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HIV/AIDS is the most threatening and challenging infectious diseases of our time, with the highest increase of newly infected cases reported. This infectious disease was discovered in the early eighties under homosexual men and was later to be discovered in heterosexuals. HIV is a systemic immunosuppressive disorder which causes a depletion of CD4+ T cells and develops into the acquired immunodeficiency syndrome - AIDS. Africa is the continent most affected by HIV/AIDS with the southern parts of Africa having the highest prevalence rates compared to the rest of Africa. Statistics indicate that AIDS is responsible for 3% of deaths in children worldwide - one in seven people dying of an HIV-related illness is a child under the age of 15 years. It was stated by the WHO that countries should develop improved antiretrovirals regimes for the prevention of mother-to-child transmission. Difficulties in administering antiretrovirals (ARVs) to patients (especially children) are the strict dosage regimes and the severe adverse reactions. These factors complicate patient adherence. The list of problems in treating patients is endless and includes the distribution, stability as well as the low efficacy of these drugs. Most of the above mentioned problems and obstacles related to ARVs and ARV treatment could be minimized or eliminated by the use of a stable and effective drug delivery system. Enhancing ARV treatment may be accomplished by the use of the Pheroid™ drug delivery system. Pheroids™ consists mainly of fatty acids and sterile nitrous oxide gassed water. Pharmacological active substances are entrapped into submicron and micron sized structures called Pheroids™. Research showed promising results and advantages in delivering drugs through oral and transdermal routes using Pheroid™ technology. The focus of this study was to test the possible enhancement of the efficacy of antiretrovirals using Pheroid™ technology. The assays used to study this possible enhancement were a modified neutral red and a modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay. These assays confirmed and illustrated the toxic and protective properties of the tested ARVs (stavudine, lamivudine and nevirapine). An MT-2 cell line was used and infected with an HIV-1 strain, SW7-TCL. Applying Pheroid™ technology in these assays resulted in massive cell death, due to increased ARV toxic levels within the cells. Viability tests proved that Pheroids™ had no effect on the viability of cells at the concentration typically used. This confirmed the enhancing properties of Pheroids™ in the delivery of drugs into the cells. The MTT assay was further adapted from a seven day incubation period to a three day incubation period. By using a low concentration series and a three day incubation period the loss of cells through toxicity was partially overcome. One of the problems that arose form this study was the non-reproducibility of the results. Absorbance levels fluctuated at specific concentrations of the same ARV, which cause difficulties in comparing results. This result was repeatedly confirmed in this syncytium forming infection model. In conclusion, Pheroid™ technology enhanced the delivery of ARVs into the cells although it resulted in cell death. Both the neutral red and MTT assays were found to be inaccurate but further development, research and assay optimization could result in improved in vitro studies. The article format was used for this thesis, as described in the general academic rules in section A.13.7.3 of the North West University. Chapter 1 deals with HIV/AIDS related problems, statistics and treatment obstacles. Chapter 2 is a summary of the cell viability assays used in this study. Pheroid™ technology and its application to ARV treatment are dealt with in chapter 3. The proposed article for submission in the journal Cell Death and Differentiation has been included in chapter 4. Some of the results from the study are reported in the article and annexures, whilst other results are shown and discussed in Chapter 5. Chapter 6 gives a conclusion and final summary of this study. All other experimental methods and results are enclosed in the annexures, as is the "Guide for authors" for the article. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

