Thesis (Ph. D.)--University of Wisconsin--Madison, 1972. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis--University of Wisconsin--Madison. / Typescript. Vita. Description based on print version record. Includes bibliographical references (leaves 273-294).

Thesis (Ed.M.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / 2031-01-01

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, September 2006. / "August 2006." / Includes bibliographical references (leaves 37-38). / This work is an attempt to explain wide variations in drug licensing deal value by using regression modeling to describe and predict the relationship between oncology drug deal characteristics and their licensing deal values. Although the reasons for large variances in value between deals may not be immediately apparent, it was hypothesized that objective independent variables, such as a molecule's phase, its target market size and the size of the acquiring/licensor company could explain a significant portion of variation in cancer drug values. This model, although not predictive when used independently, could be used to supplement other discounted cash flow and market based techniques to help assess the worth of incipient oncology therapies. Using regression analysis to study drug licensing deals is not novel: a study was published by Loeffler et al in 2002 that attempted to assess the impact of multiple variables on deal value in a wide range of pharmaceutical indications. The independent variables in Loeffler's work could explain less than 50% of differences in deal values. It was expected that refining the model could lead to improved regression R squared coefficient and, potentially, be a useful tool for managers. This current work is based on the 2002 Loeffler paper, but differs significantly by: * Focusing on just oncology licensing deals instead of deals covering many indications, * Incorporating a measure of the assets of the larger licensee company, * Accounting for the licensing experience of the smaller licensor company, * Factoring in inflation and the years the deals were signed; and * Assessing the impact of primary indication market size. The goal of the thesis was to advance the art of estimating the value of drug licensing deals by assessing the impact of the aforementioned factors. / by Paul Allen Hawkins. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, June 2007. / Includes bibliographical references (leaves 94-100). / Synaptic plasticity is the substrate of a vast variety of learning mechanisms. However, the molecular pathways and physiological patterns that regulate it are poorly understood. In the first part of this thesis, we focus on the physiological determinants of pre-synaptic plasticity. We find that a complete blockade of activity succeeds in inducing only a transient enhancement of plasticity. A permanent enhancement of synaptic plasticity is achieved by selectively reducing the NMDA-R mediated Ca2+ flux associated with uncorrelated activity, via adjustment of the voltage-dependent Mg2+ block of NMDA receptors. NR2B-containing NMDARs are up-regulated by this treatment, and this is found to be an important contributor to plasticity enhancement. Thus, the quality, but not the quantity, of activity is the important parameter to manipulate to obtain a permanent enhancement of intrinsic plasticity. In the second part, we study the relationship between activity patterns and postsynaptic NMDA-R regulation by using high-precision iontophoresis. We identified a new homeostatic mechanism of NMDA-R regulation which we have thus termed "NMDA Normalization" to differentiate it from prior uses of "NMDA homeostasis." Through this novel Ca++ dependent mechanism, we show that the neuron, by opposing NMDA-R functional expression counter to activity changes, causes the average charge transfer through NMDA-Rs to remain constant. We elucidate the activity-dependent, temporal, and spatial characteristics of this process. We propose an explanatory hypothesis. The reduction of uncorrelated activity used in the first part reduced the NMDA-R mediated average charge transfer. Through normalization, the cell increased functional NMDA-R expression to normalize NMDA-R mediated average charge transfer. However, when a burst of activity arrives in this new condition, in which an identical burst of glutamate release and depolarization now meets a larger number of very weakly activated NMDA-Rs, it is able to induce a disproportionately larger peak Ca++ flux. This increase in the maximal Ca++ flux, due to the combination of reduction of uncorrelated activity and NMDA-R normalization, is responsible in great part for the enhancement of synaptic plasticity. Our findings propose a clear strategy for the development of compounds to restore, and potentially enhance, synaptic plasticity, and thus with likelihood learning and memory. / Ph.D.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 1998. / Includes bibliographical references. / by James L. McGrath. