Includes bibliographical references and index.

Melatonin, “the hormone of darkness” is well known to regulate sleep and circadian rhythm. However, melatonin is also present in numerous peripheral tissues and the number of actions assigned to this neurohormone is growing steadily. Based on animal studies, it has been proposed that gastrointestinal melatonin is produced in enterochromaffin cells. The aims were to characterise the expression of melatonin and its receptors MT1 and MT2 in normal human gastrointestinal tract and pancreas as well as in tumours derived from enterochromaffin cells, small intestinal neuroendocrine tumours (SI-NET), using immunohistochemistry. Melatonin and receptor expression was furthermore compared to clinical symptoms, tumour prognostic factors and treatment response. In enterochromaffin cells from normal gastrointestinal tissue and in SI-NETs a strong immunoreactivity (IR) for melatonin and MT2 was found, while MT1 IR was low or absent. Melatonin, MT1 and MT2 IR was also seen in the large intestinal epithelium of normal gastrointestinal tract and in pancreatic islets, although the expression of MT1 in pancreatic tissue varied. Analyses of mRNA data confirmed the expression of the enzymes needed for melatonin synthesis as well as MT1 and MT2 in small intestine and pancreas. The intensity of melatonin IR in SI-NETs correlated to lower proliferation index and less symptoms of diarrhoea, which is well in line with the proposed actions of melatonin described in nimal studies. The intensity of MT2 IR was generally lower in metastases than in primary tumours. Plasma levels of melatonin in patients with SI-NETs and disease stabilisation/remission were reduced after treatment and higher levels were associated with nausea. In conclusion, melatonin and its receptors are present in the normal human gastrointestinal tract, pancreas and in SI-NETs. Melatonin IR intensity in tumours correlated significantly to less diarrhoea and to lower proliferation index. Plasma levels of melatonin in patients with SI-NETs were reduced with treatment response, indicating a possible tumour-derived origin of circulating melatonin levels. These results are in agreement with the suggested actions of melatonin on gastrointestinal motility and tumour growth.

