Metabolic profiling of presymptomatic Huntington’s disease sheep reveals novel biomarkers

The pronounced cachexia (unexplained wasting) seen in Huntington’s disease (HD) patients suggests that metabolic dysregulation plays a role in HD pathogenesis, although evidence of metabolic abnormalities in HD patients is inconsistent. We performed metabolic profiling of plasma from presymptomatic HD transgenic and control sheep. Metabolites were quantified in sequential plasma samples taken over a 25 h period using a targeted LC/MS metabolomics approach. Significant changes with respect to genotype were observed in 89/130 identified metabolites, including sphingolipids, biogenic amines, amino acids and urea. Citrulline and arginine increased significantly in HD compared to control sheep. Ten other amino acids decreased in presymptomatic HD sheep, including branched chain amino acids (isoleucine, leucine and valine) that have been identified previously as potential biomarkers of HD. Significant increases in urea, arginine, citrulline, asymmetric and symmetric dimethylarginine, alongside decreases in sphingolipids, indicate that both the urea cycle and nitric oxide pathways are dysregulated at early stages in HD. Logistic prediction modelling identified a set of 8 biomarkers that can identify 80% of the presymptomatic HD sheep as transgenic, with 90% confidence. This level of sensitivity, using minimally invasive methods, offers novel opportunities for monitoring disease progression in HD patients.This work was funded by CHDI Inc. (A.J.M), and supported in part by a UK Biotechnology and Biological Sciences Research Council (BBSRC) Grant BB/I019405/1 (D.J.S). D.J.S. is a Royal Society Wolfson Research Merit Award Holder

Alzheimer's disease markers in the aged sheep (Ovis aries)

This study reports the identification and characterization of markers of Alzheimer's disease (AD) in aged sheep (Ovis aries) as a preliminary step toward making a genetically modified large animal model of AD. Importantly, the sequences of key proteins involved in AD pathogenesis are highly conserved between sheep and human. The processing of the amyloid-β (Aβ) protein is conserved between sheep and human, and sheep Aβ1–42/Aβ1–40 ratios in cerebrospinal fluid (CSF) are also very similar to human. In addition, total tau and neurofilament light levels in CSF are comparable with those found in human. The presence of neurofibrillary tangles in aged sheep brain has previously been established; here, we report for the first time that plaques, the other pathologic hallmark of AD, are also present in the aged sheep brain. In summary, the biological machinery to generate the key neuropathologic features of AD is conserved between the human and sheep, making the sheep a good candidate for future genetic manipulation to accelerate the condition for use in pathophysiological discovery and therapeutic testing

Long-term outcome of chronic dialysis in children

As the prevalence of children on renal replacement therapy (RRT) increases world wide and such therapy comprises at least 2% of any national dialysis or transplant programme, it is essential that paediatric nephrologists are able to advise families on the possible outcome for their child on dialysis. Most children start dialysis with the expectation that successful renal transplantation is an achievable goal and will provide the best survival and quality of life. However, some will require long-term dialysis or may return intermittently to dialysis during the course of their chronic kidney disease (CKD). This article reviews the available outcome data for children on chronic dialysis as well as extrapolating data from the larger adult dialysis experience to inform our paediatric practice. The multiple factors that may influence outcome, and, particularly, those that can potentially be modified, are discussed

Chemical neuroanatomy of the substantia nigra in the ovine brain

The substantia nigra is an integral component of the basal ganglia circuitry for limbic and motor functions. Dysfunction and degeneration of the basal ganglia are fundamental aspects of neurodegenerative diseases such as Parkinson’s disease and Huntington’s disease. With the increasing use of sheep to model neurological diseases, it is crucial to understand the anatomy and neurochemistry of these key basal ganglia nuclei in the normal sheep brain and how they compare to the human brain. Therefore, studies of the gross anatomy, cellular morphology, and neurochemical expression patterns within the sheep substantia nigra were performed. We show that the sheep substantia nigra reflects all important aspects of the anatomy and neurochemistry of the human substantia nigra, with only minor inter-species differences evident. Many neurochemicals that are central to the functioning of the SN, and wider basal ganglia circuitry, are present throughout the sheep SN. In a wider context, the results of this study provide evidence that the sheep substantia nigra accurately reflects the anatomy of the human substantia nigra, which validates the use of sheep models of basal ganglia neurological disorders

Metabolic profiling of presymptomatic Huntington’s disease sheep reveals novel biomarkers

The pronounced cachexia (unexplained wasting) seen in Huntington’s disease (HD) patients suggests that metabolic dysregulation plays a role in HD pathogenesis, although evidence of metabolic abnormalities in HD patients is inconsistent. We performed metabolic profiling of plasma from presymptomatic HD transgenic and control sheep. Metabolites were quantified in sequential plasma samples taken over a 25h period using a targeted LC/MS metabolomics approach. Significant changes with respect to genotype were observed in 89/130 identified metabolites, including sphingolipids, biogenic amines, amino acids and urea. Citrulline and arginine increased significantly in HD compared to control sheep. Ten other amino acids decreased in presymptomatic HD sheep, including branched chain amino acids (isoleucine, leucine and valine) that have been identified previously as potential biomarkers of HD. Significant increases in urea, arginine, citrulline, asymmetric and symmetric dimethylarginine, alongside decreases in sphingolipids, indicate that both the urea cycle and nitric oxide pathways are dysregulated at early stages in HD. Logistic prediction modelling identified a set of 8 biomarkers that can identify 80% of the presymptomatic HD sheep as transgenic, with 90% confidence. This level of sensitivity, using minimally invasive methods, offers novel opportunities for monitoring disease progression in HD patients

Impact of purposefully designed learning activities in the case of information literacy self-efficacy

Objectives: Developing information literacy skills of medical students is one of the basic skills to become lifelong learners. Method: The study focuses on the development of a first year integrated information literacy course for medical students during three consecutive years. Students filled in a validated information literacy self-efficacy scale for medicine at the beginning and at the end of the course. Results: Integrating a search-report has a significant positive effect. For ‘Medical information literacy skills’, a positive difference is found for the academic year in which a peer review was introduced. Integrating personal experience has an undeniable impact and should be stimulated in the educational design in higher education. Performing a peer review impacts information literacy self-efficacy related to the specific medical information literacy skills and should be further integrated in the course. Teachers need to evaluate the impact of course development continuously, as not all adaptations always have the expected impact