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2003. / Includes bibliographical references (leaves 126-136). / Hair cells are the exquisitely-sensitive mechanosensory transducers of the inner ear. While the electrophysiology of hair cells has been extensively studied, little is known about the vital background processes that maintain the steady-state intracellular ionic environment. This study explored Na-coupled ion transport processes in isolated goldfish hair cells both in the steady state and in response to perturbations. Intracellular Na⁺ concentration ([Na⁺]i) and pH (pHi) were measured using the fluorescent probes SBFI and BCECF, respectively. The total steady-state Na⁺ entry, determined by measuring the initial rate of increase in [Na⁺]i during inhibition of Na⁺,K⁺-ATPase, was 9 mM/min, a rate higher than in many other epithelial cells involved in rapid ion transport. To uncover the entry pathways for such a high Na⁺ influx, pharmacological agents and manipulations of extracellular composition were used to dissect apart the contributions of various transporters or channels. A combination of Na⁺ entry via transduction channels, the Na⁺/H⁺ exchanger, and the Na⁺/Ca²⁺ exchanger accounted for 3/4 of the total steady-state Na⁺ entry. Consistent with a significant component via the Na⁺/Ca²⁺ exchanger, nifedipine, a blocker of L-type calcium channels, also reduced the Na⁺ entry rate. Since the Na⁺/H⁺ exchanger in goldfish hair cells, in contrast to many other cell types, displayed significant activity in the steady state, interactions between regulation of [Na⁺]i and pHi were examined during recovery from intracellular acid loads. The rate of Na+ entry or acid extrusion via the Na⁺/H⁺ exchanger increased by a factor of 6 during recovery from an acid load. In most cells, [Na⁺]i doubled after the acid load and subsequently recovered, even though the / (cont.) was not exogenously inhibited. These results indicate that intracellular acidification inhibits the Na⁺, K⁺-ATPase, and therefore poses a potential conflict for maintenance of intracellular Na⁺ homeostasis. Although hair cells were traditionally described as passive resistors, this thesis demonstrates that goldfish hair cells have a significant metabolic load, even in the steady state, arising from the activities of specific Na⁺-coupled transporters and channels. Under certain pathophysiological circumstances, such as ischemia or acoustic trauma, increased Na⁺ influx via these pathways may overwhelm the ion-homeostatic capabilities of hair cells. / by Diane Elizabeth Ronan. / Ph.D.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, February 1999. / Includes bibliographical references (p. 188-195). / by Pankaj Oberoi. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references (p. 65-66). / Many factors contribute to a company's decision to launch a product in a new market. The company must be able to identify a clinical need that the product will address and the market must be willing to pay for the new technology. This thesis explores the clinical and market need for an improved shock monitoring technology. Shock occurs when there is not enough blood flow to adequately perfuse the body's organs. In the United States, about 500,000 patients go into sudden shock every year and half of these patients die. For millions of additional patients, shock is the final stage of a terminal disease. Despite advances in many other areas of medicine, shock continues to be a serious, life threatening condition. It is my hypothesis that the limitations of the current monitoring technologies contribute to the high mortality rate associated with shock. In my research, I examined the currently available monitoring technologies and their use for the diagnosis and resuscitation of shock patients. I conducted an extensive review of the scientific literature to identify the limitations of the current monitoring technologies and to understand the challenges of diagnosing and treating shock. To supplement my research, I interviewed clinicians who treat shock patients and scientists who are trying to develop new shock monitoring technologies. The clinicians confirmed that there is a critical need for improved shock monitoring technologies. However, for a new shock monitor to be successful, it will need to address the limitations of the current technologies. A well-designed clinical trial will be necessary to demonstrate that the new technology is sensitive and specific, clinically relevant, and easy to use. / by Amanda S. Jenkins. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 41-44). / Collective intelligence techniques have been used to predict stock prices, customer purchasing habits, movies and books preferences for years, yet they remain unused in the medical profession. With the increasing adoption of electronic medical records, patients' medical data has grown exponentially and thus constitutes an untapped field where similar techniques could be applied. If data were collectively farmed and intelligently filtered, patient information could be added to traditional clinical decision support tools to arrive at personalized recommendations based on empiric evidence. The aim of this work is to use the collective, de facto, clinical experience to augment clinical guidelines thereby providing physicians with personalized clinical decision support. The pharmacological treatment of hypertension was chosen as the clinical domain in which to explore the feasibility of this approach. Twelve-thousand-three-hundred-forty-seven hypertensive patients were seen at the Internal Medical Associates (IMA) clinic at Massachusetts General Hospital (MGH) between July 2004 and September 2009. Their relevant clinical and demographic variables, drug regimens and blood pressure measurements were collected from the clinic's electronic medical record system and a dataset was generated. Back-end application software that draws upon case-based reasoning (CBR) was constructed and used to compute similarity between an index patient and existing hypertension patients. / (cont.) This program returned information regarding blood pressure control status and successful drug regimens used by similar patients. The use of EMR transactional data to provide a collective experience decision support (CEDSS) at the point-of-care using a computerized CBR approach is both technically possible and promising. Further studies are needed to evaluate the effectiveness of this method. / by Guido Alejandro Davidzon. / S.M.