RESUMO
BACKGROUND: Huntington's disease (HD) is a fatal neurodegenerative autosomal dominant disorder with prevalence of 1â:â20000 that has no effective treatment to date. Translatability of candidate therapeutics could be enhanced by additional testing in large animal models because of similarities in brain anatomy, size, and immunophysiology. These features enable realistic pre-clinical studies of biodistribution, efficacy, and toxicity. OBJECTIVE AND METHODS: Here we non-invasively characterized alterations in brain white matter microstructure, neurochemistry, neurological status, and mutant Huntingtin protein (mHTT) levels in cerebrospinal fluid (CSF) of aged OVT73 HD sheep. RESULTS: Similar to HD patients, CSF mHTT differentiates HD from normal sheep. Our results are indicative of a decline in neurological status, and alterations in brain white matter diffusion and spectroscopy metric that are more severe in aged female HD sheep. Longitudinal analysis of aged female HD sheep suggests that the decline is detectable over the course of a year. In line with reports of HD human studies, white matter alterations in corpus callosum correlates with a decline in gait of HD sheep. Moreover, alterations in the occipital cortex white matter correlates with a decline in clinical rating score. In addition, the marker of energy metabolism in striatum of aged HD sheep, shows a correlation with decline of clinical rating score and eye coordination. CONCLUSION: This data suggests that OVT73 HD sheep can serve as a pre-manifest large animal model of HD providing a platform for pre-clinical testing of HD therapeutics and non-invasive tracking of the efficacy of the therapy.
Assuntos
Doença de Huntington , Substância Branca , Animais , Humanos , Feminino , Ovinos , Idoso , Doença de Huntington/metabolismo , Distribuição Tecidual , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Substância Branca/diagnóstico por imagem , Imageamento por Ressonância Magnética , Proteínas Mutantes/metabolismoRESUMO
The QT interval is regarded as an important biomarker for the assessment of arrhythmia liability, and evidence of QT prolongation has led to the withdrawal and relabeling of numerous compounds. Traditional methods of assessing QT prolongation correct the QT interval for the length of the RR interval (which varies inversely with heart-rate) in a variety of ways. These methods often disagree with each other and do not take into account changes in autonomic state. Correcting the QT interval for RR reduces a bivariate observation (RR, QT) to a univariate observation (QTc). The development of automatic electrocardiogram (ECG) signal acquisition systems has made it possible to collect continuous (so called 'beat-to-beat') ECG data. ECG data collected prior to administration of a compound allow us to define a region for (RR, QT) values that encompasses typical activity. Such reference regions are used in clinical applications to define the 'normal' region of clinical or laboratory measurements. This paper motivates the need for reference regions of (RR, QT) values from beat-to-beat ECG data, and describes a way of constructing these. We introduce a measure of agreement between two reference regions that points to the reliability of 12-lead digital Holter data. We discuss the use of reference regions in establishing baselines for ECG parameters to assist in the evaluation of cardiac risk and illustrate using data from two methodological studies.
Assuntos
Interpretação Estatística de Dados , Eletrocardiografia , Humanos , Distribuição NormalRESUMO
OBJECTIVE: The purpose of this study was to determine if patients with balance and vestibular disorders would demonstrate clinically meaningful improvement in the Five Times Sit to Stand Test (FTSST) score as a result of vestibular rehabilitation and to determine the concurrent validity of the FTSST. DESIGN: Retrospective chart review of 351 people who underwent individualized outpatient vestibular rehabilitation programs. SETTING: Outpatient tertiary balance and vestibular clinic. SUBJECTS: One hundred and seventeen patients (45 men, 72 women), mean age 62.7 years, with peripheral, central or mixed vestibular dysfunction. MAIN OUTCOME MEASURES: FTSST, gait speed, Timed Up and Go Test (TUG), Dynamic Gait Index (DGI), Dizziness Handicap Inventory (DHI), and Activities-Specific Balance Confidence Scale (ABC). RESULTS: The mean change in FTSST score was 2.7 seconds. Subjects demonstrated statistically significant improvements in the FTSST, gait speed, ABC, DHI, DGI and TUG after vestibular rehabilitation (p < 0.01). The responsiveness-treatment coefficient (RT) was calculated as 0.58 for the FTSST indicating moderate responsiveness. Logistic regression showed that an improvement in the FTSST of greater than 2.3 seconds resulted in an odds ratio of 4.67 for demonstrating clinical improvement in DHI, compared with a change less than 2.3 seconds. The univariate linear regression model for baseline FTSST predicting FTSST change was significant (p < 0.01) and predicted 49% of the change variance. The FTSST scores demonstrated a moderate correlation with gait speed and the TUG (p< 0.01). FTSST improvement subsequent to vestibular rehabilitation was moderately correlated with improvements in the DGI and the TUG scores (p< 0.01). CONCLUSIONS: The FTSST was moderately responsive to change over time and was moderately related to measures of gait and dynamic balance.