Class of 2013 Abstract / Specific Aims: To evaluate efficacy of the current pharmacological treatment of depression in the adult advanced and terminal cancer patient population. Methods: Trials assessing a pharmacological treatment for depression in cancer patients were found using MEDLINE and PSYCINFO databases. Comprehensive Meta-Analysis software was used to generate a random effects model forest plot, a funnel plot, classical fail-safe N, I2, and Kendall’s tau. Main Results: Ten studies, with an aggregate population was 1,167 patients, were used in this meta-analysis to generate a random effects variance model. The effect size was 0.42 +/- 0.09 (p < 0.01). I2 for aggregate data was 66.16 (p < 0.01). Kendall’s tau with continuity correction was 0.272 (P-value [2-tailed] = .244). The classic fail-safe N was 151 (p < 0.1). Three studies reported a significant increase in adverse effects between treatment and comparison group. Conclusion: Antidepressants were shown to have a moderate effect size when treating depression in advanced and terminal cancer patients. These medications were well tolerated. Antidepressant medications are beneficial as part of a comprehensive treatment plan for cancer patients diagnosed with depression.

The tuberculosis epidemic is escalating in South Africa as well as globally. This escalation is exacerbated by the increasing prevalence of multidrug-resistant tuberculosis (MDRTB), which is defined by the World Health Organisation (WHO) as resistance of Mycobacteria to at least isoniazid and rifampicin. Multi-drug resistant tuberculosis is estimated to occur in 1-2% of newly diagnosed tuberculosis (TB) patients and in 4-8% of previously treated patients. MDRTB is both difficult and expensive to treat, costing up to 126 times that of drug-sensitive TB. Resource constrained countries such as South Africa often lack both the money and the infrastructure to treat this disease. The aim of this project was to determine whether the performance of a systematic review with subsequent economic modelling could influence the decision making process for policy makers. Data was gathered and an economic evaluation of MDRTB treatment was performed from the perspective of the South African Department of Health. Three treatment alternatives were identified: a protocol regimen of second line anti-tuberculosis agents, as recommended in the South African guidelines for MDRTB, an appropriate regimen designed for each patient according to the results of culture and drug susceptibility tests, and non-drug management. A decision-analysis model using DATA 3.0 by Treeage® was developed to estimate the costs of each alternative. Outcomes were measured in terms of cost alone as well as the ‘number of cases cured’ and the number of ‘years of life saved’ for patients dying, being cured or failing treatment. Drug, hospital and laboratory costs incurred using each alternative were included in the analysis. A sensitivity analysis was performed on all variables in order to identify threshold values that would change the outcome of the evaluation. Results of the decision analysis indicate that the individualised regimen was both the cheaper and more cost-effective regimen of the two active treatment options, and was estimated to cost R50 661 per case cured and R2 070 per year of life saved. The protocol regimen was estimated to cost R73 609 per case cured and R2 741 per year of life saved. The outcome of the decision analysis was sensitive to changes in some of the variables used to model the disease, particularly the daily cost of drugs, the length of time spent in hospital and the length of treatment received by those patients dying or failing treatment. This modelling exercise highlighted significant deficiencies in the quality of evidence on MDRTB management available to policy makers. Pragmatic choices based on operational and other logistic concerns may need to be reviewed when further information becomes available. A case can be made for the establishment of a national database of costing and efficacy information to guide future policy revisions of the South African MDRTB treatment programme, which is resource intensive and of only moderate efficacy. However, due to the widely disparate range of studies on which this evaluation was based, the outcome of the study may not be credible. In this case, the use of a systematic review with subsequent economic modelling could not validly influence policy-makers to change the decision that they made on the basis of drug availability.

