Ambroxol reverses tau and α-synuclein accumulation in a cholinergic N370S GBA1 mutation model

Cognitive impairment is a common non-motor complication of Parkinson disease (PD). Glucocerebrosidase gene (GBA1) variants are found in 10–15% of PD cases and are numerically the most important risk factor for PD and dementia with Lewy bodies. Accumulation of α-synuclein and tau pathology is thought to underlie cognitive impairment in PD, and likely involves cholinergic as well as dopaminergic neurons. Neural crest stem cells were isolated from both PD patients with the common heterozygous N370S GBA1 mutation and normal subjects without GBA1 mutations. The stem cells were used to generate a cholinergic neuronal cell model. The effects of the GBA1 variant on glucocerebrosidase (GCase) protein and activity, and cathepsin D, tau and α-synuclein protein levels in cholinergic neurons were examined. Ambroxol, a GCase chaperone, was used to investigate whether GCase enhancement was able to reverse the effects of the GBA1 variant on cholinergic neurons. Significant reductions in GCase protein and activity, as well as in Cathepsin D levels were found in GBA1 mutant (N370S/WT) cholinergic neurons. Both tau and α-synuclein levels were significantly increased in GBA1 mutant (N370S/WT) cholinergic neurons. Ambroxol significantly enhanced GCase activity and decreased both tau and α-synuclein levels in cholinergic neurons. GBA1 mutations interfere with the metabolism of α-synuclein and tau proteins and induce higher levels of α-synuclein and tau proteins in cholinergic neurons. The GCase pathway provides a potential therapeutic target for neurodegenerative disorders related to pathological α-synuclein or tau accumulation

Influence of airway management strategy on "no-flow-time" during an "Advanced life support course" for intensive care nurses – A single rescuer resuscitation manikin study

<p>Abstract</p> <p>Background</p> <p>In 1999, the laryngeal tube (VBM Medizintechnik, Sulz, Germany) was introduced as a new supraglottic airway. It was designed to allow either spontaneous breathing or controlled ventilation during anaesthesia; additionally it may serve as an alternative to endotracheal intubation, or bag-mask ventilation during resuscitation. Several variations of this supraglottic airway exist. In our study, we compared ventilation with the laryngeal tube suction for single use (LTS-D) and a bag-mask device. One of the main points of the revised ERC 2005 guidelines is a low no-flow-time (NFT). The NFT is defined as the time during which no chest compression occurs. Traditionally during the first few minutes of resuscitation NFT is very high. We evaluated the hypothesis that utilization of the LTS-D could reduce the NFT compared to bag-mask ventilation (BMV) during simulated cardiac arrest in a single rescuer manikin study.</p> <p>Methods</p> <p>Participants were studied during a one day advanced life support (ALS) course. Two scenarios of arrhythmias requiring defibrillation were simulated in a manikin. One scenario required subjects to establish the airway with a LTS-D; alternatively, the second scenario required them to use BMV. The scenario duration was 430 seconds for the LTS-D scenario, and 420 seconds for the BMV scenario, respectively. Experienced ICU nurses were recruited as study subjects. Participants were randomly assigned to one of the two groups first (LTS-D and BMV) to establish the airway. Endpoints were the total NFT during the scenario, the successful airway management using the respective device, and participants' preference of one of the two strategies for airway management.</p> <p>Results</p> <p>Utilization of the LTS-D reduced NFT significantly (p < 0.01). Adherence to the time frame of ERC guidelines was 96% in the LTS-D group versus 30% in the BMV group. Two participants in the LTS-D group required more than one attempt to establish the LTS-D correctly. Once established, ventilation was effective in 100%. In a subjective evaluation all participants preferred the LTS-D over BMV to provide ventilation in a cardiac arrest scenario.</p> <p>Conclusion</p> <p>In our manikin study, NFT was reduced significantly when using LTS-D compared to BMV. During cardiac arrest, the LTS-D might be a good alternative to BMV for providing and maintaining a patent airway. For personnel not experienced in endotracheal intubation it seems to be a safe airway device in a manikin use.</p

Estimating Genetic Variability in Non-Model Taxa: A General Procedure for Discriminating Sequence Errors from Actual Variation

