关键词： levodopa   dopamine agonists   neurological rehabilitation   genetic variation  

摘要： Background. The strong link between dopamine and motor learning has been well-established in the animal literature with similar findings reported in healthy adults and the elderly. Objective. We aimed to conduct the first, to our knowledge, systematic review of the literature on the evidence for the effects of dopaminergic medications or genetic variations in dopamine transmission on motor recovery or learning after a nonprogressive neurological injury. Methods. A PubMed search was conducted up until April 2018 for all English articles including participants with nonprogressive neurological injury such as cerebral palsy, stroke, spinal cord injury, and traumatic brain injury;quantitative motor outcomes;and assessments of the dopaminergic system or medications. Results. The search yielded 237 articles, from which we identified 26 articles meeting all inclusion/exclusion criteria. The vast majority of articles were related to the use of levodopa poststroke;however, several studies assessed the effects of different medications and/or were on individuals with traumatic brain injury, spinal cord injury or cerebral palsy. Conclusions. The evidence suggests that a brain injury can decrease dopamine transmission and that levodopa may have a positive effect on motor outcomes poststroke, although evidence is not conclusive or consistent. Individual variations in genes related to dopamine transmission may also influence the response to motor skill training during neurorehabilitation and the extent to which dopaminergic medications or interventions can augment that response. More rigorous safety and efficacy studies of levodopa and dopaminergic medications in stroke and particularly other neurological injuries including genetic analyses are warranted.

关键词： Neuronal cell death   Apoptosis   Autophagy   Ferroptosis   Necrosis   Necroptosis   Oncosis   Pyroptosis  

摘要： Proteases are classified into six distinct classes (cysteine, serine, threonine, aspartic, glutamic, and metalloproteases) on the basis of catalytic mechanism. The cellular control of protein quality senses misfolded or damaged proteins principally by selective ubiquitin-proteasome pathway and non-selective autophagy-lysosome pathway. The two pathways do not only maintain cell homeostasis physiologically, but also mediate necrosis and apoptosis pathologically. Proteasomes are threonine proteases, whereas cathepsins are lysosomal aspartic proteases. Calpains are non-lysosomal cysteine proteases and calcium-dependent papain-like enzyme. Calpains and cathepsins are involved in the neuronal necrosis, which are accidental cell death. Necrosis is featured by the disruption of plasma membranes and lysosomes, the loss of ATP and ribosomes, the lysis of cell and nucleus, and the caspase-independent DNA fragmentation. On the other hand, caspases are cysteine endoproteases and mediate neuronal cell death such as apoptosis and pyroptosis, which are programmed cell death. In the central nervous system, necroptosis, ferroptosis and autophagic cell death are also classified into programmed cell death. Neuronal apoptosis is characterized by cell shrinkage, plasma membrane blebbing, karyorrhexis, chromatin condensation, and DNA fragmentation. Necroptosis and pyroptosis are necrotic and lytic forms of programmed cell death, respectively. Although autophagy is involved in cell survival, it fails to maintain cellular homeostasis, resulting in autophagic cell death. Ferroptosis is induced by reactive oxygen species in excitotoxicity of glutamate and ischemia-reperfusion. Apoptosis and pyroptosis are dependent on caspase-3 and caspase-1, respectively. Autophagic cell death and necroptosis are dependent on calpain and cathepsin, respectively, but independent of caspase. Although apoptosis has been defined by the absence of morphological features of necrosis, the two deaths are both parts

关键词： History of neurology   Transcontinental exchanges   Birth of neurology in the US  

摘要： Transnational exchanges have existed for centuries, with both economic and cultural effects. At the end of the 18th century, in the aftermath of the French Revolution, medical education in France underwent radical innovations, prefiguring the training system now almost universally accepted. This paper presents 19th and early 20th century neurology-related exchanges between the United States (US) and Europe, particularly, Paris, which had become a major medical center and where many US neurologists were trained. We discuss some of the intense neurology-related exchanges between the USA and Europe, notably the role of US neurology founders William Alexander Hammond, Silas Weir Mitchell, Edward Seguin as well as Mauritius-born Charles Edouard Brown-Sequard and a few others. We emphasize the mutual benefits that resulted from such exchanges. In later years, the trend reversed with many foreigners, particularly Europeans coming to improve their knowledge in the US. More recently, a shared pattern of travel and enrichment is occurring despite current threats caused by isolationism and undue stress on local identity. (C) 2019 Elsevier Masson SAS. All rights reserved.

