Thesis (M.S.)--University of Wisconsin--Madison, 1969. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

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CYP3A4 is the most abundant P450 enzyme expressed in the human liver and it is responsible for the metabolism of approximately 50% of all clinically administrated drugs. The CYP3A4 gene is transcriptionally regulated by xenobiotics and previous work has demonstrated the first 300bp of proximal promoter to be the minimal requirement for such activation. Several nuclear receptors (CAR, SXR) have been shown to be involved in the induction of the CYP3A4 gene. The aim of this work was to further delineate the molecular basis of CYP3A4 gene expression. In vitro DNase I footprinting was carried out using HepG2 nuclear extracts to map the sites of DNA-protein interaction within the -301/+7 region of the CYP3A4 gene. Putative protein assignment for these sites using in silico analysis revealed the potential binding of transcription factors previously shown to be involved in the regulation of other CYP genes (Sp1, HNF3 and C/EBP?) at the identified protein-DNA interaction sites. These regulatory regions were then disrupted by mutagenesis and their functional effect assessed by transient transfections of reporter gene plasmids into HuH7 hepatoma cells. Statistically significant reductions of reporter gene expression were observed when putative C/EBPa and HNF sites were altered, in both the basal and rifampicin (SXR ligand) induced states. This finding suggests the involvement of proteins binding at these sites in the regulation of the CYP3A4 gene expression. An examination of the CYP3A4 promoter (-1056/+7) from 11 human DNA samples exhibiting a 14.3 fold variability in CYP3A mediated metabolism failed to show the presence of mutations. Protein-DNA interaction analysis were carried out within the newly identified CYP3A4*IE and CYP3A4*1F alleles as well as the CYP3A4 *1B allele. The results implicate the Spl transcription factor in the regulation of the CYP3A4 gene, albeit at a more distal binding site. The findings described in this thesis suggest a substantial involvement of transcription factors other than SXR/CAR in expression of CYP3A4. Because of the polymorphic expression of several liver- and hormone-dependent transcription factors their role in CYP3A4 regulation must be taken into account to understand drug-induction mechanisms and assess variability in inter-individual drug response.

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Thesis (M. Phil.)--University of Hong Kong, 1972. / Typewritten.

Dihydromyricetin (DMH) is a natural flavonoid compound with positive effects on the human organism. In traditional Chinese medicine, plants containing DMH were used to treat liver diseases and to reduce alcohol intoxication. The effects of DHM on ethanol metabolism are not yet completely understood. Effects of DHM during alcohol intoxication were studied on primary hepatocytes of rats. DCFDA and DHR probes were used to prove that DHM (depending on concentration) reduces the number of reactive oxygen and nitrogen species in primary hepatocytes. However, the hepatoprotective effects of DHM were not achieved when presence of the alanine aminotransferase (ALT) was used to measure the damage of cells exposed to alcohol. Further, the effects of DHM on alcohol metabolism were studied in vivo. Rats were administered with single dose of ethanol or ethanol combined with DHM. Measured blood levels of ethanol and acetaldehyde show that DHM has no effects on the rate or levels of alcohol metabolism. The effects of DHM were also studied with repeated alcohol administration. In the group that was administered also DHM, increased blood levels of ethanol were measured. This points that DHM slow down the metabolic rate of ethanol. Obtained results did not prove any positive effects of DHM on alcohol metabolism....

