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To investigate their importance in non-Hodgkin’s lymphoma (NHL), I enumerated Treg cells in peripheral blood mononuclear cells (PBMC) and involved tissues from 30 newly diagnosed patients CD25+FoxP3+CD127^lowCD4+ Treg cells were increased markedly in PBMC (median=20.4% CD4 T cells, n=20) versus healthy controls (median=3.2%, n=13:<i> p</i>&lt;0.001, rank sum test) and correlated with serum lactate dehydrogenase (n=14; R_s=0.79, <i>p</i>&lt;0.001) and disease stage. I documented poor proliferation of T cells with mitogen ConA and almost none with recall antigens PPD and DPT in both PBMC and involved tissue samples (n=9). T cell hyporesponsiveness was reversed by depleting CD25+ cells (n=4), or by adding anti-CDLA-4 (n=3), supporting the view that Treg cells explain the systemic immunosuppression seen in NHL. As a high percentage of Treg cells were also present in involved tissues (patients’ involved tissues median=38.8% of CD4 T cells (n=15) vs. reactive nodes median=11.6% of CD4 T cells (n=2); <i>p</i>=0.02, rank sum test), I determined if tumour cells could induce a T regulatory phenotype. I incubated CD25+ depleted PBMC with tumour cells <i>in vitro</i> for five days. A dose and time dependent T regulatory phenotype induction from CD25+ depleted PBMC fractions were seen (n=6, maximum induction of 86.7%). Partial induction was seen when these fractions were separated with transwells. These ‘induced Treg cells’ were FACS sorted and suppressed effector T cells proliferation. I conclude that NHL cells are powerful inducers of Treg cells. These cells circulate systemically and induce active immune tolerance both systematically and within tumour microenvironment, thus representing a new therapeutic target in NHL.

Tree rings have long been used to make inferences about the environmental factors that influence tree growth. Great Basin bristlecone pine is a long-lived species and valuable dendroclimatic resource, but often with mixed growth signals; in many cases, not all trees at one location are limited by the same environmental variable. Past work has identified an elevational threshold below the upper treeline above which trees are limited by temperature, and below which trees tend to be moisture limited. This study identifies a similar threshold in terms of temperature instead of elevation through fine-scale topoclimatic modeling, which uses a suite of topographic and temperature-sensor data to predict temperatures across landscapes. We sampled trees near the upper limit of growth at four high-elevation locations in the Great Basin region, USA, and used cluster analysis to find dual-signal patterns in radial growth. We observed dual-signal patterns in ring widths at two of those sites, with the signals mimicking temperature and precipitation patterns. Trees in temperature-sensitive clusters grew in colder areas, while moisture-sensitive cluster trees grew in warmer areas. We found thresholds between temperature- and moisture-sensitivity ranging from 7.4 degrees C to 8 degrees C growing season mean temperature. Our findings allow for a better physiological understanding of bristlecone pine growth, and seek to improve the accuracy of climate reconstructions.

The central theme in the following five chapters is that the native African in Rhodesia, confronted less than a century ago by modern civilization, has been deprived of his homeland and purposely restrained from progressing politically toward the leadership of his own nation.

Genetic variation may explain the heterogeneity in the lipid response to dietary change. A systematic literature review found 79 articles on dietary intervention studies, 14 articles on observational studies, and 22 reviews on diet-gene interactions. The evidence suggests that variation within the genes for apolipoprotein (apo) AI, AIV, B and E may influence the lipid response to dietary change. This study assessed the influence of six polymorphisms within the genes for apo B, apo E and lipoprotein lipase (LPL) on the association between habitual diet and lipid levels in 239 healthy men and women (91 men and 148 women) aged 18-54 years, including 110 twin pairs, who were recruited for a population-based study of coronary heart disease (CHD) risk factors. Diet was assessed by a food frequency questionnaire, which was compared with 4-day weighed records in 41 men and 40 women aged 19-58 years. The nutrients of interest had either a correlation coefficient &ge;0.5, &ge;50/&le;10% in the same/opposite third, a KW30.04. Genotypes were determined by the polymerase chain reaction and digestion with the appropriate enzyme. Significant diet-gene interactions were observed at each of the polymorphic sites, suggesting that genetic variation contributes to the framework within which diet, especially n-3 PUFAs, the P:S ratio and NSP can influence lipid levels. In particular, individuals with the apo B XbaI X+ allele, the apo B signal peptide insertion/deletion D allele, the apo &egr;4 allele, the LPL PvuII P- allele and the LPL S447X X allele may be at greater risk of developing CHD due to their poorer lipid profiles and/or poorer response to diet. At present, it is premature to recommend the use of genotyping in the design of therapeutic diets, however investigating diet-gene interactions will increase our knowledge of the mechanisms involved in the role of diet in reducing CHD risk.

