Thesis (M.S.)--University of Wisconsin--Madison, 1983. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 104-109).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1971. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (M.D.)--University of Pennsylvania, 1801. / Microform version available in the Readex Early American Imprints series.

Thesis (PH.D.) -- Syracuse University, 2004. / "Publication number AAT 3149060."

Background Malaria remains a global health issue with the burden unevenly distributed to the disadvantage of the developing countries of the world. Nigeria, a middle-income country in sub-Saharan Africa, is one of the countries with high malaria burden in the world. As a socioeconomic issue, the high level of poverty in Nigeria is an important factor that reinforces the persistent malaria burden in the population. Poverty contributes to the malaria burden as it can affect integral aspects of malaria control like treatment seeking behaviours, access to preventive measures and treatment. Presently, there have been renewed efforts in the global malaria control resulting in reductions in the global malaria burden over the last decade. However, the development of resistance to artemisinin-based combination therapies threatens the sustainability of the present success in malaria control. The mechanism behind the development and spread of antimalarial drug resistance is a complex one with multiple factors in play. Nevertheless, antimalarial drug use behaviours remain critical drivers of drug resistance as they can affect some of the other factors. This study adopted a social epidemiological stance in exploring existing antimalarial drug use behaviours that have the potential to drive drug resistance development and spread. The study went further to investigate the role of socioeconomic factors in the adoption of the identified behaviours when treating malaria. Methods An exploratory mixed methods research design was adopted in this study. This design involved an initial systematic review of the literature to create a holistic picture of what is known about the issue under study. The systematic review informed the design of a qualitative study involving the use of interviews to explore the existing antimalarial drug use practices in the Nigerian population; and the different socioeconomic factors influencing the behaviours. The qualitative interviews informed the design of a measurement instrument and hypotheses that were tested in a survey with larger number of participants from Nigeria Findings The important malaria treatment seeking and drug use behaviours identified in this study were the practice of mixing drug for malaria treatment, presumptive treatment of malaria, sharing of malaria treatment course, and saving antimalarial drugs for future use. When symptoms are experienced, socio-economic factors, like the educational level, type of settlement, and 12 | P a g e household income level, tend to determine the treatment behaviours and therefore inform and determine the experience of malaria illness. There were statistically significant relationships between socioeconomic measures and drug use behaviours like the use of mixed drugs, stopping treatment to save drugs, sharing of antimalarial drugs, adherence to recommended dose and time of administration, presumptive treatment and use of recommended drugs for malaria treatment. These behaviours differ regarding the specific socioeconomic measures that are significantly associated with them. Discussion Physical and social environments can place constraints on an individual’s choices as well as that of a population. As shown in this study, education, income level and type of settlement, as structural factors, affect the decision on how to seek malaria treatment, what antimalarial drug to get, and how to use antimalarial drugs. Practices like mixing, stopping treatment to save drugs, and sharing of antimalarial drugs with others have the potential to encourage the development and spread of antimalarial drug resistance by exposing the parasite to sub-therapeutic doses of antimalarial drugs. Also, mixing of drugs paves the way for the sale of fake as well as expired antimalarial drugs thereby affecting malaria morbidity and illness experience. Conclusions and Recommendations In malaria campaigns, there is need to broaden the scope of antimalarial drug resistance control strategies to include strategies targeted at improving the socioeconomic status of people in malaria endemic areas. The informal health facilities were significantly associated with most of the reported resistance-promoting drug use behaviours like mixing; as such efforts to improve the way antimalarial drugs are used should target these facilities. Population-wide improvements in income level, educational level, environmental and structural conditions of the rural areas in malaria endemic settings like Nigeria, will encourage behavioural changes on how antimalarial drugs are used.

Renal transplantation is the definitive treatment for the end-stage renal failure. Despite concerted efforts to increase the number of available organs there remains a wide gap. Kidneys with small renal cell carcinoma have been used for transplantation after ex vivo resection of tumours with excellent results. Concerns regarding the behaviour of tumour under standard immunosuppression prevent this source from being popularised. We studied tumour behaviour with standard immunosuppression and immunosuppressives with anti-proliferative properties and the effect of MHC matching on tumour behaviour. Luciferase labelled Wistar rat kidney tumour cells were injected subcutaneously into Wistar or Lewis rats to mimic well and poorly matched groups. These were divided into groups receiving Cyclosporine, Sirolimus high and Sirolimus low dose and Leflunomide. Effects of matching on tumour rejection were studied by immunosuppression withdrawal in half of the animals within each group. Tumour progression was monitored with IVIS spectrum imaging system. When the immunosuppression was continued for the length of the study period with Cyclosporine immunosuppression, the tumour continued to grow in both strains. With high dose Sirolimus, the tumour was eradicated within 2 weeks in both Wistar and Lewis rats (p < 0.05). Both strains receiving low dose Sirolimus also eradicated the tumour within four weeks of treatment (p < 0.05). In Leflunomide group, 4/7 animals rejected the tumour within the 4 weeks of study period (p < 0.05). To study the effects of rejection and matching on the tumour behaviour, the immunosuppression was stopped after 2 weeks of treatment and the animals followed for another two weeks to study these effects. After treatment withdrawal, the tumour rejection was noted which was significantly stronger in poorly matched animals than in well-matched animals (p < 0.05) in cyclosporine treated animals. These results appeared to be in line with our hypothesis, that newer immunosuppressive medications with anti-neoplastic effects may be better options after transplanting kidneys after small tumour ex-vivo resection. Acute rejection showed significant ability to lead to tumour eradication, more effectively in less well-matched animals than well-matched combinations. Thus perhaps clinically, recipients of such restored kidneys should be less well matched and immunosuppressed with agents with anti-proliferative properties. These results will need to be replicated with further studies including closely monitored clinical studies before it can be popularised at a significant new source of precious organs.

