More than 30,000 children and adults are diagnosed with life-threatening blood diseases such as leukemia, anemia and lymphomas in the U.S. every year. A transplant of stem cells, obtained from the bone marrow of a healthy donor, can be a cure for these diseases. The National Marrow Donor Program's registry comprises almost five million potential donors, however, many ethnic minorities are still underrepresented in comparison to their percentage in the overall U.S. population. Since patients are more likely to find a matching donor within their own ethnic community, recruitment efforts have been focusing on minority donors since a number of years. A number of other studies are currently examining the psychosocial and physical effects of the donation experience, as well as identifying barriers against and reasons for donating bone marrow, using questionnaires and health models. However, none has yet looked at which recruitment settings work well for college campuses, to what extent the target group should be educated, and how the study results should be incorporated into the recruitment efforts to improve retention. Potential donor education was therefore the most important focus of a Bone Marrow Donor Registration Drive organized by the author on the OSU campus in January. 150 potential donors registered at the OSU drive, one third of them from ethnic minorities. This study examines if the drive's extensive education and outreach component had any impact on the number of newly recruited volunteer donors in comparison to OSU's peer institutions. Using the Chi square test, a proportion comparison was performed between the percentage of newly registered volunteer donors (both in total and broken down by ethnicity) among the eligible OSU student body, and the total eligible student body at each peer institution. While the hypothesis that the extensive education and promotion activities increased the number of recruited donors could not be confirmed, targeting the minorities on campus was successful, since a significantly higher proportion of minority students registered at the BMDRD than the proportion of minority students registered at OSU. Besides data on the impact of the promotional activities and the recruitment results, which can also be used for further research, the drive also yielded a protocol that can serve as a guideline for organizing future drives at OSU and other schools with similar resources. / Graduation date: 2003

Für das Rett Syndrom, eine der häufigsten genetischen Ursachen für mentale Retardie-rung bei Frauen, gibt es bisher keine kausale Therapie, obwohl gentherapeutische Studi-en mit konditionellen knockout Mäusen gezeigt haben, dass es sich um eine therapierbare Erkrankung handelt. Um neue Therapien entwickeln zu können, werden Mausmodelle benötigt, die auf den beim Menschen am häufigsten gefundenen Mutation beruhen. In der vorliegenden Arbeit wurde ein Mausmodell mit der häufigsten humanen Nonsense-Mutation R168X im Mecp2 Gen charakterisiert. Mit Hilfe dieses Mausmodells wurden dann die Therapieansätze der „Stop-Codon Readthrough-Therapie“ und einer Knochenmarktransplantation auf ihre Wirksamkeit in vitro und in vivo untersucht. Die Charakterisierung der Mauslinie zeigte, dass männliche MeCP2R168X-Mäuse im Gegensatz zu anderen MeCP2-Mausmodellen kein verkürztes MeCP2 Protein exprimieren. Desweiteren weisen männliche MeCP2R168X-Mäuse einen Phänotyp, inklu-sive der drastisch verkürzten Lebenspanne, auf, wie er bei bereits etablierten Mausmo-dellen für das Rett Syndrom beschrieben wurde. Dagegen zeigten weibliche, heterozy-gote MeCP2R168X-Mäuse nur einen sehr mild ausgeprägten Phänotyp verglichen mit bereits etablierten MeCP2-Mauslinien. Für die „Stop-Codon Readthrough-Therapie“ wurde die Effizienz der Aminoglykoside Geniticin, Gentamicin und Neomycin, der Komponenten NB54, NB84 und NB124, sowie der niedermolekularen Substanz PTC124 auf ihre Wirksamkeit bei der Induktion eines Readthroughs mit transfizierten HeLa-Zellen und MeCP2R168X/y-Mausohrfibroblasten in vitro untersucht. Dabei zeigte sich eine deutliche Steigerung der Readthrough-Effizienz der NB-Komponenten, gemessen an der detektierbaren Menge an MeCP2, mit zunehmender Generation (NB54 --> NB84 --> NB124) und gegenüber dem klinisch angewandten Gentamicin. Während die Behandlung mit Neomycin zu einem minimalen Readthrough-Produkt führte, zeigte die Behandlung mit PTC124 kei-nen messbaren Readthrough. Anschließend wurden männliche MeCP2R168X-Mäuse mit den in vitro getesteten Sub-stanzen, mit Ausnahme von Geniticin, behandelt. Die Expression eines MeCP2-Proteins voller Länge konnte durch keine der applizierten Substanzen induziert werden. Auch bei Behandlungen über einen längeren Zeitraum mit hohen Dosierungen, im Fall von Gentamicin nahe der LD50-Dosis und nachweisbarer intrazellulärer Aufnahme, konnte in den behandelten Tieren weder ein verkürztes noch ein MeCP2 Protein nativer Länge detektiert werden. Die Ergebnisse dieser Arbeit zeigen, dass für die „Stop-Codon Readthrough-Therapie“ für das Rett Syndrom neue Komponenten entwickelt werden oder andere Applikationswege gewählt werden müssen, da mit den derzeit verfügbaren Substanzen kein therapeutischer Erfolg erzielt werden kann. Im letzten Teil dieser Arbeit wurde die Theorie einer gestörten Phagozytose MeCP2-defizienter Mikroglia, sowie die Therapie von MeCP2-defizienten Mäusen durch eine Knochenmarktransplantation überprüft. Dabei konnte weder in vitro noch in vivo eine Veränderung der Phagozytoseaktivität der MeCP2-defizienten Mikroglia nachgewiesen werden, wie sie von Derecki und Kollegen publiziert wurde. Die Transplantation von gesundem Knochenmark führte bei männlichen MeCP2R168X-Tieren zu keiner Verlängerung der Überlebensspanne oder einer allgemeinen Abmilde-rung der Symptomatik, wie sie ebenfalls von Derecki und Kollegen publiziert wurde. Bei weiblichen Tieren führte die Transplantation gesunden Knochenmarks zu einer Verschlechterung der motorischen Fähigkeiten. Diese Ergebnisse sind im Einklang mit denen Ergebnissen der Arbeitsgruppen von An-drew Pieper, Antonio Bedalov und Jeffrey Neul, die in anderen Mausmodellen die Wir-kung der Knochenmarktransplantation untersuchten. Die Ergebnisse aller beteiligten Arbeitsgruppen legen daher nahe, dass eine Knochen-marktransplantation nach einer Ganzkörperbestrahlung keine geeignete Therapie für das Rett Syndroms darstellt.