Este trabalho avaliou a bioacumulação de metais e as respostas biológicas em mexilhões Perna perna coletados na Praia da Cocanha, Ilha das Palmas e Ponta de Itaipu, e ostras Crassostrea brasiliana coletadas nos Estuários de Cananéia, Santos e Bertioga em diferentes estações do ano. Foram realizadas duas campanhas: 2008/09 e 2016/17. A Cocanha apresentou elevados níveis de metais, indução de EROD e DBF e efeitos peroxidativos e genotóxicos. Em Palmas houve ativação de EROD, DBF, GST e GSH. Itaipu evidenciou bioacumulação de metais, ativação de GST e GSH e danos no DNA. Em Cananéia houve bioacumulação de As e Cr, respostas das fases I e II e efeitos peroxidativos. Santos exibiu piores condições fisiológicas, com alterações bioquímicas em todas as estações do ano. Bertioga piorou em 2016/17 em relação a 2008/09, evidenciado por maior bioacumulação de metais e respostas de biotransformação e antioxidantes e efeitos neurotóxicos. Os dados evidenciam fontes de contaminação diferentes para cada local e variação de acordo com o período do ano em função de diversos fatores (e.g. pluviosidade, reprodução, turismo). Os locais escolhidos como referência demonstraram estar sob influência de fontes pontuais de contaminação. Deve-se considerar que Itaipu e Cananéia integram unidades de conservação. / The present study assessed the bioaccumulation of metals and the biological responses in mussels Perna perna from Cocanha Brach, Palmas Island and Ponta de Itaipu, and oysters Crassostrea brasiliana from the estuaries of Cananéia, Santos and Bertioga in different seasons. Two campaigns were carried out: 2008/09 and 2016/17. Cocanha showed high levels of metals, induction of EROD and DBF and peroxidative and genotoxic damages. Palmas exhibited induction of EROD, DBF, GST and GSH. Itaipu exhibited bioaccumulation of metals, activation of GST and GSH and DNA damage. Cananéia showed bioaccumulation of As and Cr, phases I and II responses and peroxidative damage. Santos exhibited the worst physiological conditions, with biochemical alterations in all seasons. Bertioga conditions worsened in 2016/17 compared to 2008/09, evidenced by the higher content of metals and biotransformation and antioxidant responses and neurotoxic damage. These data show different sources of contamination for each site and variation in accordance with the time of the year due to several factors (e.g. rainfall, reproduction, tourism). The sites chosen as reference may be influenced by point sources of contamination. It should be considered that Itaipu and Cananéia are within protected areas.

Este trabalho avaliou a bioacumulação de metais e as respostas biológicas em mexilhões Perna perna coletados na Praia da Cocanha, Ilha das Palmas e Ponta de Itaipu, e ostras Crassostrea brasiliana coletadas nos Estuários de Cananéia, Santos e Bertioga em diferentes estações do ano. Foram realizadas duas campanhas: 2008/09 e 2016/17. A Cocanha apresentou elevados níveis de metais, indução de EROD e DBF e efeitos peroxidativos e genotóxicos. Em Palmas houve ativação de EROD, DBF, GST e GSH. Itaipu evidenciou bioacumulação de metais, ativação de GST e GSH e danos no DNA. Em Cananéia houve bioacumulação de As e Cr, respostas das fases I e II e efeitos peroxidativos. Santos exibiu piores condições fisiológicas, com alterações bioquímicas em todas as estações do ano. Bertioga piorou em 2016/17 em relação a 2008/09, evidenciado por maior bioacumulação de metais e respostas de biotransformação e antioxidantes e efeitos neurotóxicos. Os dados evidenciam fontes de contaminação diferentes para cada local e variação de acordo com o período do ano em função de diversos fatores (e.g. pluviosidade, reprodução, turismo). Os locais escolhidos como referência demonstraram estar sob influência de fontes pontuais de contaminação. Deve-se considerar que Itaipu e Cananéia integram unidades de conservação. / The present study assessed the bioaccumulation of metals and the biological responses in mussels Perna perna from Cocanha Brach, Palmas Island and Ponta de Itaipu, and oysters Crassostrea brasiliana from the estuaries of Cananéia, Santos and Bertioga in different seasons. Two campaigns were carried out: 2008/09 and 2016/17. Cocanha showed high levels of metals, induction of EROD and DBF and peroxidative and genotoxic damages. Palmas exhibited induction of EROD, DBF, GST and GSH. Itaipu exhibited bioaccumulation of metals, activation of GST and GSH and DNA damage. Cananéia showed bioaccumulation of As and Cr, phases I and II responses and peroxidative damage. Santos exhibited the worst physiological conditions, with biochemical alterations in all seasons. Bertioga conditions worsened in 2016/17 compared to 2008/09, evidenced by the higher content of metals and biotransformation and antioxidant responses and neurotoxic damage. These data show different sources of contamination for each site and variation in accordance with the time of the year due to several factors (e.g. rainfall, reproduction, tourism). The sites chosen as reference may be influenced by point sources of contamination. It should be considered that Itaipu and Cananéia are within protected areas.