Studies have demonstrated the immune system to be significantly more plastic than previously believed. Multiple external factors have been shown to influence the immune response including alterations to the host's external environment and psychological status. This thesis details an investigation of this influence; exposing male CD1 mice to a two-week environmental enrichment paradigm then subjecting them to one of a range of inflammatory disease models chosen to assess a specific aspect of their immune function. Enriched animals were found to possess significantly higher numbers of circulating innate leukocytes compared to those animals housed in a standard lab environment. This leukocytosis was found to persist when animals were subject to a model of zymosan-induced peritonitis, where enriched animals presented an enhanced neutrophil and macrophage influx into their peritoneal cavity. Similar results were observed in a model of sepsis induced by caecal ligation and puncture where enriched animals were also found possess an enhanced capacity for systemic bacterial clearance. Across both experiments no changes in inflammatory cytokine expression were observed between enriched and standard environment animals. Genomic and proteomic profiling supported these findings, revealing the increased expression of immune-modulatory genes associated with a heightened immune and moderated inflammatory response. Ex vivo analysis of leukocytes extracted from enriched animals showed they also possessed enhanced phagocytic function and an accompanying reduction in gene expression associated with heightened cytotoxic function. When subject to a model of persistent inflammation induced by sponge implantation, enriched animals again presented heightened leukocyte infiltration to the point of immune insult. This was accompanied with a reduction in the release of pro-inflammatory cytokines and the heightened expression of genes associated with a pro-resolving, wound healing phenotype. This study provides novel insights into the mechanisms by which environmental modulation may influence the immune response and of the potentially immune-protective influence of environmental enrichment.

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Class of 2006 Abstract / Objectives: To describe the current response rate of pharmacists to mailed surveys and to identify the factors that influence pharmacist response rates. A number of hypotheses have been presented. Design: A systematic literature review. Methods: Included articles were evaluated for variables of interest using a data extraction form. Variables included length of survey, use of incentive, proximity, use of announcement, the anonymity of the survey, use of a reminder, and presence of return postage. Results: A total of 76 articles were identified of which 54 met inclusion criteria. The mean response rate for the survey was 45.8 percent. The effect on response rate was evaluated in regard to survey length, the inclusion of an incentive, and the geographical origination of the survey. The change in response rate for each single increase in the number of questions in a survey changed the response rate by 0.001 percent. Response rate for surveys without an incentive provided was 44.6 percent (SD = 0.168), while the response rate for those with an incentive was 50.7 percent (p > 0.277). Twenty seven surveys were deemed to seek responses from pharmacists in a close proximity to the organization sending out the survey (e.g., within the same state or region). Twenty-seven did not focus on a specific state or region. The mean response rates were 45.5 percent and 46.1 percent, respectively (p=0.882). There was no statistical significance in any of the other variables examined. Conclusions: This review of literature addressing pharmacist response rate to mailed surveys revealed that pharmacists’ response to surveys is not significantly affected by survey length, inclusion of an incentive, or survey origin.

