published_or_final_version / Public Health / Master / Master of Public Health

A number of risks have been proposed in the literature to be associated with hyperfunctional voice disorder (HVD), one of the most common communication disorders. Yet, it is not distributed randomly in the population, certain population groups are at higher risks of developing voice disorders. It is generally agreed that the development of voice disorders involves a multifactorial genesis. The study of risks has been documented in different diseases and also in the World Health Report (W.H.O., 2002). The probabilistic approach has been recommended to effectively manage the likelihood of health outcome in relations to disease development (Tonetti, 1988) and systematically devise prevention and intervention programs targeting population at risk. Yet, in the study of the development of HVD, the lack of a universally agreed theoretical framework prohibited the establishment of such structure and research on advancement on preventive programs. The present thesis aimed to investigate the adoption of the FMAT risk assessment framework based on the probabilistic approach (WHO) to the field of hyperfunctional voice disorders. A Voice Risk Calculator (VRC) Questionnaire was developed focusing on the vocal loading, physiological/medical and psycho-emotional indicators and all subjects completed this questionnaire. The VRC Questionnaire was then validated based on the FMAT framework using a cross-sectional study was used to identify risk indicators associated with HVD development in the local population and a longitudinal study was employed to validate these risk indicators as risk factors. A total of 192 Cantonese-speaking subjects participated in the cross-sectional study including 123 dysphonic subjects and 69 non-dysphonic control subjects and 7 in the longitudinal study. Instrumental measurements including the voice range profile, aerodynamic measurements and the Voice Activity and Participation Profile (VAPP, Ma & Yiu, 2001) were also used as part of the validation procedure. The findings showed that significant differences were found between the dysphonic and non-dysphonic group in the cross-sectional study based on results from the instrumental measurements protocol. A minimal set of selected VRC questionnaire items were also determined (Items 1, 3, 25 and somatization scale) to differences between the subject groups in this study. Thus a set of locally-applicable risk indicators have been suggested. Yet, only minimal changes have been detected in a high-risk group targeted in the longitudinal study. Research (Beck, 1994) indicated that disease progression takes over a time frame of at least more than two years. Thus the small subject size and temporal element of the longitudinal study in the present thesis limited research aim to be achieved. Nonetheless that first phase of the FMAT framework for hyperfunctional voice disorders have been established in the current study and a finalized version of the Voice Risk Calculated Questionnaire has been developed for future research. / published_or_final_version / Speech and Hearing Sciences / Doctoral / Doctor of Philosophy

Myeloproliferative neoplasms include a heterogeneous group of stem cell disorders with overproduction of myeloid cells. They have very different clinical courses and prognosis and are amenable to specific targeted therapy. A prompt and accurate diagnosis is therefore very important. Genetic characterisation plays an important role in diagnosis and classification of these disorders. BCR-ABL1fusion gene and JAK2V617F mutation are the particular major molecular markers to be detected because of availability of targeted therapy. In this study, a new molecular testing system was developed for the differential diagnosis of myeloproliferative neoplasms. A multiplex reverse-transcriptase polymerase chain reaction was developed for fast detection of JAK2 V617F mutation and BCR-ABL1fusion simultaneously. It was demonstrated to be fast and highly sensitive and specific for the mutations as validated by analysis of clinical samples. The sensitivity limit was well suited for clinical diagnosis. There was great potential saving in consumables and manpower with a much shortened turn-around-time in most cases when compared to conventional diagnostic protocol. / published_or_final_version / Pathology / Master / Master of Medical Sciences

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder affecting individuals along a continuum of severity in communication, social interaction and behaviour. The impact of ASD significantly varies amongst individuals, and the cause of ASD can originate broadly between genetic and environmental factors. Previous ASD researches indicate that early identification combined with a targeted treatment plan involving behavioural interventions and multidisciplinary therapies can provide substantial improvement for ASD patients. Currently there is no cure for ASD, and the clinical variability and uncertainty of the disorder still remains. Hence, the search to unravel heterogeneity within ASD by subgroup classification may provide clinicians with a better understanding of ASD and to work towards a more definitive course of action. In this study, a norm of physical measurements including height, weight, head circumference, ear length, outer and inner canthi, interpupillary distance, philtrum, hand and foot length was collected from 658 Typical Developing (TD) Chinese children aged 1 to 7 years (mean age of 4.19 years). The norm collected was compared against 80 ASD Chinese children aged 1 to 12 years (mean age of 4.36 years). We then further attempted to find subgroups within ASD based on identifying physical abnormalities; individuals were classified as (non)dysmorphic with the Autism Dysmorphology Measure (ADM) from physical examinations of 12 body regions. Our results show that there were significant differences between ASD and TD children for measurements in: head circumference (p=0.009), outer (p=0.021) and inner (p=0.021) canthus, philtrum length (p=0.003), right (p=0.023) and left (p=0.20) foot length. Within the 80 ASD patients, 37(46%) were classified as dysmorphic (p=0.00). This study attempts to identify subgroups within ASD based on physical measurements and dysmorphology examinations. The information from this study seeks to benefit ASD community by identifying possible subtypes of ASD in Chinese population; in seek for a more definitive diagnosis, referral and treatment plan. / published_or_final_version / Paediatrics and Adolescent Medicine / Master / Master of Philosophy

