No description available.

No description available.

Studies assessing the grip strength of older people have typically recruited community dwelling participants, or those in acute hospital settings. There are few studies of grip strength of older people in rehabilitation or long term care. The aim of this thesis was therefore to investigate the epidemiology of grip strength in these healthcare settings. The specific objectives were to study in each setting a) the feasibility and acceptability of grip measurement; b) the grip strength values recorded in comparison with published reference ranges; c) the clinical correlates of grip strength; and d) the association of grip strength with discharge outcomes for the rehabilitation inpatients. Participants were recruited prospectively between 2007 and 2010 from four healthcare settings within the same geographical area. Data on age, anthropometry, current comorbidities and medication, physical, cognitive and nutritional status, and subsequent - discharge were recorded, and grip strength was measured. The feasibility of grip strength measurement was evaluated and its acceptability was assessed by questionnaire and by semistructured interviews with a purposive sample of participants from each setting. 305 participants were recruited. Almost all could complete the grip strength assessment and would repeat the test. Qualitative data confirmed the high level of acceptability of grip strength measurement. There were significant differences in grip strength of both men and women between settings, and the grip strength of the in-patients and the nursing home residents was far below published reference values. Age, gender, body size and Barthel Score were the characteristics most consistently associated with grip strength in these settings. Among the 101 rehabilitation in-patients higher grip strength was associated with a reduced length of stay but this was only statistically significant among the men. This thesis has demonstrated that grip strength measurement of older people in these healthcare settings is both feasible and acceptable, and has described its values as well as its clinical correlates. It has shown the need for reference ranges specific to each healthcare setting since grip strength appears to be associated with length of stay even amongst those with low grip strength.

A number of pathologies are characterized by long term functional impairment of tissues and organs in the human body. Some case pathologies are directly associated with gene mutations that alter the biosynthesis of collagen; the basic structural element and most vital protein of biological tissues in vertebrates. An example is osteogenesis imperfecta, a heritable bone disorder characterized by abnormally increased number of bone fractures. Other pathologies, however, develop over time as a result of tissue remodelling. In the case of asthma, the mechanical performance of the bronchial airways are now thought to be affliated with alterations in the quality and quantity of collagen fibrils. This thesis is based on the hypothesis that both the structure and biochemistry is altered in collagen{related pathologies, and as a result of these alterations the mechanical properties of collagen fibrils are impaired. The mechanical assessment of individual collagen fibrils (of larger than 100 nm in diameter) has been accomplished with a number of techniques, but atomic force microscopy (AFM) has been most widely used between several research groups and is the most promising technique at hand for this task. The main aim of this thesis was to assess the structure{mechanical function of collagen fibrils in osteogenesis imperfecta and asthma by employing AFM cantilever based{nanoindentation. Prior to conducting scientific studies, the AFM cantilever base {nanoindentation was successfully validated with conventional nanoindentation, a well established technique in thin film nanometrology. Collagen fibrils from the oim mouse model of osteogenesis imperfecta were mechanically characterized. This, as well as an in vitro study, using ribose, to artificially cross{link collagen fibrils, demonstrated that the indentation modulus was much dependent on the amount of non{enzymatic cross{links present in collagen fibrils. Further, it became clear that alterations in the structure can have an effect on the type of cross{link predominantly formed, as well as the hydration behaviour of collagen fibrils, and hence also on elasticity and in further instance likely on the ductility. Collagen fibrils from asthmatic donors showed close a trend towards a lower indentation modulus compared to collagen fibrils from healthy donors. An unparalleled biochemistry study could in part complement on this difference but further experimentation is required to draw conclusions with certainty. To date there are several avenues that could explain the nanomechanical changes seen in asthmatic collagen fibrils, yet the biochemical assays necessary to answer to these are, unfortunately, beyond the scope of this thesis. One possible change may be the amount of collagen types I and III, the abundant collagen types found in the submucosa. It is suggested that the fibril diameter of collagen type I is decreased with increasing the amount of collagen type III. The biochemistry study suggested a trend towards lower amount of type III collagen in asthmatics. In consequence of a possible decreased fibril diameter in asthmatics the density of the subepithelial layer in the airways could change and hence the mechanical properties at the tissue level. Beyond structural changes, there could also be changes in the immature to mature cross{links which would affect the fibril mechanics. This is supported by evidence of decreasing indentation modulus with increase of the immature to mature cross{linking ratio. Moreover, a strong effect of non{enzymatic glycation end products on collagen fibril mechanics was observed. The indentation modulus of collagen fibrils with artificially induced AGEs (advanced glycation end products) was significantly increased. This finding suggests that relative amount of glycosylated collagen fibrils in asthma could also be a contributing factor to the development of mechanical impairment of asthmatic airways. Nevertheless, findings within this thesis suggest that the biochemistry of collagen is directly associated with its mechanical performance. It has become clear during this thesis that the AFM serves as an important tool to characterize mechanically basic biological elements at the submicrometre scale. The technique used was highly effective towards associating the mechanics of individual collagen fibrils with pathology and biochemistry in model systems. Paralleled data are still needed to provide a holistic picture of a clear pathology state. Importantly, the technique is able to characterize the mechanics of individual collagen fibrils and the studies presented within this thesis have brought interesting results as well as further questions to be answered. With wider use of the technique it is anticipated that some of the issues raised within this thesis can also be discussed and answered by a larger research community.

