Our laboratory has used the 1,4,5,8 Naphthalenetetracarboxylic diimine (NDI) unit to develop threading polyintercalators that bind DNA with the NDI units intercalated in between GpG steps and two different peptide linkers, which connect the NDI units, situated in either the major or minor grooves. The first generation bisintercalators, G₃K and [beta]Ala₃K, were shown to bind two different sequences of DNA, where the peptide linkers reside in the major and minor grooves respectively. These binding modules were then combined to generate threading polyintercalators that bound different DNA sequences with simultaneous occupation of both grooves. In particular, a cyclic bisintercalator was designed and DNAse I footprinting revealed a strong preference for the sequence 5'-GGTACC-3'. NMR structural studies of the complex with d(CGGTACCG)₂ verified a pseudocatenane structure in which the NDI units reside four base pairs apart, with one linker located in the minor groove and the other in the major groove. This was the first structurally well-characterized pseudocatenane complex between a sequence-specific cyclic bisintercalator and its preferred binding sequence. The ability to simultaneously occupy both groves of the same sequence is interesting for several reasons. Most significantly, it raises questions about a complex DNA intercalator's ability to locate its preferred sequence within a long strand of DNA. In order to directly assess this, the intercalator was modified (CBI-Cys) to incorporate a gold nanoparticle probe to allow for the direct visualization of the intercalator locating its preferred sequence within a long DNA strand. The appropriate protocols to visualize DNA using electron and atomic force microscopy were unsuccessful; however, the foundation has been set for future work to develop the appropriate method to determine the mechanism by which the cyclic bisintercalator locates its preferred sequence. Additionally, the bisintercalators developed in our laboratory offered a unique opportunity to exploit their sequence specificity for controlled nanoparticle assembly. Over the past decade, nanoparticles and DNA have been used to develop novel nanoparticle assembly systems with the goal of developing electronic devices and nanomaterials. The G₃K bisintercalator was synthetically modified to incorporate a gold nanoparticle probe. This intercalator-nanoparticle conjugate, BisKC·Au, maintained its binding specificity (5'-GGTACC-3') to a modified DNA fragment containing multiple G₃K binding sites. The atomic force microscope has become the most promising tool in visualizing individual DNA molecules. A modified procedure utilized APS to allow for the direct visualizing of plasmid DNA. The framework is now in place to confirm the controlled assembly of the gold nanoparticles. This protocol can then be used for the [beta]Ala₃K bisintercalator to lead to the development of a nanoparticle assembly system that can precisely control the organization of multiple types of nanoparticles. / text

Despite the rapid development of palliative care teams, evidence for their effectiveness in oncology care is lacking. This thesis reviews and contributes towards this evidence, focusing on the randomized controlled trial as a research method. We conducted a systematic review of 22 trials reviewed that measured effectiveness of specialized palliative care. Family satisfaction with care improved in seven of 10 studies, but only four of 13 trials assessing quality of life and one of 14 assessing symptoms showed a benefit of the intervention. Conclusions were limited by methodologic problems in all of the trials. We conducted a phase II study of the efficacy of a palliative care team for symptom control and satisfaction of 150 patients with advanced cancer. Symptom severity (Edmonton Symptom Assessment System Distress Score) improved at one week and one month, as did patient satisfaction (all p<0.0001). We investigated factors associated with symptom severity and response for patients enrolled in the phase II study. Symptoms at baseline were worse for women and those with worse performance status (both p<0.005); female gender and worse baseline symptom severity independently predicted symptom improvement (both p<0.05). We planned and initiated an RCT of the effectiveness of an early palliative care intervention for improvement of health-related quality of life (HRQL) and satisfaction with care. Using baseline data from this RCT, we examined factors associated with HRQL in patients with advanced cancer. The strongest determinants of overall HRQL (combined FACT-G total score and FACIT-Sp Meaning and Peace subscore) were increased age (p<0.001), good performance status (p<0.001) and survival time >6 months (p=0.001). Compared to patients receiving cancer treatment, those awaiting new treatment had worse emotional well-being (p<0.001) while those on surveillance or whose treatment had been stopped had worse existential well-being (p=0.03). Male gender predicted better emotional and physical well-being and lower income predicted worse social well-being. Lastly, we developed recommendations for those planning an RCT in a palliative care population, incorporating information from the studies presented. Although such RCTs are challenging to conduct, they are feasible and necessary to improve the evidence base for the treatment of patients with advanced cancer.

