PhD, EngD and MSc by research theses (Cranfield Health)
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Browsing PhD, EngD and MSc by research theses (Cranfield Health) by Supervisor "Bailey, Tracey A."
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Item Open Access Current and new concepts in the diagnosis and management of diabetic macular oedema(Cranfield University, 2013) Jyothi, Sreedhar; Bailey, Tracey A.; Sivaprasad, SobhaDiabetic macular oedema, which can cause rapid visual deterioration, may not have early warning signs at times. Assessment of diabetic retinal complications is made chiefly by clinical examination combined with optical coherence tomography (OCT) and fundus fluoroscein angiography (FFA). However, assessment usually does not occur until the late stages of diabetic retinopathy (DR), and, as retinal neurologic changes precede clinical changes, as tested in this thesis, by the time clinical assessment is performed, much of the functional visual loss has already occurred. More robust diagnostic modalities are required to detect progression of retinopathy in the early stages, before irreversible damage has already happened, and advances in the treatment of diabetic macular oedema is imperative as the current standard treatment in the form of laser photocoagulation is ineffective in improving the vision as authenticated in the following chapters. In this thesis, both treatment and diagnostic strategies of diabetic macular oedema (DMO) are investigated. Although laser photocoagulation is effective in short term in treating diabetic macular oedema, its mechanism of action is unknown; is associated with considerable collateral damage; and long term visual prognosis is meagre at a mean change in visual acuity at 5 years of -5.23. The 3-year outcome was also inferior to the clinical trial results with more people gaining vision (≥ 15 letter gain) in the diabetic retinopathy clinical research network (DRCRN) group compared to this cohort (26% versus 9%). Furthermore, three times more patients lost vision (> 15 letter loss) in the real-life setting of this cohort compared to the clinical trial results of the DRCRN group (27% versus 8%, respectively). Therefore, improved preventative and treatment modalities are essential to prevent progression in the early stages and to improve functional vision in late stages. In an attempt to look for new treatment strategies, we hypothesized that retinal oxygenation by inhibition of dark adaptation in the rod photoreceptor, could possibly inhibit progression of diabetic maculopathy. Illuminated-mask treatment of individuals with early diabetic maculopathy revealed encouraging results that point to an inexpensive and non-invasive therapy. Whilst 19 out of 34 study eyes with cysts at the beginning of the trial improved, 11 out of 30 fellow eyes with no demonstrable cysts at the onset developed cystic macular changes towards the end of 6 month trial. In the final chapters the correlation of visual functions with anatomic appearance were examined. The results of functional assessments, including visual acuity, colour contrast sensitivity, and microperimetry, had variable relation to structural changes at the macula with OCT. Therefore, an urgent need remains for the development of reliable diagnostic and preventative tools for the early assessment and treatment of visual function defects related to diabetic macular oedema.Item Open Access Health baseline comparisons and quality of life in people with cancer(Cranfield University, 2010-06) Davies, Nicola; Bailey, Tracey A.; Kinman, GailThis programme of research involved the development of a new health psychology concept: health baseline comparisons (HBCs). This is defined as the comparative baselines used to assess subjective health status. The following broad research questions were tested: Which HBCs are adopted by individuals with cancer?; What are the implications of different HBCs for quality of life (QoL) and other types of well-being?; How stable are HBCs throughout a course of treatment? A mixed-methodology approach was adopted to address the research questions. Five studies were conducted, all but the initial pilot study involving a clinical sample of people with cancer. A questionnaire to measure the use of different HBCs was developed and pilot tested, before being used to examine HBCs in people with breast and prostate cancer. On further refining the HBC construct, the questionnaire was re-validated and used to explore HBCs in women undergoing chemotherapy for breast cancer. The extent to which HBCs predicted QoL and psychological well-being was also examined in these studies. The stability of HBCs was sought from the same women two-months post-chemotherapy, focusing on associations with QoL and emotional well-being. The cross-sectional and longitudinal findings obtained in the first four studies were supplemented by a series of semi-structured interviews with a purposive sample of women from the longitudinal study. Interview transcripts were analysed via interpretative phenomenological analysis. Five categories of health baselines emerged from this programme of research: social; social comparison; biological; illness-specific; and turning to