关键词： drug development   BASELINE  

摘要： [...]the benefit/risk analysis of the tested interventions is constantly limited for this special population, and the lack of data may frequently result in inappropriate prescribing and hinder evidence‐based decision‐making. [...]subgroup analysis by baseline physical frailty parameters may allow (a) to better differentiate responders versus nonresponders, thus consenting to enhance the effect size of treatments, improve the drugs prescription, and contain costs; (b) to identify subgroups of patients more susceptible to treatment‐related adverse events, thus more properly defining the safety and tolerability profiles of the tested compounds; (c) to stratify individuals according to more accurate risk profile groups in order to more correctly allocate resources; and (d) to investigate the neurobiological and neuropathological changes occurring at different phases of the individual's aging process. [...]adopting baseline variables that are informative of the global health status of the participant may consent to increase the homogeneity of the study samples, thus limiting the often overlooked “horse‐racing effect” in clinical trials.

关键词： Music   Rehabilitation   Stroke   Alzheimer's disease   Parkinson's disease  

摘要： During the last decades, there have been major advances in mapping the brain regions that underlie our ability to perceive, experience, and produce music and how musical training can shape the structure and function of the brain. This progress has fueled and renewed clinical interest towards uncovering the neural basis for the impaired or preserved processing of music in different neurological disorders and how music-based interventions can be used in their rehabilitation and care. This article reviews our contribution to and the state-of-the-art of this field. We will provide a short overview outlining the key brain networks that participate in the processing of music and singing in the healthy brain and then present recent findings on the following key music-related research topics in neurological disorders: (i) the neural architecture underlying deficient processing of music (amusia), (ii) the preservation of singing in aphasia and music-evoked emotions and memories in Alzheimer's disease, (iii) the mnemonic impact of songs as a verbal learning tool, and (iv) the cognitive, emotional, and neural efficacy of music-based interventions and activities in the rehabilitation and care of major ageing-related neurological illnesses (stroke, Alzheimer's disease, and Parkinson's disease). (C) 2018 Elsevier Ltd. All rights reserved.

关键词： Ataxia-telangiectasia   ATM   Kinase-dead   DNA damage response   Double-strand breaks   Cerebellar atrophy  

摘要： The genome instability syndrome, ataxia-telangiectasia (A-T) is caused by null mutations in the ATM gene, that lead to complete loss or inactivation of the gene's product, the ATM protein kinase. ATM is the primary mobilizer of the cellular response to DNA double-strand breaks (DSBs) - a broad signaling network in which many components are ATM targets. The major clinical feature of A-T is cerebellar atrophy, characterized by relentless loss of Purkinje and granule cells. In Atm-knockout (Atm-KO) mice, complete loss of Atm leads to a very mild neurological phenotype, suggesting that Atm loss is not sufficient to markedly abrogate cerebellar structure and function in this organism. Expression of inactive ("kinase-dead") Atm (Atm(KD)) in mice leads to embryonic lethality, raising the question of whether conditional expression of Atm(KD) in the murine nervous system would lead to a more pronounced neurological phenotype than Atm loss. We generated two mouse strains in which Aten was conditionally expressed as the sole Atm species: one in the CNS and one specifically in Purkinje cells. Focusing our analysis on Purkinje cells, the dynamics of DSB readouts indicated that DSB repair was delayed longer in the presence of Atm(KD) compared to Atm loss. However, both strains exhibited normal life span and displayed no gross cerebellar histological abnormalities or significant neurological phenotype. We conclude that the presence of Atm(KD) is indeed more harmful to DSB repair than Atm loss, but the murine central nervous system can reasonably tolerate the extent of this DSB repair impairment. Greater pressure needs to be exerted on genome stability to obtain a mouse model that recapitulates the severe A-T neurological phenotype.