Philosophiae Doctor - PhD / This thesis is about HELLP Syndrome (hemolysis, elevated liver enzymes, low platelet count in pregnancy): a devastating maternal hypertensive complication that results in multi-system changes that can rapidly deteriorate into organ failure and death. Despite rapid advancesin medical technology and medical science this disease continues to take the lives of women and their infants. The only effective intervention for this disorder is immediate termination irrespective of the gestational stage of the pregnancy. The primary objective of this thesis was to explore the subjective experiences and meaningmaking processes of women in and through their high-risk pregnancies. This objective crystallised into the following aims: to facilitate and listen to the voices of women who were HELLP Syndrome survivors; to explore the reported bodily, psychological and emotional experiences of HELLP Syndrome survivors; to understand the role medical intervention and biomedical discourses play in these women’s experiences and finally to explore the subjective experiences of HELLP Syndrome in the context of traditionallyheld notions of motherhood. The study was couched in a feminist poststructuralist epistemology. A material-discursive framework which comprised phenomenological and poststructuralist theorising was usedin an attempt to understand both the lived experiences as well as the discursively constructed nature of those subjective experiences. Thus the analysis encompassed both a broadly phenomenological framework to understand the lived experiences of HELLP Syndrome, and a discourse analysis to explore the meaning-making processes of participants in relation to larger social discourses, in particular the dominant biomedical and motherhood discourses. A qualitative approach using in depth semi-structured interviews was utilisedto gather data. Eleven participants from very diverse backgrounds consented to be part of thisstudy. The findings of the study highlighted the immense trauma, difficulties and challenges participants faced in these high-risk situations. What was evident from the analysis was that their experiences were so diverse and werecompletely shaped by the severity of the disorder and the gestational stage of the pregnancy. Some women ended up in the Intensive Care Units (ICU) and had near-death experiences, some had very premature babies, while some of the participants lost their babies during the process. With regards to the emotional, psychological and corporeal aspects of the disorder,participants described their situations as a disaster, painful and difficult. Due to the rapid deterioration of symptoms, they described the tempo of these events as a whirlwind in which they felt they had no control. Emotions ranged from shock, total disbelief and surprise to anger, helplessness and powerlessness. Lacking knowledge and access to appropriate information further compounded the situation for participants. Theparticipants who had premature babies found the Neonatal Intensive Care Unit experience (NICU) extremely challenging and stressful. A discourse analysis revealed that women’s talk was shaped by the disciplinary frameworks oftechnocratic medicine and patriarchal notions of gender. Participants’ discourses about their encounters inthe medical context werelocated in, and shaped by, the structure of health care in our country. In this regard binaries (like private versus public health care, women versus men and nurses versus doctors) were evident. Furthermore their hospital stay reflected their experiences in the Intensive Care (ICU) and the Neonatal Intensive Care Units (NICU) both of which are highly technologically orientated and managed. Biomedical discourses that filtered through the participants’ talk were: medicine as indisputable truth;mechanistic model of the body as machine; medical doctors as gods and the foetus as ‘super subject’. Discourses of risk were inevitably taken up as participants tried to make sense of both their current pregnancies and the potential ones to follow. The passage into motherhood for these participants was dependent on whether they had live babies or not. For those who had live babies it was a difficult time as they had to contend with their own recovery as well as the prematurity of their infants. The NICU experience was described as tiring, trying and cumbersome. For mothers who lost their babies it was a time of profound sadness and loss coupled to the notion that motherhood itself was lost. This loss of their children symbolised broken dreams, severed connections and a powerful taboo. In addition, discourses in which motherhood was naturalised and normalised saturated their talk and framed their experience in a narrative of deficit and failure. The ideologies of mother blame and the ‘all responsible’ mother were pervasive in their discussions. In conclusion, this high-risk situation represented a time of tremendous uncertainty and unpredictability for all participants and was powerfully shaped by dominant discourses about motherhood and the biomedical discursive and institutional framework in which participants were subjugated. The study thus highlights how the HELLP syndrome experience illuminates the erasure of women’s subjectivities while the foetus/infants’ life takes precedence. This has significant implications for scholarship in general and feminist scholarship in particular and highlights the need for this type of engagement in an area that has remained on the periphery of feminist research. / South Africa

