Masters in Public Administration - MPA / The purpose of this study is to investigate what the municipalities within the greater Cape Town area are doing regarding Education, Training and Development within their different departments in relation to the National Qualifications Framework and the manner in which it affects career plans and prospects of employees and how the latter impacts on overall institutional transformation as a prerequisite for effective service delivery.

OBJECTIVE: Niacin, activating G-protein coupled receptor (GPR) 109A, stimulates release of vasodilatory prostaglandins (PGs) such as PGE2 which can elicit niacin-associated flushing side effects. Poly-lactic-coglycolic acid (PLGA) and poly-lactic acid (PLA) are used in nanoparticle (NP) drug delivery to reduce adverse effects and modulate drug release. Our study evaluated the in vitro effects of niacin-loaded PLGA or PLA-NPs on PGE2 expression in whole human blood as a model for niacin-induced flushing. MATERIALS AND METHODS: NPs were formulated using a solvent evaporation process and characterized by size, polydispersity, zeta potential, drug entrapment, morphology, and drug release. NP in vitro effects on PGE2 release were measured via ELISA analysis. RESULTS: PLGA-NPs demonstrated the lowest NP size (66.7 ± 0.21 nm) with the highest zeta potential and percent drug entrapment (42.00 ± 1.62 mV and 69.09 ± 0.29%, respectively) when compared to PLA-NPs (130.4 ± 0.66 nm, 27.96 ± 0.18 mV, 69.63 ± 0.03 %, respectively). In vitro release studies showed that PLGA-NPs underwent significant reductions in cumulative drug release when compared to PLA-NPs (p < 0.05). Furthermore, when compared to plain niacin, PLGA-NPs significantly reduced in vitro PGE2 release (p < 0.05). CONCLUSIONS: These results support the use of PLGA-NPs as a novel method of delivery for reducing niacin-associated flushing.

Introduction: Over the past few decades, nanoparticles (NPs) have gained immeasurable interest in the field of drug delivery. Various NP formulations have been disseminated in drug development in an attempt to increase efficacy, safety and tolerability of incorporated drugs. In this context, NP formulations that increase solubility, control release, and/or affect the in vivo disposition of drugs, were developed to improve the pharmacokinetic and pharmacodynamic properties of encapsulated drugs.Areas covered: In this article, important properties related to NP function such as particle size, surface charge and shape are disseminated. Also, the current understanding of how NP characteristics affect particle uptake and targeted delivery is elucidated. Selected NP systems currently used in delivery of drugs in biological systems and their production methods are discussed as well. Emphasis is placed on current NP formulations that are shown to reduce drug-induced adverse renal complications.Expert opinion: Formulation designs utilizing NP-encapsulated drugs offer alternative pharmacotherapy options with improved safety profiles for current and emerging drugs. NPs have been shown to increase the therapeutic index of several entrapped drugs mostly by decreasing drug localization and side effects on organs. Recent studies on NP-encapsulated chemotherapeutic and antibiotic medications show enhanced therapeutic outcomes by altering drug degradation, increasing systemic circulation and/or enhancing cell specific targeting. They may also reduce the distribution of encapsulated drugs into the kidneys and attenuate drug-associated adverse renal complications. The usefulness of NP formulation in reducing the nephrotoxicity of nonsteroidal anti-inflammatory drugs is an underexplored territory that deserves more attention.

Background: Metronidazole (MTZ) is an anti-oxidant and anti-inflammatory agent with beneficial therapeutic properties. The hydrophilic nature of the molecule limits its penetration across the skin. Existing commercial formulations have limitations of inadequate drug concentration present at the target site, which requires frequent administration and poor patient compliance. Objective: The aim of the current study was to develop and evaluate water in oil microemulsion of Metronidazole with higher skin retention for the treatment of inflammatory skin disorders. Methods: Pseudo ternary phase diagrams were used in order to select the appropriate ratio of sur-factant and co-surfactant and identify the microemulsion area. The selected formulation consisted of Capmul MCM as oil, Tween 20 and Span 20 as surfactant and co-surfactant, respectively, and water. The formulation was characterized and evaluated for stability, Ex vivo permeation studies and in vivo anti-inflammatory effect (carrageenan induced rat paw edema, air pouch model), anti-p-soriatic activity (mouse-tail test). Results: The particle size analyses revealed the average diameter and polydispersity index of the selected formulation to be 16 nm and 0.373, respectively. The results of ex vivo permeation studies showed statistically higher mean cumulative amount of MTZ retained in rat skin from microemul-sion, i.e., 21.90 ± 1.92 µg/cm2, which was 6.65 times higher as compared to Marketed gel (Metro-gyl gel®) with 3.29 ± 0.11 µg/cm2 (p<0.05). The results of in vivo studies suggested the microemul-sion based formulation of MTZ to be similar in efficacy to Metrogyl gel®. Conclusion: Research suggests the efficacy of the developed MTZ loaded microemulsion in the treatment of chronic skin inflammatory disorders.