This study investigated fourth year medical students’ perceptions of their learning in the clinical skills programme (CSP) in the new undergraduate medical curriculum, viz. the Graduate Entry Medical Programme (GEMP) at the University of the Witwatersrand (Wits). Fourth year medical students, officially referred to as the GEMP II students, in this programme attend clinical training activities once a week in the Health Practice Day (HPD). Following on a 2006 evaluation of the HPD changes were made resulting in a weekly programme with three activities, the Shadowing Session (SS) which involves shadowing of an assigned doctor in the hospital, the Formal Session (FS) of patient clerking and the Clinical Skills Session (CSS) which offers practice in a simulated clinical skills unit (CSU). The broad aim of the study was to evaluate the quality of the HPD as reported by students. The main questions investigated in this study were student perceptions of their experiences of learning in the new CSP in the HPD, and whether these changes had an effect, and student performance in the study period for the 2006 and 2009 cohorts. In the case of the SS the study assessed the level of student participation in their assigned units’ activities, student perception of the role of their doctor and the range of clinical problems experienced in this session. The FS programme delivery was investigated for its provision of adequate opportunities for patient clerking and level of student engagement in learning following curricular reform in 2006. Finally, the CSS was investigated in its provision of adequate resources and facilities, and medical supervision to guide hand-on clinical practice. The study also compared the GEMP II student performance in an Objective Structured Clinical Examination (OSCE) for the study period (2006 and 2009). The design of this study was a student survey of two cohorts of GEMP II students’ registered in the Faculty of Health Sciences at Wits in the 2006 and the 2009 academic years respectively. The data collected in this study was mainly descriptive but also analytical. Stratified proportionate sampling by hospital was used to select two samples, i.e., 42 and 75 students for the 2006 and 2009 student cohorts respectively. The study instrument for the 2009 cohort was a self-administered student questionnaire comprising 22 items of mainly quantitative data. The instrument used to collect data pertaining to the FS for the 2006 student survey was also a student questionnaire; data pertaining to items of this questionnaire related to the questions under the stated objectives for the FS thus enabled comparison between for the 2006 and the 2009 cohorts. A total of 68 questionnaires were returned by the 2009 sample and 32 for the 2006 cohort corresponding with a 90.2% and a 69.6% response rate respectively. Participation in this study was strictly voluntary and anonymous. The OSCE performance for all students attending the GEMP II OSCE I for the 2006 and 2006 years were compared by using their final averages for this examination, accessed from the official published lists for this examination. The quantitative data was manually entered into a database created in the Epi Info ™ 7 programme, frequencies were computed and the data exported to the programme. Data were analysed mainly with Microsoft Excel 2007 and a small number with STATA 12.0 yielding graphic representations for ease of analysis. Data from the 2006 and 2009 studies were compared statistically. Qualitative data were thematically analysed. Validation of the data obtained from students was attempted in two ways: Firstly, the data from the GEMP II OSCEs for June 2006 and 2009 which tested skills learnt in two blocks corresponding with the study period were compared. This would enable changes perceived by students to be partly corroborated. Secondly, the findings of the student end-of-block evaluations for the Endocrine and Musculoskeletal blocks for 2006 and 2009 were considered for inclusion as this evaluation is administered as a student survey of the entire class and participation is anonymous and voluntary. However, the data for the end-of-block evaluations for the 2006 cohort were not available. Data for the corresponding period for the evaluation of the end-of-block evaluation of GEMP II students in the 2009 academic year were used to corroborate the student perceptions data from this study. The results relating to the SS confirmed students’ attendance in a spectrum of the rostered activities for their assigned units but inadequate in students experience for learning about team members. The majority of students, however, perceived their role to be of a passive nature, indicating their expectation of active participation in the shadowing of doctors; this potential for encouraging students’ active engagement with the opportunities in this session for enhancing their learning in this clinical context. The findings of the FS demonstrated improved student access for practice opportunities compared to their 2006 peers but still inadequate in its delivery; specifically the inadequate provision of suitable patients for clerking and reduced tutor availability for presentation of cases and discussion. Students’ perceptions of the ‘doctors’ role’ and the organization of these clinical activities had not changed significantly between 2006 and 2009. Despite these problems students’ self-ratings of their clinical skills were increased in comparison to previous findings. The findings of the CSS indicated adequate provision of equipment and facilities but insufficient time and with reduced opportunities for all students to obtain hands-on clinical practice, and reduced medical supervision, consequent on inadequate numbers of clinical tutors with large student tutor ratios. The OSCE performance for the 2009 cohort whilst of a very high standard was significantly reduced in comparison with their peers of 2006. The main reason for this seemingly anomalous observation is judged to be the inclusion in 2009 of a ‘global rating’ to complement scoring with standardised checklists for the hands-on stations, and in the variations in weighting for these two methods for the assigned skills stations. OSCE scores were therefore not a useful parameter for assessing the validity of comparative data about the FS in the 2006 and 2009 cohorts. The findings of this study whilst limited by its generalisability for other settings can be applied to GEMP I students in this programme and to the CSP in the undergraduate medical curricula at other universities using the structure of the activities in the HPD at Wits. Following on the study findings recommendations are made to improve students’ clerking opportunities by exploring innovative ways of increasing access to suitable patients; to enhance the performance of tutors by the introduction of formal courses for tutor training and orientation of especially new tutors and the selection of sufficient numbers of appropriate patients for students’ clinical practice, to institute dedicated tutor time for teaching, to increase the numbers of clinically skilled tutors and to explore the potential for peer tutoring to increase time for students to obtain hands-on clinical practice and improved medical supervision. Students need to be motivated to take an active role in their learning and to seek opportunities in interacting with patients in any free time left over in the hospital visit. Future studies of this programme would benefit from an all inclusive methodology including other sources of information available from the evaluations of the GEMP programme and other participant groups with a variety of instruments for data collection. Follow-up OSCE evaluations are regularly required for assessing the multiple interventions in this programme and in this format of examination. At Wits, the findings of this study will enable planning of further intervention and evaluation in the CSP.

Pulmonary rehabilitation (PR) is an effective strategy to manage chronic obstructive pulmonary disease (COPD). Self-management is an evolving and under-researched area within PR. The aim of this thesis was to explore the impact of self-management on health outcomes in patients with COPD.

