Nevirapine (NVP) can cause serious idiosyncratic drug reactions (IDRs); specifically, skin rash and hepatotoxicity. Treatment of rats or mice with NVP led to covalent binding to hepatic proteins. Studies of this covalent binding including the use of a deuterated analog of NVP leading to a decrease in oxidation of the methyl group indicated that the metabolite responsible for covalent binding in the liver is a quinone methide. Covalent binding in NVP-treated rats was also observed in the epidermis but by a different pathway. Incubation of 12-OH-NVP sulfate with homogenized human and rat skin led to extensive covalent binding. Inhibition of sulfation in the liver significantly decreased 12-OH-NVP sulfate in the blood, but it did not prevent covalent binding in the skin or the rash. In contrast, topical application of a sulfotransferase inhibitor prevented covalent binding in the skin as well as the rash, but only where it was applied. In contrast to rats, treatment of mice with NVP did not result in covalent binding in the skin or skin rash. These findings provide compelling evidence that 12-OH-NVP sulfate formed in the skin is responsible for the skin rash. IL-1β and IL-18 production in the skin of rats treated with NVP were increased. An anti-IL-1ß antibody significantly decreased rash severity. These cytokines were also produced by incubation of human keratinocytes with 12-OH-NVP sulfate. These data indicate that 12-OH-NVP sulfate activates the NLRP3 inflammasome, a pathway known to be responsible for contact hypersensitivity rashes. In summary, NVP was found to produce two different reactive metabolites, a quinone methide species in the liver, and a benzylic sulfate in the skin. Significant liver injury did not occur, presumably due to immune tolerance. Although it is usually assumed that reactive metabolites are responsible for most IDRs, this is the first example to actually demonstrate that a specific reactive metabolite is responsible for an IDR. This is also the first study to show that sulfotransferase in the skin is responsible for bioactivation of a drug leading to a skin rash. It is likely that there are other drugs that cause skin rashes by a similar mechanism.

Nevirapine (NVP) can cause serious idiosyncratic drug reactions (IDRs); specifically, skin rash and hepatotoxicity. Treatment of rats or mice with NVP led to covalent binding to hepatic proteins. Studies of this covalent binding including the use of a deuterated analog of NVP leading to a decrease in oxidation of the methyl group indicated that the metabolite responsible for covalent binding in the liver is a quinone methide. Covalent binding in NVP-treated rats was also observed in the epidermis but by a different pathway. Incubation of 12-OH-NVP sulfate with homogenized human and rat skin led to extensive covalent binding. Inhibition of sulfation in the liver significantly decreased 12-OH-NVP sulfate in the blood, but it did not prevent covalent binding in the skin or the rash. In contrast, topical application of a sulfotransferase inhibitor prevented covalent binding in the skin as well as the rash, but only where it was applied. In contrast to rats, treatment of mice with NVP did not result in covalent binding in the skin or skin rash. These findings provide compelling evidence that 12-OH-NVP sulfate formed in the skin is responsible for the skin rash. IL-1β and IL-18 production in the skin of rats treated with NVP were increased. An anti-IL-1ß antibody significantly decreased rash severity. These cytokines were also produced by incubation of human keratinocytes with 12-OH-NVP sulfate. These data indicate that 12-OH-NVP sulfate activates the NLRP3 inflammasome, a pathway known to be responsible for contact hypersensitivity rashes. In summary, NVP was found to produce two different reactive metabolites, a quinone methide species in the liver, and a benzylic sulfate in the skin. Significant liver injury did not occur, presumably due to immune tolerance. Although it is usually assumed that reactive metabolites are responsible for most IDRs, this is the first example to actually demonstrate that a specific reactive metabolite is responsible for an IDR. This is also the first study to show that sulfotransferase in the skin is responsible for bioactivation of a drug leading to a skin rash. It is likely that there are other drugs that cause skin rashes by a similar mechanism.

A expressão aumentada de GSK3b em pacientes da doença de Alzheimer (DA), aparentemente está relacionada com a formação de placas senis e emaranhados neurofibrilares. Utilizamos qPCR para avaliar os efeitos do lítio sobre os níveis do mRNA de GSK3a e GSK3b em culturas primárias de neurônios corticais e hipocampais de rato tratados com lítio. Nossos resultados, sugeriram que lítio é capaz de reduzir os níveis de mRNA de Gsk3b hipocampal de modo específico e dose-dependente. Estes dados foram subsequentemente comprovados in vivo em amostras cerebrais de ratos tratados com LiCl. Utilizamos hibridização subtrativa de cDNA e eletroforese bidimensional de culturas de neurônios hipocampais tratados com o lítio. Nossos estudos sugeriram a expressão diferencial de 88 genes, além de oito proteínas com cerca de 50% de alteração de expressão. Estas observações sugerem novos efeitos regulatórios do lítio sobre GSK3b e fornecem potenciais alvos da ação do lítio. / The increased systemic expression of active GSK3b in Alzheimers disease (AD) patients apparently is associated with the formation of senile plaques and neurofibrillary tangles, the hallmarks of this disease. In this study we used qPCR to evaluate the transcriptional regulation of GSK3a and GSK3b in lithium-treated primary cultures of rat cortical and hippocampal neurons. We found a significant and dose-dependent reduction in the mRNA levels of GSK3b, which was specific to hippocampus. This same effect was further confirmed in vivo by measuring GSK3 expression in different brain regions of adult rats treated with lithium. We used subtractive hybridizations and two-dimensional electrophoresis patterns of culture of hippocampus neurons treated with lithium. Our study suggested 88 genes differently expressed besides 8 proteins identified with variation expression. These observations suggest new regulatory effects of lithium over GSK3b and suggesting new potential lithium action targets.