Despite the rapid development of palliative care teams, evidence for their effectiveness in oncology care is lacking. This thesis reviews and contributes towards this evidence, focusing on the randomized controlled trial as a research method. We conducted a systematic review of 22 trials reviewed that measured effectiveness of specialized palliative care. Family satisfaction with care improved in seven of 10 studies, but only four of 13 trials assessing quality of life and one of 14 assessing symptoms showed a benefit of the intervention. Conclusions were limited by methodologic problems in all of the trials. We conducted a phase II study of the efficacy of a palliative care team for symptom control and satisfaction of 150 patients with advanced cancer. Symptom severity (Edmonton Symptom Assessment System Distress Score) improved at one week and one month, as did patient satisfaction (all p<0.0001). We investigated factors associated with symptom severity and response for patients enrolled in the phase II study. Symptoms at baseline were worse for women and those with worse performance status (both p<0.005); female gender and worse baseline symptom severity independently predicted symptom improvement (both p<0.05). We planned and initiated an RCT of the effectiveness of an early palliative care intervention for improvement of health-related quality of life (HRQL) and satisfaction with care. Using baseline data from this RCT, we examined factors associated with HRQL in patients with advanced cancer. The strongest determinants of overall HRQL (combined FACT-G total score and FACIT-Sp Meaning and Peace subscore) were increased age (p<0.001), good performance status (p<0.001) and survival time >6 months (p=0.001). Compared to patients receiving cancer treatment, those awaiting new treatment had worse emotional well-being (p<0.001) while those on surveillance or whose treatment had been stopped had worse existential well-being (p=0.03). Male gender predicted better emotional and physical well-being and lower income predicted worse social well-being. Lastly, we developed recommendations for those planning an RCT in a palliative care population, incorporating information from the studies presented. Although such RCTs are challenging to conduct, they are feasible and necessary to improve the evidence base for the treatment of patients with advanced cancer.

Maternal and child undernutrition are a significant problem in the developing world, with serious consequences for human health and socio-economic development. In Cambodia, 55% of children, 43% of women of reproductive age, and 50% of pregnant women are anemic. Current prevention and control practices rely on supplementation with iron pills or large-scale food fortification, neither of which are affordable or feasible in rural Cambodia. In the study areas, 97% of women did not meet their daily iron requirements. The current research focuses on the design and evaluation of an innovative iron supplementation technique. A culturally acceptable, inexpensive and lightweight iron ingot was designed to resemble a fish species considered lucky in Khmer culture. The ingot, referred to as ‘try sabay’ or ‘happy fish’, was designed to supply iron at a slow, steady rate. Iron leaching was observed in water and soup samples prepared with the iron fish when used concurrently with an acidifier. More than 75% of daily iron requirements can be met with regular use. Its use in the common pot of soup or boiled water provides supplementation to the entire family. The effectiveness of the iron fish was investigated in a randomized community trial involving 310 women in rural Cambodia. Blood samples were taken at baseline and every three months thereafter, over a 12-month trial period. Significant increases in hemoglobin concentrations were observed in women allocated an iron fish when compared to controls throughout the study, with an endline difference of 11.6 g/L. Significant improvements in serum ferritin concentration were observed at 9 months (6.9 ng/mL) and endline (30.8 ng/mL) in women who used an iron fish regularly when compared to the control group. Overall, use of the iron fish led to a two-fold reduction in the prevalence of anemia. The supplement was used daily by 94% of the households at the end of the trial. The study highlights the acceptability and effectiveness of a fish-shaped iron ingot as a means of improving dietary iron content. It offers a promising, simple solution to iron deficiency anemia if the project can be scaled-up for use throughout the country. / Canadian Institutes of Health Research; International Development Research Centre; University of Guelph

