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Anxiolytics and sedatives are used in current anaesthetic practice for two main reasons: for anxiolysis before surgery and as adjuvants during anaesthesia. A wide choice of agents are available. Their safety profile is dependent on their pharmacokinetic and pharmacodynamic profiles, patient comorbidity and the experience of the clinician using them. All sedative drugs have the potential to cause severe respiratory depression, and hence they should only be used with standard physiological cardiorespiratory monitoring. This is especially true of procedural sedation administered by non-anaesthetists in remote locations. Drugs used for anaesthesia vary in their pharmacology, but have broadly similar clinical effects. The choice of drug is usually a matter of individual preference, although pharmacokinetic and pharmacodynamic parameters do influence the selection of anaesthetic agents, especially in day case surgery. Most intravenous agents are thought to alter consciousness by an effect at the γ-aminobutyric acid type A (GABAA) or N-methyl-D-aspartate (NMDA) receptors or both. Our understanding of the mechanisms of action of anaesthetic drugs is incomplete, not least because of a lack of understanding of consciousness. Several theories have been proposed over the last century, but none of them has managed to comprehensively elucidate the processes involved. There is now a sense of expectation that with the use of modern imaging techniques, anaesthetic drug action can be better understood, and that this may help in our understanding of consciousness and cognitive functions.  相似文献   
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Existing antidepressants seem to have an onset time of several weeks. However, newly found depression-related receptors and pathways may enlighten us to find more rapid-onset antidepressants, in which ketamine is one of the most potential antidepressants. By intranasal administration, drugs can be directly delivered to the brain via olfactory nerve route, which is proved to be suitable for some antidepressants. Well-designed rapid-onset antidepressants are the urgent requirements of the patients with depression. Intranasal administration, as a potential strategy to deliver antidepressants to brain, can improve drug efficacy and largely shorten the onset time. In this article, we sorted out some new formulation approaches in treating depression with different mechanisms and pathways compared with traditional treating strategies, along with new findings in clinical studies, proving that the combination of rapid-onset antidepressants with intranasal delivery will lead a new trend in treating depression.  相似文献   
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《Clinical neurophysiology》2020,131(1):213-224
ObjectiveSystematically review the abnormalities in event related potential (ERP) recorded in Rett Syndrome (RTT) patients and animals in search of translational biomarkers of deficits related to the particular neurophysiological processes of known genetic origin (MECP2 mutations).MethodsPubmed, ISI Web of Knowledge and BIORXIV were searched for the relevant articles according to PRISMA standards.ResultsERP components are generally delayed across all sensory modalities both in RTT patients and its animal model, while findings on ERPs amplitude strongly depend on stimulus properties and presentation rate. Studies on RTT animal models uncovered the abnormalities in the excitatory and inhibitory transmission as critical mechanisms underlying the ERPs changes, but showed that even similar ERP alterations in auditory and visual domains have a diverse neural basis. A range of novel approaches has been developed in animal studies bringing along the meaningful neurophysiological interpretation of ERP measures in RTT patients.ConclusionsWhile there is a clear evidence for sensory ERPs abnormalities in RTT, to further advance the field there is a need in a large-scale ERP studies with the functionally-relevant experimental paradigms.SignificanceThe review provides insights into domain-specific neural basis of the ERP abnormalities and promotes clinical application of the ERP measures as the non-invasive functional biomarkers of RTT pathophysiology.  相似文献   