A expressão aumentada de GSK3b em pacientes da doença de Alzheimer (DA), aparentemente está relacionada com a formação de placas senis e emaranhados neurofibrilares. Utilizamos qPCR para avaliar os efeitos do lítio sobre os níveis do mRNA de GSK3a e GSK3b em culturas primárias de neurônios corticais e hipocampais de rato tratados com lítio. Nossos resultados, sugeriram que lítio é capaz de reduzir os níveis de mRNA de Gsk3b hipocampal de modo específico e dose-dependente. Estes dados foram subsequentemente comprovados in vivo em amostras cerebrais de ratos tratados com LiCl. Utilizamos hibridização subtrativa de cDNA e eletroforese bidimensional de culturas de neurônios hipocampais tratados com o lítio. Nossos estudos sugeriram a expressão diferencial de 88 genes, além de oito proteínas com cerca de 50% de alteração de expressão. Estas observações sugerem novos efeitos regulatórios do lítio sobre GSK3b e fornecem potenciais alvos da ação do lítio. / The increased systemic expression of active GSK3b in Alzheimers disease (AD) patients apparently is associated with the formation of senile plaques and neurofibrillary tangles, the hallmarks of this disease. In this study we used qPCR to evaluate the transcriptional regulation of GSK3a and GSK3b in lithium-treated primary cultures of rat cortical and hippocampal neurons. We found a significant and dose-dependent reduction in the mRNA levels of GSK3b, which was specific to hippocampus. This same effect was further confirmed in vivo by measuring GSK3 expression in different brain regions of adult rats treated with lithium. We used subtractive hybridizations and two-dimensional electrophoresis patterns of culture of hippocampus neurons treated with lithium. Our study suggested 88 genes differently expressed besides 8 proteins identified with variation expression. These observations suggest new regulatory effects of lithium over GSK3b and suggesting new potential lithium action targets.

Nevirapine (NVP) can cause serious skin rashes and hepatotoxicity. It also causes an immune-mediated skin rash in rats but not hepatotoxicity. There is strong evidence that the rash is due to 12-hydroxynevirapine (12-OH-NVP), which is further metabolized to a reactive benzylic sulfate in the skin. This could both act as a hapten and induce a danger signal. In contrast, most of the covalent binding in the liver appears to involve oxidation of the methyl group leading to a reactive quinone methide. In this study we examined the effects of NVP and 12-OH-NVP on gene expression in the liver and skin. Both NVP and 12-OH-NVP induced changes in the liver, but the list of genes was different, presumably reflecting different bioactivation pathways. In contrast, many more genes were up-regulated in the skin by 12-OH-NVP than by NVP, which is consistent with the hypothesis that the 12-hydroxylation pathway is involved in causing the rash. Some genes up-regulated by 12-OH-NVP were Trim63, S100a7a, and IL22ra2, etc. Up-regulation of genes such as S100a7a, which is considered a danger signal, supports the danger hypothesis. Up-regulation of genes such as the ubiquitin ligase and Trim63 are consistent with protein-adduct formation. Up-regulation of IL-22ra2 gene suggests an immune response. These results provide important clues to how NVP causes induction of an immune response, in some cases leading to an idiosyncratic drug reaction.

Nevirapine (NVP) can cause serious skin rashes and hepatotoxicity. It also causes an immune-mediated skin rash in rats but not hepatotoxicity. There is strong evidence that the rash is due to 12-hydroxynevirapine (12-OH-NVP), which is further metabolized to a reactive benzylic sulfate in the skin. This could both act as a hapten and induce a danger signal. In contrast, most of the covalent binding in the liver appears to involve oxidation of the methyl group leading to a reactive quinone methide. In this study we examined the effects of NVP and 12-OH-NVP on gene expression in the liver and skin. Both NVP and 12-OH-NVP induced changes in the liver, but the list of genes was different, presumably reflecting different bioactivation pathways. In contrast, many more genes were up-regulated in the skin by 12-OH-NVP than by NVP, which is consistent with the hypothesis that the 12-hydroxylation pathway is involved in causing the rash. Some genes up-regulated by 12-OH-NVP were Trim63, S100a7a, and IL22ra2, etc. Up-regulation of genes such as S100a7a, which is considered a danger signal, supports the danger hypothesis. Up-regulation of genes such as the ubiquitin ligase and Trim63 are consistent with protein-adduct formation. Up-regulation of IL-22ra2 gene suggests an immune response. These results provide important clues to how NVP causes induction of an immune response, in some cases leading to an idiosyncratic drug reaction.

