摘要： Aim To report the differential diagnosis in children with progressive intellectual and neurological deterioration (PIND) in the UK. Method Since 1997 the PIND Study has searched for variant Creutzfeldt-Jakob disease (vCJD) in children, using the British Paediatric Surveillance Unit to perform prospective surveillance of those younger than 16 years with PIND. Results From May 1997 to October 2019, 2255 children meeting PIND criteria had been notified, of whom 2008 (1085 males, 923 females) had underlying diagnoses. There were over 220 different diseases, including six cases of vCJD. The numbers presenting in four age groups were: <1 year, 805 (40%);1 to 4 years inclusive, 825 (41%);5 to 9 years inclusive, 264 (13%);and 10 to 15 years inclusive, 114 (6%). The two largest ethnic groups were White and Pakistani (58.2% and 17% of diagnosed cases). The most common diseases in these two ethnic groups are shown for the four age groups. The distribution of diseases varied with age but was quite similar in White and Pakistani children. Interpretation This paper provides a unique guide to the complex differential diagnosis of childhood PIND, showing considerable differences between four age groups, but similarities between ethnic groups. The PIND Study still provides the only systematic surveillance for vCJD in children in the UK.

关键词： Blood-brain barriers   Exosomes   Extracellular vesicles   Drug delivery systems   Neurological disorders  

摘要： Cells secrete extracellular vesicles (EVs) for intercellular communication. EVs are natural nanovesicles that are surrounded by lipid bilayer for delivery of assorted cargoes for therapeutic purposes. In addition to their therapeutic roles, these vesicles are potential drug delivery systems. Exosomes are the most studied EVs as the delivery carriers that can cross the blood-brain barrier (BBB) because of their nanosize. BBB is a diffusion barrier that is selective for small molecules to transit from blood to the brain. This barrier has been an obstacle for the delivery of drugs to the brain for the treatment of neurological disorders (NDs). For efficient drug delivery, synthetic vesicles such as liposomes have been employed as carriers for delivery of therapeutic molecules in clinical practice. However, these delivery systems are not without drawbacks. Among the limitations of these drug carriers include recognition by the body as foreign particles that encounter multiple defence systems that could recognize, neutralize and eliminate them. EVs are natural vesicles that may circumvent the body defence system to remain in systemic circulation for a long time. This unique property made them excellent drug delivery vehicles for clinical application. Here I discuss the progress, challenges and future directions of EVs (especially exosomes) as vehicles for targeted delivery of drug and at the same time deliver their cargoes for regenerative purposes in NDs. Recent developments in bioengineering and microfluidic technologies, which hold promise for clinical-grade production of EVs as drug delivery systems for NDs are also highlighted.

关键词： Lanthanum   Rare-earth element   Postweaning exposure   Neurotoxicity  

摘要： Lanthanum is a rare-earth element that has been used in various fields including medicine, agriculture and industry. Previously, in utero lanthanum exposure to dams was shown to alter neurobehavior and neurotransmitter levels in rat offspring;however, the effects of postweaning exposure to lanthanum on neurological behavior is still limited. The purpose of this study was to investigate the effects of postweaning exposure to lanthanum on neurological behavior during early adulthood in rats. Rats were orally exposed to 0, 2, 20, 60 mg/kg BW of lanthanum nitrate from postnatal day (PND) 24 to PND60. Our results indicated that lanthanum treatment significantly decreased body weight and food intake. Morris water maze test results showed that lanthanum significantly decreased escape latency and travel distance. Lanthanum treatment also significantly decreased grip strength, hindlimb strength, and running time & distance in motor activity test. Further results showed that lanthanum treatment significantly decreased plasma neurotransmitter levels of acetylcholine and norepinephrine as well as the number of neurons in the CA1 area of the hippocampus. These results suggest that postweaning exposure to lanthanum have adverse effects on neurobehaviors and the central nervous system, with noobserved-adverse-effect level at 2 mg/kg BW and benchmark dose lower confidence limit at 1.7 mg/kg BW.

