluorine tooth content detected in teeth from Herculaneum and the Vesuvius area inhabitants. The adoption of PIGE technique has proved to be particularly effective in showing moderate as well as milder forms of dental fluorosis, otherwise not clearly detectable by clinical and histological analysis.Conclusions: Morphological, histological and elemental analysis of teeth of the 79 AD Herculaneum population show that in this area fluorosis occurred since Roman times. 相似文献
999.
Mild traumatic brain injuries (TBI) are common in athletes, military personnel, and the elderly, and increasing evidence indicates that these injuries have long-term health effects. However, the difficulty in detecting these mild injuries in vivo is a significant impediment to understanding the underlying pathology and treating mild TBI. In the following experiments, we present the results of diffusion tensor imaging (DTI) and histological analysis of a model of mild repetitive closed-skull brain injury in mouse. Histological markers used included silver staining and amyloid precursor protein (APP) immunohistochemistry to detect axonal injury, and Iba-1 immunohistochemistry to assess microglial activation. At 24h post-injury, before silver staining or microglial abnormalities were apparent by histology, no significant changes in any of the DTI parameters were observed within white matter. At 7 days post-injury we observed a reduction in axial and mean diffusivity. Relative anisotropy at 7 days correlated strongly with the degree of silver staining. Interestingly, APP was not observed at any timepoint examined. In addition to the white matter alterations, mean diffusivity was elevated in ipsilateral cortex at 24h but returned to sham levels by 7 days. Altogether, this demonstrates that DTI is a sensitive method for detecting axonal injury despite a lack of conventional APP pathology. Further, this reflects a need to better understand the histological basis for DTI signal changes in mild TBI. 相似文献
1000.
The perceptual processing of faces was studied using event-related potentials (ERPs) in 12 elderly patients with cognitive impairment, 15 elderly adults and 16 young adults in order to explore the sensitivity of N170/VPP to the cognitive decline associated to Alzheimer's disease. Famous and unknown faces were presented in a familiarity categorization task. Eight patients and 11 elderly adults repeated this task to obtain longitudinal data. Topographical effects were analyzed using PCA. The posterior N170 showed reduced amplitude in patients with cognitive impairment and elderly adults, compared to young adults, which could indicate perceptual impairment in configural face-encoding processing. The anterior VPP showed enhanced amplitude in patients with cognitive impairment, compared to young and elderly adults, which might relate to the prefrontal dysfunction associated to mild dementia. These preliminary findings suggest that N170/VPP could be modulated by the decline related to pathological cognitive aging. 相似文献