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The hematopoietic system supplies short-lived functional end cells of multiple lineages from a common pool of pluripotent stem cells throughout life. In man neoplastic transformation of these stem cells results in the development of the acute and chronic myeloid leukemias. An in vitro system where functional murine stem cells can be maintained for several months has recently become available. This system has been a powerful tool to analyze mechanisms regulating normal hematopoiesis and leukemogenesis in mice. The purpose of this work was to develop an analogous culture system applicable to human marrow and to evaluate its ability to support leukemic hematopoiesis. Long-term cultures were established with normal human marrow cells. In these, the more primitive progenitors were found to be almost exclusively located in the adherent layer for the duration of the culture (i.e., at least 2 months). A prerequisite for these studies was the development of a procedure for detaching adherent cells so that various colony-forming progenitors could be assayed in semi-solid media. The consistent finding of adherent layer-associated hematopoiesis suggests that cell-cell interactions between primitive hematopoietic cells and adherent layer elements may be essential for the maintenance of the former. Long-term cultures were also initiated with marrow from 11 CML patients and 13 AML patients (all untreated) and maintenance of normal and neoplastic progenitor cell populations assessed. A common finding was the rapid disappearance of neoplastic progenitor cells (recognized either by the presence of chromosomal abnormalities or by their abnormal differentiation capacity) in most cultures, even though cytogenetically normal precursors were often maintained. These differences between the behaviour of normal and neoplastic cells in long-term cultures may reflect changes at the stem cell level that are related to the acquisition of abnormal growth properties. In a minority of patients a different result was obtained. Clonal dominance persisted in vitro and normal hematopoiesis was not detected. Thus long-term cultures have also allowed differences in the behaviour of primitive neoplastic cells from different patients to be revealed. Future investigation of the basis for these differences may provide new insights into the biological heterogeneity that characterizes these disorders / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

A thesis presented for the degree of Doctor of Medicine in the University of the Witwatersrand, Johannesburg / IT2018

The purpose of this action-oriented needs assessment was to ascertain the knowledge, motivation, and culture (KMC) needs of Blacks regarding joining the Be The Match bone marrow registry and participating in the bone marrow donation process. This needs assessment will be utilized to lay the foundation for an educational and research based nonprofit organization, Angels In Disguise, that I developed. This study will also be used to inform the bone marrow registry of the KMC needs of the Blacks who participated in this study. The data collection came from nine observations, four post-observation surveys, five donor interviews, two prototype development groups, and a prototype field test. The formative results from the data collection partially aligned with the literature, which showed that a lack of knowledge resulted in Blacks not joining the Registry. An outlier materialized from the formative data, indicating that all five donor interviewees had joined the bone marrow registry without having knowledge of it, its processes, or the critical need for Blacks to join. On the other hand, the formative data supported the literature when the donor interviewees became a bone marrow match and were faced with the decision to move forward with the bone marrow donation process. All five donor interviewees sought and obtained knowledge about the bone marrow registry prior to being able to move forward with the donation process. In contrast, the formative data around motivation fully aligned with the literature. Blacks who lacked motivation do not join the bone marrow registry or participate in the bone marrow donation process, whereas the literature stated that many Blacks do not join the bone marrow registry due to cultural attitudes and beliefs. Research indicates that the Black community distrusts the medical community due to their being used as medical guinea pigs in the past. Also, Blacks fear pain and their health being compromised due to bone marrow donation. Interestingly, the formative data results did not support or show a lack of support of the literature. Cultural attributes and beliefs did not manifest themselves in the formative data results. The two prototype development groups participated in design thinking utilizing iterative brainstorming exercises, rapid prototyping, and assumption testing. The prototype development groups analyzed the data by categorizing and coding the data into themes through participatory research and collaborative analysis. The results of the two prototype development groups culminated into a final prototype. The final prototype was aimed at addressing the KMC needs of the Black participants, which were two-fold. First, the Registry needs to build a relationship with the Black community. Second, participants required knowledge about the Registry, the matching and donation processes, and the critical need for Blacks to join the Registry and participate in the donation process be provided to them in an educational setting, a symposium. The final prototype culminated into a bone marrow symposium that was tested in the field. The final prototype consisted of three videos about the bone marrow registry, a panel discussion with three Black bone marrow donors who had donated to non-relatives, and a pre- and post-prototype field test survey. The summative findings of this study were the results of the pre- and post-prototype field test surveys and post prototype field test. The findings of the pre-prototype field test survey, regarding knowledge, indicate the participants knew nothing or very little about the bone marrow registry. After being exposed to the prototype, the participants indicated in the post-prototype field test survey they had learned by joining the bone marrow registry they could possibly save a life. They also indicated they did not need any additional information about the bone marrow registry in order to make a decision to join and participate in the bone marrow donation process. Regarding motivation, there was not much change between the pre- and post-prototype field test survey results. The participants had indicated in both the pre- and post-prototype field test surveys that they would be motivated to join the bone marrow registry and participate in the bone marrow donation process if it could save a life. With regard to culture, the participants indicated in both the pre- and post-prototype field test surveys that no beliefs would affect their decision to join the registry and participate in the bone marrow donation process.

