A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy. Johannesburg, 2016. / Primary microRNA (pri-miRNA) mimics have been shown to mediate effective gene silencing and are well-suited for therapeutic applications. Pri-miRNA mimics, like natural pri-miRNA, are processed in the endogenous microRNA (miRNA) biogenesis pathway. Elements of the secondary RNA structure are crucial for processing by the Drosha-DGCR8 microprocessor, including a basal stem of - 11 bp. However, structural variation is common and the exact determinants of pri-miRNA processing have been elusive. The aim of this project were to explore the use of natural pri-miRNAs with exceptional basal stem in the design of correspondingmimics and to identify optimal stem features.[Abbreviated Abstract. Open document to view full version] / LG2017

The 37kDa/67kDa laminin receptor (LRP/LR) is thought to play a major role in the adhesion to laminin and consequently invasion resulting in the metastasis of tumor cells. This receptor is reported to be over-expressed in several neoplastic cell lines and is believed to increase tumor aggressiveness. This research aims at determining whether the application of anti-LRP/LR specific antibody (IgG1-iS18) on neoplastic cell lines would result in a decrease in invasion and adhesion. All neoplastic cell lines had significantly increased cell surface LRP/LR levels compared to NIH/3T3 cells, with the most notable increase seen in SW480 cells (10.98%). Due to a positive correlation between the cell surface LRP/LR levels and invasion potential we propose that an increased LRP/LR level correlates to an increased ability to invade. A significantly decreased adhesion potential was noted in all neoplastic cell lines except the non-invasive MCF-7 cell line, upon application of IgG1-iS18, 21% decrease in HT-1080 cells, 14% in HeLa, 20% in LNCaP, 48% and 74% in A549 and SW480 cells, respectively. Incubation with the anti-LRP/LR antibody IgG1-iS18 resulted in a significant reduction of the invasive potential of HT-1080 (44%), A549 (33%), HeLa (69%), SW480 (91%) and LNCaP cells (38%). Furthermore, a high Pearson’s correlation coefficient between adhesion potential and invasive potential was seen, confirming that adhesion is indeed a pre-requisite for invasion. The significant reduction in invasion and adhesion of HT-1080, A549, HeLa, SW480 and LNCaP cells upon application of the IgG1-iS18 antibody suggests that this macromolecule might act as a promising therapeutic tool for the treatment of various metastatic cancer types.

Thesis advisor: Tracy Regan / This study analyzes the response of pharmaceutical firms’ stock prices to the release of information regarding successful Phase III clinical studies and final FDA marketing approval. I employ an event study methodology to show that positive abnormal returns occur at these drug development stages, and that larger abnormal returns occur over a three-day window surrounding a sample of successful Phase III trial announcements in comparison to a sample of FDA approval announcements. To my knowledge, all previous literature of this kind has compared a random sample of firms making Phase III announcements to a random sample of FDA approval announcements. This study advances drug development literature by conducting a second set of event studies that compares the abnormal returns of the same drugs at the two drug development stages, and it finds that controlling for the unique characteristics of the drugs analyzed in event studies leads to a smaller difference in returns at the two drug development stages. The drugs selected for analysis were taken from IMS Health’s lists of the top 100 (or 200) best-selling pharmaceuticals from 2003 to 2010. They were split into 13 therapeutic classes, such as drugs for cardiovascular ailments and drugs for respiratory ailments. Regression analysis was conducted on the returns of the three-day window to find a positive relationship between the FDA approval of alimentary and cardiovascular drugs and stock price increases for larger pharmaceutical firms and the approval of nervous system drugs and stock price increases for smaller pharmaceutical firms. To my knowledge, this is the first study to show these relationships. / Thesis (BA) — Boston College, 2015. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Departmental Honors. / Discipline: Economics.