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Introduction : Anti‐N‐methyl‐d ‐aspartate (NMDA) receptor antibody encephalitis is an increasingly recognized form of autoimmune encephalitis. Conventional treatments include therapies such as corticosteroids, intravenous immunoglobulin (IVIg), and/or therapeutic plasma exchange (TPE). Although TPE is regularly used for treatment of anti‐NMDA receptor antibody encephalitis, the American Society for Apheresis has given it a category III recommendation only. Earlier administered immunotherapies in tumor‐negative patients may facilitate faster recoveries, but it remains unclear whether or not TPE is superior to steroids and/or IVIG. Methods : We retrospectively evaluated 10 of 14 patients that received steroids and TPE with modified Rankin scores and subjectively assessed the point of largest sustained improvement in all 14 patients. Results : In the patients that received both steroids and TPE at our institution during the same hospitalization (only 10 of 14 patients), 7/10 patients after TPE had improved with the modified Rankin score versus 3/10 patients after steroids. The average modified Rankin score improvement after steroids in this group was ?0.1 as compared with 0.4 after TPE. Based on subjective chart review analysis during which all 14 patients were assessed, the largest sustained improvement occurred immediately following the third–fifth exchange in 9/14 patients, whereas only 2/14 patients appeared to have had significant benefit immediately following steroids. Conclusions : This is compelling preliminary data that suggests that corticosteroids may not be as effective compared to steroids followed by TPE. Given the importance of time‐sensitive treatment, more formal studies may illuminate the ideal first‐line treatment for anti‐NMDA receptor antibody encephalitis. J. Clin. Apheresis 30:212–216, 2015. © 2015 Wiley Periodicals, Inc.  相似文献   
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Wnt signaling has a well-established role as a regulator of nervous system development, but its role in the maintenance and regulation of established synapses in the mature brain remains poorly understood. At excitatory glutamatergic synapses, NMDA receptors (NMDARs) have a fundamental role in synaptogenesis, synaptic plasticity, and learning and memory; however, it is not known what controls their number and subunit composition. Here we show that the receptor tyrosine kinase-like orphan receptor 2 (RoR2) functions as a Wnt receptor required to maintain basal NMDAR-mediated synaptic transmission. In addition, RoR2 activation by a noncanonical Wnt ligand activates PKC and JNK and acutely enhances NMDAR synaptic responses. Regulation of a key component of glutamatergic synapses through RoR2 provides a mechanism for Wnt signaling to modulate synaptic transmission, synaptic plasticity, and brain function acutely beyond embryonic development.Wnt ligands are highly conserved secreted glycoproteins responsible for important developmental and homeostatic processes throughout the animal kingdom (1, 2). They play a key role in morphogenesis, patterning, and lineage decision during central and peripheral nervous system development (3). Wnt ligands control gene expression (4), and their dysregulation has been implicated in cancer and major neuropathologies (59).The sustained expression of Wnt ligands and Wnt signaling components in the mature mammalian CNS and their involvement in neuropathologies suggest that these signaling cascades might also play a part in synaptic maintenance and function beyond embryonic development (10, 11). However, because of the pleiotropy and complexity of Wnt signaling, it has been difficult to dissect the components of Wnt signaling present in mature neurons and their role, if any, in the regulation of established synaptic connections and synaptic transmission.Although most excitatory glutamatergic neurotransmission in the brain is mediated by AMPA-type glutamate receptors [i.e., AMPA receptors (AMPARs)], unique properties allow the NMDA-type glutamate receptors [i.e., NMDA receptors (NMDARs)] to play a critical role in synaptic plasticity, learning and memory, and the establishment and maturation of functional neural circuits (1214). Despite their importance, it is not known what controls the number and subunit composition of synaptic NMDARs. Dysfunction of NMDARs has been implicated in numerous diseases, including Huntington disease, Parkinson disease, depression, bipolar disorder, and schizophrenia (14, 15), in which a deficit in NMDAR mediated neurotransmission may be central (16). Interestingly, NMDAR-mediated currents can be acutely and specifically up-regulated by Wnt5a, a noncanonical Wnt ligand (17), but little is known regarding the signaling pathway and mechanisms involved in such regulation.The receptor tyrosine kinase-like orphan receptor 2 (RoR2) is part of a conserved family of tyrosine kinase-like receptors that have been proposed to serve as a receptor for noncanonical Wnt ligands, participating in developmental processes like cell movement and cell polarity (18, 19). Although RoR2 protein has been detected in mammalian neurons (20), its function and signaling pathways are not known. Here we show that RoR2 acts as a receptor for noncanonical Wnt ligands capable of regulating synaptic NMDARs. In hippocampal neurons, activation of RoR2 by noncanonical Wnt ligand Wnt5a activates PKC and JNK, two kinases involved in the regulation of NMDAR currents. In addition, we show that signaling through RoR2 is necessary for the maintenance of basal NMDAR-mediated synaptic transmission and the acute regulation of NMDAR synaptic responses by Wnt5a.Identification of RoR2 as a Wnt receptor that regulates synaptic NMDARs provides a mechanism for Wnt signaling to control synaptic transmission and synaptic plasticity acutely, and is a critical first step toward understanding the role played by Wnt signaling in the regulation of glutamatergic synaptic function under normal or pathological conditions.  相似文献   