关键词： Cerebral ischemia   mitophagy   inflammasome   neurodegenerative disorder   neuroinflammation  

摘要： Mitophagy and inflammasomes have a pivotal role in the development of neuropathology. Molecular mechanisms behind mitophagy and inflammasomes are well-understood, but lacunae prevail in understanding the crosstalk between them in various neurological disorders. As mitochondrial dysfunction is the prime event in neurodegeneration, the clearance of impaired mitochondria is one of the main tasks for maintaining cell integrity in the majority of neuropathologies. Along with it, inflammasome activation also plays a major role, which is usually followed by mitochondrial dysfunction. The present review highlights basics of autophagy, mitophagy, and inflammasomes and the molecular mechanisms involved, and more importantly, it tries to elaborate the interplay between mitophagy and inflammasomes in various neurological disorders. This will help in upgrading the reader's understanding in exploring the link between mitophagy and inflammasomes, which has dealt with limitations in past studies.

关键词： Dexmedetomidine   Intracerebral hemorrhage   Neurological deficits   Oxidative stress   Mitochondrial dysfunction  

摘要： Background: Intracerebral hemorrhage (ICH) is a subtype of stroke with high disability and mortality. Dexmedetomidine (Dex) has been shown to provide neuroprotection in several neurological diseases. The aim of present study was to investigate the effects of Dex on ICH-induced neurological deficits and brain injury and the underlying mechanisms. Methods: ICH mouse model was established by intracerebral injection of autologous blood, followed by Dex or vehicle treatment. Neurological function, brain water content, neuronal activity, and oxidative parameters were determined. The protein expressions of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha), uncoupling protein 2, and manganese-dependent superoxide dismutase were examined by western blotting. Results: Dex administration significantly inhibited ICH-induced the memory impairment, dyskinesia, brain edema, and neuron loss. In addition, ICH-induced the increase in brain oxidative stress level was markedly attenuated after Dex treatment, as evidenced by increased glutathione peroxidase and superoxide dismutase levels and reduced malondialdehyde and nitric oxide levels. Compared with vehicle-treated ICH mice, Dex-treated ICH mice showed significantly decreased intracellular reactive oxygen species (ROS) and mitochondrial ROS (mROS) production in brain, but had no effects on the increased nicotinamide-adenine dinucleotide phosphate oxidase activity. However, stimulation of mROS abrogated the inhibitory effects of Dex on neurological deficits and oxidative stress. The decrease in production of adenosine triphosphate and the expressions of PGC-1 alpha, uncoupling protein 2, and manganese-dependent superoxide dismutase induced by ICH was restored by Dex treatment. Conclusions: Our results reveal that Dex improves ICH-induced neurological deficits and brain injury by inhibiting PGC-1 alpha pathway inactivation and mitochondrial dysfunction-derived oxidative stress.

关键词： HUMAN genetics   MOLECULAR diagnosis   NEUROLOGICAL disorders   GENETIC disorders   HUMAN genome  

摘要： Next-generation sequencing technologies allow for rapid and inexpensive large-scale genomic analysis, creating unprecedented opportunities to integrate genomic data into the clinical diagnosis and management of neurological disorders. However, the scale and complexity of these data make them difficult to interpret and require the use of sophisticated bioinformatics applied to extensive datasets, including whole exome and genome sequences. Detailed analysis of genetic data has shown that accurate phenotype information is essential for correct interpretation of genetic variants and might necessitate re-evaluation of the patient in some cases. A multidisciplinary approach that incorporates bioinformatics, clinical evaluation, and human genetics can help to address these challenges. However, despite numerous studies that show the efficacy of next-generation sequencing in establishing molecular diagnoses, pathogenic mutations are generally identified in fewer than half of all patients with genetic neurological disorders, exposing considerable gaps in the understanding of the human genome and providing opportunities to focus research on improving the usefulness of genomics in clinical practice. Looking forward, the emergence of precision health in neurological care will increasingly apply genomic data analysis to pharmacogenetics, preventive medicine, and patient-targeted therapies.

关键词： Baroreceptor reflex   blood pressure   cardiac output   diuresis   haemorrhage   hypertension   natriuresis   renin-angiotensin-aldosterone system   vascular resistance  

摘要： There is a relationship between arterial blood pressure, cardiac output and vascular resistance described mathematically, that helps us to understand short-term control of blood pressure in terms of a hydraulic system. Arterial baroreceptors are specialized sensors which mediate a rapid response to sudden changes in pressure through interaction with the autonomic nervous system. This in turn influences heart rate, inotropic state and vascular tone, altering distribution of blood between arterial and venous systems, thus compensating for acute changes in total blood volume. Total blood volume is controlled predominantly by the kidney, with the renin-angiotensin-aldosterone system acting as both the 'sensor' of blood pressure/volume (via renin release in the juxtaglomerular apparatus) and the 'effector' of blood pressure/volume (via aldosterone secretion by the adrenal cortex). Overall control is shared;the baroreceptors being responsible for mediating short-term changes, and renal mechanisms determining the long-term control of blood pressure. These systems have to be adaptable in order to deal with physiological variation in the delivery of blood to tissues from rest to exercise, and with the large shifts in blood volume seen in acute haemorrhage. Pathophysiological changes in these systems lead to maladaptive responses, with systemic hypertension the most commonly seen.