Genetic variation is the driving force of evolution and as such is of central interest for biologists. However, inadequate discrimination of errors from true genetic variation could lead to incorrect estimates of gene copy number, population genetic parameters, phylogenetic relationships and the deposition of gene and protein sequences in databases that are not actually present in any organism. Misincorporation errors in multi-template PCR cloning methods, still commonly used for obtaining novel gene sequences in non-model species, are difficult to detect, as no previous information may be available about the number of expected copies of genes belonging to multi-gene families. However, studies employing these techniques rarely describe in any great detail how errors arising in the amplification process were detected and accounted for. Here, we estimated the rate of base misincorporation of a widely-used PCR-cloning method, using a single copy mitochondrial gene from a single individual to minimise variation in the template DNA, as 1.62×10−3 errors per site, or 9.26×10−5 per site per duplication. The distribution of errors among sequences closely matched that predicted by a binomial distribution function. The empirically estimated error rate was applied to data, obtained using the same methods, from the Phospholipase A2 toxin family from the pitviper Ovophis monticola. The distribution of differences detected closely matched the expected distribution of errors and we conclude that, when undertaking gene discovery or assessment of genetic diversity using this error-prone method, it will be informative to empirically determine the rate of base misincorporation

Nonlinear Analysis of Motor Activity Shows Differences between Schizophrenia and Depression: A Study Using Fourier Analysis and Sample Entropy

The purpose of this study has been to describe motor activity data obtained by using wrist-worn actigraphs in patients with schizophrenia and major depression by the use of linear and non-linear methods of analysis. Different time frames were investigated, i.e., activity counts measured every minute for up to five hours and activity counts made hourly for up to two weeks. The results show that motor activity was lower in the schizophrenic patients and in patients with major depression, compared to controls. Using one minute intervals the depressed patients had a higher standard deviation (SD) compared to both the schizophrenic patients and the controls. The ratio between the root mean square successive differences (RMSSD) and SD was higher in the schizophrenic patients compared to controls. The Fourier analysis of the activity counts measured every minute showed that the relation between variance in the low and the high frequency range was lower in the schizophrenic patients compared to the controls. The sample entropy was higher in the schizophrenic patients compared to controls in the time series from the activity counts made every minute. The main conclusions of the study are that schizophrenic and depressive patients have distinctly different profiles of motor activity and that the results differ according to period length analysed

Visual Working Memory Capacity Does Not Modulate the Feature-Based Information Filtering in Visual Working Memory

Background: The limited capacity of visual working memory (VWM) requires us to select the task relevant information and filter out the irrelevant information efficiently. Previous studies showed that the individual differences in VWM capacity dramatically influenced the way we filtered out the distracters displayed in distinct spatial-locations: low-capacity individuals were poorer at filtering them out than the high-capacity ones. However, when the target and distracting information pertain to the same object (i.e., multiple-featured object), whether the VWM capacity modulates the featurebased filtering remains unknown. Methodology/Principal Findings: We explored this issue mainly based on one of our recent studies, in which we asked the participants to remember three colors of colored-shapes or colored-landolt-Cs while using two types of task irrelevant information. We found that the irrelevant high-discriminable information could not be filtered out during the extraction of VWM but the irrelevant fine-grained information could be. We added 8 extra participants to the original 16 participants and then split the overall 24 participants into low- and high-VWM capacity groups. We found that regardless of the VWM capacity, the irrelevant high-discriminable information was selected into VWM, whereas the irrelevant fine-grained information was filtered out. The latter finding was further corroborated in a second experiment in which the participants were required to remember one colored-landolt-C and a more strict control was exerted over the VWM capacity

Residual effects of esmirtazapine on actual driving performance: overall findings and an exploratory analysis into the role of CYP2D6 phenotype

INTRODUCTION: Esmirtazapine is evaluated as a novel drug for treatment of insomnia. PURPOSE: The present study was designed to assess residual effects of single and repeated doses of esmirtazapine 1.5 and 4.5 mg on actual driving in 32 healthy volunteers in a double-blind, placebo-controlled study. Treatment with single doses of zopiclone 7.5 mg was included as active control. METHODS: Treatments were administered in the evening. Driving performance was assessed in the morning, 11 h after drug intake, in a standardized on-the-road highway driving test. The primary study parameter was standard deviation of lateral position (SDLP), a measure of "weaving". All subjects were subjected to CYP2D6 phenotyping in order to distinguish poor metabolizers from extensive metabolizers of esmirtazapine. RESULTS: Overall, esmirtazapine 1.5 mg did not produce any clinically relevant change in SDLP after single and repeated dosing. Driving impairment, i.e., a rise in SDLP, did occur after a single-dose administration of esmirtazapine 4.5 mg but was resolved after repeated doses. Acute driving impairment was more pronounced after both doses of esmirtazapine in a select group of poor metabolizers (N = 7). A single-dose zopiclone 7.5 mg also increased SDLP as expected. CONCLUSION: It is concluded that single and repeated doses of 1.5 mg esmirtazapine are generally not associated with residual impairment. Single-dose administration of 4.5 mg esmirtazapine was associated with residual impairment that generally resolved after repeated administration. Exploratory analysis in a small group of poor CYP 2D6 metabolizers suggested that these subjects are more sensitive to the impairing effects of esmirtazapine on car driving