The role of the extended scope physiotherapist has developed relatively recently within health-care. The extended role has utilised the skills of allied health professionals including physiotherapists, and given them autonomy to use knowledge and clinical acumen to request investigations such as Magnetic Resonance Imaging (MRI) as part of the diagnostic process. These requests and processes are delivered outside their traditional scope of practice. Further knowledge on how these practitioners clinically reason is therefore needed as there is little within the literature regarding reasoning in this specific group of clinicians. This research aids in the development of future roles, the governance of services, whilst supporting the training of clinical reasoning for new recruits to this work. This qualitative study has explored the processes by which extended scope physiotherapists clinically reason decisions regarding patients reporting low back pain. The study has used a multiple case study design informed by grounded theory methodology with focus groups and semi-structured interviews as a method to investigate these processes. The themes identified included prior thinking, patient interaction, formal testing, time, safety and accountability, external/internal and gut feeling. Subtle differences in clinical reasoning were seen in the focus group study between ESP and non-ESP clinicians. The processes of clinical reasoning are presented that suggests how these clinicians reason whilst highlighting how they differ to non-extended scope physiotherapists.

Background: Musculoskeletal ultrasound imaging, (MSKUSI) is an appealing modality for many professions and professionals. There are indications that physiotherapists have tried to access MSKUSI but the evidence base exploring their interests and clinical use is extremely limited. Aim: To explore physiotherapists’ interest and use of MSKUSI in practice. Method: A questionnaire was developed and distributed to gain initial information relating to physiotherapists’ interest and use of MSKUSI. 75 responses were received, analysis informed topic-guide development for in-depth interviews and enabled a purposeful sampling strategy. 11 in-depth interviews explored physiotherapists’ interests, education and clinical use of MSKUSI. Results: Thematic analysis of the interview data identified 5 themes: 1. Professional skill set – physiotherapists’ suitability for MSKUSI 2. Factors that have impacted physiotherapists’ ability to use MSKUSI ii 3. Physiotherapists’ motivation to use ultrasound - improving patient focused care 4. Quality assurance strategies 5. Application of biopsychosocial model These themes revealed links between physiotherapists’ core skills, knowledge and professional experiences that align well to the requirements of MSKUSI. Some participants reported support whilst accessing education but many described challenges that had influenced their ability to use MSKUSI. A common challenge was accessing mentorship responsive to physiotherapists’ requirements. Participants observed the variation in their practice when compared to other professionals was not always reflected in education. Application of clinical reasoning processes to ensure scanning was responsive to individual patient’s requirements was emphasised. Conclusion: Physiotherapists are amongst a number of professional groups interested in MSKUSI. Proposed roles include verification of clinical assessment findings for diagnosis and facilitation of patient education. The potential to reduce patient attendances, streamline management pathways and optimise resource management warrants further investigation. Professional and regulatory issues need evaluation to support physiotherapists’ use of MSKUSI. Professional organisations including the Chartered Society of Physiotherapy should extend current guidance to protect professionals and patients.