A study of how mediators interact with the catabolic pathways of microbes was undertaken with a view towards improving the performance of microbial fuel cells. The use of mediators is known to improve the power density in microbial fuel cells, but this work suggests that no single mediator is ideally suited to the task. Instead, a carefully selected mixture of two targeted mediators (Methylene Blue and Neutral Red) might be optimal. To test this hypothesis, a yeast-catalyzed microbial fuel cell was built and empirically evaluated under different mediation conditions while keeping all other parameters constant. The results clearly show that an appropriate mix of the two mediators mentioned could indeed achieve significantly superior performance, in terms of power-density, than when either mediator is used singly. All tests were carried out using the same overall mediator concentration.

HIV/AIDS is the most threatening and challenging infectious diseases of our time, with the highest increase of newly infected cases reported. This infectious disease was discovered in the early eighties under homosexual men and was later to be discovered in heterosexuals. HIV is a systemic immunosuppressive disorder which causes a depletion of CD4+ T cells and develops into the acquired immunodeficiency syndrome - AIDS. Africa is the continent most affected by HIV/AIDS with the southern parts of Africa having the highest prevalence rates compared to the rest of Africa. Statistics indicate that AIDS is responsible for 3% of deaths in children worldwide - one in seven people dying of an HIV-related illness is a child under the age of 15 years. It was stated by the WHO that countries should develop improved antiretrovirals regimes for the prevention of mother-to-child transmission. Difficulties in administering antiretrovirals (ARVs) to patients (especially children) are the strict dosage regimes and the severe adverse reactions. These factors complicate patient adherence. The list of problems in treating patients is endless and includes the distribution, stability as well as the low efficacy of these drugs. Most of the above mentioned problems and obstacles related to ARVs and ARV treatment could be minimized or eliminated by the use of a stable and effective drug delivery system. Enhancing ARV treatment may be accomplished by the use of the Pheroid™ drug delivery system. Pheroids™ consists mainly of fatty acids and sterile nitrous oxide gassed water. Pharmacological active substances are entrapped into submicron and micron sized structures called Pheroids™. Research showed promising results and advantages in delivering drugs through oral and transdermal routes using Pheroid™ technology. The focus of this study was to test the possible enhancement of the efficacy of antiretrovirals using Pheroid™ technology. The assays used to study this possible enhancement were a modified neutral red and a modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay. These assays confirmed and illustrated the toxic and protective properties of the tested ARVs (stavudine, lamivudine and nevirapine). An MT-2 cell line was used and infected with an HIV-1 strain, SW7-TCL. Applying Pheroid™ technology in these assays resulted in massive cell death, due to increased ARV toxic levels within the cells. Viability tests proved that Pheroids™ had no effect on the viability of cells at the concentration typically used. This confirmed the enhancing properties of Pheroids™ in the delivery of drugs into the cells. The MTT assay was further adapted from a seven day incubation period to a three day incubation period. By using a low concentration series and a three day incubation period the loss of cells through toxicity was partially overcome. One of the problems that arose form this study was the non-reproducibility of the results. Absorbance levels fluctuated at specific concentrations of the same ARV, which cause difficulties in comparing results. This result was repeatedly confirmed in this syncytium forming infection model. In conclusion, Pheroid™ technology enhanced the delivery of ARVs into the cells although it resulted in cell death. Both the neutral red and MTT assays were found to be inaccurate but further development, research and assay optimization could result in improved in vitro studies. The article format was used for this thesis, as described in the general academic rules in section A.13.7.3 of the North West University. Chapter 1 deals with HIV/AIDS related problems, statistics and treatment obstacles. Chapter 2 is a summary of the cell viability assays used in this study. Pheroid™ technology and its application to ARV treatment are dealt with in chapter 3. The proposed article for submission in the journal Cell Death and Differentiation has been included in chapter 4. Some of the results from the study are reported in the article and annexures, whilst other results are shown and discussed in Chapter 5. Chapter 6 gives a conclusion and final summary of this study. All other experimental methods and results are enclosed in the annexures, as is the "Guide for authors" for the article. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