Storage of Factor VIII Variants with Impaired von Willebrand Factor Binding in Weibel-Palade Bodies in Endothelial Cells

BACKGROUND: Point mutations resulting in reduced factor VIII (FVIII) binding to von Willebrand factor (VWF) are an important cause of mild/moderate hemophilia A. Treatment includes desmopressin infusion, which concomitantly increases VWF and FVIII plasma levels, apparently from storage pools containing both proteins. The source of these VWF/FVIII co-storage pools and the mechanism of granule biogenesis are not fully understood. METHODOLOGY/PRINCIPAL FINDINGS: We studied intracellular trafficking of FVIII variants implicated in mild/moderate hemophilia A together with VWF in HEK293 cells and primary endothelial cells. The role of VWF binding was addressed using FVIII variants displaying reduced VWF interaction. Binding studies using purified FVIII proteins revealed moderate (Arg2150His, Del2201, Pro2300Ser) to severe (Tyr1680Phe, Ser2119Tyr) VWF binding defects. Expression studies in HEK293 cells and primary endothelial cells revealed that all FVIII variants were present within VWF-containing organelles. Quantitative studies showed that the relative amount of FVIII storage was independent of various mutations. Substantial amounts of FVIII variants are co-stored in VWF-containing storage organelles, presumably by virtue of their ability to interact with VWF at low pH. CONCLUSIONS: Our data suggest that the potential of FVIII co-storage with VWF is not affected in mild/moderate hemophilia A caused by reduced FVIII/VWF interaction in the circulation. These data support the hypothesis that Weibel-Palade bodies comprise the desmopressin-releasable FVIII storage pool in vivo

Elevated Plasma Von Willebrand Factor and Propeptide Levels in Malawian Children with Malaria

In children with malaria plasma VWF and propeptide levels are markedly elevated in both cerebral and mild paediatric malaria, with levels matching disease severity, and these normalize upon recovery. High levels of both markers also occur in retinopathy-negative 'cerebral malaria' cases, many of whom are thought to be suffering from diseases other than malaria, indicating that further studies of these markers will be required to determine their sensitivity and specificity

Head-and-neck paragangliomas are associated with sleep-related complaints, especially in the presence of carotid body tumors

Item does not contain fulltextOBJECTIVES: The carotid body functions as a chemoreceptor. We hypothesized that head-and-neck paragangliomas (HNP) may disturb the function of these peripheral chemoreceptors and play a role in sleep-disordered breathing. DESIGN: This is a case-control study. SETTING: This study was conducted in a tertiary referral center. PARTICIPANTS AND MAIN OUTCOME MEASURES: We assessed fatigue, sleep, and exercise capacity in 74 HNP patients using three questionnaires (Epworth Sleepiness Scale, St. George Respiratory Questionnaire, and a standard clinical sleep assessment questionnaire). Outcomes were compared to those of age- and sex-matched controls. RESULTS AND CONCLUSIONS: Activity, disturbance of psychosocial function, and total score were worse compared to controls (15.4 +/- 18.5 vs. 7.2 +/- 9.9, P = 0.007; 5.3 +/- 10.5 vs. 1.2 +/- 2.6, P = 0.008; and 10.4 +/- 12.9 vs. 5.0 +/- 4.8, P = 0.006, respectively). Patients reported more daytime fatigue, concentration difficulties, and depression (51% vs. 24%, P = 0.006; 31% vs. 10%, P = 0.010; and 19% vs. 2%, P = 0.012). Waking up was reported to be less refreshing in HNP patients (53% vs. 73%, P = 0.038). Dysphonia was a predictor of symptoms, activity, disturbance of psychosocial function, and total scores. Remarkably, the presence of a carotid body tumor was an independent predictor of increased daytime sleepiness (beta = 0.287, P = 0.029). In conclusion, patients with HNP have remarkable sleep-related complaints. Especially the presence of carotid body tumors appears to be associated with increased daytime somnolence.1 juni 201