Phospholipases C (PLCs) are a large family of enzymes that regulate the cleavage of phosphatidylinositol-4,5- bisphosphate into Inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). This project included research on PLCζ and PLCβ1 on male infertility and thyroid cancer respectively. Human PLCζ (hPLCζ) is the key protein for egg activation following sperm-egg fusion and triggers the release of Ca2+ producing a series of oscillations which initiate embryogenesis. Defects in hPLCζ lead to infertility, thus the project aimed at its expression and enrichment suitable for biomedical applications. The results included 1) Comparison of hPLCζ bacterial expression from twenty four plasmid constructs with varying protein tags. 2) Expression of active soluble hPLCζ, free from its bacterial solubility partners. The PLCβ1 project involved a novel InDel (1076 bp deletion, ATAA junction insertion) identified in the 3rd intron of PLCβ1 (Chr 20) by genome-wide linkage analysis (GWLA, LOD score 3.01) of a large kindred with multinodular goitre (MNG) progressing to papillary thyroid cancer (PTC). Affected individuals exhibited increased PLCβ1 transcript levels in their thyroids and the InDel has a putative ERα binding site. The project aimed to, 1) Develop a genotyping technique for high-throughput PLCβ1 InDel screening in large cohorts 2) Determine the InDel’s mechanism of action in modifying thyrocyte proliferation. 3) Next generation sequencing (NGS) of the chr20 region identified by GWLA to identify potential variants responsible for MNG. 1) A QPCR genotyping method was established and the InDel identified in patients with benign thyroid disease. 2) Reporter gene assays suggested silencer elements within the InDel. 3) PLCβ1 knockdown using siRNA exhibited a trend in inhibiting proliferation of a thyroid cell-line. 4) NGS of the 20cM-Chr20 GWLA identified region found no additional disease loci confirming a role for the PLCβ1 InDel. The InDel provides a biomarker for MNG patients most likely to develop PTC.

Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by expansion of a trinucleotide CAG repeat in the Huntingtin gene (HTT) on chromosome 4. HD symptomatology is characterised by a triad of motor, cognitive, and psychiatric disturbances, as well as transcriptional dysregulation. The identification of HTT as the single causative gene in HD has led to the development of a number of animal models that are designed to recreate the molecular and behavioural phenotypes of the human disease; one such model is the HdhQ150 mouse model of HD. Investigation into the cognitive capacities of animals heterozygous for the HdhQ150 mutant allele (HdhQ150/+) revealed a series of novel cognitive impairments that recapitulate aspects of the cognitive phenotype observed in human HD patients; deficits in conditioning task acquisition and performance were identified in HdhQ150/+ mice, as were impairments in visuospatial attention, and delayed acquisition and cognitive processing of spatial discrimination (SD) learning. However, implicit learning capabilities of HdhQ150/+ animals were analogous to those of wild-type mice. Microarray and reverse transcription quantitative polymerase chain reaction (RT-qPCR) investigations into the transcriptional correlates of cognition did not identify significant learning-dependent gene expression level changes in the striata of HdhQ150/+ or wild-type mice. Similarly, these techniques did not report significant striatal gene expression level alterations across distinct stages of SD and reversal learning operant task performance in wild-type animals. In contrast, RT-qPCR revealed significant differences in the striatal expression levels of Adora2A, Arc, Drd2, and Homer1 genes between HdhQ150/+ and wild-type mice at 44-60 weeks of age, supporting previous evidence of abnormal expression or signalling of these genes in the HD phenotype. Overall, this body of work contributes novel evidence that HdhQ150/+ animals present with molecular and cognitive phenotypes comparable to those seen in the human form of the disease.

The aetiology and pathogenesis of type 2 diabetes (T20) are yet to be fully understood. However, there is a degree of agreement that the most important pathological factors of T20 are p-cell dysfunction and insulin resistance. Moreover T2D is characterised by varying degrees of impaired pancreatic p-cell responsiveness and/or insulin resistance. The ability to easily quantify insulin sensitivity is useful for investigating the role of impaired insulin secretion and action in the pathophysiology ofT2D. The current work provided novel knowledge in both clinical and methodological areas. On the clinical side, it provided new information about pathology of T2D. On the methodological side, it assessed validity, performance, and/or reproducibility of two powerful models to assess insulin responsiveness and sensitivity. The aim was to use modelling techniques employing data collected during tolerance tests to progress our understanding of pathology of type 2 diabetes. This research evaluated and/or validated two approaches namely, the insulin secretion model and the minimal model, respectively, to assess pancreatic p-cell responsiveness and insulin sensitivity. These methods were then applied to study the aetiology and pathology of T2D on its first clinical appearance (newly diagnosed SUbjects). The insulin secretion model was assessed with two reduced sampling schemes. The model was validated during the oral glucose tolerance test (OGTT). and its performance was compared during OGTT and the meal tolerance test (Mm). The reproducibility of the model indices was also assessed during MTT and OGTT. The one and two compartmental minimal model performance was evaluated and compared to the clamp in subjects with T20. The insulin secretion model and the one compartment minimal model were then applied to study newly presenting T2D in order to gain more understanding of the disease pathology. The output results showed the ability of these approaches to explain the inter-individual variability of important glucose clinical measures such as FPG and HbA1C• In conclusion the insulin secretion model and the one compartment minimal model demonstrated their validity and utility in assessing insulin sensitivity and p-cell responsiveness to provide better Wlderstanding of type 2 diabetes.

