Thesis (M.S.)--West Virginia University, 2007. / Title from document title page. Document formatted into pages; contains ix, 117 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 60-68).

While proponents of process saw a contradiction in the current-traditional pedagogy--teaching toward product marginalized valuable practices embedded in the processes of writing--post-process scholars sought to move beyond attempts to codify writing processes for easy instruction. Because it avoids resting upon foundations, the critical focus of post-process does not allow for easy pedagogical application. In order to navigate the post-process theoretical impasse, I argue for an approach to composition pedagogy that emphasizes a performative and sophistic aspect of topical reasoning that when practiced challenges Cartesian self-certainty and works to transform subjectivity. Through communicating judgments of similarity and difference within any given situation, the performance of topical reasoning serves to either reproduce or transform the customary understanding of the rhetor's community; the latter is the exception, the former the rule within our inherited rhetorical traditions. Derivative of the efforts of Plato and Aristotle to discipline rhetoric, and especially following the emergence of the Enlightenment project, rhetorical traditions that exclude sophistic perspectives have continued to understand topics as codified sets of rules a rhetor simply follows to invent discourse, making the topics easily dismissible because invention had become a matter of reporting on reality or of following inner inspiration. While several projects to employ topics in composition pedagogy have emerged during the late 20th century--spanning process, post-process, and new rhetorical pedagogies--the performative dimension of topical reasoning has been overlooked, or left to the realm of theory because of its radical nature vis-a-vis university composition courses. Building from a Heideggerian reading of the topics, and through an extensive analysis of the sophistic pedagogic practices employed in a weekend seminar called the Landmark Forum, I work to develop a full understanding of topical reasoning as primarily performative, where only in risky moments of performance can one undergo an experience with language and so develop a rhetorical subjectivity receptive to recalcitrance while maintaining integrity to one's commitments. I claim that to "learn" topical reasoning requires a program of rigorous dialogic exercise, an ontological paideia, which calls for performances that revise identity and the networks of rhetorical relationships that reinforce identity.

1,25-dihydroxyvitamin D3 (Vitamin D) is a potent immunomodulator capable of generating regulatory T cells (Tregs) and contributing to immune tolerance. Additionally, vitamin D has been shown to promote mucosal immunity when used as a vaccine adjuvant. We show here that pretreatment of an area of skin with the synthetic vitamin D analog calcipotriol combined with transcutaneous immunization results in the induction of CD4⁺CD25⁺ Tregs capable of inhibiting the elicitation of a contact hypersensitivity response. We also demonstrate that topical calcipotriol has significant effects on the immune response to subcutaneously injected vaccines, and compare it with another common topical immunosuppressant, the corticosteroid betamethasone-17-valerate (BMV). Functionally, calcipotriol and BMV treatment both result in the suppression of CD8⁺ T cell priming in response to subcutaneous vaccination, despite the topical co-administration of the potent Th1 inducing TLR9 agonist unmethylated CpG DNA. The effects of calcipotriol on the humoral response are subtler as we observe marginally increased production of antigen-specific IgG1 immunoglobulins along with a strong suppression of the IgG2a isotype. This is in contrast to pretreatment with BMV, which instead suppresses the production of IgG1 and IgA antibodies. In the draining lymph nodes of calcipotriol treated animals, we see no change in the percentage of Foxp3⁺ CD4⁺ T cells post-immunization, but show that tolerance is transferable with the adoptive transfer of CD4⁺CD25⁺ cells. Despite a decrease in the percentage of antigen-bearing APCs in the DLN of calcipotriol treated animals, the DCs maintain high expression of co-stimulatory markers and can induce CD4⁺ T cell proliferation ex vivo. Our data indicate that calcipotriol has distinct effects on immune responses to subcutaneous vaccines consistent with its role as an immunomodulator, although the mechanism(s) through which it is acting remain unclear. We believe that further research is warranted into its potential use as part of a treatment modality for allergy and autoimmune disorders.

