No description available.

PhD by publication.

No description available.

No description available.

The purposes of this study were to identify and analyze characteristics of patients who fall, the types and circumstances of their falls, and analyze risk factors for fall-related injuries. In this retrospective study of 137 patients who fell between July 1, 2002 and December 31, 2005 at the neurological unit of a medical center located in the south of Taiwan. Data on patient characteristics, fall circumstances, and injuries were collected by reviewing of adverse event reports. Analyses were performed by use of SPSS statistical software. The result of this study found that the average age of patient who fell was 59.6 years. The majority of sex of the patient falls is male (61.3%). Many patients who fell had caregivers taking constant care (84%), and occurred in the patient room (68.6%). The most frequent diseases related to falls were cerebrovascular disease (47.5%). They usually falls happened during 12AM to 8AM (50.4%). Most falls (81%) did not result in severe injury, or disturbances of gait (78.8%). The most common activity performed at time of fall was during ambulation (39.4%), and getting out of bed (29.9%).The study found that significant risk factors for dizziness were correlated with fall injury (P<0.05); location and activity at time of fall were related to fall injury (P<0.05). The logistic regression model revealed that the significant risk factors for fall-related injuries were activity at time of fall sit and trying to pick up something (OR=18.15 with 95% CI of 1.15 to 285.92). The identified factors associated with injury may provide the information on reducing falling injuries for neurological patients, and development of fall intervention programs. The preventive strategies can ensure patient safety, improve health care quality and reduce resource utilization.

Conventional methods such as serology and microscopy are unreliable for diagnosis of encephalitozoonosis in domestic rabbits. Previous studies have reported PCR to be insensitive but it is unclear whether this is because of inherent limitations or the lack of assay optimization and validation. The studies described in this thesis assess DNA quality and quantity for combinations of six DNA extractions kits and four spore disruption methods. The resulting DNA underwent PCR using a published primer set. The optimal method had a detection threshold of 100 spores/ml in saline. However, when repeated in urine, the detection threshold was much higher (10,000 spores/ml) and non-target DNA amplification was present. Various methods were used to improve analytical sensitivity and eliminate non-target amplification. One method involving PEG 8000 treatment produced a detection threshold of 1,000 spores/ml and decreased non-target DNA amplification. Ultimately, new primers were designed and when the optimized method was tested with these primers, a detection threshold of 100 spores/ml with no non-target DNA amplification was achieved. The optimal method and new primers were tested using clinical samples of rabbit urine and 32.4% were found to be positive for E. cuniculi. The final assay was shown to be both analytically sensitive and specific; however further clinical investigation is warranted to determine clinical utility. / OVC Pet Trust

Dystonia is a little known neurological disease of the central nervous system and consists of a group of related movement disorders, characterised by involuntary and prolonged spasms of muscle contraction. Although it is nearly 90 years since this neurological disorder was first named, relatively little research had been undertaken into dystonia, for the first 65 years and it was not until the mid 1970's that researchers started to look at the disorder. This particular programme of research has taken place exactly over a six year period, starting in May 1993, and relates to a large number of different areas of study. This research has proven that dystonia is far more prevalent than previously thought, it is next to Parkinson's Disease in degree of prevalence and is far more common than other better known neurological conditions, such as Motor Neurone Disease, and yet it remains largely unknown to most members of the medical profession and the general public at large. Dystonia has been historically extremely difficult to diagnosis and this meant it has been previously very difficult to obtain sufficient numbers for study, which in turn has created a number of significant social and economic consequencesw, hich has mainly meant that most cases of people with dystonia have remained undiagnosed or misdiagnosed for many years. This research was designed to measure the severity and prevalence of dystonia in the northern part of the UK, the implication the disease has had on the working life and environment of each patient and how that person is coping with the various personal, social and family relationships caused by the onset and potential gradual deterioration of the disorder, as well as measuring the quality of life of each patient during a number of different therapies. Although there has been research into other neurological disabilities, very little is known about the implications that dystonia can have on the affected person and their families. This is the first time that all types of dystonia have been studied and that certain related subjects have been specifically included. This research has been enormously helped by the tremendous expansion in the use of Botulinurn Toxin therapy and although an enormous amount of work has been completed and accomplished during this research programme, it should never be forgotten that the subjects of this thesis are real people and that the implications and results of this research have had, and will have, a tremendous impact on their lives and that of their families.