others. Some evidence was found that HBCs can change over time or be affected by illness and its treatment. Some HBCs, particularly social comparison and illness-specific baselines, were found to be significant predictors of QoL and psychological well-being, but the variance accounted for in these outcomes was generally small. Although the HBC questionnaire had acceptable internal consistency and reflected the experiences of people during cancer treatment and in the survivorship period, evidence was also found that the type and pattern of HBCs are subject to individual differences. This indicates that assessment of the construct also requires a qualitative and personalised component. The implications of the findings for the development of interventions are discussed and ideas for future research explored.Item Open Access Molecular basis for maize as a risk factor for oesophageal cancer in a South African population(Cranfield University, 2007-03) Pink, Ryan; Woodman, Anthony C.; Bailey, Tracey A.; Sammon, A.Throughout the world squamous cell carcinoma of the oesophagus seems to be an increasing problem. There is a huge variation in prevalence globally; locations such as Japan, Iran, China and Finland can have ten times the prevalence compared to other western countries. One place that is hugely affected is Transkei, a 16,000 square mile area of South Africa. Some of the factors proposed to be implicated with squamous cell carcinoma in this region include tobacco smoking, alcohol consumption, bacterial infections and fungal infection of common food crops. In addition, the ‘Sammon theory’ links carcinogenesis in Transkei to the high consumption of maize by the population. Through a chain of reactions it is postulated that a component of maize inhibits the breakdown of growth factors, which have already been implicated in cancer. This study investigates the Transkei population and updates the Sammon theory with current research to predict a theory at a molecular level. This theory is then tested with novel research to show PGE2, shown here in high concentrations in gastric fluid samples, directly increases the proliferation of oesophageal cell lines. Gastric fluid samples from the Transkei population are then shown to have a mitogenic effect on oesophageal cells, supporting a theory that gastric fluid regurgitation commonly found in this population predisposes them to cancer. Further experimentation on the expression of related proteins shows how high PGE2 may increase its own production by increasing COX 2 expression, leading to a positive feedback loop causing constant proliferative stimulation of the oesophageal squamous tissue in the presence of the COX 2 substrate, aracadonic acid. Therefore this thesis suggests that a high maize diet provides the correct conditions for regurgitation of increased concentrations of PGE2 into the oesophagus leading to squamous hyper-proliferation over long periods of time through self stimulated production, which would normally have ceased over a much shorter time if only localised PGE2 was produced through natural restitution.Item Open Access Molecular Profiling of Prostate Cancer Patients(Cranfield University, 2009-06) Nna, Emmanuel Okechukwu; Bailey, Tracey A.; Tothill, Ibtisam E.In the UK, more than 30 000 men are diagnosed annually with prostate cancer (PCa) and about 10 000 men die from it each year. Although several molecular markers have been associated with prostate cancer development and/ or progression, only few of them are used in diagnostic pathology. The current standard tests include serum PSA test, digital rectal examination and histology of prostate biopsy. Recently the PCA-3 molecular test was approved in the European Union, and it is now used in many laboratories. But these tests are not sufficient to molecularly characterise the behaviour of prostate cancer in many patients. Through extensive literature review, a panel of sixteen molecular markers were selected for further evaluation in prostate cancer cases. They included KLK2, KLK3, MCM2, MCM5, TP53, Bcl-2, CD44, CDH1, AURKA, AURKB, and AURKC; ESR , ESR , AR, FASN, TMPRSS2: ERG, and TMPRSS2:ETV1. The aim was to examine the link between development/progression of prostate cancer and the production of diagnostic/prognostic biomarkers. An in vitro model consisting of PC-3 and PNTIA, MDA PCa 2b prostate cell lines were used to investigate the influence of steroid hormones on these biomarkers using molecular and proteomic techniques. All the three cell lines expressed AR, ESR , ESR and PSA at mRNA and protein levels. The AR expressed in PC-3 and MDA PCA 2b cells was 60 kDa while the PNT1A expressed a 90 kDa AR protein. The ESR was over-expressed in the MDA PCA 2b cells, and was also significantly up-regulated by 17 oestradiol treatment. At a concentration of 4.92 and 33.96μM 17 oestradiol inhibited the growth of 10 to 50% of PNT1A cell line and increased the doubling time three folds. Although the PC-3 cells expressed AR, it was still androgen insensitive and could not produce PSA in culture supernatants. AR and PSA were up-regulated in PNT1A cells in response to testosterone and dihydrotesterone treatment but were reduced in response to 17 oestradiol and