Insect repellent N,N-diethyl-m-toluamide (DEET) and sunscreen oxybenzone are commonly incorporated into commercially available repellent and sunscreen preparations. Both compounds have demonstrated an increased percutaneous permeation and systemic disposition after concurrent application in vitro and in vivo. The permeation enhancement between DEET and oxybenzone not only compromises their respective protective efficacy against biting insects and UV radiation, but also potentiates toxicological properties in susceptible subjects. The pharmacokinetic and toxicological profiles from concurrent use of DEET and oxybenzone were evaluated and compared in this thesis. DEET and oxybenzone were administered by intravenous and topical routes in rats, either alone and/or in combination, to compare the pharmacokinetics of parent compounds and their primary metabolites in vivo. To evaluate toxicological characteristics, rat primary cortical neurons and astrocytes, and rat hepatoma 1548 cells were exposed to DEET, oxybenzone and their metabolites in vitro, and cell viability was analyzed. Various behavioral testing protocols were also performed to assess arousal, locomotion, habituation, and motor coordination of rats over a 30-day study period. Concurrent topical application of DEET and oxybenzone enhanced the disposition of DEET and its metabolites in rats, but did not consistently affect the distribution of oxybenzone and its metabolites. The disappearance of DEET from skin application site was accelerated; its apparent elimination half-life was decreased while its plasma and tissue concentrations were predominantly increased. Cellular toxicity occurred at 1 μg/ml for neurons and 7-day exposure for both astrocytes and neurons. Viability of hepatoma cells was also reduced when treated with DEET, oxybenzone and their metabolites, either alone or in combination, most notably after 72 hours of exposure. However, no overt signs of toxicity were observed from behavioral testing in rats after a 30-day topical study. The pharmacokinetic data obtained was beneficial in understanding and elucidating absorption and biodistribution of DEET and oxybenzone in vivo. The toxicological data suggested that the risk for increasing adverse effects from concurrent skin application of repellents and sunscreens would be low and marginal in healthy individuals. Nevertheless, further studies should be carried out to assess the long-term health impact of these compounds in susceptible subjects, especially at higher application doses.

The aim of this in vitro study was to investigate the feasibility of the transdermal delivery of isoniazid (INH) and rifampicin (RMP) by means of the novel PheroidTM technology system. 'The application of the latter is being investigated in combination with various actives such as peptides (insulin, human growth hormone), anti-malarial drugs (chloroquine), anti-fungals (ketoconazole), local anaesthetics (lidocaine, prilocaine) as well as tuberculostatics (ethambutol, pyrazinamide etc.) via different administration routes at the North- West University. PheroidTM, a stable skin-friendly carrier, comprises of a submicron (200 nm - 2 m) emulsion type formulation for which previous studies have confirmed the ability to penetrate keratinised tissue, skin, intestinal linings, the vascular system, fungi, bacteria and even parasites. Studies involving an oral PheroidTM formulation containing the current approved regime of four anti-tuberculosis drugs showed improved efficacy results whilst an in vitro analysis of bacterial growth indicated a reduction in drug resistance in multidrug resistant tuberculosis (MDR-TB) strains. Therefore we thought it prudent to ascertain whether or not the PheroidTM system would be able to improve the transdermal delivery of a combination of INH and RMP as a possible treatment against cutaneous tuberculosis (tuberculosis involving the skin). The latter refers to pathological lesions of the skin caused by any one of the following: Mycobacterium tuberculosis, Mycobacterium bovis or the bacilli Calmette- Guerin (BCG) vaccine. Demonstration of M. tuberculosis within the infected tissues by traditional acid-fast bacilli (AFB) staining, culture or polymerase chain reaction (PCR) confirms the diagnosis. CTB lesions are associated with various degrees of one or more of the following ulceration, plaque formation, hyperkeratosis or the presence of necrotic matter. Seeing as C-TB is mostly associated with systemic involvement, current treatment comprises of the standard three/four drug regimens used for pulmonary 'TB in general. Cases of CTB usually show improvement within 1 month of therapy with anti-TB drugs, but complete resolution is only attained after 4 - 6 months. 'The major drawback to current therapy is that patients not only remain a source of infection (viable organisms can still be demonstrated in the lesions), but they also suffer from constant embarrassment due to the disfiguring nature of CTB until these lesions have healed completely. No evidence of an already existing topical formulation of this kind could be found. Therefore in vitro permeation studies were conducted using vertical Franz diffusion cells and female abdominal skin as permeation membrane over a period of 12 hours. Concentrations of 5 mg/ml and 10 mg/ml for isoniazid( INH) and rifampicin (RMP) respectively, were applied to the donor phase suspended in either phosphate buffered saline (PBS) or entrapped in PheroidTM. Permeation studies were conducted at pH 5.5. In vitro penetration of INH and RMP were assayed directly by HPLC. Particle size distribution for rifampicin and entrapment of actives within the PheroidTM carrier system was determined by polarized light and laser scanning microscopy (CLSM) respectively and revealed definite entrapment. Permeation profiles obtained for INH in PheroidTM indicated a biphasic character, whilst that obtained for RMP in PheroidTM showed a triphasic character. The PheroidTM delivery system proved more efficacious for delivery of both anti-tubercular drugs and resulted in greater percentage yield as well as flux values than that for a PBS solution. Furthermore, the PheroidTM formulation was able to deliver, the entrapped INH and RMP in concentrations sufficient to exceed their respective minimum inhibitory concentrations (MIC). / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