With the incidence of many cancers, including brain tumours, increasing worldwide, the diagnostic pathway and new innovative treatments have often failed to keep pace. The main stay of cancer diagnosis remains at the Histopathologists' microscope, with little change in light microscopy within recent times. Research promises many new diagnostic tools, aiming to improve turn around times and provide instant accurate answers. One such tool is vibrational spectroscopy. This thesis aims to use spectroscopy as a proof of concept within brain tumour diagnostics to demonstrate its abilities within the cancer diagnostic pathway. Proof of concept studies aimed at targeting both biofluid and tissue diagnosis of primary and metastatic brain tumours has been performed, along with involvement of Patients' and Clinicians' to aid development of diagnostic tools. Spectrochemical methods including Raman and attenuated total reflectance- Fourier transform infrared spectroscopy (ATR-FTIR) have shown an ability to diagnose primary and metastatic tumours; with fresh frozen tissue ATR-FTIR proved superior with a classification accuracy of non-tumour brain versus primary brain tumours of 97.2%, though this decreased when comparing tumour types (79% accuracy); when differentiating metastatic brain tumours from formalin fixed tissue accuracy was similar for both spectroscopic techniques at 60% for colorectal adenocarcinomas, 68% for lung adenocarcinomas and 70% for melanoma; finally, with biofluids, using ATR-FTIR to determine a primary versus metastatic tumour and the type of each tumour, accuracy was low at non tumour 85%, high grade glioma 92%, low grade glioma 61%, meningioma 43%, melanoma metastasis 21%, colorectal adenocarcinoma metastasis 50% and lung adenocarcinoma metastasis 24%. The final, novel study, trialled a handheld Raman spectrometer within the histopathology department at Royal Preston Hospital, Lancashire Teaching Hospitals NHS Trust, to determine if the benefits of spectroscopy lay within the intraoperative diagnosis. The final results demonstrate accuracies from 64-94% depending on tumour type, demonstrating that with further training, Raman spectroscopy may provide a clinically useful diagnostic tool within the operating theatre, to replace the need for intraoperative smear preparations and diagnosis by a Neuropathologist. Overall, this thesis highlights the need to involve Patients' and Clinicians' within research to ensure uptake and accurately targeted diagnostic tools. It also demonstrates the potential of spectroscopy, when well targeted within the diagnostic pathway. Moving forward, further work to move Raman spectroscopy into the operating theatre, is likely to prove beneficial to patients.