Doctor of Philosophy / Department of Agricultural Economics / Nathan P. Hendricks / Price changes affect the profitability of agricultural land use at the intensive margin (i.e. crop choice) and the extensive margin (i.e. land devoted to crop production). Understanding how prices impact localized land use decisions is important for predicting how production and its allocation across producers change with prices. Due to its wide expanse and diverse geography, the productivity US land differs across space and uses. Understanding the drivers of land use decisions while accounting for such diversity is essential for accurately modeling supply response at the regional and national level. This dissertation contains two studies that provide insight into how price changes impact land use decisions at the extensive and intensive margins. In the first chapter examine the corn supply-price relationship in the United States. I perform this analysis using field-level data across the contiguous US (CONUS). This study is unique in that it incorporates micro-level data from over 3 million fields to estimate region-specific supply response and then aggregates results to the national level. The dataset used in this study is nearly comprehensive, representing field-level decisions across fields that accounted for over 88% of national corn production between 2009 and 2016. The findings from this study illustrate the importance of incorporating heterogeneity in supply response models. Supply response to price differed substantially across regions with high supply sensitivity in the north-central US and Mississippi River Delta, moderate sensitivity in Corn Belt states, andlow sensitivity in the western and Gulf Coast states. The relative importance of corn production in the in the Corn Belt states of Iowa, Illinois, Indiana, and Nebraska meant that it was far less sensitive and, in the long-run, more stable to price changes than national corn supply as a whole. Including heterogeneity in supply response also provided policy relevant context to supply response studies. Overall supply response was negatively correlated with area yields. This meant that price changes have a larger effect on planted corn acres and a smaller effect quantity of corn itself. In the last chapter I examine the impact that ethanol plant capacity has on local land use at the extensive margin. The Renewable Fuel Standard (RFS) has been one of the most influential agricultural policies in the past 20 years, increasing general US crop prices by over 20% and inducing a substantial in US ethanol production capacity (Carter et al., 2016; Roberts and Schlenker, 2013). Its effect on cropland extensification was a concern before it was passed since the policy includes a stipulation forbidding ethanol production on cropland converted after 2007. Lands at the extensive margin tend to be less productive and more environmentally sensitive. Extensive transitions also tend to be less frequent than transitory breaks in crop rotations making their impacts longer-lasting. The goal of this final analysis is to isolate the impact of ethanol expansion on cropland transitions from the general price changes. The concurrent increase in general crop prices and ethanol construction from the RFS complicates the estimation of plants’ effects. I isolate these effects using difference- in-differences (DID) which removes impact from common price trends between the treatment and control group. The standard DID approach results show significant pre-treatment effects stemming from non-random ethanol plant construction. Treatment is likely non-random since ethanol plants lo- cate in areas that provide better returns. Factors that impact the returns to plants confound the analysis since they likely also impact cropland transition decisions. To address this, I use propensity score matching to ensure these confounding factors are identically distributed between the treatment and control groups. Under the matched DID models, the expansion of ethanol plants tended to increase cropland retainment and reduce lands transitioning from non-cropland to cropland. While these results seem contradictory, they are consistent with the findings in recent literature. These impacts are thought to arise due to higher program retention in the major US cropland retirement program CRP due to changes that disproportionately impacted major ethanol production areas.

THE DEPARTMENT OF SPEECH PATHOLOGY AND AUDIOLOGY. FACULTY OF ARTS, UNIVERSITY OF THE WITWATERSRAND, JOHANNESBURG In partial fulfillment of the requirements for the degree of Master of Arts by coursework in Audiology June 1999 / High stimulus repetition rates have been proposed as a solution to the poor sensitivity and specificity of the standard electrocochleogram. The use of this approach has been confounded, however, by conflicting literature reports on the effects of high stimulus repetition rates on normal subjects. This study aimed to confirm the effects of high stimulus repetition rates on normal hearing subjects as a precursor to clinical high stimulus repetition rate electrocochleography trials. Electrocochleogram tracings were recorded binaurally from 51 normal hearing subjects at 7.1 cps, 51.1 cps, 101.1 cps and 151.1 cps and the summating potential and action potential latencies and amplitudes, summating potential/action potential amplitude ratios and waveform widths were recorded. Statistical analyses showed that increasing the stimulus repetition rate caused statistically (p<O.05) and clinically (p<O.O1 for latency and p<O.005 for amplitude) significant changes to the action potential latency and amplitude, summating potential/action potential amplitude ratio and waveform width, but caused only limited statistical (p<O.05) and clinical (p<O.OI for latency and p<O.005 for amplitude) changes to the summating potential amplitude and latency. Subject age had no effect on the results and there was no interaction between age and stimulus repetition rates. These findings provide the most comprehensive data on the effects of fast stimulus repetition rates to date, and have provided the beginnings of a valid clinical normative database for high stimulus repetition rate tympanic electrode electrocochleography.