Aging can be described as an extremely complex occurrence from which no organism can be excluded. Intrinsic and extrinsic aging make out the two components of skin aging and they differ on the macromolecular level while sharing specific molecular characteristics which include elevated levels of reactive oxygen species (ROS) and matrix metalloproteinase (MMP) while collagen synthesis decreases. The skin functions as a protective barrier against the harsh environment and is essential for regulating body temperature. The stratum corneum (SC) is responsible for the main resistance to the penetration of most compounds; nevertheless the skin represents as an appropriate target for delivery. The target site for anti-aging treatment includes the epidermal and dermal layers of the skin. Calendula oil and L-carnitine L-tartrate was utilised as the cosmeceutical actives as they can be classified as a mixed category of compounds/products that lie between cosmetics and drugs. Both show excellent properties which can prove valuable during anti-aging treatment, whether it is due to the scavenging of ROS (calendula oil), moisturising effects (calendula oil and L-carnitine L-tartrate) or the improvement of the skin turnover rate (L-carnitine L-tartrate). The Pheroid™ delivery system can enhance the absorption of a selection of active ingredients. The aim of this study was to determine whether the Pheroid™ delivery system will enhance the flux and/or delivery of the named actives to the target site by performing Franz cell diffusion studies over an 8 h period, followed by tape stripping experiments. The Pheroid™ results of the actives were compared to the results obtained when 1 00 % calendula oil was applied and the L-carnitine L-tartrate was dissolved in phosphate buffer solution (PBS), respectively. In the case of calendula oil only a qualitative gas chromatography mass spectrometry (GC/MS) method could be employed. No calendula oil was observed to permeate through the skin, but linoleic acid (marker compound) was present in the epidermis and dermis layers. Components in the Pheroid™ delivery system hampered the results as the marker compound identified is a fundamental component of the Pheroid™, making it difficult to determine whether or not the Pheroid™ delivery system enhanced calendula oil's penetration. The aqueous solubility and log D partition coefficient of L-carnitine L-tartrate was determined. Inspection of the log D value of -1.35 indicated that the compound is unfavourable to penetrate the skin, whereas the aqueous solubility of 16.63 mg/ml in PBS at a temperature of 32º C indicated favourable penetration. During the Franz cell diffusion and tape stripping studies it was determined by liquid chromatography mass spectrometry (LC/MS) that carnitine may be inherent to human skin. Pheroid™ enhanced the flux (average of 0.0361 µg/cm2.h, median of 0.0393 µg/cm2.h) of the L-carnitine L-tartrate when compared to PBS (average of 0.0180 µg/cm2.h, median of 0.0142 µg/cm2.h ) for the time interval of 2 -8 h. The PBS was more effective in delivering the active to the target site (0.270 µg/ml in the epidermis and 2.403 µg/ml in the dermis) than Pheroid™ (0.111 µg/ml and 1.641 µg/ml in the epidermis and dermis respectively). Confocal laser scanning microscopy (CLSM) confirmed the entrapment of L-carnitine L-tartrate in the Pheroid™ vesicle, while in the case of calendula oil it was impossible to differentiate between the oil and the Pheroid™ components. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2009.

Insect repellent N,N-diethyl-m-toluamide (DEET) and sunscreen oxybenzone are commonly incorporated into commercially available repellent and sunscreen preparations. Both compounds have demonstrated an increased percutaneous permeation and systemic disposition after concurrent application in vitro and in vivo. The permeation enhancement between DEET and oxybenzone not only compromises their respective protective efficacy against biting insects and UV radiation, but also potentiates toxicological properties in susceptible subjects. The pharmacokinetic and toxicological profiles from concurrent use of DEET and oxybenzone were evaluated and compared in this thesis. DEET and oxybenzone were administered by intravenous and topical routes in rats, either alone and/or in combination, to compare the pharmacokinetics of parent compounds and their primary metabolites in vivo. To evaluate toxicological characteristics, rat primary cortical neurons and astrocytes, and rat hepatoma 1548 cells were exposed to DEET, oxybenzone and their metabolites in vitro, and cell viability was analyzed. Various behavioral testing protocols were also performed to assess arousal, locomotion, habituation, and motor coordination of rats over a 30-day study period. Concurrent topical application of DEET and oxybenzone enhanced the disposition of DEET and its metabolites in rats, but did not consistently affect the distribution of oxybenzone and its metabolites. The disappearance of DEET from skin application site was accelerated; its apparent elimination half-life was decreased while its plasma and tissue concentrations were predominantly increased. Cellular toxicity occurred at 1 μg/ml for neurons and 7-day exposure for both astrocytes and neurons. Viability of hepatoma cells was also reduced when treated with DEET, oxybenzone and their metabolites, either alone or in combination, most notably after 72 hours of exposure. However, no overt signs of toxicity were observed from behavioral testing in rats after a 30-day topical study. The pharmacokinetic data obtained was beneficial in understanding and elucidating absorption and biodistribution of DEET and oxybenzone in vivo. The toxicological data suggested that the risk for increasing adverse effects from concurrent skin application of repellents and sunscreens would be low and marginal in healthy individuals. Nevertheless, further studies should be carried out to assess the long-term health impact of these compounds in susceptible subjects, especially at higher application doses.