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by communication difficulties, social interaction impairments, and stereotyped patterns of behavior. Prior studies have shown that ASD is associated with differences in neuroanatomy in the cerebral cortex and the subcortical regions as well as the connectivity among these regions. However, findings have been mixed due to the varying age group sampled and the methods used to measure these brain structures. In view of the heterogeneous findings in ASD, three cross-sectional design studies were conducted in this thesis to examine brain structural pathologies that may be related to the clinical and behavioural phenotype of the disorder across development. In the childhood and adolescent sample, two studies were carried out. The first one examined cortical thickness using a vertex-wise approach. Results revealed thinner cortex in the occipital, parietal and frontal regions, and thicker cortex in the inferior parietal and caudal anterior cingulate regions. These regions also showed age-related differences that deviated markedly from the typical developmental trajectories observed in the control group. Some of these regions with significant differences in cortical thickness were found to be associated with clinical symptoms in ASD. The second study in the childhood and adolescent sample examined the volume of subcortical structures and CSF using a spatially non-biased parcellation approach. It was found that intracranial volume was enlarged in children with ASD, accompanied by smaller bilateral cerebellum and left thalamus. These regions showed an age-related increase in volume in children with ASD, whereas the typically developing children showed a general age-related decrease in volume of the same regions. The volumes of the cerebellum, thalamus and basal ganglia structures were associated with relatively weaker motor control in ASD, and in particular greater volume of the left thalamus rather than age predicted worse motor performance in the clinical group. The third study was carried out in a large adult sample. The cerebellar white matter system, that interconnects cortical and subcortical targets, was examined. Using a diffusion-tensor imaging tractography approach, the cerebellar input and output white matter pathways were dissected. Both the input and output pathways were observed to be disrupted in ASD, supporting the hypothesis that ASD may be a “disconnectivity disorder”. Lower fractional anisotropy of the left middle cerebellar peduncles was associated with increased difficulties in communication and social interaction, and lower fractional anisotropy in the right superior cerebellar peduncle was linked to worse motor performance in adults with ASD. Therefore, my studies confirmed differences in neuroanatomy of cortical and subcortical regions with altered brain developmental trajectories in children and adolescence with ASD, and revealed disrupted cerebellar network system in adults with ASD. Dysmaturation of cortical and subcortical regions as well as cerebellar white matter pathways may contribute to clinical and motor phenotype of the disorder. Lastly, postmortem and early life imaging studies, together with evidence that prenatal stressors during 21 to 32 weeks of gestation may increase incidence of ASD, lead me to speculate whether the abnormalities reported here may have origins prior to 31 weeks of gestation. / published_or_final_version / Psychiatry / Doctoral / Doctor of Philosophy

Previous research had demonstrated cognitive biases towards threatening stimuli in anxious individuals, such as in attention, interpretation and memory. The present study aimed to examine the differences in memory-related information processing between anxious and nonanxious children and the effectiveness of a Cognitive-Bias Modification (CBM) based positive training in altering these differences. The study adopted a directed forgetting paradigm, where children with anxiety disorders (N=12) and healthy controls (N=12) were asked to either forget or remember word lists comprised of words of negative or positive valence, and were later asked to recall and recognize target words. The CBM training was subsequently administered, in which subjects were trained to endorse positive interpretations to ambiguous situations, followed by a similar directed forgetting task for post-training assessment. Results revealed that the CBM training was effective in reducing the hypervigilance towards negative words in anxious children, as well as reducing recall of negative words in all subjects. Clinical implications and limitations of the study were discussed. / published_or_final_version / Clinical Psychology / Master / Master of Social Sciences

