Regular physical activity among children with Type 1 Diabetes Mellitus (T1DM) can help optimise long-term health outcomes. This thesis explores the experience of physical activity among children aged 9-11 years with T1DM and their parents, develops a physical activity intervention and evaluates its feasibility. Social cognitive theories have been drawn upon to develop our understanding and inform theoretically-driven behaviour change strategies. First, a systematic review with meta-analysis evaluates existing physical activity interventions for children with T1DM. The findings confirm the health benefits associated with regular physical activity, including improved glycaemic control and lipid profile. Gaps in the existing literature are identified, such as the need for theoretically-driven interventions. Second, the experience of physical activity for children with T1DM from the perspective of i) parents and ii) paediatric diabetes healthcare professionals are explored. Qualitative research findings highlight the challenges faced, as well as the methods used by families to overcome obstacles to physical activity. Healthcare professionals recognise their role in promoting physical activity, but perceive barriers to the successful fulfilment of this role. Third, the feasibility and acceptability of wrist-worn ActiGraph GT3X+ accelerometers in children with T1DM is explored. The findings demonstrate that the accelerometer is feasible, acceptable, sensitive to change and objective data correlates with self-reported physical activity. Fourth, correlates of physical activity are explored alongside children’s values, beliefs and expectations. The findings suggest that self-efficacy and enjoyment have a role in physical activity and children perceive few diabetes-related barriers to participation. Finally, the feasibility and acceptability of the Steps To Active Kids-Diabetes (STAK-D) programme for children with T1DM is explored using mixed-methods. The capacity to detect change over time in selected health outcomes is also explored (e.g., physical activity level, self-efficacy and parental fear of hypoglycaemia) All findings are discussed in terms of their implications for knowledge and understanding, a future definitive trial and clinical practice.

Background: The practice of diabetes self-care plays an important role in glycaemic control. However, not all patients with insulin-treated diabetes engage in their self-care activities. Although there is evidence that self-care practices in patients with insulin-treated diabetes can be understood and predicted by health beliefs proposed by Health Belief Model (HBM), little is known about adult patients due to several methodological weaknesses of previous studies. Furthermore, knowledge is lacking about adults with insulin-treated diabetes in Malaysia. Aim: To examine whether health beliefs suggested by the HBM can predict self-care practices in patients with insulin-treated diabetes in Malaysia. Methods: A longitudinal design was chosen to conduct this study for a six month period at three endocrinology clinics in Malaysia. Data for self-care practices (diet, insulin intake, exercise and SMBG) and health beliefs were measured using a self-reported questionnaire. In addition, participants’ glycaemic control was also examined as the objective measure for the self-care practices. These data were measured based on the participants’s glycated hemoglobin (HbA1c) results. All data were collected twice: at baseline (Time 1) and at six months follow up (Time 2). Differences in all study variables between Time 1 and Time 2 were tested using paired t-test and McNemar’s. Multiple linear regression and multiple logistic regression were used to predict the dependent variables at different points of time. Age, gender, race and diabetes-related knowledge were statistically controlled in the regression analyses. In addition, a qualitative evaluation was carried out to explore the context of the self-care practices by interviewing diabetes educators in the study setting about their diabetes education practice. Results: A total of 159 patients with insulin-treated diabetes (aged 18-40 years) participated in this study. Of these, only 108 (67.9%) completed the study. The participants were more likely to adhere to their insulin injection than to engage in good dietary habits, regular exercise and testing SMBG ≥ 3 times per day. The mean value of HbA1c was 9.8% (SD 2.61). The self-care practices and HbA1c as well as the participants’ health beliefs remained consistent at six (6) months follow up (p >.05). The HBM significantly predicted dietary self-care, insulin intake practice and HbA1c. Of the HBM costructs, perceived benefits significantly predictive of good dietary habits at Time 1 (OR 1.92) and Time 2 (OR .23) and adherence to insulin injection at Time 1 (OR 3.17) and Time 1-2 (OR 2.68). Meanwhile, except perceived severity, all other HBM contructs were predictive of HbA1c [perceived susceptibility (β .169), perceived barriers (β -.206), perceived benefits (β -.397) and cues to action (β -.233)]. The findings of the qualitative data indicate that some participants might not have been provided with diabetes education while those who did might have received inconsistent and inaccurate information regarding their self-care activities. These data were provided by 27 diabetes educators in the study settings. Conclusion: Self-care practices and glycaemic control in this study were related to health beliefs and also could be a result of limitations in the diabetes education that they had received. These findings should be given attention by diabetes educators in their efforts to improve diabetes self-care in patients with insulin-treated diabetes aged 18-40 years in Malaysia. More studies on health beliefs in diabetes self-care are needed for Malaysian patients.