Glucocorticoid excess promotes visceral obesity, which is closely associated with morbidity and cardiometabolic disease. Similar features are found in the Metabolic Syndrome in the absence of elevated plasma cortisol. Whilst elevated activity of the intracellular glucocorticoid amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) within adipocytes might explain this paradox, the potential role of preadipocyte 11β-HSD1 is less clear. Data from murine cell lines suggested 11β-HSD1 was expressed at late stages of preadipocyte differentiation, where it exhibited keto-reductase activity, converting inactive into active glucocorticoids. In contrast, data from human preadipocytes suggested expression of 11β-HSD1 inactivated glucocorticoids (dehydrogenase action) in a depot-specific manner. In this study 11β-HSD1 mRNA levels and activity in homogenates were measured in preadipocyte-enriched stromal/vascular fraction (SVF), from metabolically “disadvantageous” visceral (mesenteric) and “safer” peripheral (subcutaneous) adipose tissue in mice. The results suggest that levels of 11β- HSD1 mRNA and enzyme are similar, within a given adipose tissue depot, in freshly isolated SVF and adipocytes. Crucially, 11β-HSD1 exclusively functioned as a keto-reductase in intact SVF, whatever the adipose depot of origin. Consistent with this, hexose-6-phosphate dehydrogenase (H6PDH), which drives 11β-HSD1 keto-reduction, is expressed in SVF. Unexpectedly, glucocorticoid reactivation was higher in freshly isolated intact mesenteric SVF cells than those from subcutaneous adipose, despite lower levels of 11β- HSD1 mRNA and enzyme in mesenteric SVF, suggesting a novel posttranscriptional control over enzyme activity. Mice with a targeted deletion of 11β-HSD1 (11β-HSD1-/-) showed no difference in expression of pref-1 (a preadipocyte marker) in adipose tissue, compared to control C57BL/6J mice, suggesting that 11β-HSD1 has no influence on preadipocyte proliferation. Upon high fat feeding, higher preadipocyte differentiation, as inferred from pref-1 mRNA levels, was higher within mesenteric than subcutaneous fat in 11β-HSD1+/+ mice. This differed from 11β-HSD1-/- mice where preadipocyte differentiation was greater in subcutaneous than mesenteric fat. These observations corroborate the literature in which mesenteric fat accumulation is more pronounced in 11β- HSD1+/+ mice than in 11β-HSD1-/-. Further, following HF diet, 11β-HSD1 and GR mRNA expression in SVF were decreased more markedly in mesenteric than in subcutaneous fat in 11β-HSD1+/+. This suggests an adaptive mechanism to counteract detrimental effects of high GC levels occurring at both pre-receptor and receptor level, mainly in the mesenteric adipose. Preliminary data from human preadipocytes suggested lower levels of 11β-HSD1 activity in preadipocytes compared to mice. Importantly, cortisone was being metabolised into an as yet unknown compound. Taken together, these results allow a greater understanding of specific regulation of 11β-HSD1 between preadipocytes from different depots. As well, the results in this thesis suggest that in vivo, in addition to effects on adipocyte hypertrophy, 11β-HSD1 expression in preadipocytes influences preadipocyte differentiation and this may be important in determining regional fat distribution.

Background. Influenza and pneumococcal vaccinations are important therapies supported by national and international guidelines for preventing morbidity and mortality from respiratory illnesses in high-risk groups. The responsibility for delivering these vaccinations in the United Kingdom lies with primary care. Little is known about how rates of influenza and pneumococcal vaccination can be increased in high-risk groups in primary care. Aim. To research methods of improving rates of influenza and pneumococcal vaccination in high-risk groups in primary care. Objectives. To investigate the impact of educational interventions for primary care teams on influenza and pneumococcal vaccination rates in high-risk groups. Method. The research had the following components: a. Literature search examining current practice and policy in relation to influenza and pneumococcal vaccination and studies undertaken to improve performance, both in general and specifically in relation to improving adult vaccination rates. b. Pilot study of targeting influenza and pneumococcal vaccination to high-risk groups in a single general practice. c. Effect of audit and feedback with an information pack to primary care teams on influenza and pneumococcal vaccination in primary care: before-and-after multipractice study. d. Effect of audit and feedback with an information pack to primary care teams, as part of a clinical governance programme, on influenza and pneumococcal vaccination in a primary care trust: before-and-after multipractice study. e. Randomised controlled study of an educational outreach intervention partly nested within primary care trust study with audit, feedback and information (passive dissemination of guidelines and recommendations) directed at primary health care teams compared with audit feedback and information alone using multifaceted interventions to increase influenza and pneumococcal vaccine uptake in high-risk groups in primary care. Results. The studies demonstrated significant improvements in influenza and pneumococcal vaccination rate in high-risk groups in primary care, showed the levels of improvement that could be expected from these types of intervention and described how primary care teams responded to direct and indirect educational interventions supported by measurement of performance. Conclusions. Education to multiprofessional teams is an important method for diffusion of innovations in the highly professionalised organisations of primary care and general practice. Educators need to understand the complex nature of primary care organisations and teams, when and how education for teams is likely to be successful, the barriers to implementation of new ideas and how to address these. Education when applied appropriately can have important effects in improving health care. This is more likely to occur when careful assessments are made around the nature of the evidence, clear outcomes are sought and measured and the healthcare intervention is understood from the perspective of the patient, the healthcare team and other stakeholders.

Thesis (MSoSc(AppliedSocialResearch))--University of South Australia, 2002.

Thesis (Ph. D.)--University of Texas at Austin, 1998. / Vita. Includes bibliographical references (leaves 231-248). Available also in a digital version from Dissertation Abstracts.

Includes bibliographical references and index.