Medicine (St Vincent's) - Theses
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ItemRegulation of bone and fat cells by zinc-finger protein- 467(University of Melbourne, 2010)
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ItemThe assessment of the coronary microcirculation using the index of microvascular resistance in patients with ischaemic heart disease( 2013)Despite improvements in medical therapy, ischaemic heart disease (IHD) remains a significant cause of morbidity and mortality in western societies. The link between epicardial stenosis and myocardial ischaemia is well documented, yet improvements in outcome have come from a focus on myocardial perfusion rather than just restoration of epicardial flow. Myocardial perfusion is comprised of collateral flow; epicardial flow and microcirculatory flow yet the key regulator of this process is the coronary microcirculation. Thus focusing on the coronary microcirculation may provide a further pathway for improving outcomes in patients with ischaemic heart disease. However, factors affecting the coronary microcirculation, in particular the effect of percutaneous coronary intervention, have not extensively studied. Furthermore, the role of the coronary microcirculation in defining key relationships in coronary physiology is also unresolved. There are a variety of methods that can be utilized to assess the coronary microcirculation both invasive and non-invasive. Each method has its own potential advantages and disadvantages but invasive methods would seem intuitively more useful amongst patients presenting to the catheter laboratory. The Index of Microvascular Resistance (IMR) is a novel invasive technique that has been extensively validated in both in-vivo and in-vitro models. The principle aim of this thesis is to use the index of microvascular resistance to examine the coronary microcirculation in patients with ischaemic heart disease. Specifically I will examine the predictors of IMR and the influence of the collateral circulation on IMR in patients with stable angina. I will also examine the predictors of microcirculatory dysfunction following PCI and look at factors both clinical and biochemical, effecting IMR measured following PCI. I will also use IMR to define controversial relationships in coronary physiology. Specifically I will examine the relationship between coronary flow reserve and fractional flow reserve and also the ability of the microcirculation to vasodilate in patients with NSTEMI. A variety of patients with IHD were recruited into the study. 80 patients with stable angina, 50 patients with NSTEMI and 40 patients with STEMI were included in the analysis. Coronary Physiological measurements were taken pre and following PCI in the culprit vessel and where possible, in an angiographically normal reference vessel. Bloods were taken at the time of the procedure and sequentially every 6 to 12 hours up to 24 hours following percutaneous coronary stenting. In summary, the main findings of this thesis are: i) Epicardial Stenosis does not increase microvascular resistance when collateral flow is accounted for. ii) The resting status of the coronary microcirculation is a key predictor of post PCI coronary microvascular function. iii) The resting status of the coronary microcirculation is an independent predictor of periprocedural myocardial infarction. Specifically localized impairment of the coronary microcirculation as determined by the relative pre IMR ratio was a predictor of periprocedural myocardial infarction. iv) The ability of the coronary microcirculation to vasodilate is preserved in selected patients with NSTEMI. This property is directly correlated with the baseline level of IMR and myocardial injury and suggests that the use of diagnostic tests that rely on hyperemia may be suitable for use in selected patients with NSTEMI. v) The discordance between fractional and coronary flow reserve is not explained by variations in microvascular resistance. The findings of this PhD are novel and have implications for the prediction of myocardial injury caused by percutaneous coronary intervention (PCI). Specifically that targeting a high IMR prior to stenting may allow for further improvements in outcome in elective PCI. I have also clearly shown (in the largest studied cohort to date) that the measurement of collateral flow is mandated when calculating microvascular resistance to avoid overestimation. Furthermore, that maximal hyperemia is possible in high acuity patients with non-ST segment myocardial infarction, potentially allowing the use of diagnostic tests such as fractional flow reserve that rely on an intact microcirculation. This may have far reaching clinical implications but warrants confirmation in a large prospective, randomised study.
