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ABSTRACT Objectives: This study aimed to investigate the feasibility and acceptability of a narrative therapy group approach for adolescents with type 1 diabetes (T1D). Design: The study employed a between-group, repeated measure design comparing a narrative therapy group intervention to a control group who received treatment-as-usual. Methods: 75 adolescents aged between 12 and 15 years old who had been identified as having poorly controlled T1D (HbA1c > 8%), were invited to participate in a one-off narrative therapy group. A total of eight individuals agreed to take part and were randomly allocated to either the intervention group (n=4) or treatment-as-usual (n=4). Information on the acceptability of this approach was gathered from follow-up interviews three months after attendance at the group. Outcome measures included HbA1c, diabetes-related distress and self-efficacy. Results: The adolescents who did attend the intervention group reported it to have been a beneficial experience which had helped them to feel less isolated in their experience of living with diabetes. Additionally, some participants reported that the group had provided them with a ‘wake-up’ call and had encouraged them to re-think the way they manage their condition. However, no significant changes in HbA1c, diabetes-related distress or self-efficacy were observed in either the intervention or the control group at three month follow-up. Conclusions: This novel group approach was considered to be an acceptable adjunct to treatment-as-usual. All adolescents who attended the group reported that they would recommend it to other young people with T1D. A larger scaled study would be required in order to determine whether this approach can improve glycaemic control and psychosocial outcomes in an adolescent population.

Diabetic nephropathy is associated with secondary hypertension arising from aberrant sodium reabsorption in the kidney. This thesis characterises a novel human cell line derived from the human cortical collecting duct (HCD) to assess glucoseevoked changes in key elements, such as the serum and glucocorticoid inducible kinase (SGKI) and the epithelial sodium channel (ENaC), involved in the regulation of sodium transport. In addition I have also examined the effects of TGF-f3I and [Ci+]i on SGKI and ENaC expression. RT-PCR, western blot analysis, immunocytochemistry and single cell imaging were employed to determine presence, localisation and function of these elements under various glycaemic conditions. Our data suggest that high glucose, TGF-f3I and [Cl+]i up-regulate both SGKI and [alpha]ENaC protein expression, which in turn stimulates Na+ transport. In pathological conditions associated with aberrant Na + reabsorption, excessive levels of Na + may further exacerbate the state of hypertrophy, a common manifestation associated with diabetic nephropathy. Mechanical stress evoked TRPV4 m~diated changes in [Ca2+]i. Propagation of this Ca2+ signal via the gap junction protein connexin 43 (Cx-43) was enhanced following glucose treatment, as was Cx-43 expression. Under pathophysiological conditions these changes and the increased expression levels of our key signaling elements, may lead to deranged Na+ handling and inhibition of cell volume recovery mechanisms which together may further enhance the condition of diabetic nephropathy in Type 11 diabetes.

The molecular basis for the use of synthetic growth factors (GFs) in tissue reparation has been poorly investigated. More recently, autologous derived platelet rich growth factor has gained popularity in the field of regenerative/ reparative medicine, mostly because it fits the description of an ideal naturally existing constellation of GFs. However, its efficacy remains controversial. Hence, this study is designed to further elucidate the physiological role of PRP in treating chronic diabetic foot ulcers. Platelet -rich plasma (PRP) and Platelet -poor plasma (PPP) were prepared from blood samples taken from healthy donors and diabetic patients through the use of platelet collecting and concentrating system. The GFs released were measured through immunoassay technique. The effects of the varying concentrations of PRP/PPP in culture media was assessed through tissue culture assay (proliferation, cell migration and angiogenesis assay) on human epithelia keratinocyte, dermal fibroblast and umbilical vein endothelia cell. Furthermore, immuno-histochemistry technique was used to evaluate the differentiation, proliferation, migration and extracellular matrix alterations occurring along wound margins of patients with chronic diabetic ulcers following PRP treatment. A significant difference was observed when the expression of platelet derived growth factor-AA, epidermal growth factor, vascular endothelia growth factor, transforming growth factor and thrombospodin-I released from PRP/PPP were compared between the two groups. There was a significant proliferative, migratory and angiogenic effect of PRP over PPP in the tissue culture assay; however this effect was most prominent with 5% PRP. Overall, hyperproliferative keratin, CD44 and β1-integrin were upregulated in diabetic ulcer keratinocytes as compared with normal foot skin. The clinical study showed that 3 of the 7 diabetic foot ulcer patients treated with PRP achieved complete wound re-epithelisation. We have been able to demonstrate through in vitro studies that PRP has a positive biological effect which mimics normal physiological tissue reparation process.

