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.

关键词： Abnormal cord insertion   cerebral palsy   developmental disorder   fetal growth restriction  

摘要： Objective: To clarify and compare if the neurological outcomes of fetal growth restriction (FGR) cases with abnormal cord insertion (CI) are associated with a higher risk of a poor neurological outcome in subjects aged 3 years or less versus those with normal Cl. Methods: A multicenter retrospective cohort study was conducted among patients with a birth weight lower than the 3(rd) percentile, based on the standard reference values for Japanese subjects after 22 weeks' gestation, who were treated at a consortium of nine perinatal centers in Japan between June 2005 and March 2011. Patients whose birth weights were less than the 3(rd) percentile and whose neurological outcomes from birth to 3 years of age could be checked from their medical records were analyzed. The relationship between abnormal CI and neurological outcomes was analyzed. Univariate and multivariate models of multivariate logistic regression were employed to estimate the raw and odds ratio (OR) with 95% confidence intervals comparing marginal (MCI) and velamentous cord insertion (VCI) to normal Cl. Results: Among 365 neonates, 63 cases of MCI and 14 cases of VCI were observed. After excluding 24 cases with neonatal or infant death from the total FGR population, the assessment of the outcomes of the infants aged 3 years or younger showed the following rates of neurological complications: 7.3% (n = 25) for cerebral palsy, 8.8% (n = 30) for developmental disorders, 16.7% (n = 57) for small-for-gestational-age short stature (SGA), 0.6% (n = 2) for impaired hearing, 0.9% (n = 3) for epilepsy, 1.2% (n = A). The ORs (95% confidence intervals) based on multivariate analysis were as follows: cerebral palsy =10.1(2.4-41.5) in the VCI group and 4.3 (1.6 - 11.9) in the MCI group, developmental disorders = 6.7 (1.7 -26) in the VCI group and 3.9 (1.1-14.2) in the single umbilical artery (SUA) group, 5.1 (1.4-18.7) for birth weight <1000 g and 2.8 (1.2-6.7) for placental weight <200 g. Conclusions: The present result

关键词： Heart arrest   Cardiopulmonary resuscitation   Critical care   Diabetes mellitus   Glucose   HbA1c  

摘要： Aim: Resuscitation guidelines do not recommend a target blood glucose (BG) level specifically tailored for diabetics experiencing an in-hospital cardiac arrest (IHCA). The glycosylated haemoglobin (HbA1c) level may be associated with neurological prognosis and used to identify the optimal BG level for diabetic IHCA patients. Methods: This study was a retrospective study in a single medical centre. Patients with an IHCA between 2006 and 2015 were screened. The estimated average glucose (eAG) level was converted from the HbA1c level measured within three months prior to the IHCA. The minimum glycaemic gap was calculated from the post-resuscitation minimum BG level minus the eAG level. Results: A total of 141 patients were included in this study. The mean HbA1c was 7.2% (corresponding eAG: 160.2 mg/dL [8.9 mmol/L]). Multivariable logistic regression analysis indicated an eAG level of less than 196 mg/dL (10.9 mmol/L;corresponding HbA1c: 8.5%) was positively associated with a favourable neurological outcome at hospital discharge (odds ratio [OR]: 5.12, 95% confidence interval [CI]: 1.11-23.70;p-value = 0.04). An absolute minimum glycaemic gap of less than 70 mg/dL (3.9 mmol/L) was also positively associated with a favourable neurological outcome (OR: 5.41, 95% CI: 1.41-20.78;p-value = 0.01). Conclusion: For diabetic patients, poor long-term glycaemic control correlated with worse neurological recovery following an IHCA. The HbA1c-derived average BG level could be used as a reference point for glycaemic management during the early stage of post-cardiac arrest syndrome. The glycaemic gap could be used to identify the optimal glycaemic range around the reference point.

关键词： biochemistry   Category   systems biology   Nervous System Diseases   Brain Injuries   cytology   base size   neurology   Inborn errors of metabolism  

摘要： It has become increasingly evident that inborn errors of metabolism (IEMs) are particularly prevalent as diseases of the nervous system and that a broader, more inclusive definition of IEM is necessary. In fact, as long as biochemistry is involved, any kind of monogenic disease can become an IEM. This new, extended definition includes new categories and mechanisms, and as a general trend will go beyond a single biochemical pathway and/or organelle, and will appear as a connection of multiple crossroads in a system biology approach. From one side, a simplified and updated classification of IEM is presented that mixes elements from the diagnostic approach with pathophysiological considerations into three large categories based on the size of molecules (small and simple or large and complex) and their implication in energy metabolism. But from another side, whatever their size, metabolites involved in IEM may behave in the brain as signalling molecules, structural components and fuels, and many metabolites have more than one role. Neurometabolism is becoming more relevant, not only in relation to these new categories of diseases but also as a necessary way to explain the mechanisms of brain damage in classically defined categories of IEM. Brain metabolism, which has been largely disregarded in the traditional approach to investigating and treating neurological diseases, is a major clue and probably the next imminent revolution in neurology and neuroscience. Biochemistry (metabolism) and cell neurobiology need to meet. Additionally, the brain should be studied as a system (connecting different levels of complexity).