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ItemMolecular mechanisms regulating chemotherapy resistance in ovarian carcinomas( 2013)Epithelial ovarian cancer is the second most common and most lethal gynaecological malignancy. Due to lack of early diagnostic modalities this aggressive form of cancer is frequently diagnosed once it is at an advanced stage with a low 30% five year survival rate. Following primary cytoreductive surgery, ovarian cancer patients are treated with adjuvant or neo-adjuvant systemic administration of platinum and taxane based chemotherapy as part of first line chemotherapy regimens. A positive response to this form of treatment is seen in the majority of cases, with patients enjoying a short remission period. However, treatment is rarely curative and in nearly all cases within 16-22 months there is an emergence of fatal chemoresistant recurrent disease. It is believed that this phenomenon of chemoresistance and recurrence is attributed to the activation of specific cell signalling pathways associated with cancer cell survival and the emergence of cancer stem cell-like populations within the chemotherapy treated residual ovarian tumours. In order to increase the low 30% five year survival rate for this distressing disease, an understanding of the molecular processes that govern the enrichment of cancer stem cell-like cells and the activation of pro-survival signalling pathways in chemotherapy surviving residual cells is needed, as these are the ultimate source of the recurrent disease. Hence with the aim of elucidating such molecular processes, this thesis aimed to answer the following two critical questions: 1. Do first line taxane based chemotherapies facilitate the activation of pro-survival pathways such as the JAK2/STAT3 pathway which is involved in the enrichment of cancer stem cell-like characteristics and cancer cell survival in epithelial ovarian cancer? 2. Does targeting the JAK2/STAT3 pathway with small molecule inhibitors enhance the efficacy of current taxane based therapies? To answer the above question, this thesis diligently characterised the cancer stem cell-like profiles that emerged in response to taxane based chemotherapy of ovarian cancer cell lines as well as ovarian tumour cells isolated from the ascites of advanced stage ovarian cancer patients. Moreover, this thesis assessed the effects of inhibiting the JAK2/STAT3 pathway on chemoresistance and enrichment of cancer stem cell-like phenotypes. Finally, using an in vivo mouse xenograft model, this thesis validated the demonstrated results obtained from in vitro experimentations. The results of this thesis demonstrate that treatment with taxane and platinum based therapies does indeed activate the JAK2/STAT3 pathway in both ovarian cancer cell lines as well as tumour cells isolated from the ascites fluid of advanced stage ovarian cancer patients. Moreover, this thesis is the first to demonstrate that the activation of the JAK2/STAT3 pathway in response to taxane based therapies coincides with the enrichment of cancer stem cell-like phenotypes which was shown to contribute to cancer cell survival and the development of a significantly larger tumour burden in mice. Furthermore, this thesis is the first to demonstrate that inhibiting the JAK2/STAT3 pathway reduces the emergence of cancer stem cell-like populations and enhances the efficacy of current taxane based therapies resulting in the significant reduction of tumour burden in mice. The results demonstrated in this thesis have important implications for ovarian cancer patients who are being treated with taxane and or platinum based first line therapies. These findings warrant further pre-clinical investigation and may be used as a platform for the development of adjuvant therapies used in combination with the gold standard therapy that is currently offered to ovarian cancer patients.
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ItemAdenosine generation and signalling in diabetes and islet transplantation( 2013)Clinical islet transplantation is a potential cure for type 1 diabetes, however, hurdles such as the instant blood-mediated inflammatory reaction (IBMIR), recurrent autoimmunity and allograft rejection restrict the effectiveness of this therapy. During the IBMIR process, thrombotic and inflammatory cascades are activated, resulting in the loss of more than 50% of islet graft mass. This poor engraftment, combined with the ongoing destruction of islets by recurrent autoimmunity and the allo-immune response, means that more than one donor per recipient is needed to achieve normoglycemia. CD39 is an anti-thrombotic and anti-inflammatory molecule, which promotes the generation of extracellular AMP and adenosine, and has been shown to mitigate IBMIR in vitro when over-expressed on islets. We hypothesised that the over-expression of CD39 on the islet surface would confer in vivo protection against chemically induced diabetes and attenuate IBMIR-mediated graft loss via adenosine-related signalling pathways. The aim of the thesis was to evaluate the impact of adenosine generation and signalling in mouse models of T cell-mediated diabetes and islet transplantation. CD39 over-expression protected against T cell mediated diabetes and this effect persisted in the presence of defective regulatory T cells. The absence or inhibition of particular adenosine receptors increased susceptibility to diabetes. Surprisingly, in the absence of an important generator of extracellular adenosine (i.e. CD73), mice were protected in this model. Finally, islets over-expressing CD39 showed prolonged graft survival in a syngeneic intraportal islet transplant model, implicating an effect of CD39 in inhibiting IBMIR. Together these results support the notion that the over-expression of CD39 promotes islet engraftment and survival. The clinical translation of these findings could lead to greater insulin independence and the need for fewer donors to achieve this.