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Aims: Aspirin is recommended in secondary prevention (SP) in diabetes and macrovascular disease. Recommendation in primary prevention (PP) remains controversial as does the dose of aspirin prescribed. To ascertain whether these controversies are reflected in clinical practice, we conducted a survey of healthcare professionals' views on aspirin prescribing in diabetes. Methods: An anonymous online survey consisting of 26 questions (Likert scale) covering demographic characteristics and aspirin prescribing habits in primary prevention and secondary prevention was circulated via email. Results: 152 people responded with variable response rates: Primary care (96/152, 63%) - mixture of doctors/Diabetes Specialist Nurses; Secondary care were predominantly diabetes specialists (56/152, 37%). Primary prevention (PP): 39/103(37%) did not routinely prescribe aspirin whilst 16/121(13.2%) would consider using aspirin in all diabetes patients as primary prevention. Using Chi-square contingency tables showed that there were differences when prescribing aspirin with regards to hypertension as a risk factor in primary prevention between primary care (20/68[29.4%] opting for aspirin) and secondary care (24/49 [48.98%], p-value-0.03) and doctors and nurses (38/60 vs 16/58, p=0.0009) and also with microalbuminuria - primary care vs secondary care (15/67vs 21/48, p=0.015), and doctors versus nurses (26/60 vs 11/59, p=0.004). Nurses were less likely to prescribe aspirin as primary prevention in smokers (11/57[19.2%] vs 22/60 [36%]; OR-0.41 [0.16-1.03], p=0.042). Secondary prevention (SP): Despite no contraindications 8/125(6.4%) would not give aspirin. 75mg/day or 300mg/day preferred doses in various settings. There were no statistically significant differences between primary and secondary care (62/73 vs 47/52 or 84.9% vs 90.4%, p=0.36) but doctors prescribed aspirin more often compared to nurses (59/67 vs 51/85 or 60% vs 88.1%, p=0.006).In patients with history of peptic ulceration respondents recommended a) use of PPI cover in PP-37/103(35.9%) and SP-60/103(58.3%), b) enteric coated aspirin PP- 13/103(12.6%) and SP-11/103(10.7%), c) not use any anti-platelet agents in PP-53/103(51.5%) and SP-8/103(7.8%). Enteric coated aspirin recommended by respondents as follows: Always-8/109(7.3%), sometimes-16.5%, occasionally-37.6%, and never-35.8%. 89/103(86.5%) had stated their patients had raised issues with them regards aspirin use. 27/103(26.2%) would definitely take aspirin themselves if they had diabetes. The differences were not significant either in a primary prevention setting or a secondary prevention setting when primary care was compared to secondary care but doctors were more likely to prescribe aspirin with PPI cover or in the enteric coated form compared to nurses (48/57[84.2%] vs 23/46 [50%]; OR=0.188 (0.067-0.511), p<0.001). Conclusions: This survey confirmed that the controversy with regards to aspirin use particularly in primary prevention was reflected in a heterogeneous prescribing of aspirin in patients with diabetes. Further clarification and guidance on the optimum dose of aspirin in diabetes is required. b) Summary of Interventional Results Aims: To study the effects of aspirin at different doses on markers of oxidative stress, insulin resistance, dysglycaemia, endothelial function, and vascular inflammation in the primary prevention setting in a population with type 2 diabetes and high risk of cardiovascular disease. Methodology: Following baseline assessment subjects had aspirin (75mg, 300mg, 3.6 gm) or placebo (with minimum 2 week washout) and pre-intervention and post-intervention assessment of markers for metabolic indices (Blood pressure, weight, BMI, Fructosamine, Lipids, Creatinine),oxidative stress (TAOS, FRAP, & Glutathione assays), insulin resistance (HOMA), vascular inflammation (HsCRP, sVCAM-1), and endothelial function (photoplethysmography). Results: (reported in Mean±1SD or Median and Interquartile ranges) (See Table 28, P114) 17 Caucasians, 12 males, 5 females with age range between 40 and 75 years, completed the study. Mean age of the cohort was 57.4±9.1yrs (mean±1SD), with baseline characteristics summarized in Table-6 & Appendix B. Briefly HbA1c was 7.9±1.2%, blood pressure systolic- 130.8±11.5 mmHg & diastolic-73.95±6.97 mmHg, total cholesterol-4.57±1.01 mmol/l, and HDL-C-1.13±0.46 mmol/l. At baseline TAOS concentration was 59.3±9.7 (ascorbate equivalent antioxidant concentration micromolar or AEAC (μM)), total glutathione-302.2±183.3μM, FRAP- 0.86±0.23 (mM Fe II), HOMA-IR-1.41±1.04 Units, HOMA-S–76.27±45.20 %, Fructosamine- 282.9±50.6 μM/l, RI-GTN- 7.17% (3.17-12.83), RI-Salbutamol- 18.5% (13-21.5), Hs-CRP (15 subjects)=0.66 mg/L (0.41 to 2.06 mg/L, Median & IQR), and sVCAM-1 (15 subjects)=487.04 ng/ml (IQR = 450.4 to 572.3). There was a trend towards significance for the TAOS assay with an increase in antioxidant capacity but it did not reach significance. Reduced glutathione (GSH): p=0.12, oxidised glutathione (GSSG): p=0.38, or Glutathione ratio (GSH:GSSG): p=0.367 were not significantly different following any of the interventions. Differences in FRAP were nonsignificant following any of the interventions. Measurements of insulin resistance (HOMA-IR), and insulin sensitivity (HOMA-S) seemed to improve with aspirin 75mgs/day & 300mgs/day but did not reach significance (see figure 18, 19). Neither the different doses of aspirin nor placebo had a significant impact upon glycaemic control (Fructosamine, P=0.39), endothelial function (photoplethysmography, RI-GTN-p=0.36, RI-Salb-p=0.46), Vascular inflammation (Hs-CRPp> 0.05, sVCAM-1>0.05), fasting glucose, BMI, blood pressure, or lipid parameters. Multiple regression analyses showed a good correspondence between the metabolic factors at baseline but were not repeated with different doses as there were no significant differences demonstrated with any of the parameters. Conclusions: Aspirin at the doses studied and over the 2 week duration caused no significant changes in any of the markers studied. Good metabolic control (blood pressure, glycaemia, lipids), and widespread use of statins may be responsible for the lack of effect demonstrated.