The aim of this in vitro study was to investigate the feasibility of the transdermal delivery of isoniazid (INH) and rifampicin (RMP) by means of the novel PheroidTM technology system. 'The application of the latter is being investigated in combination with various actives such as peptides (insulin, human growth hormone), anti-malarial drugs (chloroquine), anti-fungals (ketoconazole), local anaesthetics (lidocaine, prilocaine) as well as tuberculostatics (ethambutol, pyrazinamide etc.) via different administration routes at the North- West University. PheroidTM, a stable skin-friendly carrier, comprises of a submicron (200 nm - 2 m) emulsion type formulation for which previous studies have confirmed the ability to penetrate keratinised tissue, skin, intestinal linings, the vascular system, fungi, bacteria and even parasites. Studies involving an oral PheroidTM formulation containing the current approved regime of four anti-tuberculosis drugs showed improved efficacy results whilst an in vitro analysis of bacterial growth indicated a reduction in drug resistance in multidrug resistant tuberculosis (MDR-TB) strains. Therefore we thought it prudent to ascertain whether or not the PheroidTM system would be able to improve the transdermal delivery of a combination of INH and RMP as a possible treatment against cutaneous tuberculosis (tuberculosis involving the skin). The latter refers to pathological lesions of the skin caused by any one of the following: Mycobacterium tuberculosis, Mycobacterium bovis or the bacilli Calmette- Guerin (BCG) vaccine. Demonstration of M. tuberculosis within the infected tissues by traditional acid-fast bacilli (AFB) staining, culture or polymerase chain reaction (PCR) confirms the diagnosis. CTB lesions are associated with various degrees of one or more of the following ulceration, plaque formation, hyperkeratosis or the presence of necrotic matter. Seeing as C-TB is mostly associated with systemic involvement, current treatment comprises of the standard three/four drug regimens used for pulmonary 'TB in general. Cases of CTB usually show improvement within 1 month of therapy with anti-TB drugs, but complete resolution is only attained after 4 - 6 months. 'The major drawback to current therapy is that patients not only remain a source of infection (viable organisms can still be demonstrated in the lesions), but they also suffer from constant embarrassment due to the disfiguring nature of CTB until these lesions have healed completely. No evidence of an already existing topical formulation of this kind could be found. Therefore in vitro permeation studies were conducted using vertical Franz diffusion cells and female abdominal skin as permeation membrane over a period of 12 hours. Concentrations of 5 mg/ml and 10 mg/ml for isoniazid( INH) and rifampicin (RMP) respectively, were applied to the donor phase suspended in either phosphate buffered saline (PBS) or entrapped in PheroidTM. Permeation studies were conducted at pH 5.5. In vitro penetration of INH and RMP were assayed directly by HPLC. Particle size distribution for rifampicin and entrapment of actives within the PheroidTM carrier system was determined by polarized light and laser scanning microscopy (CLSM) respectively and revealed definite entrapment. Permeation profiles obtained for INH in PheroidTM indicated a biphasic character, whilst that obtained for RMP in PheroidTM showed a triphasic character. The PheroidTM delivery system proved more efficacious for delivery of both anti-tubercular drugs and resulted in greater percentage yield as well as flux values than that for a PBS solution. Furthermore, the PheroidTM formulation was able to deliver, the entrapped INH and RMP in concentrations sufficient to exceed their respective minimum inhibitory concentrations (MIC). / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