关键词： Alzheimer's disease   Pyroglutamate   Glutaminyl cyclase   Inhibitor   X-ray crystallography  

摘要： Recent evidence links the role of human glutaminyl cyclase (hQC) to the amyloidogenic process involved in Alzheimer's disease (AD). hQC is a zinc enzyme present in neuronal tissue and its activity is responsible for the cyclization of N-terminal Gln or Glu beta-amyloid peptides, leading to N-pyroglutamic acid peptides (pE-A beta) that is probably a crucial event in the initiation and progress of the disease. Indeed, pE-containing peptides exhibit an elevated neurotoxicity and a tendency to aggregate. These observations render hQC inhibition an attractive strategy for developing new molecules active against AD. We present here the crystal structure of hQC in complex with SEN177, a newly designed molecule. The SEN177-binding mode to hQC differs from that of the known hQC inhibitors. SEN177 K (i) on hQC is 20 nM, comparable or better than that of the most potent known hQC inhibitors PBD150 and PQ912. In addition, SEN177 already demonstrated relevant pharmacological properties in in vivo models of Huntington's disease. All these properties make SEN177 an important scaffold for developing molecules acting on AD and related diseases. [GRAPHICS] .

关键词： epilepsy   infants   liver transplantation   neurological complications   seizure  

摘要： pLT is a highly standardized therapy for children with end-stage liver disease and liver-based metabolic diseases. However, NCs after transplantation occur and especially younger children are considered as more vulnerable and susceptible to NCs. Up to now, detailed data particularly for the very young age group do not exist. We therefore retrospectively studied NCs in children after pLT under age of 24 months. Forty children aged between 19 days and 22 months were evaluated according to type of NC and potential risk factors. NCs occurred in 8/40 patients (20%). All experienced new-onset seizures and in 1/6 surviving patients, seizures evolved into epilepsy. Other NCs were intracerebral abscess (1/8 patients) and subdural hemorrhage (1/8 patients). The overall 3-year mortality rate was 10% (4/40 patients). Significant risk factors for NCs and therefore seizures were HAT (P = 0.020), total surgery time (P = 0.009), retransplantation (P < 0.001), period of catecholamine therapy (P = 0.024), period of mechanical ventilation (P = 0.014), and period of sedation (P = 0.010). Our study is the first to provide detailed information on NCs after pLT in children under 24 months of age. The incidence of NCs in this particular group of very young patients was not increased compared to previously published data of children of all ages. Main NC was new-onset seizure. In the surviving infants, prognosis of seizure was excellent and the risk of developing epilepsy was low. Even more, the occurrence of NCs did not significantly affect mortality or survival in this particular age group.

关键词： Monochorionic twins   neurological complications   neurological development   TTTS  

摘要： Objective: The main objective of this study was to review the available scientific evidence about mid-term neurological outcomes in twins after laser therapy for twin-to-twin transfusion syndrome (TTTS). Methods: A systematic review of studies on neurodevelopmental outcomes (cognition, motor development, communication skills and cerebral palsy) of twins after laser therapy for TTTS was conducted. Outcomes at 24 months of age and the use of validated scales for assessment were the selected criteria. Electronic and manual research identified 25 studies, and nine of them were eligible for the review. Results: The global mean rate of neurological injury in twins treated with laser was 14.07%. The mean rate of cognitive impairment was 8.41%, 11.14% for motor delay, 16.5% for communication delay and 5.73% for cerebral palsy. These rates were higher than the results found in dichorionic twins, but lower than the results found in twins treated with amnio-reductions or conservative management. Conclusion: Laser therapy is associated with a lower rate of neurological injury at 24 months of age compared to other therapeutic techniques. This tendency was also observed with specific incidences regarding cognition, motor skills and cerebral palsy.

关键词： Out-of-hospital cardiac arrest   Targeted temperature management   Post-cardiac arrest syndrome   Neurologically favorable outcome  

摘要： Background: It has been insufficiently investigated whether neurological function after out-of-hospital cardiac arrest (OHCA) would differ by 1 degrees C change in ordered target temperature of 33-36 degrees C among patients undergoing targeted temperature management (TTM) in the real-world setting. Methods: This nationwide hospital-based observational study (The Japanese Association for Acute Medicine-OHCA Registry) conducted between June 2014 and December 2015 in Japan included OHCA patients aged >= 18 years who were treated with TTM. The primary outcome was one-month survival with neurologically favorable outcomes defined by cerebral performance category 1 or 2. To investigate the effect of TTM by 1 degrees C change in ordered target temperature of 33-36 degrees C on each outcome, random effects logistic regression analyses were performed. Results: The final analysis included 738 patients. The proportion of patients with neurologically favorable outcome was 30.4% (7/23), 31.7% (175/552), 28.9% (11/38), and 30.4% (38/125) in the 33 degrees C, 34 degrees C, 35 degrees C, and 36 degrees C groups, respectively. In the multivariable logistic regression analysis, no group had a higher proportion of neurologically favorable outcome compared with the 34 degrees C group (vs. 33 degrees C group, adjusted odds ratio [AOR] 0.90;95% confidence interval [CI] 0.25-3.12, vs. 35 degrees C group, AOR 1.17;95% CI 0.44-3.13, vs. 36 degrees C group, AOR 1.26;95% CI 0.78-2.02). Conclusions: In this population, we evaluated the difference in outcomes after adult OHCA patients received TTM by 1 degrees C change in ordered target temperature of 33-36 degrees C and demonstrated that there was no statistically significant difference in neurologically favorable outcomes after OHCA irrespective of target temperature.