Lung diseases are one of the leading causes of mortality and morbidity worldwide. Understanding these diseases at a molecular level remains a critical component to developing effective therapeutics. Previous work has shown that gene expression alterations play an important role in disease initiation, maintenance, and progression as well as serve as diagnostic tools in disease. However, much remains to be uncovered regarding the role that microRNAs play in both healthy and diseased lung tissue. This thesis seeks to utilize methods of bioinformatics, cell biology, and molecular biology to examine the effect of miR-4423 on lung epithelial cell differentiation (Aim 1), miR-424 on never smoker derived lung adenocarcinoma (Aim 2), and miR-34c isomiRs in interstitial lung disease (ILD) (Aim 3). First, we examined the role of miR-4423 in lung mucociliary epithelium by employing the use of an air-liquid interface culture system, finding miR-4423 has an effect in ciliated cell differentiation and that a loss of miR-4423 is associated with cancer progression. These findings suggest that miR-4423’s actions in airway epithelium differentiation may potentially provide a therapeutic role in lung cancer. Next, we validated transcriptomic differences between lung tumor tissues resected from never and ever smokers. Specifically, miR-424, a predicted regulator of a large number of gene expression changes in never smoker lung adenocarcinoma, was found to regulate cell migration, potentially identifying a novel target and/or pathway for therapeutic action. Lastly, the function of microRNA isomiRs is relatively unknown. We validated miR-34c as upregulated in ILD and modulated both miR-34c and a miR-34c 5’ isomiR in lung relevant cell lines to explore their differing biological roles. We found that they are capable of targeting differing mRNA, indicating an independent role for isomiRs in disease. The studies contained in this dissertation offer valuable insight into the biology of microRNAs in the lung and how they might be employed as therapeutic targets for a number of common lung diseases. In addition, biological insights into the complexity of microRNAs in the lung highlight the need to better understand diseases influenced by microRNA expression and microRNA variants in regards to actionable therapeutics. / 2017-12-01T00:00:00Z

Thesis (MTech (Horticulture))--Peninsula Technikon, 2004 / The term "horticultural therapy" is unfamiliar to most South Africans. However it is well accepted in South Africa that horticulture plays an important role in human well being both physically and psychological. It is generally believed that people who engage in gardening tend to benefit. The research study investigates whether plant related activities integrated into rehabilitation programme, actually benefit participants. It shows how patients at a chosen healthcare institution respond upon exposure to various horticulture activities in order to identify activities appropriate for the inclusion and design in a horticultural therapy programme. The study identifies factors necessary for the design of a business plan for a horticulturist engaging in a horticultural therapy programme under local conditions. The methodology adopted was mainly quantitative. The study is also descriptive in nature. It seeks to develop a model from a range of activities that would best meet the needs of specific groups subjects, through the careful and deliberate observation and evaluation of patients as they engage with the activities. The measuring instruments have been designed for experimentation research purpose. It involved setting up an experiment (patients engaged in a designed horticulture activity) and collecting the data. Information regarding the participant response to designed activities was also gathered on the basis of observations and interviews. The population consisted of patients admitted at a public (State) psychiatric institution in the Western Cape. The sample consisted of 12 patients, four patients from each of the following categories: Forensics, Intellectually Challenged, and Psychiatric. The designed activities consisted of 10 activities, and were centered around the following activities: Growing of herbs, learning to take cuttings, planting cuttings, planting seeds for outdoor garden, preparing a garden site, vegetable gardening, weeding, watering, and planting flowering annuals. The first objective of the study was to determine whether the response of different categories of patients to specific horticulture activities differ, in order to select the appropriate activity for each category. Forensic patients responded positively to all ten activities and recorded a high level (70%) of task accomplishment. Intellectually challenged patients had a medium level (46% to 69%) of task accomplishment for the majority of the activities. Psychiatric patients had a high level (70%) for 50 percent of the activities and a medium level (46% to 69%) of task accomplishment for the remainder of the activities. The second objective of the study was to evaluate the degree of effect of the different horticulture activities on each category of patients, in order to determine the relative importance of each activity in the programme in meeting the patients needs. The general findings are that the various categories responded differently to the subsections as shown in the results. Individual patients within the categories also differed in their response to various activities. The results of the study indicate that certain horticultural activities have an impact on patient's deficiencies and encourage their specific needs in the areas of a vocational/educational, interpersonal/social, and responsibility/development The study identified factors necessary for the design of a business plan for a horticulturist to engage in a horticultural therapy programme under local conditions. The business plan provides an outline to develop, market, and implement a horticultural therapy service. The business plan helps identify important ramifications of setting up a business and practicing as a contract worker. The research process has highlighted valuable aspects, which may be easily incorporated into a future horticulture therapy programme. It has shown that certain plant related activities, when successfully integrated into a rehabilitation programme, will benefit participants. The findings and recommendations provide guidelines for the formulation of a structured horticultural therapy programme. It encourages the concept of utilizing gardening in a structured/organized manner to benefit the well being of individuals. / TABEISA, SANTAM