Aging can be described as an extremely complex occurrence from which no organism can be excluded. Intrinsic and extrinsic aging make out the two components of skin aging and they differ on the macromolecular level while sharing specific molecular characteristics which include elevated levels of reactive oxygen species (ROS) and matrix metalloproteinase (MMP) while collagen synthesis decreases. The skin functions as a protective barrier against the harsh environment and is essential for regulating body temperature. The stratum corneum (SC) is responsible for the main resistance to the penetration of most compounds; nevertheless the skin represents as an appropriate target for delivery. The target site for anti-aging treatment includes the epidermal and dermal layers of the skin. Calendula oil and L-carnitine L-tartrate was utilised as the cosmeceutical actives as they can be classified as a mixed category of compounds/products that lie between cosmetics and drugs. Both show excellent properties which can prove valuable during anti-aging treatment, whether it is due to the scavenging of ROS (calendula oil), moisturising effects (calendula oil and L-carnitine L-tartrate) or the improvement of the skin turnover rate (L-carnitine L-tartrate). The Pheroid™ delivery system can enhance the absorption of a selection of active ingredients. The aim of this study was to determine whether the Pheroid™ delivery system will enhance the flux and/or delivery of the named actives to the target site by performing Franz cell diffusion studies over an 8 h period, followed by tape stripping experiments. The Pheroid™ results of the actives were compared to the results obtained when 1 00 % calendula oil was applied and the L-carnitine L-tartrate was dissolved in phosphate buffer solution (PBS), respectively. In the case of calendula oil only a qualitative gas chromatography mass spectrometry (GC/MS) method could be employed. No calendula oil was observed to permeate through the skin, but linoleic acid (marker compound) was present in the epidermis and dermis layers. Components in the Pheroid™ delivery system hampered the results as the marker compound identified is a fundamental component of the Pheroid™, making it difficult to determine whether or not the Pheroid™ delivery system enhanced calendula oil's penetration. The aqueous solubility and log D partition coefficient of L-carnitine L-tartrate was determined. Inspection of the log D value of -1.35 indicated that the compound is unfavourable to penetrate the skin, whereas the aqueous solubility of 16.63 mg/ml in PBS at a temperature of 32º C indicated favourable penetration. During the Franz cell diffusion and tape stripping studies it was determined by liquid chromatography mass spectrometry (LC/MS) that carnitine may be inherent to human skin. Pheroid™ enhanced the flux (average of 0.0361 µg/cm2.h, median of 0.0393 µg/cm2.h) of the L-carnitine L-tartrate when compared to PBS (average of 0.0180 µg/cm2.h, median of 0.0142 µg/cm2.h ) for the time interval of 2 -8 h. The PBS was more effective in delivering the active to the target site (0.270 µg/ml in the epidermis and 2.403 µg/ml in the dermis) than Pheroid™ (0.111 µg/ml and 1.641 µg/ml in the epidermis and dermis respectively). Confocal laser scanning microscopy (CLSM) confirmed the entrapment of L-carnitine L-tartrate in the Pheroid™ vesicle, while in the case of calendula oil it was impossible to differentiate between the oil and the Pheroid™ components. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2009.

1,25-dihydroxyvitamin D3 (Vitamin D) is a potent immunomodulator capable of generating regulatory T cells (Tregs) and contributing to immune tolerance. Additionally, vitamin D has been shown to promote mucosal immunity when used as a vaccine adjuvant. We show here that pretreatment of an area of skin with the synthetic vitamin D analog calcipotriol combined with transcutaneous immunization results in the induction of CD4⁺CD25⁺ Tregs capable of inhibiting the elicitation of a contact hypersensitivity response. We also demonstrate that topical calcipotriol has significant effects on the immune response to subcutaneously injected vaccines, and compare it with another common topical immunosuppressant, the corticosteroid betamethasone-17-valerate (BMV). Functionally, calcipotriol and BMV treatment both result in the suppression of CD8⁺ T cell priming in response to subcutaneous vaccination, despite the topical co-administration of the potent Th1 inducing TLR9 agonist unmethylated CpG DNA. The effects of calcipotriol on the humoral response are subtler as we observe marginally increased production of antigen-specific IgG1 immunoglobulins along with a strong suppression of the IgG2a isotype. This is in contrast to pretreatment with BMV, which instead suppresses the production of IgG1 and IgA antibodies. In the draining lymph nodes of calcipotriol treated animals, we see no change in the percentage of Foxp3⁺ CD4⁺ T cells post-immunization, but show that tolerance is transferable with the adoptive transfer of CD4⁺CD25⁺ cells. Despite a decrease in the percentage of antigen-bearing APCs in the DLN of calcipotriol treated animals, the DCs maintain high expression of co-stimulatory markers and can induce CD4⁺ T cell proliferation ex vivo. Our data indicate that calcipotriol has distinct effects on immune responses to subcutaneous vaccines consistent with its role as an immunomodulator, although the mechanism(s) through which it is acting remain unclear. We believe that further research is warranted into its potential use as part of a treatment modality for allergy and autoimmune disorders.