Until the beginning of this decade the antioxidant, melatonin, had been considered as little more than a tranquilizing hormone, responsible for regulating certain circadian and circannual rhythms. However, it is the discovery of melatonin as a free radical scavenger that has generated the most interest in recent years. The reduction of melatonin with age has been associated with neurodegenerative diseases such as Alzheimer’s disease (AD)and therefore, melatonin has been implicated to have an important clinical role in neuroprotection. Thus, for several years melatonin has attracted increasing attention from the general press with many advertisements touting this indoleamine to act as an aphrodisiac, rejuvenator, protector against diseases and a general wonder drug. However, melatonin formulations appear with no labelling for the correct storage conditions, dosage and side effects, as well as no control for purity and self-medicating with an unregulated product. In addition, there is much controversy surrounding the antioxidative properties of the indolemaine, 6-hydroxymelatonin (6-OHM). Therefore, the first part of this study aims to elucidate the physico-chemical and various stability characteristics of the pineal antioxidant, melatonin, while the second part is devoted to investigating the neuroprotective properties of the primary hepatic metabolite of melatonin, 6-OHM. The physical properties of melatonin were determined using various chemical techniques. This information served to both characterize and confirm the identity of melatonin raw material used in this study. In addition, this information serves to be essential as the physical properties of melatonin have not been reported in detail in literature, to date. Thereafter, using a validated high performance liquid chromatography (HPLC) method, the various physico-chemical and stability characteristics of melatonin were determined. Melatonin was shown to be extremely lipophilic, while the hygroscopic study indicates that melatonin raw material is extremely hygroscopic at temperatures above 40°C, whereas melatonin tablets are hygroscopic when left out of the original container. This study highlights the need for consumers to be aware of the proper storage of melatonin tablets to improve the stability and ensure long term integrity of the compound. Since, melatonin is most often administered orally, thus exposing it to a large variations in pH, within the gastrointestinal tract, it was decided to investigate the stability of melatonin over a range of pH’s and temperatures. The findings imply that melatonin is relatively stable at body temperature when ingested orally and that orally administered slow release preparations of melatonin should be relatively stable and therefore exhibit favourable bioavailability. However melatonin was shown to be unstable in solution. This provides important information and a challenge to the formulators of this drug substance in a liquid dosage form. An assessment of the photostability of melatonin dosage forms using International Committee on Harmonization (ICH) conditions revealed melatonin to be light sensitive and thus indicates a need for careful consideration of the packaging of these drug products. In addition a detailed assessment of the photochemistry and photoproducts formed during the UV photodegradation of melatonin is reported. Melatonin is shown to rapidly degrade in the presence of UV light, with the presence of oxygen accelerating the photodegradation. N1-acetyl-N2-formyl-5-methoxykynurenamine(AFMK) and 6-OHM were identified as the major photoproducts formed and these agents have been shown previously to retain antioxidant activity. One of the concerns of using melatonin in sunscreens is its photostability. However, it is reported in this study that the degraded solution of melatonin still possesses equipotent free radical scavenging ability as melatonin, despite the absence of melatonin in solution. In addition, melatonin is shown to reduce UV-induced oxidative stress in rat skin homogenate. Thus, these results make melatonin a likely candidate for inclusion in sunscreen preparations. Neuronal damage due to oxidative stress has been implicated in several neurodegenerative disorders. 6-OHM is not only formed as the major hepatic metabolite of melatonin, but also when melatonin reacts with toxic radicals as well as UV light. Thus the second part of the study aims to elucidate and further characterize the mechanism behind 6-OHM’s neuroprotection. The results show 6-OHM to be a more potent singlet oxygen and superoxide anion scavenger than melatonin. In addition, the results show 6-OHM to offer protection against, oxidative stress and lipid peroxidation induced by several neurotoxins in the rat brain and hippocampus. The hippocampus is an important region of the brain responsible for the formation of memory and any agent that induces stress in this area has detrimental effects and could lead to various types of dementia. Such agents include quinolinic acid (QA) and iron (II). Histological studies undertaken reveal that 6-OHM is able to protect hippocampal neurons against QA and iron (II) induced necrotic cell death. Immunohistochemical investigations showed that QA moderately induces apoptotic cell death in the hippocampus which is inhibited by both melatonin and 6-OHM. The study sought to elucidate possible mechanisms by which 6-OHM exerts its neuroprotective capabilities and the results show 6-OHM to inhibit the action of cyanide on the mitochondrial electron transport chain (ETC), one of the most common sources of free radicals. In addition, 6-OHM treatment alone, increased ETC activity above basal control levels and the results show 6-OHM to increase complex I activity in the mitochondrial ETC. Electrochemical, ultraviolet/visible spectroscopy (UV/Vis) and HPLC assessment show that an interaction exists between 6-OHM and iron (III) and 6-OHM is able to reduce iron (III) to a more biologically usable form viz. iron (II) which can be incorporated into important biomolecules such as heme. One dire consequence of this interaction is the ready provision of iron (II) to drive the Fenton reaction. However the biological and histological assessments show 6-OHM to prevent iron (II)-induced lipid peroxidation and necrotic cell death and thus, provide evidence of its antioxidant properties. The results also show 6-OHM to promote Hsp70 induction in the hippocampus. Heat shock proteins, especially Hsp 70 plays a role in cytoprotection by capturing denatured proteins and facilitating the refolding of these proteins once the stress has been relieved. 6-OHM treatment alone and together with QA was shown to increase the level of expression of Hsp70, both inducible and cognate forms of the protein. This suggests that 6-OHM helps to protect against cellular protein damage induced by any form of stress the cell may encounter. Melatonin treatment alone and in combination with QA was shown to prevent increases in the level of Hsp70 in the hippocampus, indicating that melatonin was able to reduce oxidative stress induced by QA such that Hsp70 expression was not required. The discovery of neuroprotective agents, such as melatonin and 6-OHM, is becoming important considering the rapid rise in the elderly population and the proportionate increase in neurological disorders. The findings of this study indicate the need for important information regarding the correct storage conditions and stability characteristics of melatonin dosage forms. In addition, the results indicate that 6-OHM has a definite role to play as an antioxidant. Thus further research may favour the use of these agents in the treatment of several neurodegenerative disorders.