关键词： Outcomes research   Prognostic markers  

摘要： Study design This was a secondary analysis on an observational cohort study. Objective To determine if serum albumin significantly associates with long-term neurological outcome (i.e., 1-year post-injury) in a contemporary cohort of individuals with spinal cord injury. Setting Six rehabilitation centers across the United States. Methods A secondary analysis of neurological outcomes and serum albumin concentrations was performed on data from the Spinal Cord Injury Rehabilitation study. Data was accessed from the Archive of Data on Disability to Enable Policy and research (ADDEP). The primary analysis applied unbiased recursive partitioning to examine the relationship between serum albumin, injury severity, and long-term outcomes. The analysis is accessible via. Results Serum albumin concentration was significantly associated with lower extremity motor scores (LEMS) and American Spinal Injury Association Impairment Scale (AIS) grade at admission to rehabilitation. Serum albumin concentrations alone were also significantly associated with change of LEMS and marked recovery (improvement of at least 2 AIS grades and/or recovery to walking) at 1-year post injury. However, after adjusting for admission to rehabilitation LEMS and AIS grade, serum albumin was not significant. Conclusion The current study partially confirms our previous observations that serum albumin concentrations are associated with neurological outcome after spinal cord injury. As a crude prognostic biomarker, serum albumin concentration could be useful in cases where injury severity cannot be accurately assessed.

关键词： Ischemic stroke   Activin A   White matter remyelination   ACVR1B   Neurological outcome  

摘要： Activin A plays important roles in ischemic injury and white matter remyelination, but its mechanisms are unclear. In this study, the adult male C57BL/6 J mice were used to establish the model of 1 h middle cerebral artery occlusion/reperfusion (MCAO/R) 1 d to 28 d-induced ischemic stroke in vivo. We found that the neurological outcome was positively correlated with the levels of myelin associated proteins (include MAG, CNPase, MOG and MBP, n = 6 per group) both in corpus callosum and internal capsule of mice with ischemic stroke. The dynamic changes of Luxol fast blue (LFB) staining intensity, oligodendrocyte (CC1(+)) and proliferated oligodendrocyte precursor (Ki67(+)/PDGFR alpha(+)) cell numbers indicated demyelination and spontaneous remyelination occurred in the corpus callosum of mice after 1 h MCAO/R 1 d-28 d (n = 6 per group). Activin receptor type I (ACVR1) inhibitor SB431542 aggregated neurological deficits, and reduced MAG, MOG and MBP protein levels of mice with ischemic stroke (n = 6 per group). Meanwhile, recombinant mouse (rm) Activin A enhanced the neurological function recovery, MAG, MOG and MBP protein levels of mice with 1 h MCAO/R 28 d. In addition, the injection of AAV-based ACVR1B shRNA with Olig2 promoter could reverse rmActivin A-induced the increases of CC1(+) cell number, LFB intensity, MAG, MOG and MBP protein levels in the corpus callosum (n = 6 per group), and neurological function recovery (n = 10 per group) of mice with 1 h MCAO/R 28 d. These results suggested that Activin A improves the neurological outcome through promoting oligodendroglial ACVR1B-mediated white matter remyelination of mice with ischemic stroke, which may provide a potential therapeutic strategy for ischemic stroke.

关键词： COVID-19   Neurology   Stroke   Cerebrovascular disease   Dementia  

摘要： Objective Neurological symptoms of COVID-19 patients have been recently described. However, no comprehensive data have been reported on pre-existing neurological comorbidities and COVID-19. This study aims at evaluating the prevalence of neurological comorbidities, and their association with COVID-19 severity. Methods We evaluated all consecutive patients admitted to the Emergency Room (ER) of our hospital between the 3rd March and the 14th April 2020, and diagnosed with COVID-19. Data on neurological and non-neurological diseases were extracted, as well as data on demographic characteristics and on severity degree of COVID-19. The prevalence of neurological comorbidities was calculated, and multivariate binary logistic regression analyses were used to estimate the association between neurological diseases and COVID-19 severity. Results We included 344 patients. Neurological comorbidities accounted for 22.4% of cases, with cerebrovascular diseases and cognitive impairment being the most frequent. Neurological comorbidity resulted independently associated with severe COVID-19 (OR 2.305;p = 0.012), as well as male gender (p = 0.001), older age (p = 0.001), neoplastic diseases (p = 0.039), and arterial hypertension (p = 0.045). When neurological comorbidity was associated with non-neurological comorbidities, the OR for severe COVID-19 rose to 7.394 (p = 0.005). Neurological patients, in particular cerebrovascular and cognitively impaired ones, received more respiratory support indication. Conclusion Neurological comorbidities represent a significant determinant of COVID-19 severity, deserving a thorough evaluation since the earliest phases of infection. The vulnerability of patients affected by neurological diseases should suggest a greater attention in targeting this population for proactive viral screening.

