Pharmacokinetic evaluation of 5-chloro-2-methoxy-N-[2-(4- sulfamoylphenyl)ethyl]benzamide in mouse plasma demanded for a suitable bioanalytical method. No reported bioanalytical method exists to-date that can quantify concentration of this compound in any biological matrix. The purpose of this study was 1) to develop and validate a new bioanalytical method using a micro-extraction and LC-MS/MS to quantify the target analyte in mouse plasma and 2) to partially validate the method in whole blood. A bioanalytical method was developed and validated in both matrices for a linear concentration range of 2-1000 ng/ml. For both matrices, the reverse predicted concentration of calibration standards (-8.95% to 12.16% and -9.54% to 12.90% respectively) and precision and accuracy (QCs) were within ±15% (%RSD and %BIAS). Four-hour bench top stability and post preparative stability results for plasma and whole blood matrices were within ±15% and ±20% respectively. Blood –plasma concentration correlation co-efficient was 0.9956 with a slope value of 1.018.

This thesis is a comparative study of variables affecting differentiation and proliferation of progenitor cells from various embryonic and fetal tissue sites as they differentiate into mast cells. Embryonic stem cells from gestation day 4.5 (d4.5) differentiated exclusively into mast cells when cultured in semi-solid media with stem cell factor (SCF) and Interleukin-3 (IL-3). The same was true of d8-1 1 yolk sac cells and d8-1 1 cells from the embryo itself. However, culture with SCF and IL-3 of cells from dl4 fetal livers differentiated into mast cells, cells of the erythrocyte lineage and a few "macrophages" which may have been similar to the stromal cell found in the bone marrow that supplies iron to and removes the nucleus from erythrocytes. An rythrocyte-nurturing role for the fetal liver "macrophages" was substantiated by removing cells expressing Mac1, and sorting for cells expressing the early mast cell marker, Kit, resulting in cells that differentiated only into mast cells with SCF and IL-3. The variables affecting proliferation that were studied were brief incubation at very high cell density, and co-culture with fibroblasts. In addition, a few experiments were done to determine the mechanism of the effect of these variables on proliferation. High cell density incubation increased proliferation of yolk sac, fetal liver and bone marrow cells. The increased proliferation of yolk sac and bone marrow cells was attenuated by an inhibitor of the sodium-ionlhydrogen-ion exchanger, 5-(N,N-hexamethylene) amiloride (HMA). The exchanger was also found to play a role in the subsequent proliferation of mast cells from bone marrow cells co-cultured with fibroblasts since, if HMA was present during the first thirty minutes of contact, mast cell proliferation decreased by 75%. Using fluorescent imaging, activation of this exchanger was monitored by an increase in intracellular pH. Altogether these results demonstrate a growing concept in developmental biology regarding the normal stem cell in its niche (tissue site) and the effects of exogenous variables on it. They substantiate the concept that the differentiation path and proliferation of a stem cell depends both on its past history and on its future circumstances.

In certain experimental situations, the data observed are pseudo-proportional. By this, we observe the numerator, the number of responders, but the denominator, the total number, is random and, possibly, unobserved. In such situations, the data often exhibit "extra" variability due to the randomness of the denominator. Analysis of these data should account for this overdispersion. Several authors have proposed parametric approaches to this problem. Finney [Biometrika (1949) 36, 239-256] proposed the use of a mixture of the binomial and Poisson distributions. Anscombe [Annals of Applied Biology (1949) 36, 203-205] discussed the use of a mixture of the binomial and negative binomial distributions. Margolin et al. [Proceedings of the National Academy of Sciences (1981) 78, 3779-3783] suggested the use of a gamma mixture of Poisson distributions. While it is true that these approaches provide a means of handling overdispersion, the choice of the distributions used often is based on mathematical convenience. To avoid making full distributional assumptions, Kim [Unpublished Ph.D. dissertation (1991), UCLA] applied quasi-likelihood methodology to overdispersed binomial data. In his method, he assumed that the conditional mean and variance of the numerator was that of a binomial distribution, and that the mean of the distribution of the denominator was known, but that its variance was unknown. Using conditional arguments, he arrived at the unconditional mean and variance of the numerator. With the form of the first two moments of the numerator, Kim used quasi-likelihood method of moments estimation to get estimates of the unknown parameters. In this dissertation, Kim's results are generalized to allow the denominator to have an unknown mean and variance, and estimation is achieved using a generalized quasilikelihood method of moments technique. In addition, methodology is developed that allows for overdispersion in both the numerator and denominator. Here, extended quasilikelihood techniques are used for estimation of any unknown parameters. Properties of the estimators were studied via a simulation study which suggests the extended quasilikelihood estimates are not asymptotically normally distributed. Also, goodness-of-link testing is described for use in maximum likelihood, as well as, quasi-likelihood estimation. The methods developed here are illustrated by the analysis of data from a colony formation assay involving serial dilutions.

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The digital game industry is evolving fast and games are increasing in scale, both regarding the size of the development teams, as well as the size of the digital worlds provided for the players. Much time and effort is put on creating these worlds, and there are multiple techniques in use with the purpose of the creation of visually appealing games. One of the issues that follows the design of these vast fictional landscapes, is the risk of the world looking repetitive, thus unappealing for the player that spends several hours in that world.   This thesis covers the approach in the creation of a 3D environment by using different techniques with the goal of avoiding visual repetition within a game environment created as a practice based fundament for testing, and comparing the different approaches that a 3D artist can take when constructing a game environment. In the thesis, examination is made of how the different techniques contribute to visual diversity, trying to draw a conclusion on what role they play within a modular 3D environment.  The 3D environment was used to conduct a comparative case study. The environment was displayed for the participants where their opinion on how the different visual elements helped to avoid visual repetition was analyzed. The results from the survey proved that the different techniques applied to the elements, was perceived according to the theory applied to the construction of the 3D scene.

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