Thesis (M. Environmental Management)--North-West University, Potchefstroom Campus, 2009.

Patient-related barriers may reduce the effectiveness of screening for depression. This study aimed to explore perceived barriers to participation in a Screening Program for Depression by hemodialysis patients. In a cross-sectional study of hemodialysis patients, the Perceived Barriers to Psychological Treatment questionnaire was used to measure barriers to the Screening Program. Of 160 participants, 73.1% perceived at least one barrier (95% CI, 66.2% to 80.0%). The most common barriers were concerns about the side effects of antidepressant medications (40%), concerns about having more medications (32%), feeling that the problem is not severe enough (23%), and perceiving no risk of depression (23%). A high depression score was an independent predictor of barriers related to perceiving no benefit of the Screening Program and psychological, social, and practical barriers. We believe that patient-related barriers need to be addressed before implementing any case identification and treatment program for depression.

As a barrier to metastases, cells normally undergo apoptosis after they lose contact with their extra cellular matrix or their neighbouring cells. This cell death process has been termed “anoikis”. Tumour cells that acquire malignant potential have developed mechanisms to resist anoikis and thereby survive after detachment from their primary site and while travelling through the lymphatic and circulatory systems. The understanding of the molecular regulators of anoikis resistance will allow for a better understanding of the metastatic process and the development of novel anti-metastatic therapeutics. To better determine the molecular underpinnings of anoikis resistance, we have used both chemical biology and genetic approaches. Using chemical biological approaches such as small molecule screens, we determined that both FLIP and Na+/K+ ATPase could modulate a cell’s response to anoikis. Through the use of a shRNA genome wide lentiviral screen we determined that ABHD4 was able to inhibit a cell’s response to anoikis. We also showed the importance of anoikis resistance in the ability of malignant cancer cells to survive in circulation. By decreasing a cell’s ability to resist anoikis, one is able to decrease the ability of a cancer cell to survive in circulation and form tumours in distant organs. Taken together, we have identified novel regulators of anoikis resistance and demonstrated the importance of anoikis in metastatic progression, which may lead to the development of novel treatments for metastatic cancers.

The implementation of school-wide behavior supports is considered typical educational practice. A main component of school-wide behavior support is the systematic screening for behavioral and emotional problems. Students' ability to utilize executive functions greatly affects both academic and social success and it is associated with behavior and emotional problems (Lehto, Juujarvi, Kooistra, & Pulkkinen, 2003). This study uses a sample of fourth grade students to analyze the relationship between executive function skills and a screening measure of behavior. This study will examine if deficits in executive function may account for variance in the first level of behavior support screening systems. This may help educators understand the relationship between behavior screening results and executive functions, and possibly explain how social and emotional difficulties may be affected by deficits in executive functions. / School of Education / School Psychology / PhD / Dissertation

Cancer is a common disease and due to problems with resistance against cancer drugs and the limited benefit from chemotherapy in many diagnoses, there is a need to develop new cancer drugs. In this thesis new methods to screen for cancer drugs and to evaluate their mechanism of action are discussed. In Paper I, it was found that by studying the gene expression of a cell line panel and combining the data with sensitivity data of a number of cytotoxic drugs, it was possible to cluster compounds according to mechanism of action as well as identifying genes associated with chemosensitivity. In Paper II, studies of compounds with selective activity in drug-resistant cell lines revealed the glucocorticoids as a group of interesting compounds. The glucocorticoid receptor was overexpressed in 8226/Dox40 and the difference in sensitivity was abolished when the cells were treated with a glucocorticoid receptor antagonist. In Paper III, an image-based screening method for new proteasome inhibitors was successfully developed and the compounds disulfiram, PDTC and NSC 95397 were identified as inhibitors of the proteasome. In Paper IV, disulfiram and PDTC were shown to induce cytotoxic activity, to inhibit the activation of the transcription factor NFkappaB and to inhibit the degradation of proteins normally degraded by the proteasome. In Paper V, NSC 95397 was shown to be cytotoxic to all cells in the resistance-based cell line panel as well as to patient samples from a variety of cancer diagnoses. Connectivity Map was successfully used as a tool to propose a new mechanism of action of NSC 95397. The gene expression induced by NSC 95397-treatment was similar to that induced by several proteasome inhibitors not present in the Connectivity Map.