Approximately 3 million people throughout the UK suffer with Type 2 diabetes mellitus (T2DM), and are 32% more likely to die early. There remains a lack of evidence for the long-term effectiveness and safety of anti-diabetic drugs in preventing diabetes-related complications, making it unclear how to optimally manage diabetes. Work to date includes observational studies subject to bias, and randomised controlled trials (RCTs), which may not reflect the ‘real world’ situation. The aim of this thesis is to combine such findings via systematic reviews, meta-analyses and retrospective cohort studies to provide more water-tight evidence of the effectiveness and safety of glucose-lowering therapies (GLT) in the long term. Firstly, a systematic review of observational studies was performed, identifying and providing a simple description of the types of biases and control measures employed in retrospective cohort studies on treatment outcomes of GLTs. Secondly, retrospective cohort studies were conducted to strengthen the evidence of the clinical effectiveness of DPP-4 inhibitors, compare their durability when combined with other anti-diabetic drugs and assess their cardiovascular safety when used in patients with T2DM, using data from The Health Improvement Network (THIN) database. Linear and logistic regression, Cox proportional hazard regression models and propensity score techniques were used to analyse routine clinical data. Thirdly, a meta-analysis was conducted on RCTs investigating the risk of bone fracture following the administration of DPP-4 inhibitor, based on data from an extensive literature search. Conducting this research has led to a better understanding of how biases may have influenced retrospective cohort studies on oral anti-diabetic drugs. An algorithm was developed to illustrate strategies for addressing biases. Potential clinical factors associated with ‘response’ to DPP-4 inhibitor treatment were found to include the addition of DPP-4 inhibitor to ongoing metformin (MET), or MET plus sulphonylurea (SU) therapy. High HbA1c at the time of treatment intensification and longer duration of diabetes were associated with the lack of HbA1c target attainment. In terms of the durability of second-line glucose-lowering agents, the co-administration of thiazolidinedione with MET was associated with the most durable glycaemic response, followed by a SU and then a DPP-4 inhibitor. Compared with a SU, adding a DPP-4 inhibitor to MET was associated with an increased need for earlier treatment intensification with a third agent. The use of statins, being a female, a smoker, having longer duration of diabetes and higher HbA1c at baseline were identified to be associated with earlier dual therapy failure. In terms of cardiovascular safety, routine clinical data showed patients who intensified MET + SU dual therapy with a DPP-4 inhibitor were associated with a decreased risk of a composite of non-fatal cardiovascular outcomes and all-cause mortality compared to those who added insulin. Furthermore, the results from meta-analysis showed DPP-4 inhibitors are not associated with increased bone fracture risks in patients with T2DM. This research is valuable in informing the choices of healthcare professionals in prescribing treatments for T2DM. For the users of this treatment, it is good news that DPP-4 inhibitors are not generally associated with fracture incidence, and that findings support the use of DPP-4 inhibitors as a second line therapeutic option, especially among non-obese patients whose glucose control remains suboptimal following MET treatment. It is recommended that treatment should be characterised on an individual basis. There remains a need for robust RCTs to investigate the influence of obesity and longer treatment durations on the efficacy of co-administering DPP-4 inhibitors to patients who are unresponsive to other oral GLTs.

Philosophiae Doctor - PhD / Endocrine disrupting chemicals (EDCs) are compounds found in the environment that have the potential to disrupt normal endocrine function. Estrogenic EDCs (e-EDCs) is a subclass of EDCs and is defined as substances contaminating the environment that may mimic or inhibit the effect of endogenous estrogen and therefore may influence developmental and reproductive health in humans and animals. The aim of this study was to develop, validate and implement a battery of in vitro and in vivo screening assays for e-EDCs. The study was concluded by implementing this battery of assays to assess the Eerste River, South Africa at three sampling sites, namely Jonkershoek, Stellenbosch sewage treatment works (STW) effluent and Spier for e-EDCs. The control site, Jonkershoek contained very low levels of estrone. Water from this site showed no estrogenic activity when the E-screen and the ER_ induction in MCF-7 cells. Some of the water samples collected at this site tested positive for estrogenicity when analysed with the juvenile tilapia VTG assay, whereas the rest were negative. The estrone levels in the sewage effluent extracts as well as Spier were significantly higher. The assay using ER_ protein induction by the MCF-7 cell line, the MCF-7 proliferation assay and the tilapia in vivo screen for estrogenicity showed that these samples are estrogenic. Results obtained for estrogenicity at the three different sampling sites for each of the assays in the battery were comparable. In this study we developed, validated and also implemented a battery of assays encompassing both in vitro and in vivo assays, based on different biological mechanisms, to detect estrogenic EDCs. To our knowledge, this is the first study that has used a battery of bioassays to specifically assess a South Africa river for estrogenicity. / South Africa

Centralised multidisciplinary management of breast cancer occurs in KwaZulu-Natal, South Africa and requires a diagnostic and staging pathway at the referring hospital. Delays in this pathway are unknown. This study, conducted at a referring hospital, R K Khan (RKK), quantifies and analyses these delays. A retrospective folder review included all patients with breast cancer diagnosed at RKK from January 2008 to January 2009. Data extraction included demographic data, time to diagnosis and initial staging using a standardised datasheet. Specific care steps were identified, namely delays to initial imaging with mammography, pathology confirmation, staging workup and eventual referral to a centralised breast clinic.