AIDS Dementia Complex (ADC) is a neurodegenerative disorder implicated in HIV-1 infection that is associated with elevated levels of the neurotoxin, quinolinic acid (QA) which causes a cascade of events to occur, leading to the production of reactive oxygen species (ROS), these being ultimately responsible for oxidative neurotoxicity. In clinical studies, Non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz (EFV) and nevirapine (NVP) have been shown to potentially delay the progressive degeneration of neurons, thus reducing the frequency and neurological deficits associated with ADC. Despite these neuroprotective implications, there is still no biochemical data to demonstrate the mechanisms through which these agents offer neuroprotection. The present study aims to elucidate and further characterize the possible antioxidant and neuroprotective mechanisms of NVP and EFV in vitro and in vivo, using QA-induced neurotoxicity as a model. Research has demonstrated that antioxidants and metal chelators have the ability to offer neuroprotection against free radical induced injury and may be beneficial in the prevention or treatment of neurodegeneration. Hence the antioxidant and metal binding properties of these agents were investigated respectively. Inorganic studies, including the 1, 1-diphenyl-2 picrylhydrazyl (DPPH) assay, show that these agents readily scavenge free radicals in vitro, thus postulating the antioxidant property of these agents. The enhancement of superoxide radical generation and iron mediated Fenton reaction by QA is related to lipid peroxidation in biological systems, the extent of which was assayed using the nitroblue tetrazolium and thiobarbituric acid method respectively. Both agents significantly curtail QA-induced lipid peroxidation and potentially scavenge superoxide anions generated by cyanide in vitro. Furthermore, in vivo results demonstrate the ability of NVP and EFV to protect hippocampal neurons against lipid peroxidation induced by QA and superoxide radicals generated as a consequence thereof. The alleviation of QA-induced oxidative stress in vitro possibly occurs through the binding of iron (II) and / or iron (III), and this argument is further strengthened by the ability of EFV and not NVP to reduce iron (II)-induced lipid peroxidation in vitro directly. In addition the ferrozine and electrochemistry assay were used to measure the extent of iron (II) Fe[superscript 2+] and iron (III) Fe[superscript 3+] chelation activity. Both assays demonstrate that these agents bind iron (II) and iron (III), and prevent redox recycling of iron and subsequent complexation of Fe[superscript 2+] with QA which enhances neuronal damage. Both NNRTIs inhibit the endogenous biosynthesis of QA by inhibiting liver tryptophan 2, 3-dioxygenase activity in vivo and subsequently increasing hippocampal serotonin levels. Furthermore, these agents reduce the turnover of hippocampal serotonin to 5-hydroxyindole acetic acid. NVP and not EFV increase 5-hydroxyindole acetic acid and norepinephrine levels in the hippocampus. The results of the pineal indole metabolism study show that NVP increases the synthesis of melatonin, but decreases N-acetylserotonin, 5-hydroxyindole acetic acid and 5-hydroxytryptophol levels. Furthermore, it shows that EFV decreases 5-hydroxyindole acetic acid and melatonin synthesis. Behavioural studies using a Morris water maze show that the post-treatment of rats with NVP and EFV significantly improves QA-induced spatial memory deficits in the hippocampus. This study therefore provides novel information regarding the neuroprotective mechanisms of NVP and EFV. These findings strengthen the argument that these NNRTIs not only have antiviral effects but possess potential neuroprotective properties, which may contribute to the effectiveness of these drugs in the treatment of ADC.