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Intensified poultry production to meet global food demands has faced challenges associated with the removal of in-feed antibiotics due to concerns over antibiotics resistance. The reduction of low-dose antibiotics in feed has allowed for reemergence of intestinal diseases that diminish animal welfare and producer economics. Alternative mechanisms to preventing disease are therefore required. The objective of this dissertation was to examine factors that contribute to chicken development and health including intestinal structure and function, environment, and genetic selection. Chapter 2 investigated the host response to infection of the parasite Eimeria maxima that predisposes chickens to a bacterial infection Clostridium perfringens. Intestinal structure, function, inflammatory response, and epithelial composition was examined during a mild subclinical infection. Analysis of E. maxima and C. perfringens as individual infections revealed how each pathogen contributes to a co-infection. E. maxima caused a more severe inflammatory response, increasing pathology scores, shortening intestinal villi, and elongating crypts in the jejunum at peak infection. C. perfringens was shown to manipulate intestinal epithelial composition by influencing stem cells to differentiate into secretory goblet cells. The most deleterious effects were observed when the pathogens were introduced together, increasing pathology scores further, damaging intestinal villi, and increasing crypt depth. The introduction of C. perfringens and E. maxima also increased signaling for the production of reactive oxygen species, stimulation of tumor necrosis factor- that is involved in innate immunity, and decreased transcription of Hes1, which is involved in Notch signaling towards absorptive cell differentiation. Hes1 has previously been shown to be involved in the inflammatory response and could be an area of interest in determining new treatments to prevent or relieve the effects of E. maxima and C. perfringens. Chapter 3 applied an environmental perspective to disease prevention and examined the properties of C. perfringens that allow it to persist in the poultry house environment. Spores resist treatments used to sanitize poultry houses and litter has been shown to be a reservoir for disease, potentially increasing occurrence in certain houses. The metabolic and physiological properties of C. perfringens were utilized to separate the microbe from other poultry litter bacteria to enumerate spores within houses. A selective and differential medium combined with a heat treatment was developed to isolate C. perfringens spores from poultry litter samples. On average, houses that had histories of necrotic enteritis harbored a greater abundance of C. perfringens spores. Colonies that were isolated on the specialized medium were confirmed using PCR as C. perfringens. Lastly, Chapter 4 examined how genetic selection for multiple traits has influenced early intestinal development compared to divergently selected lines based on eight-week body weight. This study showed the morphological and gene expression differences between lines and revealed that most pathways involved in intestinal development are conserved through genetic selection. The major differences between lines were an increase in peptide transporter PepT1 on d5 and d7 in chicks selected for low eight-week body weight (LWS) compared to high weight selected (HWS) chicks and modern broiler Cobb500 chicks. In HWS chicks, the opposite mechanism was observed with an increase in expression of secretory goblet cell marker Muc2. The findings of these studies give multiple perspectives into poultry production and how major factors in management including nutrition, environment, and genetics can be used to increase efficiency while preventing disease. / Doctor of Philosophy / In poultry production, it is important to use management methods that help chickens grow efficiently while preventing illnesses. A few factors that contribute to the success of a producer include the use of nutrition to enhance intestine health and efficiency, a healthy environment in the poultry house, and using genetics to select for multiple traits to increase productivity. These factors have become even more significant after concerns of antibiotic resistance has eliminated the use of in-feed antimicrobials, allowing for reemergence of diseases that were suppressed. Therefore, the objective of this dissertation was to utilize each of these management strategies to determine how a common disease to the poultry industry affects the chicken intestine, how the environment influences the occurrence of this disease, and how genetic selection impacts the early development of chicks that may contribute to how they handle incidences of disease. Chapter 2 investigated how the bacteria Clostridium perfringens and parasite Eimeria maxima that are commonly seen together in the industry impact the intestinal function, structure, and how the chicken's immune systems respond to invasion by these pathogens. The major finds of this chapter included an increased inflammatory response after E. maxima infection that damaged intestinal structures. These pathogens also decreased the expression of a gene involved in absorptive cell formation that contributes to the inflammatory response. In Chapter 3, environment was investigated to determine if poultry houses that harbored more C. perfringens spores, which are resistant to sanitary treatments, predispose chickens to disease. On average, houses with more spores were correlated with increased disease occurrence. The method developed to determine isolate C. perfringens spores can also be used to monitor the abundance in poultry litter and used as a management tool to prevent or diagnose disease outbreaks. In Chapter 4, the influence of genetic selection on early intestinal development was studied using a modern line of broiler chicks compared to chicks selected for low or high body weights. This study gave insight into how intestinal development is mostly conserved after selecting for multiple genetic traits or a single trait (growth). The main differences were greater body weight in the modern line and high weight selected chicks compared to low weight selected chicks and an increase in gene expression of a peptide transporter in low weight chicks and a decrease in secretory cell expression in high weight chicks. These projects investigated multiple management strategies to address intestinal development and response to pathogens, disease occurrence, and genetic selection as tools to shape intestinal structure and composition.