Alzheimer’s disease and vascular dementia are the leading causes of cognitive disorders in the elderly worldwide. Increasing cases with overlaps in neuropathology between both disorders are becoming evident, giving rise to the concept of “mixed dementia”, which is characterized by cerebrovascular dysregulations along with tauopathies and β-amyloid (Aβ)-associated neurotoxicity. While the exact mechanisms leading to the exhibited vascular-neurodegenerative pathophysiology are still unclear, it is often found that ischemic-stroke contributes to amyloid pathogenesis, thus exacerbating cognitive impairment. Astrocytes, the most abundant cell type in the brain, appear to be important mediators in the central nervous system homeostasis and pathophysiology. This study proposes that upon ischemic stress, endothelin-1 (ET-1) overexpression in astrocytes leads to β-site APP cleaving enzyme 1 (BACE1) upregulation, hence contributing to enhanced amyloid pathology. ET-1 is a potent vasoconstrictor associated to Aβ pathogenesis in the brain, and BACE1 is the rate-limiting enzyme for Aβ synthesis. In order to assess astrocytic responses to ischemic stress, two previously modified astrocytic cell lines, mock-transfected control astrocytes (WT) and ET-1 overexpressing astrocytes (C6), were used. The exposures of WT and C6 cells to oxygen and glucose deprivation (OGD) – to mimic ischemic stress in vitro – evoked no abrupt differences between both cell lines. After OGD, astrocytes were characterized by cellular swelling, detachment from neighboring cells, increased cell death, decreased cell proliferation, and reduced BACE1 expressions during reperfusion. In addition, the attempt to modulate BACE1 protein levels, by blocking the receptor for advanced glycation end products, induced no significant differences. This study also investigated astrocytic ET-1 influences in the neuropathology of the transgenic mouse models APPGET-1 (amyloid precursor protein and astrocytic ET-1 overexpression) and GET-1 through a proteomics approach. The abnormal expressions of tropomyosin-3, transgelin-3, ATP synthase α chain, 3-hydroxyisobutyrate dehydrogenase, superoxide dismutase 1, glutathione S-transferase P1, and peroxiredoxin-6 in the mice hippocampi were identified. It is most likely that these proteins participate in cytoskeleton structural changes, energy metabolism impairment, and oxidant-antioxidant system imbalances that contribute to the observed increased brain atrophy displayed in these two animal models. In summary, this study has identified the possible participation of several proteins in the accelerated declination of cognitive functions exhibited by GET-1 and APPGET-1 mice through a proteomics approach. However, our in vitro results suggest that ET-1 did not play any pivotal role in C6 response to the hypoxic conditions evaluated. Furthermore, results showed no correlation between astrocytic ET-1 and BACE1. Further investigations examining alternative BACE1-independent pathways are required to elucidate the intricate relationship between ET-1 and Aβ in astrocytes. / published_or_final_version / Psychiatry / Master / Master of Philosophy

Secretin, the first hormone commencing the field of endocrinology, has been studied for its pleiotropic role in the body inclusive of its neuroactive and body water homeostatic and gastrointestinal functions. Yet, the metabolic effect of secretin remains elusive and is being proposed recently for a revisit. Recent discovery from our lab showed an anorectic response for secretin, while its role in lipid homeostasis remains largely unexplored. Exerting functions such as exocrine pancreatic secretion and gastric motility inhibition, intestinal fatty acid induced release of secretin was recently shown to be mediated by CD36. Fasting related increase in plasma secretin concentration has been proposed to be involved in lipolysis but evidences regarding lipolytic actions of secretin remain contradictory. Recent report has suggested that secretin stimulates both lipolysis and lipogenesis in adipose cells. Thus, we hypothesize that secretin modulates lipid homeostasis, which was examined under two opposite, energy deficient and energy excess, conditions. Under energy deficient/starved state, secretin level in circulation and secretin receptor level in epididymal adipose tissue were found to be upregulated. Using secretin receptor knockout (SCTR-/-) and secretin knockout (SCT-/-) mice as controls, it was found that secretin stimulated a dose- and time-dependent lipolysis in vitro and acute lipolysis in vivo. H-89, a protein kinase A (PKA) inhibitor, attenuated the lipolytic effects of secretin in vitro, while secretin induced an increase in cAMP dependent PKA activity in vivo. Using western blot analysis, secretin was found to phosphorylate hormone sensitive lipase (HSL) at serine residue 660. Additionally, immunofluorescent studies revealed that secretin stimulated translocation of HSL from cytosol to surface of lipid droplet subsequently leading to lipolysis. Under excess energy condition, when SCTR-/- mice and its littermates SCTR+/+ mice were subjected to high fat diet (HFD) feeding for 3 months, it was found that SCTR-/- mice gained lesser weight. Nuclear magnetic resonance imaging revealed that SCTR-/- mice exhibited lower body fat content. Additionally, HFD-associated hyperleptinaemia was alleviated in SCTR-/- mice along with metabolic syndrome as they performed better in insulin and glucose tolerance tests. Continuous monitoring by indirect calorimetry revealed similar food intake, energy expenditure and locomotor activity between SCTR-/- and SCTR+/+ mice. Interestingly, intestinal fatty acid absorption, measured by a noninvasive method, was impaired in HFD-fed SCTR-/- mice. While postprandial triglyceride release was reduced in SCTR-/- mice, it also had a significant reduction in transcript and protein levels of CD36 and its downstream mediator MTTP. Secretin, when incubated with isolated enterocytes, upregulated the expression of CD36. In summary, during starvation, secretin stimulates lipolysis through a HSL and PKA mediated pathway. When fed a HFD, SCTR-/- mice is resistant to diet induced obesity due to impaired intestinal lipid absorption. A novel short positive feedback pathway between CD36 and secretin, functioning to maximize lipid absorption, is also being proposed. Thus for the first time, two independent role of secretin in lipolysis and in intestinal lipid absorption were discovered along with their mechanistic insights. This study paves way for developing new therapeutic strategies against metabolic disorders associated with lipid metabolism. / published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