M.Tech. / Diaper dermatitis (Nappy Rash) is an acute inflammation of the skin in the diaper area and is the most common cutaneous disease among infants and children (Concannon et al., 2001). It is estimated that 7% - 35% of diaper wearing infants are affected by Diaper dermatitis during the period of wearing diapers (Barkin and Rosen, 2003). The exact prevalence is not known as many cases are selfmedicated by parents or guardians (Wolf et al., 2000). Diaper dermatitis causes severe discomfort to the infants as well as anxiety and worry for the parents. Diaper dermatitis is characterised by redness, inflammation, dryness, scaling, itching, irritability, pain, satellite lesions, papulovesicular or pustular eruptions, and in severe cases ulceration of the skin (Visscher and Hoath, 2006). This study aimed to assess the efficacy of a Homoeopathic complex cream as a topical treatment for Diaper dermatitis. The complex consisted of Atropa belladonna 6cH, Calendula officinalis D1 and Sulphuricum acidum 6cH. Madaji milking cream was used as a base which contained: chlorhexidene; vitamin E; and lanolin. The treatment group received the medicated Madaji milking cream whereas the control group received the unmedicated Madaji milking cream. The Diaper dermatitis was evaluated using a 4-Point Grading Scale (Appendix D) and The Modified Lund and Browder Chart (Appendix E). Forty participants who met the inclusion and exclusion criteria were recruited to participate in this double blind control study by means of advertisements (Appendix A) that were placed on notice boards at the various campuses of the University of Johannesburg, nursery schools and hospitals, with relevant permission given. Participants were also recruited via word of mouth. Once participants were accepted into the study they were allocated to either Group A or Group B using matched pairs according to severity in order to ensure equal v distribution in both groups. There were 20 participants in each group. Group A was the treatment group which received the medicated Madaji milking cream. Group B was the control group which received the unmedicated Madaji cream. The study was completed over a seven day period. The ten areas most commonly affected by Diaper dermatitis were evaluated on the initial visit, day two, day four and day seven.

Appalachian writing brings a voice to the region that is often obstructed or excluded by popular culture throughout the United States. Crowded with stereotypes, many stories of Appalachian culture are misconstrued or never heard at all. This makes the work of modern Appalachian writers especially significant. Perhaps one of the best ways to reach a broader audience of people in this fast-paced digital time is through shorter writings, and in this thesis I will be presenting my process of writing modern flash fiction and poetry and of sharing the truths of working class, Appalachian people.

Ron Rash’s Serena and Ann Pancake’s Strange as This Weather Has Been are two contemporary Appalachian novels that have yet to be analyzed from a biblical ecocritical perspective. While some literary scholars acknowledge the environmental aspects of the novels, little of their research goes beyond examining the land and its resources as commodities or metaphorical extensions for the characters. In this thesis, I elaborate on those interpretations by scrutinizing the natural descriptions in both novels and comparing those findings to some of the landscapes and environmental verses located within the Bible. Unlike the pastoral ideal found in a portion of the literature preceding the twentieth century, contemporary Appalachian writers such as Rash and Pancake have moved away from such a bucolic, prelapsarian idealization in favor of limning a more industrialized, postlapsarian Appalachia. Following both analyses, I conclude by predicting how emerging Appalachian writers will portray the landscape in future works.

Hudutslag ären vanlig kontaktorsak inom primärvården och därför möter distriktssköterskan dagligen patienter med olika typer av hudutslag. Hudutslag oavsett diagnos eller etiologi, drabbar stora delar av världens befolkning och kan påverka människors livskvalitet negativt. I rollen som distriktssköterska innebär det att självständigt kunna bedöma och undersöka hudutslag. Genom förskrivningsrätten har distriktssköterskan möjlighet att förskriva behandling och därmed lindra patientens besvär men också kontakt med andra professiner för att remittera vidare. Syfte: Syftet med studien är att belysa distriktssköterskors erfarenheter av att bedöma personer med hudutslag inom primärvården. Metod: En kvalitativ intervjustudie med åtta distriktssköterskor inom primärvården i Hallands län. Data analyserades med en manifest kvalitativ innehållsanalys med induktiv ansats. Resultat: Tre kategorier med fem subkategorier indentifierades; Regelbundna bedömningar, Organisatoriska förutsättningar, Erfarenhetens betydelse. Slutsats: Studien belyser distriktssköterskans erfarenhet av att bedöma hudutslag och utmärkande för studien är att det är den yrkesverksamma tiden som skapar erfarenheten samt vikten av teamarbete vid bedömningar. Samtliga distriktssköterskor upplever att hudbedömningar är komplexomvårdnad och önskar mer utbildning inom området. En förbättrad kunskap inom området kan leda till minskat vårdbehov då flera korrekta bedömningar utförs.