MR allows non-invasive means of evaluating the non-mineralized components of bone, particularly the bone marrow. This thesis focuses on potential changes occurring in bone marrow perfusion and marrow fat in osteoporosis, - changes which may improve our understanding of osteoporosis pathophysiology. We know from histology studies that as osteoporosis develops and bone tissue is lost, it is replaced by fat filling the vacated marrow space. MR allows non-invasive quantification of this fat component. Although fat content may be increasing, it is not known whether any change in fat composition occurs with osteoporosis i.e. does the type of fat within bone change. Epidemiological studies have indicated a link between arterial disease and osteoporosis. It is not known, however, whether any changes occur in bone perfusion in osteoporosis and how these may be related to increasing fat within the marrow. / The hypothesis to be tested is that: Advanced magnetic resonance (MR) techniques can be applied to investigate the non-mineralised components of bone tissue in osteoporosis thereby providing more information on bone physiology both in health and disease / This thesis is based on a series of eight studies designed to study the relationship between bone marrow perfusion, bone marrow fat content, bone marrow fat composition and bone mineral density. These studies showed that as bone mineral density decreased, bone marrow perfusion decreased. A strong reciprocal relationship was found between decreasing bone marrow perfusion and increasing marrow fat. The reduction in perfusion occurred only with bone and did not affect the extra-osseous tissues alongside bone with the same arterial supply. This indicates that the reduction in bone perfusion is not simply a reflection of a more generalized circulatory impairment in subjects with osteoporosis. This same effect is seen in both males and females and in the proximal femora as well as the spine. / In animal-based studies, we found that reduction in bone perfusion was apparent as little as two weeks after orchidectomy or oorphorectomy and closely paralleled features of impaired endothelial function as well as decreased bone mineral density and a hitherto unrecognized reduction in red marrow fraction within the medullary canal. Nitric oxide synthase, produced by the endothelium, is a potent stimulator of angiogenesis and osteoblastic activity. Mesenchymal stem cell differentiation may switch from osteoblastogenesis to adipocytogenesis under hypoxic conditions, while haematopoetic stem cells also supply endothelial stem cells. Potentially endothelial dysfunction, mesenchymal stem cell differentiation and haematopoetic stem cell maturation may be implemented in the development of osteoporosis. / In normal subjects, blood perfusion was markedly reduced in the femoral head compared to the femoral neck. In osteoporotic subjects, a further reduction in blood perfusion occurred in both areas. Overall perfusion indices reduced relatively more in the femoral neck than the femoral head region. These changes in bone perfusion help explain why subjects with osteoporosis have impaired healing of femoral neck fractures though do not seem to be at increased risk of avascular necrosis. At a micro-architectural level, reduced bone perfusion may also help explain the impaired healing of microfractures seen in subjects with osteoporosis, a feature likely to contribute to reduce bone strength, microfracture accumulation and eventually clinical insufficiency fracture. / Marrow fat was increased in subjects with osteoporosis. Our studies showed that percentage marrow fat content increased even allowing for the quantitative effect increased marrow fat has on the bone densitometry measurements. This effect was shown