Background: Adults with intellectual disabilities experience equivalent or higher rates of obesity in comparison to the general population. This increases the risk for health conditions associated with adverse weight gain including cardiovascular disease and type II diabetes. Clinical guidelines on the management of obesity recommend multi-component interventions which include an energy deficit diet (EDD) of 600 kcal per day, support to increase physical activity and key behaviour change techniques including goal setting and self-monitoring to facilitate these healthy lifestyle changes. However, the current evidence base and provision of health services on the management of obesity in adults with intellectual disabilities is limited. A systematic review of multi-component weight management interventions was conducted and identified only seven randomised controlled trials of weight management interventions in adults with intellectual disabilities and obesity. The intervention components primarily focussed on a health education approach including diet, physical activity, and behaviour change techniques. However, no intervention adhered to clinical recommendations in terms of including an EDD, a weight maintenance intervention or investigating the long term efficacy of the intervention at 12 months. Meta-analyses revealed that post intervention (Weighted mean difference; WMD: -0.92kg; 95% CI -2.11kg, 0.28kg; p = 0.13) and at 12 months (WMD: -1.15 kg (95% CI -4.15 kg to 1.86 kg; p = 0.45), current multi-component weight management interventions are not more effective than no treatment. The results of this review illustrate that the current evidence base is insufficient to support multi-component weight management interventions focussed on a health education approach and therefore, future studies should investigate the efficacy of an alternative approach and the inclusion of an EDD to examine the efficacy of this approach to the management of obesity in adults with intellectual disabilities. Methods: The primary aim of this thesis was to add to the limited evidence base on multi-component weight management interventions in adults with intellectual disabilities by examining the feasibility of conducting a full-scale trial of a multi-component intervention, TAKE 5. TAKE 5 adheres to clinical recommendations on weight management and was specifically designed for adults with intellectual disabilities, and where applicable implemented with support from carers. The study design was a single blind cluster randomised controlled trial comparing two active interventions. The comparator intervention, WWToo, was based on a health education approach and consisted of multiple components focussed on diet, physical activity and behaviour change techniques. A multi-point recruitment strategy was piloted. Participants were recruited from multiple organisations, from specialist intellectual disabilities services, provider organisations and local day centres. Additional feasibility outcomes included retention rates and the fidelity and implementation of the intervention. The primary efficacy outcome was change in body weight at 12 months. Additional secondary outcomes included anthropometric outcomes (BMI, waist circumference, percentage body fat), objective measure of physical activity (time spent in light, moderate to vigorous intensity and total physical activity) and sedentary behaviour and health related quality of life. Results: The multi-point recruitment strategy was shown to be feasible and 50 participants were successfully recruited to the study. This study design was shown to be acceptable to adults with intellectual disabilities as retention to both interventions was high with 90% of participants completing the intervention. The TAKE 5 multi-component weight management intervention with support from carers led to significant reductions in weight, BMI, waist circumference and percentage body fat at six and 12 months. Furthermore, 50% of the participants in the TAKE 5 intervention achieved a clinically significant weight loss of 5% or greater of initial body weight in comparison to 21% of the participants in the WWToo intervention. Significant improvements in the above outcomes were not found in participants completing the WWToo intervention. A limitation of both interventions was the inability to engage participants in physical activity, reduce the sedentary lifestyle behaviours and improve health related quality of life of this population group. Both interventions were implemented as intended, and both interventions were shown to be feasible and accessible to all adults with varying levels in intellectual disabilities due to the social support provided by carers in implementing the interventions. Conclusion: This study is the first ever randomised controlled trial of a weight management intervention that adheres to clinical recommendations in adults with intellectual disabilities. This study provided evidence on the feasibility of this study design in adults with intellectual disabilities and demonstrated the acceptability of the EDD approach tailored to meet the needs of adults with intellectual disabilities. Furthermore, this study has provided preliminary evidence that an EDD may be an efficacious approach to weight management, and provided further evidence that current service provision based on health education approach is ineffective in the treatment of obesity in adults with intellectual disabilities. On the basis of these findings a future full-scale randomised controlled trial is necessary to confirm these findings and provide evidence on the optimum approach to weight management in this population group.