Cancer is a disease with poor response rates on available treatments. Problems with resistance and intolerance against cancer drugs are major reasons for failure of the drugs. The need to discover new cancer drugs is important. In this thesis screening of new cancer drugs and evaluation of their mechanism of action are discussed. The aim of the thesis was to find new compounds active against neuroendocrine tumors (NETs). In paper I, we screened 1280 substances on two bronchial carcinoid cell lines and one pancreatic carcinoid cell line. Eleven of these compounds were found to have antitumor activity at low concentrations. The most active agents were brefeldin A, emetine, bortezomib and idarubicin, having IC50 values (the concentration of the drug where > 50% of the cells die) < 1μM. In addition, sanguinarine, Bay11-7085, mitoxantrone, doxorubicin, β-lapachone, NSC 95397 and CGP- 74514A were active with IC50 values < 10 μM.  In paper II, additional studies have been undertaken to investigate the combination effect of the most active drugs with conventional cytotoxic drugs used in clinical practice. If synergistic or additive effects are found, drugs with different mechanism of action and toxicity profiles may be combined, making it possible to reduce the toxic effects yet maintaining the antitumor activity. In paper III, studies were undertaken to find the mechanistic action, apoptosis or necrosis, of the drugs NSC 95397, brefeldin A, bortezomib and sanguinarine in NETs. All four drugs were shown to induce caspase-3 activity and nuclear fragmentation/condensation in the neuroendocrine tumor cell lines, indicating that their antitumor activity was induction of apoptosis. In paper IV, the mechanism of action was studied for CGP-74514A and emetine. Both drugs worked by induction of apoptosis. In addition, their cytotoxic activity was studied in a three-dimensional model, the in vitro hollow fiber model. The Hollow Fiber model permits more realistic simulation of in vivo drug effects in a controlled system providing data that more accurately reflects biological responses. Our results showed that the hollow fiber model may be suitable for studies of new drugs in the neuroendocrine tumor cell lines. / Title corrected from: Analyses of Dos-Response and Mechanistic Action of Different Anti-Cancer Drugs for Neuroendocrine Tumor Cell Lines

Informed consent, based on patient autonomy, is seen as necessary if medical interventions are to be seen as legally and ethically acceptable. While 'informed consent' protocols within antenatal care, including prenatal screening regimes are presumed to be robust, emerging research outside of Australia suggests most women do not adequately understand the medical purpose, limitations or potential ethical implications, such as selective termination, of the medical procedures 'consented' to. While the consent given in these situations may well fulfil the minimal legal criteria for informed consent, the required level of knowledge and understanding necessary to meet the ethical standards informed or understood consent often appears not be met. The presumption that legally informed consent equates to morally informed consent inherent within institutional protocols for screening must therefore be questioned, and the ethical integrity of these increasingly routine interventions demand further scrutiny. The purpose of this research was to explore whether the problems identified in research overseas might also exist locally. Underpinned by a phenomenological philosophical approach to understanding the ethical dimensions of clinical practice, the research sought to engage with a small cohort of mothers and practitioners locally. The study adopted a qualitative narrative methodology, analysing individual in-depth interviews using the Listening Guide (Gilligan et al, 2003). The experiences of mothers and health practitioners interviewed exposed a range of institutional, social, personal and philosophical constraints that mirrored the overseas research findings and also illuminated how informed consent may be unintentionally undermined in the clinical setting. A positive outcome of the study was that it provided a locally informed and contextually sensitive basis from which to strengthen existing organisational informed consent protocols and thus support women's ethical decision making. As the process of becoming 'informed' to consent is largely educational, promoting patient learning in the clinical context is an ethical imperative. However, there seems limited awareness at either the clinical or theoretical level of the critical link between patient education and ethically robust medical intervention. Hence a significant contribution of this research was to explore this underdeveloped but practically important link. As the process of gaining informed consent has far reaching applications across a broad spectrum of medical interventions, the contextual and educational insights offered throughout this research may have significant relevance beyond the immediate context of this research.