Background: When shifting the company’s strategies to develop more sustainability conscious strategies, it can be challenging to effectively implement them if they are unaware of the level of complexity of the problem. Researchers have evidenced the lack of research regarding sustainability strategies’ implementation in practice. Thus, this study will investigate how companies implement their formulated sustainability strategies, including how challenges to sustainability strategy implementations are overcome. Purpose: The purpose is to investigate the formulation and the implementation of sustainability strategies focusing on how companies bridge the gap between the formulation and implementation of sustainability strategies. Method: To fulfil the purpose of this study, the authors adopt qualitative study approach using a multiple Case study design to investigate in depth the different factors that affect the process sustainability strategies. Primary data is collected through interviews with managers of seven Swedish companies. Conclusion: This study has identified that depending on the sustainability strategy approach, emergent or deliberate, impacts the challenges that companies may face when formulating and implementing sustainability strategies. Additionally, motivation and engagement, stakeholder pressure, knowledge sharing, and industry constraints are underlying challenges when implementation of sustainability strategies. For companies to bridge the gap, solutions have been suggested accordingly to the challenges.

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<p>  </p> <p>As the pharmaceutical industry moves towards molecular obesity with the use of high throughput screening for identification of promising candidates, the low aqueous solubilities of new chemical entities pose significant challenges to achieving adequate oral absorption and bioavailability. Enabling formulations are often needed to address this issue. Amorphous solid dispersion (ASD), where an amorphous drug and a polymer are molecularly mixed, has gained popularity as a dissolution/solubility enhancing strategy over the years. Upon ASD dissolution, the release rate of drug is much higher than that of the neat amorphous form of the drug. More importantly, the apparent concentration of drug in the solution can exceed its amorphous solubility through the formation of a drug-rich colloidal phase in the solution, also called nanodroplets. The presence of nanodroplets has been shown to be beneficial for oral absorption and bioavailability and their formation during release is therefore desirable. However, such release profiles are only achieved at relatively low drug loadings (DLs) and release tends to drop with increasing DL. For ASDs based on polyvinylpyrrolidone/vinyl acetate (PVPVA), drug release drops drastically once the DL exceeds a certain value, called limit of congruency (LoC). The low DL at which the ASD demonstrates good release also presents additional challenges since it can create a pill burden for patients due to the large amount of polymer needed in the formulation. Therefore, to achieve optimal drug product performance, it is crucial to understand the mechanisms of drug release. Therefore, this thesis focuses on understanding the factors affecting, and the mechanisms of ASD drug release, as well as enhancing drug release through addition of surfactants. </p> <p>The glass transition temperature of a drug and its interaction with the polymer were identified as important factors affecting the drug release and LoC. Another phase transition occurring during ASD hydration/dissolution, amorphous-amorphous phase separation (AAPS), was shown to affect drug release from ASD significantly. During dissolution, water-induced AAPS occurs, and the initially miscible ASD separates into two phases, an insoluble drug-rich phase and a soluble water/polymer-rich phase. The formation of a continuous drug-rich phase at the ASD-solution interface was shown to be detrimental to drug release as it could act as barrier that blocked any further drug release. When the drug-rich phase formed adopted a discrete morphology or when phase separation occurred in the solution outside of the dissolving ASD matrix, good release could be achieved. Surfactants could interrupt the formation of the continuous drug-rich both kinetically and thermodynamically, improving drug release as a result. Other mechanisms of release enhancement by surfactants included increased polymer release rate, increased water ingress and plasticization. The findings in this thesis will provide insight into ASD release mechanisms, and facilitate rational excipient selection when designing ASD formulations.  </p>