<p>Human genetics has been experiencing a wave of genetic discoveries thanks to the development of several technologies, such as genome-wide association studies (GWAS), whole-exome sequencing, and whole genome sequencing. Despite the massive genetic discoveries of new variants associated with human diseases, several key challenges emerge following the genetic discovery. GWAS is known to be good at identifying the locus associated with the patient phenotype. However, the actually causal variants responsible for the phenotype are often elusive. Another challenge in human genetics is that even the causal mutations are already known, the underlying biological effect might remain largely ambiguous. Functional evaluation plays a key role to solve these key challenges in human genetics both to identify causal variants responsible for the phenotype, and to further develop the biological insights from the disease-causing mutations. </p><p>We adopted various methods to characterize the effects of variants identified in human genetic studies, including patient genetic and phenotypic data, RNA chemistry, molecular biology, virology, and multi-electrode array and primary neuronal culture systems. Chapter 1 is a broader introduction for the motivation and challenges for functional evaluation in human genetic studies, and the background of several genetics discoveries, such as hepatitis C treatment response, in which we performed functional characterization. </p><p>Chapter 2 focuses on the characterization of causal variants following the GWAS study for hepatitis C treatment response. We characterized a non-coding SNP (rs4803217) of IL28B (IFNL3) in high linkage disequilibrium (LD) with the discovery SNP identified in the GWAS. In this chapter, we used inter-disciplinary approaches to characterize rs4803217 on RNA structure, disease association, and protein translation.</p><p>Chapter 3 describes another avenue of functional characterization following GWAS focusing on the novel transcripts and proteins identified near the IL28B (IFNL3) locus. It has been recently speculated that this novel protein, which was named IFNL4, may affect the HCV treatment response and clearance. In this chapter, we used molecular biology, virology, and patient genetic and phenotypic data to further characterize and understand the biology of IFNL4. The efforts in chapter 2 and 3 provided new insights to the candidate causal variant(s) responsible for the GWAS for HCV treatment response, however, more evidence is still required to make claims for the exact causal roles of these variants for the GWAS association. </p><p>Chapter 4 aims to characterize a mutation already known to cause a disease (seizure) in a mouse model. We demonstrate the potential use of multi-electrode array (MEA) system for the functional characterization and drug testing on mutations found in neurological diseases, such as seizure. Functional characterization in neurological diseases is relatively challenging and available systematic tools are relatively limited. This chapter shows an exploratory research and example to establish a system for the broader use for functional characterization and translational opportunities for mutations found in neurological diseases. </p><p>Overall, this dissertation spans a range of challenges of functional evaluations in human genetics. It is expected that the functional characterization to understand human mutations will become more central in human genetics, because there are still many biological questions remaining to be answered after the explosion of human genetic discoveries. The recent advance in several technologies, including genome editing and pluripotent stem cells, is also expected to make new tools available for functional studies in human diseases.</p> / Dissertation

Nearly one billion people worldwide have a neurological disease, and one out of every six adults in the United States has a mental illness. For rare and severe neurodevelopmental disorders, like Timothy syndrome (TS), exact genetic causes have been identified and studied extensively. TS is caused by a single point mutation in CACNA1C, a voltage-gated calcium channel (VGCC), which results in severe developmental defects, cardiac arrhythmia, and autism. Studies using patient derived cells are useful in identifying impaired cellular function, especially for TS and other neural activity-dependent disorders. Also, functional high-throughput screening assays that use disease-relevant cell types can lead to more targeted therapeutics that regulate cellular activity. Although these approaches are promising, cell-based assays do not consider the diversity of disease pathology or efficacy of broad-acting therapeutics in multi-cellular organisms. Therefore, we developed several whole-organism disease models using CRISPR-Cas9 and transgenes in the nematode C. elegans that harbor human VGCC mutations. We evaluated and identified behavioral, morphological, and functional phenotypes, and invented new high-throughput functional screening technologies to identify transient and potent suppressors of neural activity in these animals. We expect that these new disease models and methods will provide a pipeline for investigating activity- dependent neurological disorders in whole organisms to identify more effective therapeutics. Altogether, we aim to deepen our understanding about the brain and discover treatments for the millions of individuals that suffer from neurological disease.

<p>Lysosomal storage diseases (LSDs) are devastating neurological disorders caused by mutations in lysosomal hydrolases that result in accumulations of hydrolase substrates. Tay-Sachs disease (TSD) is an LSD that specifically results in the accumulation of GM2 gangliosides causing the activation of inflammatory signaling pathways, and leading to microglial activation and apoptotic cell death. The detailed mechanisms through which cell death occurs have not been completely elucidated, however, excitotoxicity is thought to play a major role. Here, we investigated the role of hypoxia-inducible factor-1α (HIF- 1α) and its effector microRNA, miR-210, and the impact they have on the expression of important molecules involved in excitotoxicity, namely neuronal pentraxin 1 (NPTX1) and potassium channel KCNK2 (KCNK2). We discovered that TSD neuroglia are inefficient at stabilizing HIF-1α in hypoxic conditions. Furthermore, miR-210 expression is significantly higher in TSD neuroglia compared to normal neuroglia at baseline and during hypoxia. In addition, TSD neuroglia expressed <em>NPTX1</em>, <em>NPTX2 </em>and <em>KCNK2 </em>at higher levels, and neuronal pentraxin receptor at lower levels than normal neuroglia, implicating excitotoxicity in disease pathogenesis. We also confirmed that miR-210 binds to the 3’ UTR of <em>NPTX1 </em>to repress its expression in TSD neuroglia. The presence of reverse hypoxia response elements in the promoter of KCNK2 and the repression of <em>KCNK2 </em>expression by HIF-1α stabilization suggest that KCNK2 is directly regulated by HIF-1α. Moreover, the glucosylceramide synthase inhibitor, NBDNJ, which is used to reduce ganglioside synthesis, caused expression of <em>NPTX1 </em>to decrease but <em>KCNK2 </em>expression to increase, indicating this drug can modify multiple parameters of disease. This study identifies major gene expression changes between normal and TSD neuroglia that affect the excitability and therefore the viability of TSD cells. This information provides new insight into the mechanisms of neurodegeneration experienced by TSD neuroglia.</p> / Master of Science (MSc)