Living radical polymerization has proved to be a powerful tool for the synthesis of polymers as it allows for a high degree of control over the polymer microstructure and the synthesis of tailored molecular architectures. Although it has great potential, its use on an industrial scale is limited due to environmental and economical aspects. Nitroxide mediated polymerization is explored to bring this technology closer to adoption in commercial applications. One of the obstacles encountered using nitroxide mediated polymerization in microemulsion systems is the difficulty in controlling both the particle size and target molecular weight. Due to the nature of the formulation, a decrease in the target molecular weight is coupled to an increase in the particle size. For many applications, it is important to be able to design polymer particles with both specifications independently. Strategies to decouple these two properties and processing conditions required for targeting a range of particle sizes and molecular weights for n butyl acrylate latexes are presented. Furthermore, in an attempt to reduce the large amounts of surfactant typically used in microemulsions, these methods were explored at low surfactant to monomer ratios (0.2 to 0.5 by wt.) in order to reduce the costs associated with excess surfactant and post processing steps for surfactant removal (high surfactant levels also give poor water-resistance in coatings). Stable nanolatexes with particle sizes <40 nm have been obtained by other groups using NMP in microemulsions with SG1 but have done so by using much higher surfactant to monomer ratios (~2.5 by wt.) and at much lower solids content (6 10 wt. %). In this work, molecular weights of 20,000 to 80,000 g∙mol-1 were targeted and stable, n-butyl acrylate microemulsions with particle sizes ranging from 20 120 nm were prepared at a solids content of 20 wt. % using much lower surfactant concentrations. Although numerous studies have shown the effects of process parameters on particle sizes and methods to control the molecular weight, the decoupling of the molecular weight and particle size effect in NMP microemulsions under these conditions has not been done to this extent. In copolymer systems, nitroxide mediated polymerization also provides an efficient method to synthesize well defined block copolymers. Random copolymers are widely used as protective colloids, but the use of block copolymers for these applications has not been well studied. It is unclear what effects do the importance of a narrow molecular weight distribution and purity of block copolymers have on their performance as protective colloids. In order to investigate this, a range of block copolymers with different properties would need to be synthesized for systematic analysis. The direct synthesis of polystyrene b poly(acrylic acid) copolymers of varying lengths and compositions was successful by use of nitroxide mediated polymerization in bulk and solution polymerization. The characterization of these amphiphilic block copolymers was explored by titration and nuclear magnetic resonance spectroscopy. / Thesis (Master, Chemical Engineering) -- Queen's University, 2012-09-28 15:43:00.513

Thesis (M.Tech.: Chiropractic)--Durban University of Technology, 2009 / Objective: The efficacy of manipulation as compared to placebo in the treatment of two groups of weight trainers with Acromioclavicular (AC) Joint Dysfunction. Methods: Twenty patients (n=20), using randomised sampling were allocated to two intervention groups. Patients in each group received four treatments each over a two-week period and assessed at initial, one week, two weeks and one month follow ups. Objective measures included Algometer and Inclinometer readings. Numerical Pain Rating Scales (NRS), Shoulder Rating Questionnaire (SRQ) and the Shoulder Pain and Disability Index (SPADI) measured subjective outcomes. Results: Manipulation demonstrated significant improvement in objective findings. Subjective outcomes did not show significant difference between the manipulation and placebo groups. Conclusion: Manipulation, when compared to placebo, can be considered as an effective treatment intervention for the treatment of AC joint dysfunction with particular reference to objective outcomes. Although, caution needs to be utilised in accepting this outcome due to limitations in sample size, subjective measure sensitivity and specificity as well as the stringency of the inclusion and exclusion criteria.