No description available.

published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

Young, middle-aged and old rat adrenal gland steroidogenesis was measured in isolated, superfused glands and in their subcellular fractions before and after adrenocorticotropic hormone treatment. In the latter experiment, five corticosteroids were extracted from six different subcellular fractions. Superfused glands initially produced relatively high glucocorticoid levels; thereafter, production decayed asymptotically. Steroidogenesis by young and middle-aged glands was maintained at least 1.5 to 2.5 hours before it decayed; old glands were 50% less active than younger ones and production decayed within one hour. High cholesterol and progesterone levels in certain old gland fractions were associated with correspondingly reduced 11-deoxycorticosterone and corticosterone. It is suggested that synthesis of these glucocorticoids from their accumulating precursors weakens with age.

Because of the structural resemblance to the female hormone, phytoestrogen is another important class of endocrine disruptor. In the present project, we evaluated the effects of phytoestrogens isoliquiritigenin (ILN), hesperetin (HES), genistein, (GEN) and naringenin (NAR) on estrogen metabolism and also their effects on MCF-7 tumor growth in ovariectomized nude mice. We found that these phytoestrogens had differential effect on MCF-7 xenografts. NAR and GEN had totally different responses in the tumor growth. In contrast, ILN and HES only deterred MCF-7 xenograft growth when CYP19 was overexpressed in the graft. / Breast cancer is one of the most prevalent female cancers in Hong Kong and western countries. Prolonged exposure to estrogen has been associated with increased risk of breast cancer. Many enzymes are responsible for estrogen metabolism, for instance, aromatase (CYP19) is responsible for biosynthesis; CYP1 family enzymes hydroxylate estrogen; COMT (catechol-O-methyltransferase) inactivates the hydroxyestrogen; and UDP-glucuronosyltransferase 1A1 (UGT1A1) eliminates the estrogen metabolites. In this project, we employed cell and animal models to address estrogen metabolism-related questions under the influence of endocrine disruptors. / TCDD is a prototype compound of a whole class of halogenated aromatic hydrocarbons termed dioxin-like contaminants, which are also known to be endocrine disruptors. Because of their persistence in the environment dioxins are one of the most concerned classes of carcinogens. Humans can be exposed to this pollutant through contaminated food, air, drinking water, etc. We found that pre-ovariectomy administration of TCDD could significantly reduce aromatase expression in the brain but increase the expression in the adipose tissue. Our results suggested that the timing of exposure to the toxicant could determine the estrogenicity of TCDD. / The present project indicated that endocrine disruptors can alter the metabolism of estrogen; however, the significance of this alteration may be specific to tissues' phenotype and the timing of exposure. / Ye Lan. / Source: Dissertation Abstracts International, Volume: 73-01, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 169-192). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Sexual maturation and sex differentiation comprise facets of a common theme: reproduction. The endocrine system regulates many of the critical physiological processes necessary for reproduction and offers a framework within which technologies can be developed for controlling sexual maturation and sex differentiation. The studies described in this thesis were undertaken to improve the understanding of the endocrine control of these critical stages of development in salmonids. Final ovarian maturation in salmon is accompanied by dynamic changes in plasma hormone levels. Ovulation can be accelerated through the use of hormones such as gonadotropin releasing hormone or its analogs (GnRHa). The effectiveness of GnRHa often depends on the timing of treatment. To determine if plasma concentrations of steroids can be used to predict the sensitivity of adult female coho salmon (Oncorhynchus kisutch) to GnRHa, circulating levels of testosterone, 17α,20β-dihydroxyprogesterone (DHP), and estradiol were measured before and after injection with GnRHa to accelerate ovulation. We found that high levels of testosterone were predictive of early response of coho salmon to GnRHa treatment. The correlation between testosterone and ovulatory response to GnRHa suggested a possible functional relation. However. implantation or injection of testosterone. 17α-methyltestosterone (MT), or the antiandrogen, cyproterone acetate (CA), before or with GnRHa treatment did not affect the ovulatory response of coho or chinook salmon ( 0. tshawytscha) to GnRHa. Chinook salmon treated with MT alone had accelerated ovulation in comparison to controls. If steroids are involved in sex differentiation. steroids must be produced early in development. In vitro production of steroids in both coho salmon and rainbow trout (0. mykiss) was assessed from hatch through sex differentiation. Cortisol, androstenedione, testosterone, and estradiol were produced just after hatching by tissue explants that contained anterior kidneys and gonads of coho salmon. To circumvent the problem of not knowing the sex of individuals until after sex differentiation, single-sex populations of rainbow trout were produced by gynogenesis or androgenesis. Tissue explants produced more androstenedione than testosterone or estradiol. More androgens were produced by testes and more estradiol was produced by ovaries within 6 to 10 weeks of hatching. Dietary treatment with estradiol or MT inhibited gonadal steroid secretion. Electrophoresis of gonadal homogenates from salmonids revealed several sex-specific bands. In particular, a prominent band of about 50,000 daltons was apparent in ovaries but not testes. Production of sex-specific proteins may be affected by dietary steroid treatment. / Graduation date: 1991