Natural Killer (NK) cells, members of the innate lymphoid cells (ILCs), are known to play an important role in the defense against foreign cells and abnormal host cells that have arisen due to viral infection or cancer inducing mutations. The typical immune response of NK cells involves the release of cytotoxic granules containing perforin and granzyme, and the secretion of immune-regulatory cytokines such as interferon gamma (IFN-γ). Unlike the adaptive lymphocytes such as T cells and B cells, NK cells do not require prior sensitization, enabling them to initiate an immune response much faster. This unique feature of NK cells is made possible by the utilization of an array of germline encoded receptors; but on the other hand, it limits NK cells ability to respond against rapidly evolving pathogens. NK cells overcome this shortcoming with an antibody-assisted process called antibody dependent cellular cytotoxicity (ADCC). A novel subset of human NK cells, which displays potent and broad antiviral responsiveness in concert with virus-specific antibodies, was recently discovered in cytomegalovirus positive (CMV+) individuals. This NK cell subset, called g-NK cell, was characterized by a deficiency in the expression of FcεRIγ, an adaptor protein that associates with CD16 which enables ADCC. Surprisingly, despite this deficiency, g-NK cells displayed an enhanced ADCC as compared to their conventional counterparts. Furthermore, having a long-lasting memory-like NK-cell phenotype suggests a role for g-NK cells in chronic infections. This study investigates the importance of g-NK-cells in clinical settings, first by investigating whether the presence of g-NK cells is associated with the magnitude of liver disease during chronic hepatitis C virus (HCV) infection. Analysis of g-NK cell proportions and function in the peripheral blood mononuclear cells (PBMCs) of healthy controls and chronic HCV subjects showed that chronic HCV subjects had slightly lower proportions of g-NK cells, while having similarly enhanced ADCC responses compared to conventional NK cells. Notably, among CMV+ chronic HCV patients, lower levels of liver enzymes and fibrosis were found in those possessing g-NK cells. g-NK cells were predominant among the CD56neg NK cell population often found in chronic HCV patients, suggesting their involvement in the immune response against HCV. Rituximab is a chimeric anti-CD20 antibody used to treat B cell lymphoma patients; and studies have suggested that its efficacy is associated with the ADCC potency and CD16 affinity. Since g-NK cells are characterized by their superior ADCC compared to their conventional counterpart, I decided to investigate whether the presence of g-NK cells can improve the effectiveness of rituximab against malignant B cells in the context of lymphoma and leukemia. The analysis of g-NK cells’ ADCC response against rituximab-coated lymphoma cell lines and B cells from a CLL patient indicated a superior ADCC by g-NK cells compared to their conventional NK cell counterparts. Taken together, for the first time, my findings indicate that the presence of g-NK cells in CMV+ individuals is associated with milder liver disease in chronic HCV infection. In addition, an enhanced ADCC response by g-NK cells upon encountering rituximab coated target cells suggests the beneficial roles of g-NK cells, and opens an avenue for novel therapeutic approaches where g-NK cells can be utilized to treat persistent diseases such as chronic viral infection and cancer.

Fasioloides magna is a trematode parasitizing in the liver parenchyma of ruminants. Its life cycle is associated with the humid environment and includes intermediate freshwater snail hosts from family Lymnaeidae. According to the ability of host to form a certain type of a pseudocyst during fascioloidosis, they can be,divided in three groups, specific definitive hosts (red deers, fallow deers, roe deers), nonspecific definitive hosts (cattle, wild boars and elks) and atypical hosts (sheeps and goats). Beside the natural infections also the experimental infections of other potential host species has been realized (chamois, llama and bighorn sheep and traditional laboratory animals such as mice, guinea pigs, rats and rabbits). In the context of different diseases, many changes in infected organism can occur. These can be qualitatively and quantitatively evaluated. Similarly, during fascioloidosis the changes associated with the presence of the parasite in the host's body is possible to monitor, e.g. antibody production, increase in the number of eosinophils, release of eggs in faeces, internal bleeding, or the level liver damage. The liver damage is corresponding primarily to biochemical parameters of blood, not only the liver enzymes, but also other blood components, like blood proteins, lipids,...