Introduction: Feeding difficulty and dysphagia are common problems in elderly patients with dementia. Malnutrition and aspiration pneumonia may result from feeding problem and swallowing dysfunction. There were limited previous reports on the course of cognitive functional decline and the relationship among cognitive function, feeding performance and swallowing function in dementia patients. Objectives: The objectives of the present study were to investigate the association between cognitive function and feeding performance in elderly with dementia, and to investigate the association between cognitive function and severity of dysphagia in elderly with dementia. Method: In this cross-sectional study, we recruited 215 Chinese participants from hospital clinics and old aged homes from March 2014 to July 2014. The participants were over 65-year-old, with diagnosis of dementia and without history of other neurological diseases. Sociodemographic information of the participant was interviewed. Medical records were reviewed for the diagnoses of dementia and associated medical conditions. The Abbreviated Mental Test (AMT) was adopted to assess participants’ cognitive function. The feeding performance was evaluated by the Chinese version of Edinburgh Feeding Evaluation in Dementia (EdFED) Scale. The swallowing function was assessed by the Gugging Swallowing Screen (GUSS) test and Therapy Outcome Measure (TOM) impairment scale. Results: Significant negative correlation was demonstrated between AMT score with EdFED score (rho= -0.571, p<0.001). After adjustment of confounders, AMT score was an independent predictor of EdFED score (p=0.034), with age (p=0.016) and functional status (p=0.001) being two additional independent factors. The AMT score manifested significant associations with the measures of severity of dysphagia from the bivariate analysis of results from GUSS (p<0.001) and TOM (p<0.001). After adjustment of confounders, the AMT score was not a significant independent predictor when the swallowing function was assessed by GUSS, but it was an independent predictor when the former was assessed by TOM (p=0.004). Age, functional status, male gender, living in old aged homes, caregivers being children/family members and maids were also independent factors of dysphagia. Conclusion: In this pilot study, we found the cognitive function of elderly with dementia was related to feeding performances. Those with the poorest cognitive function had the worst feeding performance. We also found poor cognitive function was related to poor swallowing function in elderly with dementia. Furthermore, age and functional status were also predictors of feeding performance in dementia. Future prospective studies are recommended to examine the effects of other possible confounding factors including co-morbid neurological diseases, medications and behavioral symptoms, on the association between cognitive function and feeding performance and swallowing function. Early assessment, education and intervention on feeding problem and dysphagia to elderly with dementia and their caregivers are recommended in daily clinical practice. / published_or_final_version / Medicine / Master / Master of Medical Sciences

Introduction: Cognitive impairments occur frequently in stoke survivors, yet current conventional post-stroke care focuses mainly on motor function. Transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) are noninvasive brain stimulation techniques (NIBS) that are used in neurological rehabilitation. Its efficacy is well-established in motor recovery post-stroke, but research on its effects on the associated cognitive decline after stroke is fairly new. The aim of this review is to evaluate recent studies and provide a summary on the effects of NIBS on post-stroke cognitive decline. Methods: PubMed and CINAHL were searched using the keywords: “cerebrovascular accident”, “stroke”, “NIBS” or “noninvasive brain stimulation”, “tDCS” or “transcranial direct current stimulation”, and “TMS” or “transcranial magnetic stimulation”. PEDro system was used to assess the quality of the studies that passed the inclusion and exclusion criteria. Results: The initial search returned 1081 citations, among which 12 were included in this review. The mean PEDro score of the studies was 7.5 out of 10. The trials had a total of 176 participants with stroke. Lesion site was heterogeneous. Six trials investigated tDCS, and the other 6 investigated rTMS. The main outcome measures were grouped into 3 domains: memory, visuospatial, and attention. Both tDCS and rTMS resulted in significant changes in the visuospatial domain in terms of improving spatial neglect. The results on memory and attention are mixed, but tDCS shows more consistent results. Conclusion: NIBS is a safe and low-cost treatment that can improve cognitive decline post-stroke. However, the evidence is still lacking due to the small number of trials and sample sizes. More studies need to be conducted in order to establish a proper guideline for usage. Long term effects also need to be investigated. / published_or_final_version / Public Health / Master / Master of Public Health