Hydrocortisone treatment. All the molecular markers except the TMPRSS2: ERG and TMPRSS2:ETV1 were expressed in the cell lines. The MCM2 and MCM5 were not differentially expressed in response to hormonal treatment. However, the Aurora kinases A, B and C were up-regulated in response to steroid modulation. The KLK2 was only up-regulated by the androgens. Three candidate control genes: ABL1, GUS and G6PD were also evaluated in the cell lines and clinical samples; the ABL1 gene emerged as the most stably expressed house keeping gene and was subsequently used in the normalization of real time PCR assays (RQ-PCR). Analysis of the sixteen biomarkers in prostate tissues and exfoliated urine cells of benign, prostate cancer and non-involved cases (n = 228) showed that seven of the molecular markers were significantly strongly associated with prostate cancer progression (P<0.05). The Aurora kinases A and B were consistently significantly over-expressed in prostate cancer cases. The CD44 was also over-expressed in prostate cancer, and was associated with Gleason score. The TMPRSS2 fusion genes were detected in 15.6% of the prostate cancer cases. The TP53 was also over-expressed in prostate cancer, and significantly associated with tumour grade. The ESR was over-expressed in prostate cancer, and was significantly associated with high tumour grade. This implied a proliferative role for the ESR in prostate cancer progression, because the ESR was not differentially expressed among the sample groups. Concomitantly, the AR was also over-expressed in same pattern with ESR . The combination of these biomarkers: AR, ESR , CD44, TP53, TMPRSS2 fusion genes, AURKA and AURKB could molecularly characterise most prostate cancers. Therefore 2 sets of pentaplex RQ-PCR assays including ABL1 for normalization would provide a cost-effective, flexibly high throughput assay for molecular grading of tissue sections in diagnostic pathology. In addition to the gene expression studies, the genetic variation in KLK2 gene was further investigated by direct DNA sequencing, pyrosequencing and TaqMan allelic discrimination assay. Two SNPs in the gene were found significantly associated with prostate diseases. The T/T allele of rs198977 predicted the presence of prostate cancer at biopsy and was associated with high tumour grade. The A/A variant of rs2664155 was also significantly associated with the presence of benign nodular hyperplasia. The combination of gene expression and genetic variation using real time PCR applications would provide an accurate, reproducible and cheap method for molecular profiling of prostate cancer patients. An exploratory study of organic volatiles in urine of one prostate cancer patient and eight BPH patients using thermal desorption GC-MS showed that Ethanethiol, Dimethyl sulfide, Propyn-1-ol acetate, Nitro-2-propanone, pentane, Hydrazine and Nitrous oxide were differentially over-expressed in the prostate cancer patient compared to the benign cases. Further studies would be required to rule out possible contamination and drug metabolites.Item Open Access Prevalence of visual impairment and severity of diabetic retinopathy in various ethnic groups in the UK(Cranfield University, 2011-04) Gupta, Bhaskar; Bailey, Tracey A.; Sivaprasad, S.Diabetic Retinopathy (DR) is a leading cause of visual impairment (VI) in the working population. Minor ethnic groups are at increased risk of diabetes. Diabetic Retinopathy In Various Ethnic groups in the United Kingdom (DRIVE UK) is a cross-sectional study to estimate the prevalence of DR, VI and associated risk factors for sight threatening diabetic retinopathy (STDR) in Afro-Caribbeans (AC) and South Asians (SA) compared to Caucasians. People with diabetes in two regions in the United Kingdom who were screened and/or treated for DR from September 2008 to September 2009 were included in this study. VI and severe visual impairment (SVI) were defined as Snellen visual acuity of ≤ 6/18 and ≤ 6/60 respectively. DR was graded according to National Screening Committee (NSC) for diabetes guidelines UK. There were 57,144 people on the diabetic register, of which retinopathy data was available from 50,285 (88.1%) subjects (type 1 n=3,323, type 2 n=46,962). In type 1 and type 2 diabetes, any DR was detected in 53.1%, 39.5%, diabetic maculopathy in 13.1%, 8.4% and STDR in 9.91%, 4.0% of people respectively. STDR was significantly more prevalent in the SA (10.3%) and AC (11.5%) populations compared to Caucasians (5.5%). Overall VI was significantly higher in the ethnic minority population. A total of 7.5% (95% CI 7.3, 7.8) people with diabetes were not eligible for driving based on their visual acuity, 3.4% (95% CI 3.2, 3.5) were classified as VI and 0.4% (95% CI 0.33, 0.44) as SVI. Risk factors for STDR were found to include longer duration of diabetes and higher mean HbA1c. This study provides information that could be used to help develop future service frameworks and guidelines for local health bodies responsible for delivery of end userservices. The study also supports the need to explore the role of inflammatory, genetic and epigenetic factors as markers for ethnic differences in DR and potential treatment avenues for diabetic retinopathy.