Introduction : La fibrose kystique (FK) est une maladie génétique qui atteint plusieurs organes dont le pancréas, le foie et les poumons. Elle s’exprime par une accumulation de mucus visqueux qui va entraîner une altération des fonctions de ces organes. Les progrès scientifiques ont permis d’améliorer la condition de vie et d’augmenter considérablement l’espérance de vie des patients atteints de FK. L’amélioration de l’espérance de vie des patients FK est associée à l’apparition d’anomalies de la tolérance au glucose précédant l’apparition du diabète associé à la FK (DAFK). Le DAFK présente des similitudes avec le diabète de type 1 [DT1] (faible poids, faible sécrétion d’insuline) et le diabète de type 2 [DT2] (intolérance au glucose, anomalies de la sensibilité à l’insuline), mais il est spécifique pour ses causes et ses conséquences. Le DAFK est associé à un risque accru de perte de poids, de réduction de la fonction pulmonaire et de mortalité précoce et touche 50 % des patients adultes. La principale cause de ce diabète est décrite par une sécrétion d'insuline réduite et retardée. Les facteurs de risque, menant au développement du DAFK et les conséquences de son apparition ne sont pas encore bien comprises. La diète (riche en lipides et en énergie) recommandée en FK visant à maintenir un poids adéquat pourrait être responsable de l’accumulation de graisse ectopique, de résistance à l’insuline, de stéatose hépatique et d’anomalies du bilan lipidique rapportés en FK. Pour les patients sans FK, ces anomalies sont associées au développement du DT2. Objectif : Le but de ce travail de thèse visait à l’identification de nouveaux facteurs de risque d’anomalies de la tolérance au glucose dans une population d’adultes atteints de FK. Méthode : Pour cela nous avons i) observé l’évolution de la sécrétion d’insuline chez les patients FK âgés ; ii) identifié l’association entre les enzymes hépatiques et la prévalence du DAFK ; iii) identifié la prévalence de dyslipidémie chez les patients FK adultes et l’association avec le risque de développement du DAFK. Résultats : Nos résultats ont montré que les patients FK adultes présentent une sécrétion d’insuline altérée, mais qu’elle ne se dégrade pas davantage sur une décennie. Par contre, sur la même période, les patients deviennent plus résistants à l’insuline. Nous avons mis en évidence l’existence d’une relation entre le niveau d’enzymes alanine aminotransférase (ALT) élevé et la prévalence de DAFK. Enfin, nous avons montré l’existence d’une forte prévalence de dyslipidémie en FK, mais ces anomalies ne sont pas associées à la survenue du DAFK. Conclusion : Ces travaux ont permis de mieux comprendre l’association entre différents facteurs de risque en lien avec les anomalies de la tolérance au glucose chez des patients adultes FK. Nous avons identifié un mécanisme et un possible biomarqueur du DAFK, les enzymes hépatiques ALT, chez les patients FK adultes. Ces données peuvent fournir un rationnel pertinent pour la poursuite d’autres études cliniques dans le but d’améliorer la qualité de vie des patients atteints de FK. / Introduction: Cystic fibrosis (CF) is a genetic disorder that affects several organs including the pancreas, liver, and lungs. It is expressed by an accumulation of viscous mucus which will cause an impairment of the functions of these organs. Scientific advances have improved the condition of life and significantly increased the life expectancy of patients with CF. This improved life expectancy of CF patients is associated with the onset of glucose tolerance abnormalities before the onset of CF-associated diabetes (CFRD). CFRD has similarities with type 1 diabetes [T1D] (low body weight, low insulin secretion) and type 2 diabetes [T2D] (glucose intolerance, abnormal insulin sensitivity), but it is specific for its causes and consequences. CFRD is associated with an increased risk of weight loss, reduced lung function and early mortality and affects 50% of adult patients. The main cause of this diabetes is described as a reduced and delayed insulin secretion. The risk factors leading to the development of CFRD and the consequences of its appearance are not well understood. The diet (rich in lipids and energy) recommended in CF, that aims at maintaining an adequate body weight, could be responsible for the accumulation of ectopic fat, insulin resistance, fatty liver and abnormalities of the lipid balance reported in FK. For patients without CF these anomalies are associated with the development of T2D. Objective: The aim of this thesis work was to identify new risk factors for abnormal glucose tolerance in a population of adults with CF. Method: For this we have i) observed the evolution of insulin secretion in elderly CF patients; ii) identified the association between liver enzymes and the prevalence of CFRD; iii) studied the prevalence of dyslipidemia in adult CF patients and the association with the risk of developing CFRD. Results: Our results have shown that adult CF patients have impaired insulin secretion, but it has not degraded further over a decade. However, over the same period, patients become more resistant to insulin. We have highlighted a relationship between the high alanine aminotransferase (ALT) enzyme level and the prevalence of CFRD. Finally, we have shown the existence of a high prevalence of dyslipidemia in CF but these anomalies are not associated with the occurrence of CFRD. Conclusion: This work has made possible to better understand the association between different risk factors linked to glucose tolerance abnormalities in adult CF patients. We have identified a mechanism and a possible biomarker, ALT hepatic enzyme, of CFRD in adult CF patients. These data may provide a relevant rationale for the pursuit of other clinical studies in order to improve the quality of life of patients with CF.