Class of 2006 Abstract / Objectives: To examine the manner in which the DTSQ was used with a variety diabetic populations in different countries. The DTSQ is an 8 item questionnaire assessing satisfaction with diabetes treatment (6 items) and 2 items on glycemic control. Methods: Intensive search of published scientific literature was conducted to identify studies in which the DTSQ has been used in different countries. Data was extracted from each study on the following variables: country, ethnicitiy, DTSQ scores, Hg A1cgender, treatment, type of diabetes, and education level. Results: A total of twenty-four studies reporting the use of the DTSQ were identified. The majority studies (14/24) were treatment comparisons. The other studies were various other questions investigated. T he DTSQ was used for studies ranging in size from 15 to 1918 (mean 436.3 (SD=541.4) The DTSQ was used with patients who had thye 1, type 2, and gestational diabetes. Average HgA1c level was 7.6, and average DTSQ score was 29.9. Most studies did not describe the educational or ethnic background of their study participants. Most of the studies (18) were done in Europe with ten in the United Kingdom, two were in the USA, one in New Zealand, one in Nigeria, one in Canada, and one in Israel and Slovenia combined. Conclusions: The DTSQ appears useful with a variety of patient populations, although little information was presented on population characteristics.

Dissertation submitted in partial compliance with the requirements of the Master's Degree in Technology: Homoeopathy, Technikon Natal, 2002. / The purpose of this study was to determine the effect of herbal extracts of certain Labiatiae species (Rosmannus officinalis, Salvia officinalis and Thymus vulgaris) in the inhibition of in vitro growth of Candida albicans as compared to ethanol as a control and nystatin in terms of the disc diffusion test. / M

Dissertation submitted in partial compliance with the requirements for the Masters Diploma in Technology: Homoeopathy, Technikon Natal, 1995. / The purpose of this study was to investigate the action of the homoeopathic remedy, Staphylococcinum and the antibiotic Penicillin G, on Staphylococcus aureus, with respect to its growth parameters and enzyme producing ability, in order to determine the effectiveness of homoeopathic remedies on living organisms and to attempt a better understanding of how these remedies work. The hypothesis put forward was that the homoeopathic remedy would have an effect on the growth parameters and enzyme producing ability of the organism, but that the effect would be more subtle than that of Penicillin G. / M

Professionals in the mental health industry often attach a stigma to Borderline Personality Disorder (BPD). It is commonly thought of as a frustrating disorder to treat. As a result many professionals avoid dealing with BPD individuals. In an attempt to promote positive treatment outcomes, the aim of the study is to explore how the introduction of altruistic behaviours would affect the outcome of the overall treatment of individuals with BPD. Snowball sampling procedures were implemented. Data were collected through the use of semi-structured interviews with six mental health professionals and analysed through qualitative data processing and thematic analysis procedures. To the researcher’s knowledge, no research has been conducted specifically exploring the relationship between altruistic behaviour and BPD to date. The following superordinate themes emerged: treatment challenges, treatment context, treatment approach, diagnostic challenges, altruism/prosocial influences, and altruism/prosocial behaviour. It is the researcher’s hope that the findings of this study will increase awareness of this possible avenue in the treatment of BPD, so that the results of this study can then be taken to the next level of exploration in research and in clinical practice.