摘要： Therapies for psychiatric and neurological disorders have been in the development and refinement process for the past 5 decades. Yet, most of these therapies lack optimal therapeutic efficacy and have multiple debilitating side effects. Recent advances in understanding the pathophysiological processes of psychiatric and neurological disorders have revealed an important role for beta-arrestins, which are important regulators of G-protein-coupled receptor (GPCR) function, including desensitization and intracellular signaling. These findings have pushed beta-arrestins to the forefront as potential therapeutic targets. Here, we highlight current knowledge on beta-arrestin functions in certain psychiatric and neurological disorders (schizophrenia, Parkinson's disease, and substance abuse disorders), and how this has been leveraged to develop new therapeutic strategies. Furthermore, we discuss the obstacles impacting the field of beta-arrestin-based therapeutic development and future approaches that might help advance strategies to develop optimal beta-arrestin-based therapies.

关键词： gastrointestinal tract   microbiota   neurodegenerative   pattern recognition receptor  

摘要： In recent years, the gut microbiota has been increasingly implicated in the development of many extraintestinal disorders, including neurodevelopmental and neurodegenerative disorders. Despite this growing connection, our understanding of the precise mechanisms behind these effects is currently lacking. Pattern recognition receptors (PRRs) are important innate immune proteins expressed on the surface and within the cytoplasm of a multitude of cells, both immune and otherwise, including epithelial, endothelial and neuronal. PRRs comprise four major subfamilies: the Toll-like receptors (TLRs), the nucleotide-binding oligomerization domain leucine rich repeats-containing receptors (NLRs), the retinoic acid inducible gene 1-like receptors and the C-type lectin receptors. Recognition of commensal bacteria by PRRs is critical for maintaining host-microbe interactions and homeostasis, including behaviour. The expression of PRRs on multiple cell types makes them a highly interesting and novel target for regulation of host-microbe signalling, which may lead to gut-brain signalling. Emerging evidence indicates that two of the four known families of PRRs (the NLRs and the TLRs) are involved in the pathogenesis of neurodevelopmental and neurodegenerative disorders via the gut-brain axis. Taken together, increasing evidence supports a role for these PRRs in the development of neurological disorders, including Alzheimer's disease, Parkinson's disease and multiple sclerosis, via the microbiota-gut-brain axis.

关键词： Children   Discontinuation rate   Efficacy   Levetiracetam   Monotheraphy   Safety  

摘要： Objectives: Levetiracetam (LEV) is a second-generation antiepileptic drug with high efficacy and tolerability in children and adults with epilepsy. We aimed to retrospectively assess the long-term efficacy, tolerability, and safety of LEV monotherapy in children with epilepsy. Methods: All patients who received LEV monotherapy at the Ankara University Children Hospital between January 2010 and June 2020 were evaluated. This retrospective pediatric cohort study determined the efficacy and safety of LEV monotherapy in 281 outpatients with epilepsy. Results: There were 281 patients, 50.5% female, aged 5 months to 18 years with a mean age of 9 years. Of these, 48% of patients had idiopathic epilepsy, 40.6% had symptomatic epilepsy, and 11,4% had cryptogenic/genetic epilepsy. Primary generalized seizures occurred in 61.6% of patients, focal seizures in 19.6%, both generalized and focal seizures in 15,3%, focal to bilateral tonic-clonic seizures in 2.5%, and undefined type of seizure in 1.1%. A total of 22.8% patients had an accompanying extra neurological disease, mostly cardiological and hematological. The range of final daily dose was 10-71 mg/kg/day, with mean 29.5 mg/kg/day. Duration of therapy ranged from 7 days to 96 months, with median 12 months (IQR: 6-22). For the all cohort, a 6th month retention rate was 81%, a 12th month retention rate was 71.4%, and a 24th month retention rate was 61.8%. Eighty five percent of the patients had a seizure reduction of at least 50% and 55.9% of patients remained seizure-free for median 12 months treatment duration with LEV monotherapy. Improvement of electroencephalography (EEG) findings was found in 42% of patients on control EEGs. A total of 67 adverse events were documented in 45 (16%) patients. The most common adverse events were behavioral problems such as aggression (n:18) and irritability (n:17). The discontinuation rate due to adverse events was 2.5%, and due to inefficacy was 5.3%. Conclusion: The present study suggest