to be of negligible clinical significance. We found a strong reciprocal relationship between increasing fat and decreasing bone perfusion in both the proximal femur and vertebral body. Although fat content increased, very little difference in marrow fat composition was apparent between normal subjects and those with osteoporosis. We found no difference was apparent in either the N3/N6 marrow fat ratio or the spectrum of individual fatty acids in the marrow of subjects with either normal bone mineral density or osteoporosis. This suggests that alternation of marrow fat composition is not likely to be a direct contributory factor in osteoporosis. Also marrow fat increase was shown to be due to an increase in number rather than size of marrow fat cells. This suggests that marrow fat increases as a result of a switch in mesenchymal cell maturation to adipocytes rather than osteoblasts. / Below average perfusion indices in the acetabulum and adductor muscle is predictive of more pronounced bone loss at the femoral neck over the ensuing four years. Perfusion indices can also predict between fast and slow losers with a high sensitivity / To summarise, in the eight studies presented, it was shown that osteoporosis is associated with a significant reduction in bone perfusion and a reciprocal increase in marrow fat content though no change in marrow fat composition. Reduction in bone perfusion is most likely due to an accompanying reduction in functioning marrow fraction. Marrow fat increase is most likely the result of a switch in mesenchymal cell maturation to adipocytes rather than osteoblasts. The studies present in this thesis confirmed the initial hypothesis that “Advanced magnetic resonance techniques can be applied to investigate the non-mineralised components of bone tissue in osteoporosis thereby providing more information on bone physiology both in health and disease. / Griffith, James Frances. / "June 2009." / Thesis (M.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 227-250). / Appendix includes Chinese. / PREFACE AND DECLARATION --- p.1 / DEDICATION --- p.2 / ACKNOWLEDGEMENT --- p.3 / PRECIS --- p.4 / PUBLICATIONS AND PRESENTATIONS OF STUDIES RELATED TO THIS THESIS --- p.8 / INTRODUCTION --- p.16 / Chapter STUDY 1 --- What is the relationship between bone perfusion, marrow fat and bone mineral density? --- p.76 / Chapter STUDY 2 --- Vertebral marrow fat content, molecular diffusion, and perfusion indices in women with varying bone density, including osteoporosis: MR evaluation --- p.94 / Chapter STUDY 3 --- Could the results of Study 1 and Study 2 be spurious due to the effect of increasing marrow fat lowering BMD estimation by DEXA? --- p.111 / Chapter STUDY 4 --- Are the same changes in perfusion and marrow fat seen in the proximal femur as were seen in the lumbar spine (Study 1 & Study 2)? --- p.128 / Chapter STUDY 5 --- What is the reproducibility of MR perfusion studies and 1H spectroscopy of bone marrow? --- p.150 / Chapter STUDY 6 --- Marrow fat content increases but does the composition of marrow fat change in osteoporosis? --- p.159 / Chapter STUDY 7 --- Likely causes of reduced bone perfusion in osteoporosis: novel findings in an ovariectomy rat model --- p.180 / Chapter STUDY 8 --- Do perfusion indices or marrow fat content predict rate of bone loss? --- p.204 / SUMMARY --- p.222 / REFERENCES --- p.227 / ABBREVIATION LIST --- p.251 / APPENDIX --- p.253

Thesis (Ph. D.)--University of Washington, 1991. / Vita. Includes bibliographical references (leaves [218]-228).

Thesis (Ph. D.)--West Virginia University, 2006. / Title from document title page. Document formatted into pages; contains x, 180 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.

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