关键词： Community practice   Enablement   Neurological disorders   Social participation  

摘要： Background. Although community integration (CI) is the ultimate goal of rehabilitation, it is rarely achieved in clinical settings. Purpose. The purpose of this study was to (a) synthesize the state of occupational therapy knowledge related to CI for people with neurological issues and to (b) illustrate how CI is conceptualized within the literature. Method. A scoping review was completed using two reviewers, resulting in the selection of 47 articles pertaining to four study populations. Themes common across all client populations were identified through content analysis, and an iterative synthesis was used to analyse the evolution of knowledge. Findings. The selected articles covered craniocerebral trauma (n = 21, 9 experimental categories [EXP]), medullar injuries (n = 11, 4 EXP), cerebrovascular injuries (n = 9, 4 EXP), and multiple sclerosis (n = 4, 1 EXP). CI was used interchangeably with the term social participation. Fifty-one percent of the articles defined CI solely as part of a measurement tool, and 10% did not provide a definition of CI. The physical dimension of CI had been studied more frequently than the social and psychological dimension

关键词： Autonomic nervous system   Breathing   Sleep   Sympathetic   Parasympathetic  

摘要： Cardiovascular and respiratory parameters change during sleep and wakefulness. This observation underscores an important, albeit incompletely understood, role for the central nervous system in the differential regulation of autonomic functions. Understanding sleep/wake-dependent sympathetic modulations provides insights into diseases involving autonomic dysfunction. The purpose of this review was to define the central nervous system nuclei regulating sleep and cardiovascular function and to identify reciprocal networks that may underlie autonomic symptoms of disorders such as insomnia, sleep apnea, restless leg syndrome, rapid eye movement sleep behavior disorder, and narcolepsy/cataplexy. In this review, we examine the functional and anatomical significance of hypothalamic, pontine, and medullary networks on sleep, cardiovascular function, and breathing.

关键词： Frailty   Chronic pain   Metabolite   GWAS   EWAS   Path analysis  

摘要： Chronic widespread musculoskeletal pain (CWP) and frailty are prevalent conditions in older people. We have shown previously that interindividual variation in frailty and CWP is genetically determined. We also reported an association of frailty and CWP caused by shared genetic and common environmental factors. The aim of this study was to use omic approaches to identify molecular genetic factors underlying the heritability of frailty and its genetic correlation with CWP. Frailty was quantified through the Rockwood Frailty Index (FI) as a proportion of deficits from 33 binary health deficit questions in 3626 female twins. Common widespread pain was assessed using a screening questionnaire. OMICS analysis included 305 metabolites and whole-genome (>2.5 x 10(6) SNPs) and epigenome (similar to 1 x 10(6) MeDIP-seq regions) assessments performed on fasting blood samples. Using family-based statistical analyses, including path analysis, we examined how FI scores were related to molecular genetic factors and to CWP, taking into account known risk factors such as fat mass and smoking. Frailty Index was significantly correlated with 51 metabolites after correction for multiple testing, with 20 metabolites having P-values between 2.1 x 10(-6) and 4.0 x 10(-16). Three metabolites (uridine, C-glycosyl tryptophan, and N-acetyl glycine) were statistically independent and thought to exert a direct effect on FI. Epiandrosterone sulphate, previously shown to be highly inversely associated with CWP, was found to exert an indirect influence on FI. Bioinformatics analysis of genome-wide association study and EWAS showed that FI and its covariation with CWP was through genomic regions involved in neurological pathways. Neurological pathway involvement accounts for the associated conditions of aging CWP and FI.