In the present study, a grounded theory approach was employed with the purpose of developing a substantive theoretical model to identify and illustrate changes in sibling relationships after pediatric bone marrow transplantation (BMT). Further investigation of the impact of sibling relationship quality on children's adaptation following this life-threatening medical procedure was examined. Two families, each consisting of a sibling dyad that included a child who received a BMT and a well sibling that ranged in age from 10-14 and a parent, participated in the study. Siblings were interviewed individually, and in the dyad, to capture an insider's view of the sibling relationship after BMT and factors that impact child adaptation to pediatric BMT. Child observational and parent survey data provided a multiple-informant and multiple-method approach which helped to foster a more complete picture of the broader family context. Findings suggest that children's sibling relationships improved after BMT, as evidenced by their building a close relationship, establishing intimacy and gaining trust, and learning to get along and settle differences better. Positive coping strategies included identifying and utilizing supports and resources, praying/prayer, making life easier for the sibling, and redefining what is important in life. Children's individual adaptation outcomes included accepting the illness, recognizing the longevity of the relationship, reducing worry/stress, and moving beyond the illness. Analyses that were grounded in the data from the present study suggest four theoretical propositions. First,children's sibling relationships have the potential for positive change after BMT. Second, close sibling relationships can serve as a buffer, or protective factor, to the adverse conditions and extremely stressful situations encountered after BMT. Third, positive changes in children's sibling relationships after BMT can positively influence children's coping strategies which may have a direct influence on children's adaptation to BMT. The fourth, and primary hypothesis, suggests that positive changes in children's sibling relationships after BMT potentiate new coping strategies in the dyad that are more facilitative to child adaptation than managing stress on one's own. Findings add to the general knowledge on sibling relationships and shed light on the complexities of children's sibling relationships when one child is severely ill.

