Medicine (St Vincent's) - Theses
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ItemDetection and monitoring of diabetic polyneuropathy with specialised markers of small and large nerve fibres( 2020)Routine nerve conduction studies (NCS) are the current standard test for the evaluation of suspected peripheral neuropathy, but are often normal in patients with diabetic polyneuropathy (DPN). This is because: i. NCS are unable to detect dysfunction of small fibres, which may be affected earlier and are the cause of painful neuropathic symptoms; and ii. Significant large fibre axonal loss +/- demyelination may need to occur before NCS detect this is an abnormality. This research project critically evaluates various newer/novel methods to detect and potentially monitor diabetic neuropathy, and to provide a feasible way that this can be routinely assessed in the neurophysiology laboratory. I chose to specifically analyse the diabetic population as this is by far the most common cause of peripheral neuropathy in the global community, causing significant burden of disease. The various known novel techniques to assess and monitor DPN are evaluated, firstly through that which is available in current literature. These are compared in terms of diagnostic accuracy, as well as availability and cost-effectiveness. Based on the findings from this literature review, various prospective clinical studies are developed to further evaluate the more promising techniques identified. A focus was made towards techniques that can be performed in the neurophysiology laboratory, as routine NCS have, and will remain likely to have a significant role in the assessment of diabetes-related neuropathy. Thus, this clinical visit provides an opportune time to perform these additional tests as a way of providing supplementary information on patient’s peripheral nerve status. Small and large nerve fibres are both affected by diabetes. However, these fibres display very different physiological properties, not just in terms of structure and function, but they are also evaluated by completely different techniques. Small fibres can then be further subdivided into different populations of thinly myelinated A-delta fibres and unmyelinated C-fibres, which again have very different properties and assessment modalities. This thesis is divided into two main sections with research focussed on providing more accurate measurement of the various small fibre populations in the first section, and then improving large fibre testing beyond that of routine NCS in the second section.
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ItemThe contribution of the pulmonary circulation and cardiac function to exercise intolerance in people with diabetes( 2019)Diabetes mellitus (DM), and in particular type 2 DM (T2DM), is approaching epidemic proportions globally. Relative to people without diabetes, exercise performance is reduced by approximately 20% in T2DM subjects universally, whereas impairment in type 1 DM (T1DM) is less consistently reported. Risk of cardiovascular disease (CVD) is significantly elevated in both T1DM and T2DM, and thus emphasis is placed on cardiovascular constraints to exercise capacity, including subclinical cardiac dysfunction and the entity of diabetic cardiomyopathy (DMC). A clear bidirectional association between heart failure and T2DM exists, with numerous pathophysiological mechanisms identified in animal models. Longitudinal data suggests a low prevalence of heart failure in T1DM, on the other hand, which insinuates the pathological mechanisms thought to underpin DMC may be exclusive of chronic hyperglycemia which unifies the diagnosis of T1DM and T2DM. The pulmonary microvasculature is targeted in diabetes, meanwhile, and may be an under-appreciated contributor to exercise limitation. It is thought that the lungs are protected from deleterious effects of subclinical microvascular disease by virtue of their substantial size, although the ability to assess pulmonary microvascular function during exercise has been limited. This thesis assesses exercise performance (VO2peak) in people with T1DM and T2DM, evaluates the contribution of cardiac function and the pulmonary circulation using comprehensive traditional and novel echocardiographic analyses, and investigates the effect of phosphodiesterase type 5 (PDE5) inhibitor Sildenafil on exercise capacity. VO2peak is demonstrated to be impaired in only the T2DM cohort of the study group, and independently associated with sedentary lifestyle and reduced left ventricular end diastolic volume. Comprehensive resting and exercise echocardiographic measurements of biventricular systolic function and LV diastolic function, in addition to speckle-tracking global longitudinal strain and LV twist mechanics, are normal. The novel echocardiographic assessment of pulmonary microvascular function by measuring the pulmonary transit of agitated contrast (PTAC) identifies less PTAC (low-PTAC) in DM subjects, and associations with reduced RV function, higher pulmonary artery pressures, and lower exercise capacity. Finally, Sildenafil improves a number of central hemodynamic parameters but does not improve VO2peak. Results of this thesis support the argument that in the presence of impaired exercise performance and longstanding DM, subclinical cardiac dysfunction and DMC should not be universally anticipated. Diagnosis of pulmonary microvascular dysfunction using PTAC is feasible and readily accessible, and pulmonary microvascular disease is associated with reduced exercise capacity. Nonetheless, quantification of pulmonary microvascular disease remains imperfect, and the pulmonary vasodilator Sildenafil is ineffective in improving exercise performance presumably due to the mismatch between the pathophysiology thought to underpin diabetic lung disease and the more proximal smooth muscle vascular target of Sildenafil.