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ItemThe role of Trig: a novel toll-like receptor induced gene, in dendritic cell function and autoimmune disease( 2013)The immune system is comprised of a complex network of cells and signalling pathways that must be tightly regulated to maintain immune homeostasis. Defective negative regulation results in enhanced immunogenicity, loss of immune tolerance and, eventually, the development of autoimmune disease. Toll-like receptors (TLRs) are an essential component of the immune system as they act as early sensors of microbial pathogens and play a critical role in linking the innate and adaptive arms of the immune response. There is also increasing evidence that aberrant TLR signalling and TLR-mediated immune responses contribute to the development of autoimmune diseases, such as type 1 diabetes (T1D), although investigating these abnormalities and the underlying genetic defects in humans is often difficult. Instead, the non-obese diabetic (NOD) mouse strain, which spontaneously develops T1D, has proven to be a useful animal model for investigating genetic variants that contribute to autoimmune disease by altering TLR-mediated immune responses. Predisposition to T1D in the NOD mouse is due to allelic variation at multiple loci across the genome. More than 30 susceptibility loci have been linked to T1D development in the NOD mouse. Positional cloning of one of these loci, termed Idd11, has led to the identification of a novel gene termed Trig (AK005651). Allelic variation for Trig is associated with T1D development and this gene is differentially expressed in immune-related tissues between diabetes-resistant and diabetes-susceptible mouse strains. Preliminary experiments also revealed that Trig is upregulated in a dendritic cell (DC) line in response to TLR9 stimulation. It was therefore hypothesised that genetic variation for Trig alters TLR-mediated immune responses that affect the development of autoimmune disease. The first aim of this thesis was to perform a preliminary characterisation of a novel mouse strain deficient for Trig. Trig-deficient mice were observed to be viable and fertile, were indistinguishable from wildtype littermates for weight and gross anatomical development, and did not develop any observable signs of ill health. Furthermore, no statistical differences between Trig-deficient and wildtype littermates were identified for immune cell number or frequency in the peripheral blood, thymus or spleen. This study indicates that Trig is not an essential gene for the basic development and viability of B6 mice housed in specific pathogen-free conditions. The second aim was to investigate the experimental conditions that alter expression of Trig. Trig was found to be upregulated in an immortalised DC line, primary DCs and bone-marrow-derived macrophages, after exposure to ligands that activate MyD88-dependent TLR signalling pathways. This upregulation was abrogated by interferon (IFN)γ signalling, indicating that TLR/IFNγ signalling cross-talk regulates the expression of Trig. These studies suggest that Trig might act as a negative feedback regulator of TLR-mediated immune responses. The third aim was to determine which TLR-mediated immune responses were regulated by Trig in DC subsets. A series of in vitro assays were performed to assess the capacity of TLR9-stimulated Trig-deficient DC subsets to produce cytokines, upregulate cell-surface molecules and present antigen to T cells. This revealed that Trig-deficiency leads to enhanced cytokine production in specific DC subsets. Subsequent analysis of DC subsets isolated from NOD, B6 and Idd11 congenic mice revealed that strain variation for Trig also affects TLR9-mediated cytokine production. Collectively, these findings indicate that Trig negatively regulates TLR9-mediated cytokine responses in specific DC subsets. The fourth aim of this thesis was to explore the role of Trig in systemic inflammation and autoimmune disease. The serum cytokine levels of Trig-deficient mice treated with a TLR9 agonist were similar to those of wildtype littermates, indicating that Trig is not an essential negative regulator of TLR9-mediated cytokine production under the experimental conditions tested. Instead, Trig-deficiency had a subtle affect on the onset and/or severity of three inducible models of autoimmune disease. Therefore, this thesis presents cumulative evidence that supports a role for Trig in attenuating TLR-mediated immune responses that contribute to immune dysregulation and the development of autoimmune disease.