Anaerobic co-digestion of organic fraction of municipal solid waste (OFMSW), with thickened waste activated sludge (TWAS) and primary sludge (PS) has the potential to enhance (biodegradation) of solid waste, increase longevity of existing landfills and lead to more sustainable development by improving waste to energy production. This study reports on mesophilic batch anaerobic biological methane potential (BMP) assays carried out with different concentrations and combinations (ratios) of OFMSW, TWAS (microwave (MW) pre-treated and untreated) and PS to assess digester stability and potential improved specific biodegradability and potential increased specific biogas production by digestion of OFMSW with PS and TWAS in various tri-substrate mixtures. Results indicated improvements in specific biogas production with concomitant improvements in COD and volatile solid (VS) removal for co-digestion of OMSW, TWAS and PS vs. controls. In terms of improvements in biogas production and digester stability the OFMSW:TWAS:PS:50:25:25 ratio with or without TWAS MW treatment was deemed best for further continuous digester studies. At a 15d HRT which is the regulatory policy in the province of Ontario for municipal mesophilic anaerobic TWAS:PS treatment, co-digestion of OFMSW:TWAS:PS, and OFMSW:TWASMW:PS resulted in a 1.38 and 1.46 fold relative improvement in biogas production and concomitant waste stabilization when compared to TWAS:PS and TWASMW:PS digestion at the same HRT and volumetric VS loading rate respectively. Treatment of OFMSW with PS and TWAS provides beneficial effects that could be exploited at MWWTP that are being operated at loading rates less than design capacity.

Microconstituents (MCs) have become an emerging concern to scientists and researchers. Due to the development of analytical technology, it is now possible to study MCs at ηg/L to μg/L levels. Wastewater treatment plants (WWTPs) are the major point source for MCs entering the environment based on the literature. WWTPs are known to be unable to remove many MCs to a safe level. In order to fully understand the fate of MCs in WWTPs and to further improve the design of WWTPs in terms of MC removal, it is necessary to examine removal mechanisms such as sorption and biodegradation in WWTPs. Three MCs, bisphenol A (BPA), 17-α-ethinylestradiol (EE2) and triclosan (TCS), were chosen for this study. They are chemicals reported to be hydrophobic and have low vapor pressure, which makes sorption a highly potential removal mechanism. Primary sludge and activated sludge (AS) were used to perform sorption kinetics and isotherm experiments for BPA, EE2 and TCS. Primary sludge was collected from local WWTPs, and AS was generated from a lab-scale continuous flow bioreactor system maintained at solids retention times of 15, 10 and 5 d and hydraulic retention time (HRT) of 6 h. Alum was added to synthetic wastewater influent at concentrations typically used for phosphorus removal at some plants. Alum has the potential to change sludge structure and influence the sorption process. A comparison was made with AS as the adsorbent with and without alum addition to the AS to study the influence of alum on the sorption processes. The selected MCs were found to reach sorption equilibrium with primary sludge within 7 h. A pseudo second-order kinetic model was an excellent fit to describe the sorption processes of selected MCs. The solids-liquid partitioning coefficient (Kd) was determined for the three chosen MCs. The Kd values found for primary sludge and AS are very close. The Kd for MCs sorbed to AS in this study were compared with the Kd for AS without alum addition. Although alum addition showed no influence on effluent soluble chemical oxygen demand, it decreases the Kd for BPA and EE2 sorbed to AS. In contrast, a much higher Kd for TCS was observed for AS with alum addition. Judging from the R2 values, the linear sorption model is not suitable for some of the isotherms. Langmuir and Freundlich sorption isotherms were further used to fit the experimental data by applying linear regression and nonlinear regression approaches. The Freundlich isotherm was found to be the most suitable model to describe the experiment data.