"Collection of published works ... prefaced by a commentary on the progression of the studies"--p. 2 / Includes bibliographies / 1 v. (various pagings) : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--University of Adelaide, 1989

Xerostomia (dryness of the mouth) is a prevalent condition amongst elderly and diabetic populations which leads to marked alterations in oral health. The parotid glands play major roles in maintaining salivary secretions to assist in the lubrication and protection of the oral cavity and in digestion. This study investigated the effects of ageing and streptozotocin (STZ)-induced diabetes on the structure and function of the rat parotid gland. Rats (2-6, 12, 16-18 and 22-24 months old) were obtained from a recommended Home Office supplier and diabetic rat models were achieved by employing STZ. The results showed that aged glands were disorganised and infiltrated with connective tissues, lipid droplets and mast cells compared to younger control glands. A significant (P < 0.05) reduction in the mean acinar cell number was also observed in aged glands. Parotid glands taken from STZ-induced diabetic rats showed extensive infiltration of lipid droplets when compared to glands of agematched control rats. Acetylcholine (ACh), noradrenaline (NA) or isoprenaline (ISOP) elicited marked increases in amylase release from parotid acini of 2-6 month old (control) rats. However, this amylase release was significantly (Pc0.05) reduced in parotid acini of 12, 16-18 and 22-24 month old rats. In parotid segments of STZinduced diabetic rats, both ACh and NA (1xl0 5 M for both) evoked a significant (P < 0.05) reduction in amylase secretion when compared to responses obtained from age-matched control rats. Similarly, in parotid acini from STZ-induced diabetic rats, both ACh and NA induced the dose-dependent release of aniylase, but this response was significantly (Pc0.05) reduced compared to the results from age-matched control rats. In Fura-2-loaded parotid acinar cells, significant (Pc0.001) reductions in the peak and plateau phases of ACh-evoked Ca 2 signals (17340/17380) from parotid acinar cells isolated from animals aged 16-18 months were observed, compared to parotid acinar cells of 2-6 month old rats. In parotid acinar cells of STZ-induced diabetic rats a significant (PcO.00l) reduction in only the plateau phases of the Ca 2 signals was observed, in 2.5 mM [Ca2 ]0. However, in 0 mM [Ca2 ]3 the plateau phase remained inhibited, but basal Ca2 signals were also reduced in parotid acinar cells of STZinduced diabetic rats, but not in parotid acinar cells of age-matched control rats. An elevation in the total Ca 2 concentration in whole gland segments from STZ-induced diabetic rats was also observed compared to age-matched control rats. Treatment of glands from 2-6 and 12 month old rats with .t-butyl hydroperoxide (tH202) resulted in marked time-dependent (2 and 4 Lu) increases in cytochrome c fluorescence, compared to untreated glands. In contrast, treatment of glands from 22-24 month old rats for the same time periods showed no apparent increases in cytochrome c compared to the other two age groups. Incubation of acini with either 0.5, 1 or 2 mM H202 resulted in significant (Pc0.05) increases in amylase release compared to basal levels in the absence of H202. In addition, stimulation of acini suspensions with either ACh, NA or ISOP (1x10 7 M-lxlO4 M for all) resulted in the dose-dependent release of amylase above basal level. However, pretreatment of acini with 1 mM H202 followed by the addition of either ACh, NA or ISOP resulted in significant (Pc0.05) decreases in amylase release compared to responses with secretagogues alone. Analysis of acyl lipids showed that the TAGIPL ratio was significantly (PC0.01) higher in glands from aged animals compared to younger animals. Glands from STZinduced diabetic animals showed significant (P < 0.05) alterations in total acyl lipid profiles, 16:1/16:0 and 18:1/18:0 fatty acid ratios, relative proportions ofPL and TAG aèyl lipids and [ 14C] labelled TAG/PL ratios. The results of this study showed that both ageing and STZ-induced diabetes was associated with marked morphological and physiological changes in the rat parotid gland.