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ItemNovel biomarkers in the early detection of pulmonary arterial hypertension in systemic sclerosis( 2013)Systemic sclerosis (SSc) is a complex disease characterised by extensive fibrosis, vascular abnormalities and autoantibodies. Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality in SSc, and the early detection of PAH has emerged as an essential component of disease management. The hypothesis for this thesis is that biomarkers, either alone or in combination with other non-invasive screening investigations, may improve screening in patients with SSc-PAH. In this way, it may be possible to shift the burden of routine screening away from echocardiography. To begin, I present a comprehensive review of SSc-PAH focusing on the rationale and methods used to facilitate the early detection of SSc-PAH. Next, I present a systematic review highlighting some of the limitations in current screening practices, demonstrating the clinical need to further evaluate and refine current screening before making recommendations regarding the nature and frequency of screening. I then evaluate the screening utility of N-terminal-pro brain natriuretic peptide (NT-proBNP) in SSc-PAH, first proposing, and later validating a novel screening strategy combining NT-proBNP with pulmonary function tests (PFT) in a high-risk group of patients for SSc-PAH. Using this strategy, only patients who screen ‘positive’ to the proposed screening algorithm undergo echocardiography and further confirmatory testing for PAH. I show that asymmetric dimethylarginine, a novel biomarker of endothelial dysfunction involved in nitric oxide metabolism, may be an important screening and diagnostic biomarker for SSc-PAH, especially when combined with NT-proBNP. I also evaluate various other cytokines, chemokines and growth factors, previously suggested to play a role in SSc-PAH, and show in a well-characterised population of SSc-PAH patients that serum levels of interleukin-6 (IL-6), interleukin-13 (IL-13), vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), fractalkine (FKN), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) are not specific biomarkers of SSc-PAH. However, VEGF and ICAM-1 levels appeared to correlate with markers of PAH severity and deserve further study. I showed the wide variability of measured levels of these cytokines, chemokines and growth factors in SSc patients, possibly reflecting the heterogeneity of this complex disease. Overall, I demonstrate that biomarkers, particularly when combined with other non-invasive screening investigations such as PFT, may identify patients with SSc-PAH.
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ItemAdipose-derived mesenchymal cell derivation, characterization and differentiation for potential use in cell replacement therapy for diabetes( 2013)Type 1 diabetes (T1D) is characterized by the loss of insulin-producing β-cells in the pancreas. T1D can be treated using cadaveric islet transplantation, but this therapy is severely limited by a lack of donor pancreas. To develop an alternative cell therapy, candidate populations were identified through epigenetic characterization of multiple tissues. Histone modification status at the promoter region of key endocrine pancreatic genes was assessed using chromatin immunoprecipitation sequencing (ChIP-seq) and validated using promoter-specific TaqMan-based quantitative PCR (qPCR). Visceral fat was identified as a tissue retaining epigenetic signatures similar to those observed in the pancreas. Human adipose-derived mesenchymal cells (AMCs) were characterized using flowcytometry, confocal microscopy, qPCR, in situ PCR and next generation sequencing technologies. Multiple transcription factor-encoding adenoviruses (e.g. Pdx1, MafA, Ngn3) were employed to determine the differentiation potential of these cells. Analysis of multiple pancreatic hormones and transcription factors in these samples demonstrated consistent differentiation. The differentiation potential was further explored using AMCs isolated from transgenic mice that express GFP under the regulation of Pdx1 (pancreatic and duodenal homeobox 1) or insulin-1 gene promoters. GFP expression was quantitated as an index of gene promoter activity during differentiation to insulin-producing cells, in the presence of various pro-differentiation small molecules. Human AMCs were exposed to a standard differentiation protocol and seen to migrate to form islet-like cell aggregates (ICAs), showing significant increases in islet hormone transcripts in vitro. These adipose-derived ICAs were transplanted into immunocompromised animals using two models of transplantation. Cells were transplanted in a Theracyte immunoisolation device into the peritoneum, and within a blood clot under the kidney capsule. Transplanted cells maintained expression of endocrine pancreatic transcription factors and did not undergo a regressive mesenchymal transition following surgery. Circulating blood samples collected from peripheral circulation of these mice, following a glucose injection, showed that differentiated and engrafted human AMCs could sense, transcribe, translate, package and secrete insulin in response to a glucose stimulus. These studies indicate that human AMCs can differentiate into insulin-producing cells in vitro and have potential for cell replacement therapy in diabetes.