The severity of cardiac dysfunction predicts mortality in septic patients. In this thesis, I have investigated the pathophysiology and the novel therapeutic strategy to attenuate cardiac dysfunction in experimental sepsis. I have developed a model of cardiac dysfunction caused by lipopolysaccharide (LPS)/peptidoglycan (PepG) co-administration or polymicrobial sepsis in young and old, male and female mice. There is good evidence that females tolerate sepsis better than males. Here, I have demonstrated for the first time that the cardiac dysfunction caused by sepsis was less pronounced in female than in male mice; this protection was associated with cardiac activation of a pro-survival pathway [Akt and endothelial nitric oxide synthase], and the decreased activation of a pro-inflammatory signalling pathway [nuclear factor (NF)-κB]. Patients with chronic kidney disease (CKD) requiring dialysis have a higher risk of sepsis and a 100-fold higher mortality. Activation of NF-κB is associated with sepsis-induced cardiac dysfunction and NF-κB is activated by IκB kinase (IKK). Here, I have shown that 5/6th nephrectomy for 8 weeks caused a small, but significant, cardiomyopathy, cardiac activation of NF-κB and expression of inducible nitric oxide synthase (iNOS). When subjected to LPS or polymicrobial sepsis, CKD mice exhibited exacerbation of cardiac dysfunction and cardiac activation of NF-κB and iNOS expression, which were attenuated by a specific IKK inhibitor (IKK 16). Thus, selective inhibition of IKK may represent a novel therapeutic approach for the sepsis-induced cardiac dysfunction in CKD patients. Activation of transient receptor potential vanilloid receptor type 1 (TRPV1) improves outcome in sepsis/endotoxaemia. The identity of the endogenous activators of TRPV1 and the role of the channel in the cardiac dysfunction caused by sepsis/endotoxaemia is unknown. Here, I have shown that activation of TRPV1 by 12-(S)-HpETE and 20-HETE (potent ligands of TRPV1) leads to the release of calcitonin gene-related peptide (downstream mediator of TRPV1 activation), which protects the heart against the cardiac dysfunction caused by LPS.

No description available.