Controlled release formulations deliver an active ingredient over an extended period of time. It is an ideal dosage form for an active ingredient with a short elimination half-life. An active ingredient with a short elimination half-life would be released in small portions over an extended period of time and thus less frequent administration is necessary and this improve patient compliance. Other advantages of these formulations include: decreased side effects, constant drug levels in the blood, improvement in treatment efficiency and reduction in cost of administration. Controlled release beads are formulated in such a way that the active ingredient is embedded in a matrix of insoluble substance like chitosan; the dissolving drug then has to find its way through the pores of the matrix into the surrounding medium. The chitosan matrix swells to form a gel, the drug then has to first dissolve in the matrix and diffuse through the outer surface into the surrounding medium. Chitosan is a biocompatible, biodegradable polymer of natural origin. It has mucoadhesive properties as well as the ability to manipulate the tight junctions in the epithelium membrane and these properties have qualified chitosan as an effective drug carrier in controlled release dosage forms. The effect of a modern controlled release polymer namely Kollidon® SR in combination with chitosan on drug release was investigated. Ketoprofen was chosen as model drug. Ketoprofen is an anti-inflammatory drug that causes gastrointestinal side effects in conventional dosage forms. Ketoprofen has a short elimination half-life of 2.05 ± 0.58 h and this characteristic makes it an ideal candidate for use in a controlled release formulation. The aim of this study was to achieve controlled release and minimize gastrointestinal effects of ketoprofen with chitosan particles. Kollidon® SR was used as polymer because it exhibits pH independent release characteristics and previous studies have shown potential for this combination. Chitosan beads and chitosan-Kollidon® SR beads, as well as chitosan granules and chitosan-Kollidon® SR granules, were prepared and investigated as potential controlled release formulations. Chitosan beads were prepared through the inotropic gelation method using tripolyphosphate as a cross linking agent. Granules were prepared through wet granulation using 2% v/v acetic acid as the granulating fluid or by dissolving ketoprofen in ethanol and Kollidon® SR in 2-pyrrolidinone and using the solution as granulating fluid. Kollidon® SR was added in concentrations of 0.25, 0.5 and 1% (w/v) in the bead formulations and concentrations of 1, 5 and 10% (w/w) in the granule formulations. The beads and granules were characterised by evaluating the following properties: morphology, drug loading and drug release. Additionally swelling and friability tests were also conducted on the bead formulations. The cross linking times of the bead formulations were varied to investigate the effect of cross linking time on the characteristics of the beads. Chitosan-Kollidon® SR beads showed promising results for controlled release formulations and ketoprofen were released over an extended period of time. Drug loading of the plain chitosan beads was 74.65 ± 0.71% and it was noted that the inclusion of Kollidon® SR in the beads resulted in an increase in drug loading and the formulation containing 1% (w/v) Kollidon® SR, cross linked for 30 minutes had a drug loading of 77.38 ± 0.01%. Drug loading of the beads that were cross linked for a longer time were slightly lower which is an indication that some of the drug might have leached out during cross linking. The degree of swelling was promising with some beads swelling to a degree of 2.5 in phosphate buffer solution pH 5.6. Granules had a drug loading between 81.73 ± 1.53% and 93.30 ± 0.50%. Ketoprofen release from the beads and the granules in PBS pH 7.40 at 37 °C over a period of 6 hours were investigated. The bead formulations were more effective in achieving controlled release and it was noted that the bead formulations that was cross linked for a longer period was more efficient in achieving controlled release. The granules did not form a matrix and were not effective in achieving controlled release. Controlled release of ketoprofen were achieved and the results show potential for chitosan-Kollidon® SR formulations in the future. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