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ItemAssessment of inflammatory bowel disease epidemiology in Barwon, Victoria: an observational prospective population based study( 2013)Background: The Inflammatory bowel diseases (IBD) Crohn’s disease (CD), ulcerative colitis (UC), and IBD unspecified (IBDU), are chronic conditions with significant health-related disability and potentially expensive therapies. Recent research locally suggests high IBD incidence rates. However, no Australian population-based prevalence data is available, nor has the natural history of newly diagnosed community-based IBD patients been studied. Aims: To estimate current IBD burden by calculating incidence and prevalence rates in an Australian population, and to assess for recent changes in IBD incidence. We also aimed to form a pilot IBD registry, allowing longitudinal observations of natural history in newly diagnosed community-based patients. Methods: The study region of Barwon, Victoria (population 293,426) was studied from July 1st 2010 to June 30th 2011. Capture-recapture methodology was used, with cases identified from multiple overlapping sources including clinicians (gastroenterologists, surgeons and paediatricians), histopathology databases, endoscopy records, hospital coding and medication dispensing records. Strict internationally recognised diagnostic criteria were used to define incident cases. All incident cases were individually verified by 2 clinicians and phenotypes defined by Montreal criteria. Incident cases were enrolled in a registry with opt-out consent. Prevalent case ascertainment required extension of data collection into General Practices across the region. Three-month clinical outcomes were assessed for incident cases, including surgical rates, hospitalisation and medication use. Results: 71 incident IBD cases were identified (incident rate 24.2 per 100,000). This was stable compared to local data from 2007/08. Incidence rates for CD, UC and IBDU were 14.7, 7.5 and 2.0 per 100,000 respectively. 1011 prevalent IBD cases were recorded (point prevalence rate on June 30th 2011 344.6 per 100,000). Prevalence rates for CD, UC and IBDU were 197.3, 136.0 and 8.5 per 100,000 respectively. All incident cases were enrolled in the registry. Within three months of diagnosis 28% had been hospitalised, and 11% required surgery (all with CD). Peri-anal disease was present in 14% of CD cases. 55% were under 40 years of age. Corticosteroids were prescribed in 59% and immunosuppression in 11%. None received biological therapy within three months of diagnosis. Conclusion: This study has produced Australia's first epidemiologically sound population-based IBD prevalence data, demonstrating a large burden of disease. Stable high IBD incidence rates were reconfirmed. Three month outcome data from the incident inception cohort shows a high proportion have aggressive disease, defined by age less than 40 at onset, hospitalisation and surgery rates, steroid use, and the presence of peri-anal disease. This inception cohort will be followed longitudinally to further define the natural history of IBD.
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ItemDiabetes telephone coaching study: a randomised controlled trial and economic analysis( 2013)Aims: The randomised controlled trial (RCT) aimed to assess the efficacy of telephone coaching on glycaemic control, risk factor status and adherence to monitoring requirements in patients with poorly controlled type 2 diabetes (T2DM), both at the intervention’s conclusion (six months) and in the post-intervention period (12 months). The study also involved a cost-effectiveness analysis of the intervention, both in a within-trial setting and in a 10 year modelled scenario. Finally, this study sought to estimate the annual cost of treating Australians with poorly controlled T2DM. Method:Participants with T2DM, HbA1C >7% (n=94) were randomised to receive usual care plus six months of telephone coaching, or usual care only. Coaching involved assessment, education and goal setting regarding diet, exercise, medications and adherence to diabetes monitoring requirements. The primary outcome was HbA1C at six months. Secondary outcomes included HbA1C at 12 months and other physiological and monitoring measures. The within-trial economic analysis used cost and efficacy data collected between baseline and six months of the RCT to estimate the cost-effectiveness of the telephone coaching intervention, compared to usual diabetes care. The primary outcome was an incremental cost effectiveness ratio, expressed as cost per quality adjusted life year (QALY) saved. Items costed included those attributable to medication use, general practitioner presentations, outpatient appointments, emergency department presentations, inpatient admissions and delivery of the intervention. To estimate the annual cost of treating a person with T2DM, six-monthly costs of all participants were doubled to reflect the annual cost. The modelled economic analysis used the UKPDS Outcomes Model to extrapolate outcomes collected at six months in the RCT over 10 years, assuming the ongoing delivery of the telephone coaching intervention. Outcomes included life expectancy, quality-adjusted life expectancy (QALE) and costs. A 5% discount rate was applied to all future costs and benefits. Sensitivity analyses were conducted to reflect uncertainty surrounding key input parameters. Results: The six month intervention contributed to significant improvements in HbA1C (p=0.03), fasting glucose (p=0.02), diastolic blood pressure (BP) (p=0.03) and physical activity (p=0.02). At six months, adjusted mean HbA1C in the intervention group was 7.7% (7.4 to 8.1) compared to 8.5% (8.1 to 8.8) in controls. Intervention group participants also improved their compliance with routine foot checks and pneumococcal vaccination by six months and retinal screening by 12 months. However, the intervention’s effects on glycaemic control had disappeared by 12 months. For the within-trial economic analysis, the intervention was dominated by the control condition. This is because six monthly diabetes-related costs in the intervention group were significantly higher than the control group, $5403 versus $2260, p=0.009. Owing to one death, the intervention group also experienced a non-significant decline in health utility, -0.01 (-0.03-0.01), equating to a reduction in QALE of 0.005. The estimated mean annual cost of treating a person with poorly controlled T2DM was $7020. The intervention dominated the control condition in the modelled economic analysis, contributing to cost savings of $3327 and non-significant improvements in QALE (0.2 QALE) and life expectancy (0.3 years). The intervention also dominated the control condition in most sensitivity analyses. When the baseline imbalance in terms past history of stroke was controlled, the intervention remained highly cost-effective at a cost of $4365 per QALY saved. Conclusions: Telephone coaching improves glycaemic control and adherence to complication screening in patients with poorly controlled T2DM. The effects were not sustained in the post-intervention period, therefore strategies that facilitate the maintenance of intervention gains are required to improve long term outcomes. The intervention was not cost effective during the within-trial period, but over 10 years, the intervention’s cost was predicted to be fully recovered through cost savings from the prevention of downstream morbidity. The estimated annual cost of treating a person with T2DM updates former cost estimates that were based on data collected over 10 years ago. Collectively, these results are of major relevance to clinical practice, public health practice and health policy. Findings from this study support the need for a larger, prospective multi-centre trial of telephone coaching to confirm both the clinical and economic benefits prior to their implementation in routine clinical practice.
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ItemA study of female pattern hair loss( 2013)A full head of luscious hair is a very desirable trait for humans and loss of this hair which is a common problem is a devastating affliction, particularly for females. Apart from its cosmetic and social significance the human hair follicle forms an intricate anatomical structure called the follicular unit consisting of a combination of terminal and vellus hairs as well as an arborising arrector pili muscle and sebaceous gland. The importance of this anatomical structure and its individual components in maintaining human hair growth is increasingly being realised. The main emphasis of this thesis is the study of this remarkable micro-anatomical unit in hair loss disorders. After establishing that individual hairs are lost from follicular units rather than entire follicular units in female pattern hair loss, possibly due to a hierarchy of susceptibility to miniaturization within follicular units, the research comprising this thesis then goes on to explore the potential role of the arrector pili muscle in this process. In fact it appears that loss of attachment of this microscopic muscle to the bulge of miniaturized hair follicles which are a repository of stem cells, equates to an inability to reverse hair follicle miniaturization as seen in female and male pattern hair loss. On the other hand when the arrector pili muscle maintains its attachment to the bulge of the miniaturized follicle as seen in alopecia areata, there is a potential for complete reversibility of the miniaturization process. Thus the attachment of the arrector pili muscle to the bulge is more than just by chance and the arrector pili muscle is likely to be more than just a vestigial muscle of piloerection. Furthermore it seems that the follicular unit is a dynamic structure showing further development post-partum with increasing numbers of total hairs as well as increasing proportions of two, three and four haired follicular units in adulthood compared to infancy. The composition of follicular units in female pattern hair loss however more closely resembles that of the infant with a larger proportion of single haired follicular units than the adult unaffected by hair loss. The research contained within this thesis has led to the development of a new model for the pathogenesis of female pattern hair loss in which the follicular units, in particular the arrector pili muscle play an important role in the pathophysiology of hair loss disorders.