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SHANK3 is a postsynaptic structural protein localized at excitatory glutamatergic synapses in which deletions and mutations have been implicated in patients with autism spectrum disorders (ASD). The expression of Shank3 ASD mutations causes impairments in ionotropic glutamate receptor‐mediated synaptic responses in neurons, which is thought to underlie ASD‐related behaviors, thereby indicating glutamatergic synaptopathy as one of the major pathogenic mechanisms. However, little is known about the functional consequences of ASD‐associated mutations in Shank3 on another important set of glutamate receptors, group I metabotropic glutamate receptors (mGluRs). Here, we further assessed how Shank3 mutations identified in patients with ASD (one de novo InsG mutation and two inherited point mutations, R87C and R375C) disrupt group I mGluR (mGluR1 and mGluR5) expression and function. To identify potential isoform‐specific deficits induced by ASD‐associated Shank3 mutations on group I mGluRs, we surface immunolabeled mGluR1 and mGluR5 independently. We also induced mGluR‐dependent synaptic plasticity (R,S‐3,5‐dihydroxyphenylglycine [DHPG]‐induced long‐term depression [LTD]) as well as N‐methyl‐D‐aspartate receptor (NMDAR)‐dependent LTD. ASD‐associated mutations in Shank3 differentially interfered with the ability of cultured hippocampal neurons to express mGluR5 and mGluR1 at synapses. Intriguingly, all ASD Shank3 mutations impaired mGluR‐dependent LTD without altering NMDAR‐dependent LTD. Our data show that the specific perturbation in mGluR‐dependent synaptic plasticity occurs in neurons expressing ASD‐associated Shank3 mutations, which may underpin synaptic dysfunction and subsequent behavioral deficits in ASD.  相似文献   
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《Clinical therapeutics》2019,41(5):836-847
PurposeA role for the immune system in causing myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is long suspected, but few studies have looked for specific autoantibodies that might contribute to the symptoms. Our aim was to look for evidence of antibodies to neuronal proteins in patients with ME/CSF.MethodsSera samples from 50 patients and 50 healthy individuals were sent coded to the Neuroimmunology Laboratory in Oxford. Screening for antibody binding to neuronal tissue was performed on brain tissue and neuronal cultures. Specific serum antibodies were assessed by antigen-specific cell-based assays and radioimmunoassays. After antibody testing, the associations between seropositive status and clinical data were investigated.FindingsOverall, 8 patients and 11 participants were found to have some serum immunoreactivity toward neuronal or neuromuscular junction proteins, but only 1 patient and 2 participants had specific serum antibodies. Nevertheless, seropositive status in patients with ME was associated with shorter duration since onset and a more severe disease.ImplicationsThe results indicate no overall increased frequency of antibodies to neuronal proteins in ME/CSF and no evidence of a specific antibody that might be causative or contribute to clinical features in patients. However, the association of seropositive status with shorter duration of disease and more severe symptoms suggests a possible role of antibodies at onset in some patients and should be the focus of future studies.  相似文献   
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The time‐dependent forgetting of long‐term spatial memories involves activation of NMDA receptors (NMDARs) in the hippocampus. Here, we tested whether NMDARs regulate memory persistence bidirectionally, decreasing or increasing the rate of forgetting. We found that blocking NMDAR activation with AP5 or the GluN2B‐selective antagonist Ro25‐6981 in the dorsal hippocampus (dHPC) prevented the natural forgetting of long‐term memory for the locations of objects in an open field arena. In contrast, while enhancing NMDAR function with the partial agonist D‐Cycloserine did not affect the speed of forgetting for these types of memories, infusing the NMDAR co‐agonist D‐Serine significantly shortened their persistence. These results suggest that NMDAR activity can modulate the speed of constitutive long‐term memory decay in the dHPC and that regulating NMDAR expression and D‐Serine availability could provide a mechanism to control the duration of long‐term memory.  相似文献   
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