A multidisciplinary literature survey revealed that copolymeric nanoparticles could be applied in various technologies such as the production of paint, adhesives, packaging material and lately especially drug delivery systems. The specialized application and investigation of copolymers in drug delivery resulted in the synthesis of two series of copolymeric materials, i.e. poly(styrene-co-methyl methacrylate) (P(St-co-MMA)) and poly(styrene-co-ethyl methacrylate) (P(St-co-EMA)) were synthesized via the technique of o/w microemulsion copolymerization. These copolymers have not as yet been utilized to their full potential in the development of new drug delivery systems. However the corresponding hydrophobic homopolymer poly(styrene) (PS) and the hydrophilic homopolymer poly(methyl methacrylate) (PMMA) are known to be biocompatible. Blending of homopolymers could result in novel applications, however is virtually impossible due to their unfavorable mixing entropies. The immiscibility challenge was overcome by the synthesis of copolymers that combined the properties of the immiscible homopolymers. The synthesized particles were analyzed by gel permeation chromatography combined with multi-angle laser light scattering (GPC-MALLS) and attenuated total reflectance Fourier infrared spectroscopy (ATR-FTIR). These characterizations revealed crucial information to better understand the synthesis process and particle properties i.e. molecular weight, nanoparticle size and chemical composition of the materials. Additionally, GPC-MALLS revealed the copolymer chain conformation. These characterizations ultimately guided the selection of appropriate copolymer nanoparticles to develop a controlled-release drug delivery system. The selected copolymers were dissolved in a pharmaceutically acceptable solvent, tetrahydrofuran (THF) together with a drug, rifampin. Solvent casting of this dispersion resulted in the evaporation of the solvent and assembly of numerous microscale copolymer capsules. The rifampin molecules were captured in these microcapsules through a process of phase separation and coacervation. These microcapsules finally sintered to produce a multi-layer film with an unusual honeycomb structure, bridging yet another size scale hierarchy. Characterization of these delivery systems revealed that both series of copolymer materials produced films capable of controlling drug release and that could also potentially prevent biofilm adhesion. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

A multidisciplinary literature survey revealed that copolymeric nanoparticles could be applied in various technologies such as the production of paint, adhesives, packaging material and lately especially drug delivery systems. The specialized application and investigation of copolymers in drug delivery resulted in the synthesis of two series of copolymeric materials, i.e. poly(styrene-co-methyl methacrylate) (P(St-co-MMA)) and poly(styrene-co-ethyl methacrylate) (P(St-co-EMA)) were synthesized via the technique of o/w microemulsion copolymerization. These copolymers have not as yet been utilized to their full potential in the development of new drug delivery systems. However the corresponding hydrophobic homopolymer poly(styrene) (PS) and the hydrophilic homopolymer poly(methyl methacrylate) (PMMA) are known to be biocompatible. Blending of homopolymers could result in novel applications, however is virtually impossible due to their unfavorable mixing entropies. The immiscibility challenge was overcome by the synthesis of copolymers that combined the properties of the immiscible homopolymers. The synthesized particles were analyzed by gel permeation chromatography combined with multi-angle laser light scattering (GPC-MALLS) and attenuated total reflectance Fourier infrared spectroscopy (ATR-FTIR). These characterizations revealed crucial information to better understand the synthesis process and particle properties i.e. molecular weight, nanoparticle size and chemical composition of the materials. Additionally, GPC-MALLS revealed the copolymer chain conformation. These characterizations ultimately guided the selection of appropriate copolymer nanoparticles to develop a controlled-release drug delivery system. The selected copolymers were dissolved in a pharmaceutically acceptable solvent, tetrahydrofuran (THF) together with a drug, rifampin. Solvent casting of this dispersion resulted in the evaporation of the solvent and assembly of numerous microscale copolymer capsules. The rifampin molecules were captured in these microcapsules through a process of phase separation and coacervation. These microcapsules finally sintered to produce a multi-layer film with an unusual honeycomb structure, bridging yet another size scale hierarchy. Characterization of these delivery systems revealed that both series of copolymer materials produced films capable of controlling drug release and that could also potentially prevent biofilm adhesion. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

Current treatment methods for non-union bone defects present problems. The objective of this study was to genetically engineer primary and immortalized cell types to express osteogenic molecules BMP2, RUNX2, OSX, or VEGF in a doxycycline dose-dependent manner for tissue regeneration. Coding cDNA sequences for all four factors were sub-cloned into the pRTS-1 expression plasmid and transfected into HUCPVCs, RBMCs, ROS cells. Electroporation was the most effective method of transfection for all cells but stably transfected cells could only be established for RBMCs and ROS cells. Cells achieved maximum expression within 72hours of induction and returned to basal levels after 18 days. Enhanced osteogenic bioactivity was only observed upon activation of BMP-2. The tight regulation of the pRTS-1 system allowed for a controlled gene expression. Future transplantation experiments using these engineered RBMC and ROS cells in vivo will evaluate the usefulness of the dox-inducible gene expression system in bone defects.