Abstract not available

The therapeutic relationship is the central focus of nursing work in mental health (Peplau, 1992, 1997). However, there is currently little research that has examined influences on the nurses’ capacity to effectively engage in this relationship. This study investigated the impact of nurse, patient and work environment factors on the willingness and ability of nurses to engage in therapeutic relationships. This attribute of the nurse, identified as therapeutic commitment, is essential for an effective therapeutic relationship (Lauder, et al., 2000; Rogers, 1957), which has been identified by users of mental health services as the foundation of their care (Forchuk & Reynolds, 2001). The therapeutic relationship is central to nursing in mental health and has been linked to improved patient outcomes (Horvath, 2005). Environmental factors hypothesised to impact the nurse’s therapeutic commitment included leadership, collegial nurse-doctor relationships, participation in hospital affairs, the foundations of quality nursing, clinical supervision, staffing, skill mix and patient turnover (Aiken, et al., 2008; Duffield, et al., 2009a; Estabrooks, et al., 2002; Kramer & Schmalenberg, 2004; Lake & Friese, 2006; McGillis-Hall & Doran, 2004; Needleman, et al., 2002; Proctor, 1986). These factors, together with measures of the nurse’s qualifications and experience, were assembled into an hypothesised model, based on an earlier framework that included the nurse’s perception of support, adequacy and legitimacy in their role along with their therapeutic commitment (Lauder, et al., 2000; Shaw, et al., 1978). Data were collected from 76 nurses across six mental health wards in general acute hospitals in New South Wales. A nurse survey collected the identified factors using the Practice Environment Scale of the Nursing Work Index (Lake, 2002), the Mental Health Problems Perception Questionnaire (Lauder, et al., 2000), and other questions. A ward profile was used to collect staffing, skill mix and patient movement data. Partial least squares path modelling was applied to the model in order to identify the most influential relationships. The most significant factors in the model were the foundations for quality care, nurse experience, participation in hospital affairs and clinical supervision. Services should enhance the support provided to clinical nurses in mental health through improved access to preceptorship, continued education and clinical supervision. In addition, the therapeutic commitment of nurses in mental health can be increased through improved continuity of care, access to career development opportunities such as the involvement of mental health nurses in the governance of the hospital, and improved responsiveness of administration to the needs of nurses in mental health. Engagement in these supportive activities should be enacted through structured mechanisms that both facilitate involvement and encourage evaluation. This study provides a basis on which to modify the operation of mental health services in general hospitals in order to improve the nursing work environment.

The therapeutic relationship is the central focus of nursing work in mental health (Peplau, 1992, 1997). However, there is currently little research that has examined influences on the nurses’ capacity to effectively engage in this relationship. This study investigated the impact of nurse, patient and work environment factors on the willingness and ability of nurses to engage in therapeutic relationships. This attribute of the nurse, identified as therapeutic commitment, is essential for an effective therapeutic relationship (Lauder, et al., 2000; Rogers, 1957), which has been identified by users of mental health services as the foundation of their care (Forchuk & Reynolds, 2001). The therapeutic relationship is central to nursing in mental health and has been linked to improved patient outcomes (Horvath, 2005). Environmental factors hypothesised to impact the nurse’s therapeutic commitment included leadership, collegial nurse-doctor relationships, participation in hospital affairs, the foundations of quality nursing, clinical supervision, staffing, skill mix and patient turnover (Aiken, et al., 2008; Duffield, et al., 2009a; Estabrooks, et al., 2002; Kramer & Schmalenberg, 2004; Lake & Friese, 2006; McGillis-Hall & Doran, 2004; Needleman, et al., 2002; Proctor, 1986). These factors, together with measures of the nurse’s qualifications and experience, were assembled into an hypothesised model, based on an earlier framework that included the nurse’s perception of support, adequacy and legitimacy in their role along with their therapeutic commitment (Lauder, et al., 2000; Shaw, et al., 1978). Data were collected from 76 nurses across six mental health wards in general acute hospitals in New South Wales. A nurse survey collected the identified factors using the Practice Environment Scale of the Nursing Work Index (Lake, 2002), the Mental Health Problems Perception Questionnaire (Lauder, et al., 2000), and other questions. A ward profile was used to collect staffing, skill mix and patient movement data. Partial least squares path modelling was applied to the model in order to identify the most influential relationships. The most significant factors in the model were the foundations for quality care, nurse experience, participation in hospital affairs and clinical supervision. Services should enhance the support provided to clinical nurses in mental health through improved access to preceptorship, continued education and clinical supervision. In addition, the therapeutic commitment of nurses in mental health can be increased through improved continuity of care, access to career development opportunities such as the involvement of mental health nurses in the governance of the hospital, and improved responsiveness of administration to the needs of nurses in mental health. Engagement in these supportive activities should be enacted through structured mechanisms that both facilitate involvement and encourage evaluation. This study provides a basis on which to modify the operation of mental health services in general hospitals in order to improve the nursing work environment.