关键词： Functional neurological disorder   Functional motor disorder   Psychosomatics   Conversion disorder   Polypharmacy  

摘要： Objective: This study describes medication prescribing patterns in patients with motor functional neurological disorder (mFND) treated in South London and Maudsley NHS Foundation Trust (SLaM), comparing outcomes to a control group of psychiatric patients from the same hospital trust. Method: This is a retrospective case-control study using a psychiatric case register. Cross-sectional data were obtained from 322 mFND patients and 644 psychiatry controls who had had contact with SLaM between 1st January 2006 and 31st December 2016. Results: A slightly lower proportion of mFND patients received medication compared to controls (76.6% v. 83.4%, OR: 0.59, CI: 0.39-0.89, p < 0.05). Of medication recipients, mFND patients were prescribed a higher number of agents (mean: 4.7 v 2.9, p = 0.001) and had higher prescription rates of antidepressants, anti-epileptics, analgesics, and certain non-psychotropic medications. Higher numbers of prescriptions were associated with co-morbid physical conditions, and previous psychiatric admissions. Conclusions: This is the first study to describe medication prescriptions in a large cohort of mFND patients. Patients were prescribed a wide range of psychiatric and physical health medications, with higher rates of polypharmacy than controls. Psychotropic medication prescription is not necessarily the first line treatment for mFND, where physiotherapy and psychotherapy may be offered initially. There is limited, early-phase evidence for pharmacological therapies for mFND, and as such, the benefit-to-risk ratio of prescribing in this complex and poorly understood disorder should be carefully assessed.

关键词： Prolyl oligopeptidase inhibitors   Neurological disorders   3D QSAR   Molecular docking   Molecular dynamics   Free energy calculations  

摘要： Prolyl oligopeptidase (POP) is a potential therapeutic target for treatment of several neurological disorders and cc-synucleinopathies including Parkinson's disease. Most of the known POP inhibitors failed in the clinical trials due to poor pharmacokinetic properties and blood-brain impermeability. Therefore, a training set of 30 structurally diverse compounds with a wide range of inhibitory activity against POP was used to generate a quantitative pharmacophore model, Hypo 3, to identify potential POP inhibitors with desirable drug-like properties. Validations through test set, cost analysis, and Fisher's randomization methods proved that Hypo 3 accurately predicted the known inhibitors among inactive compounds. Hypo 3 was employed as 3D query for virtual screening on an in-house drug-like chemical database containing compounds with good brain permeability and ADMET parameters. Database screening with Hypo 3 resulted in 99 compounds that were narrowed down to 21 compounds through molecular docking. Among them, five compounds were identified in our earlier studies, while two compounds showed in vitro POP inhibition. The current study proposed new 16 virtually screened compounds as potential inhibitors against POP that possess Gold docking score in the range of 64.61-75.74 and Chemscore of -32.25 to -38.35. Furthermore, the top scoring four hit compounds were subjected to molecular dynamics simulations to reveal their appropriate binding modes and assessing binding free energies. The hit compounds interacted with POP effectively via hydrogen bonds with important active site residues along with hydrophobic interactions. Moreover, the hit compounds had key inter-molecular interactions and better binding free energies as compared to the reference inhibitor. A potential new hydrogen bond interaction was discovered between Hit 2 with the Arg252 residue of POP. To conclude, we propose four hit compounds with new structural scaffolds against POP for the lead development of P

关键词： Spinal injection steroids   Spinal nerve roots   Spinal cord compression   Intervertebral disk displacement  

摘要： We describe the case of a 30-year-old patient who was referred for lumbar epidural corticosteroid injection due to right L5 radiculopathy. Two months earlier, MRI demonstrated a right large paracentral L4-L5 disk extrusion causing disabling L5 radiculopathy. The L4-L5 level was selected for interlaminar injection, using fluoroscopic guidance. During injection, the patient developed severe pain in both lower extremities. Thus, the procedure was immediately terminated. Paraplegia occurred within several minutes. Urgent lumbar spine CT and MRI demonstrated contrast material in a massive extruded disk fragment and substantial increase in size of the disk extrusion compared to pre-injection MRI. Emergency surgery was performed for lumbar decompression and discectomy. Although rare, serious neurological complication can result from inadvertent intradiscal injection of contrast material during lumbar epidural injection. This case illustrates the importance of recognizing the possibility of dynamic change in the size of an extruded disk fragment when the MRI precedes injection by a substantial time *** of EvidenceIV, Case Series.