Thesis (M. Sc.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 32-36).

Thesis (M. Sc.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 65-73).

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 121-136).

Thesis (M.Communication Pathology)--Universiteit van Pretoria, 2002. / Summary in English and Afrikaans. Includes bibliographical references.

Thesis (M. Aud.)--University of Canterbury, 2009. / Typescript (photocopy). Includes bibliographical references (p. 92-96). Also available via the World Wide Web.

Thesis (M. Communication Pathology)--University of Pretoria, 2005. / Includes bibliographical references.

Thesis (Ph. D.)--Ohio State University, 2005. / Available online via OhioLINK's ETD Center; full text release delayed at author's request until 2006 Sep 21

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Thesis (M.Communication Pathology)--Universiteit van Pretoria, 2002. / Summary in English and Afrikaans. Includes bibliographical references (leaves 107-118).

Clinical ototoxicity - permanent hearing loss caused by medications - is estimated to affect millions of patients annually. Two classes of drug are largely to blame: platinum-based chemotherapeutics, primarily cisplatin, and aminoglycoside antibiotics. Development of methods to prevent ototoxicity depends upon an understanding of its mechanisms and may benefit from an understanding of native protective pathways of the inner ear. As the mechanisms behind cisplatin ototoxicity remain unclear, I first sought, and herein report, a refined mouse model of cisplatin ototoxicity which will allow for further in vivo investigation of cisplatin ototoxicity and potential methods for its prevention. This low-dose, multi-cycle model was found to accurately reproduce cisplatin ototoxicity as it has been described clinically and histopathologically. I then used this mouse model of cisplatin ototoxicity to investigate cisplatin pharmacokinetics in the cochlea and their role in driving cisplatin ototoxicity. Cisplatin was found to be retained within the cochlea for months following its administration. This initial finding in mice was extended to cochlear tissue samples from deceased human patients. Analysis of intra-cochlear cisplatin distribution in murine and human tissue identified the stria vascularis region of the cochlea as a promising target for intervention. With the nature of aminoglycoside ototoxicity better understood, I investigated a native inner ear protective pathway which could be leveraged to promote sensory hair cell survival. The improved hair cell survival that has previously been demonstrated as a result of heat stress was found to be mediated by cell-cell communication via extracellular vesicles. Further, hair cell protection against aminoglycosides could be reproduced through the application of exogenous, non-inner ear-derived extracellular vesicles. In sum, these data provide new insight into mechanisms of ototoxicity and details of cellular pathways which can help protect against it.