An investigation of luminescent sensing has been presented. Neutral Red, a common pH luminescent sensor, was shown to be an effective carbon dioxide sensor for the first time. Sensing experiments were performed both through fluorometric and fluorescent microscopy studies, giving rise to the possibility of carbon dioxide sensing for biological applications. Neutral Red was benchmarked against the well-established carbon dioxide sensor Pyranine (8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt), HPTS. Neutral Red was shown to have improved response times and higher consistency within the sensing drift compared to HPTS. Trinuclear Au(I) complexes have previously shown to sense metal ions through changes in their luminescent properties. A computational study on d10-d10 interactions, which exist in complexes where Cu+, Ag+, and Au+ are intercalated with [Au(μ-C2,N3-ethylImidazolate)]3 in the form of both half and full sandwich adducts. Binding energies, total density plots, and Morse and Dunham analyses of potential energy surfaces are employed to better understand the metal-metal interactions and the effects of electron correlation, basis set superposition error, and dispersion of metallophilic interactions of the adduct complexes. As metal-metal interactions within these types of complexes become better understood, the tuning of trinuclear Au(I) complexes for luminescent sensing of metals becomes increasingly possible.

Bei Thiomersal handelt es sich um ein quecksilberhaltiges Konservierungsmittel in Medizinprodukten, welches auch in Impfstoffen Verwendung findet. In dieser Arbeit wurden die Toxizität von Thiomersal und von Glutathionkonjugaten seiner Dissoziationsprodukte sowie zum Vergleich die Toxizität von zwei strukturell mit Thiomersal bzw. seinen Metaboliten verwandten Referenzsubstanzen, p-Chlormercuribenzoesäure und Ethylquecksilberchlorid, in Zellsystemen mit humanen Zellen vom Typ A-549 und Hep-G2 untersucht. Alle fünf Substanzen führten zu einer dosisabhängigen Vitalitätsreduktion bei beiden Zelllinien. Die stärkste Vitalitätsreduktion wurde durch Ethylquecksilberchlorid erzielt, danach folgten in absteigender Reihenfolge Thiomersal, Ethylquecksilber-L-Glutathion und p-Chlormercuribenzoesäure. Den schwächsten vitalitätsreduzierenden Effekt zeigte Thiosalicyl-L-Glutathion-Disulfid. Diese Ergebnisse sprechen dafür, dass die Glutathion-Konjugation von Thiomersal zu einer Abschwächung der Toxizität im menschlichen Organismus führt und untermauern die Annahme einer protektiven Wirkung von Glutathion. Die giftende Rolle von Glutathion in Bioaktivierungsprozessen anderer Noxen wird diskutiert. Es wurde im Rahmen dieser Arbeit ein Beitrag zum besseren Verständnis der Toxizität von Thiomersal im humanen Organismus geleistet und darüber hinaus Bezüge zum potentiellen allergenen Potential von Thiomersal hergestellt.

Bei Thiomersal handelt es sich um ein quecksilberhaltiges Konservierungsmittel in Medizinprodukten, welches auch in Impfstoffen Verwendung findet. In dieser Arbeit wurden die Toxizität von Thiomersal und von Glutathionkonjugaten seiner Dissoziationsprodukte sowie zum Vergleich die Toxizität von zwei strukturell mit Thiomersal bzw. seinen Metaboliten verwandten Referenzsubstanzen, p-Chlormercuribenzoesäure und Ethylquecksilberchlorid, in Zellsystemen mit humanen Zellen vom Typ A-549 und Hep-G2 untersucht. Alle fünf Substanzen führten zu einer dosisabhängigen Vitalitätsreduktion bei beiden Zelllinien. Die stärkste Vitalitätsreduktion wurde durch Ethylquecksilberchlorid erzielt, danach folgten in absteigender Reihenfolge Thiomersal, Ethylquecksilber-L-Glutathion und p-Chlormercuribenzoesäure. Den schwächsten vitalitätsreduzierenden Effekt zeigte Thiosalicyl-L-Glutathion-Disulfid. Diese Ergebnisse sprechen dafür, dass die Glutathion-Konjugation von Thiomersal zu einer Abschwächung der Toxizität im menschlichen Organismus führt und untermauern die Annahme einer protektiven Wirkung von Glutathion. Die giftende Rolle von Glutathion in Bioaktivierungsprozessen anderer Noxen wird diskutiert. Es wurde im Rahmen dieser Arbeit ein Beitrag zum besseren Verständnis der Toxizität von Thiomersal im humanen Organismus geleistet und darüber hinaus Bezüge zum potentiellen allergenen Potential von Thiomersal hergestellt.