Blood and marrow transplantation (BMT) has become an increasingly acceptable treatment for children with life threatening malignant diseases. Survival rates for transplant recipients vary from 23% to 63%. Children with complications from BMT, typically die in the hospital after a prolonged stay. The parental decision to allow a child to die a natural death is typically made in an aura of emotional duress and bewilderment at the complexity and volume of new information that must be assimilated.The purpose of this study was to describe the process of parental decision making for Do Not Resuscitate (DNR) or to withdraw life support in pediatric BMT.The framework for this study was developed from the author's epistemology that blends neo-modernism (recognition of individual uniqueness yet acknowledgment that certain underlying universal principals exist) with the idea that the nature of all things may be viewed as an ongoing, self-constructing process.Grounded theory methodology was used. The sample (determined through theoretical sampling) consisted of seven parents of children who died following BMT and for whom the parent made an end-of-life decision. Data was analyzed using constant comparative analysis, a method that combines both substantive and theoretical coding of data with a qualitative style of theory development.The realization of parental knowing was the process that parents used to navigate the human problem of having to make the end-of-life decision for their children who were dying following blood and marrow transplantation. This process consisted of four categories: Developing Trust, Committed to Seeing It Through, Facing My Worst Fear, and Acceptance of Self.The knowledge gained from this study will inform nurses who care for children who are dying following pediatric BMT. Strategies may be developed that will assist nurses to support the development of parental trust, to help sustain the commitment of parents as they move through the BMT treatment journey, and to assist parents as they face their worst fear. As a result, parents should be better able to achieve an acceptance for themselves that will facilitate a more satisfying experience of the ever changing process occurring in their own lives.

Bone marrow transplantation (BMT) involves the use of maximal doses of chemotherapy and total body irradiation. As a result, even well-nourished patients exhibit negative nitrogen balance and hypoproteinemia in the post-transplant period, despite a high energy and protein intake from Total Parenteral Nutrition (TPN). The purpose of this research was to investigate the impact of cytotoxic therapy, with a view toward explaining and improving the response to nutritional support. Stool, urine and serum biochemistry were studied prospectively in 10 BMT patients. Analysis of stool revealed increased sodium and decreased potassium. Examination of serum electrolytes indicated hyponatremia and hyperkalemia. A significant decrease in nitrogen balance, serum albumin and net protein utilization immediately followed the disturbances in serum electrolytes; improvement began as serum sodium and potassium returned to normal. Thus, electrolyte imbalance may have reduced the capacity of cells to utilize nitrogen. Lowering the volume of TPN dramatically decreased serum electrolyte aberrations and improved nitrogen utilization.

CBL proteins are E3 ubiquitin ligases and adaptor proteins. The mammalian homologs – CBL, CBL-B and CBL-3 show broad tissue expression; accordingly, the CBL proteins play roles in multiple cell types. We have investigated the function of the CBL-B protein in hematopoietic cells and fibroblasts. The causative agent of chronic myeloid leukemia (CML) is BCR-ABL. This oncogenic fusion down-modulates CBL-B protein levels, suggesting that CBL-B regulates either the development or progression of CML. To assess the involvement of CBL-B in CML, bone marrow transduction and transplantation (BMT) studies were performed. Recipients of BCR-ABL-infected CBL-B(-/-) cells succumbed to a CML-like myeloproliferative disease with a longer latency than the wild-type recipients. Peripheral blood white blood cell numbers were reduced, as were splenic weights. Yet despite the reduced leukemic burden, granulocyte numbers were amplified throughout the animals. As well, CBLB(-/-) bone marrow (BM) cells possessed defective BM homing capabilities. From these results we concluded that CBL-B negatively regulates granulopoiesis and that prolonged latency in our CBL-B(-/-) BMT animals was a function of perturbed homing.To develop an in vitro model to study CBL-B function we established mouse embryonic fibroblasts (MEFs) deficient in CBL-B expression. Transduction of the wild-type and CBL-B-deficient MEFs with BCR-ABL did not confer transformation; nevertheless, the role of CBL-B in fibroblasts was evaluated. The CBL-B(-/-) MEFs showed enhanced chemotactic migration toward serum in both Transwell migration and time-lapse video microscopy studies. The biochemical response to serum was extensively evaluated leading to the development of a model. We predict that CBL-B deficiency either: (a) augments GRB2-associated binding protein 2 (GAB2) phosphorylation leading to enhanced extracellular signal-regulated kinase (ERK) and protein kinase B (PKB / Akt) signaling, or (b) alleviates negative control of Vav3 resulting in stimulation of Rho effectors. In either case, our results reveal a negative regulatory role for CBL-B in fibroblast migration. The two studies detailed herein expand our knowledge of CBL-B function. They strongly suggest that CBL-B can modulate granulocyte proliferation and point toward a role for CBL-B in the motility of numerous cell types.

Thesis (M.A.)--University of Hawaii at Manoa, 2004. / Includes bibliographical references (leaves 97-107). / ix, 107 leaves, bound ill. 29 cm

Dissertation (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2006. / Vita. Bibliography: p. 132-142.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 5 uppsatser.

Thesis (M.S.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed June 2, 2008). Includes bibliographical references (p. 33-42).