The developments in the use of the nitrogen "mustards" as chemotherapeutic agents are discussed against the back-ground or the general chemotherapy of cancer. Their cytotoxic activity, for which different mechanisms have been advanced, presents the possibility of using the nitrogen "mustards" to Inhibit the growth of tumours and the development of the various lymphadenopathies the aromatic series of chloroalkylmines was prepared in the search for active growth inhibitors of lower toxicity than the original aliphatic nitrogen "mustards" and the syntheses described in this thesis extend that series. The attempts to elucidate the mode of action of these compounds by seeking correlation between chemical reactivity and physiological activity underlies the sections that deal with the reactions of the halogenoalkylamines. The mode of hydrolysis of the chloroethylamines and the evidence supporting an SN1 mechanism are discussed, Their hydrolysis rates are compared with their structures and the effects of substituents of the aromatic nucleus are interpreted in terms of the electron-attracting or -releasing character of those substituents. the differing rates of hydrolysisresulting from the exchange of one halogen by another were investigated by following reactions in the presence of thiosulphate, when it became apparent that la the case of the iodo-compounds hydrolysis is of a complex nature, the experimental results being accounted for by assuming simultaneous SN1 and SN2 machanisms. The reactions of the nitrogen "mustards" with primary amines to give 1:4-dioubstituted piperazines is demonstrated and the biological significance of this reaction is discussed. In the third section on the reactions of the aryl-2-halogonolkylamies, the stability of the derived esters to alkaline hydrolysis is measured and comparison made with simple esters and esters derived from other radiomimetic agents - epoxides and sulphur "mustards". The results of biological tests of the compounds whose syntheses were described are recorded in the final chapter and the degree of correlation between activity and chemical properties is discussed.

Thesis (M.A.)--Boston University

Gastroretentive drug delivery systems might enhance bioavailability of some drugs formulated in sustained release dosage forms by providing a longer residence time in the stomach. The aim of this study was to develop and evaluate a swellable floatable gastroretentive drug delivery system utilizing an effervescent mechanism.

Hypertension and type II diabetes are key components of metabolic syndrome affecting one third of US population. Insulin-sensitizing thiazolidinediones (TZDs) are high affinity synthetic ligands for Peroxisome Proliferator-Activated Receptor gamma (PPARG), a nuclear receptor and ligand-activated transcription factor. Clinical data show that TZDs are cardioprotective and lower blood pressure even with increased water and salt retention, suggesting a direct role for PPARG in blood pressure regulation. Human subjects with PPARG mutations exhibit severe early onset hypertension, insulin resistance and type II diabetes. These PPARG mutations, V290M and P467L, affect the ligand-binding domain of PPARG and have dominant negative effect on transcriptional activity. However, the mechanism by which PPARG regulates blood pressure remains elusive. A common feature of hypertension is increased RhoA activity and transgenic mice expressing dominant negative PPARG in vascular smooth muscle cells (S-P467L) exhibit hypertension and severe aortic dysfunction dependent on over-activation of the RhoA/ROCK signaling. Previously published data from our group report that smooth muscle-specific interference of PPARG impairs Cullin-3 E3 ubiquitin ligase-mediated regulation of RhoA and identify Cullin-3 as a novel regulator of vascular function. Patients with de novo mutations that lead to deletion of 57 amino acids encoded by exon 9 in Cullin-3 have early onset hypertension, but the mechanistic basis for this effect is lacking. We show that Cul3 mutation resulted in reduced RhoA ubiquitination and degradation. Reduced Cullin-3 activity increases the RhoA pool that can be activated to a GTP bound state by cellular RhoGEFs in response to contractile agonists promoting hypertension. We have identified a novel PPARG target gene-RhoBTB1, a component of the Cullin-3 RING E3 ubiquitin ligase (CRL3) complex. SiRNA-mediated knockdown of RhoBTB1 significantly decreased Cul3 protein levels resulting in a modest increase in RhoA protein. To understand the fundamental mechanisms by which vascular PPARG regulate vascular function, we generated a transgenic mice with smooth muscle-specific overexpression of RhoBTB1 (S-RhoBTB1) and crossed with the S-P467L mice. We show that replacement of RhoBTB1 in the vascular smooth muscle complements the defects observed in S-P467L due to PPARG interference. This study will advance our understanding on how PPARG regulates blood pressure so that new therapies that maximize the beneficial effects of PPARG can be developed.