Screening is generally considered a useful strategy in the prevention of chronic diseases. The notion is that early detection through the use of certain screening tests can facilitate effective preventive measures to be undertaken which can then lead to improved prognosis from or ultimate avoidance of serious clinical diseases. The enthusiasm for screening in the United States is high and can be seen by the size of public demand for it. Rapid technological advances and knowledge expansion in the past decade have further facilitated the introduction of new tests and screening opportunities. In the mean time, the concept of screening has undergone subtle changes. Previous emphasis on clear and demonstrable population health benefits has been slowly replaced by an emphasis on individual responsibility for the surveillance of personal health risks. Disease screening is frequently advocated as part of a health promotion programme. As a clinician who has worked in breast cancer screening and who is wary of the complexities and problems associated with disease screening, my contention is that the enthusiasm for screening may not ultimately be conducive to health and well-being. This thesis represents an effort to understand the popularity and enthusiasm for disease screening, how it has come about and, why it may not be conducive to health and well-being. The thesis begins with a description of the phenomenon to be followed by a detailed examination of the scientific principles behind disease screening. It then moves on to discover how the phenomenon might have come about by first considering the evolution of biomedicine over the centuries and then its present endeavour in the form of surveillance medicine as well as the latter�s relationship with today�s market economy. Using relevant case studies that involve, for example, cancer and prenatal genetic screening, this thesis explores different concerns relating to health and well-being, including such topics as the creation of health roles, the reconfiguration of human values and interpersonal relationships as well as medicalisation. A final chapter offers an account of health and well-being and sums up why the enthusiasm for screening may not be conducive to health and well-being. The enthusiasm for screening compels people to assume health as a moral virtue. Screening is turned into a ritual that people consume to attain salvation. Since diseases may lead to death, diseases must be avoided though screening. Yet health is not just about the absence of disease. Health and well-being can only be realised by the individual within the context of the individual�s life as a whole. The institution of biomedicine has undeniable responsibility to ensure that screening will not be used to the detriment of individuals� health and well-being. Without condemning disease screening as a potentially useful tool in the prevention of disease, this thesis advocates prudence in its utilisation. People must not be compelled to attend screening through programmes of promotion (commercially related or not). Rather, autonomous decisions must be facilitated as far as possible through the provision of clear, accurate and factual information.

This thesis provides a social history of the introduction the Pap smear and the expansion of population-based cervical screening programs in Australia throughout the latter decades of the twentieth century. By placing cervical screening in a broad social context, this history helps to reveal the complex interrelationship between developments in scientific medicine, social, political and economic concerns, changing beliefs and attitudes, and the growing influence of commercialisation and consumerism. It also highlights the tendency for public health strategies to serve as a means of social and moral control. Furthermore, the thesis examines the conflict between the population-based approach of public health and the concern of clinicians for the welfare of individual patients. This conflict has emerged in other areas of medicine. In casting light on such conflict, the thesis will provide historical insight into reasons for why medicine is often perceived to be in a state of crisis today.

Screening is generally considered a useful strategy in the prevention of chronic diseases. The notion is that early detection through the use of certain screening tests can facilitate effective preventive measures to be undertaken which can then lead to improved prognosis from or ultimate avoidance of serious clinical diseases. The enthusiasm for screening in the United States is high and can be seen by the size of public demand for it. Rapid technological advances and knowledge expansion in the past decade have further facilitated the introduction of new tests and screening opportunities. In the mean time, the concept of screening has undergone subtle changes. Previous emphasis on clear and demonstrable population health benefits has been slowly replaced by an emphasis on individual responsibility for the surveillance of personal health risks. Disease screening is frequently advocated as part of a health promotion programme. As a clinician who has worked in breast cancer screening and who is wary of the complexities and problems associated with disease screening, my contention is that the enthusiasm for screening may not ultimately be conducive to health and well-being. This thesis represents an effort to understand the popularity and enthusiasm for disease screening, how it has come about and, why it may not be conducive to health and well-being. The thesis begins with a description of the phenomenon to be followed by a detailed examination of the scientific principles behind disease screening. It then moves on to discover how the phenomenon might have come about by first considering the evolution of biomedicine over the centuries and then its present endeavour in the form of surveillance medicine as well as the latter�s relationship with today�s market economy. Using relevant case studies that involve, for example, cancer and prenatal genetic screening, this thesis explores different concerns relating to health and well-being, including such topics as the creation of health roles, the reconfiguration of human values and interpersonal relationships as well as medicalisation. A final chapter offers an account of health and well-being and sums up why the enthusiasm for screening may not be conducive to health and well-being. The enthusiasm for screening compels people to assume health as a moral virtue. Screening is turned into a ritual that people consume to attain salvation. Since diseases may lead to death, diseases must be avoided though screening. Yet health is not just about the absence of disease. Health and well-being can only be realised by the individual within the context of the individual�s life as a whole. The institution of biomedicine has undeniable responsibility to ensure that screening will not be used to the detriment of individuals� health and well-being. Without condemning disease screening as a potentially useful tool in the prevention of disease, this thesis advocates prudence in its utilisation. People must not be compelled to attend screening through programmes of promotion (commercially related or not). Rather, autonomous decisions must be facilitated as far as possible through the provision of clear, accurate and factual information.