The active state of plasminogen activator inhibitor type-1 (PAI-1) is prolonged when it forms a complex with vitronectin (VN), a major serum protein. Active PAI-1 in the PAI-1:VN complex serves many functions related to fibrinolysis and cell migration but key to these effects is its extracellular distribution. PAI-1:VN complexes can bind to exposed vimentin (VIM) on activated platelet and platelet microparticles, resulting in the assembly of PAI-1:VN:VIM ternary complexes. However, the manner in which the vimentin cytoskeleton is presented extracellularlyi s not well understood. I hypothesized that PAI-1:VN:VIM ternary complex assembly occurs on cell surfaces when microparticle release leads to exposure of vimentin cytoskeleton which can lead to either assembly of the ternary complex or become involved in an autoimmune response specific for vimentin. To follow the intracellular and extracellular fate of PAI-1, I constructed an expression vector encoding PAI-1-dsRed, a fluorescent form of PAI-1, which would permit live cell tracking of PAI-1 in megakaryocytes and endothelial cells. Secondly, to study how vimentin is expressed on platelets and platelet microparticles, flow cytometry was used to isolate vimentin positive platelets or PMP's and atomic force microscopy was performed to image platelets or PMP's at nanoscale resolution. From these studies, I propose a model of vimentin expression in which the junction of microparticle release results in the exposure of cytoskeletal vimentin on both the cell and the microparticle. This exposed vimentin could potentially induce VN multimerization on the same cell surface leading to incorporation of multiple PAI-1:VN complexes. Finally, I investigated how anti-vimentin antibodies can induce platelet:leukocyte conjugate formation. To achieve this, in vitro tests were performed to determine the binding site of anti-vimentin antibodies (AVA's) and how they induce blood cell activation. Overall, my results suggest that vimentin exposure in our model of microparticle release can lead to ternary complex assembly if suitable quantities of PAI-1 are released during platelet activation. In the setting of transplant vasculopathy with high titres of AVA's, vimentin-positive granulocytes can bind these autoantibodies, which then leads to platelet activation and the formation of platelet:leukocyte conjugates. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

The results of previous studies indicated that block grafts of fetal hippocampal tissue made into cavities produced by aspiration lesions of the hippocampus in rats given the neurotoxin trimethyltin (TMT) significantly worsened the TMT-induced deficit in water maze acquisition. The purpose of the present study was to test the hypothesis that a procedure for transplantation that produced less destruction to the host brain and resulted in transplants with less mass might produce recovery in a spatial learning task in TMT-exposed rats. Acquisition of an externally cued (spatial) version of the radial arm maze (RAM), an internally cued version of the RAM, and of a differential reinforcement of low rate (DRL) operant schedule was assessed in normal rats, rats given TMT, and rats given TMT and stereotaxic implants of either fetal Ammon's horn or entorhinal cortex. The rats receiving Ammon's horn transplants made significantly fewer reentries into the baited arms in both maze configurations and fewer reentries into the nonbaited arms in the spatial RAM than rats in the TMT-only and TMT/entorhinal cortex transplant groups. The rats receiving transplants of Ammon's horn made significantly fewer responses and received more reinforcements during training on the DRL-20 schedule than rats receiving just TMT or rats receiving TMT and transplants of fetal entorhinal cortex. These results support the proposal that transplantation procedures that cause less damage to the host brain and result in transplants that do not occupy a large extent of the ventricular space increase the probability of behavioral recovery.

Osteoporosis and osteopenia are long-term side effects of bone marrow transplant (BMT). The purpose of this study was to determine the prevalence of bone mineral density (BMD) abnormalities in pediatric patients prior to BMT. Forty-four pediatric patients were evaluated with DEXA scans. The average Z-score was -0.37. Thirty-six percent had abnormal BMD. Sixty-seven percent of ALL patients had abnormal BMD. Patients with non-malignant diseases were significantly more likely to have abnormal BMD. Patients with ALL had more defects than solid tumor patients. Females had more defects than males. These results demonstrate BMD defects are common in children prior to BMT, especially in patients with ALL.

Background. Relapsed acute promyleocytic leukemia (APL) is treated with re-induction chemotherapy, commonly arsenic trioxide, and stem cell transplantation (SCT). The effect of arsenic trioxide on autologous peripheral blood stem cell collection is unknown. Procedure. Five pediatric patients with relapsed APL had PML-RARA negative peripheral blood stem cells mobilized (four after arsenic trioxide) and underwent autologous SCT after cyclophosphamide (60 mg/kg x 2) and total body irradiation (TBI-fractionated 1,200 cGy) conditioning. Results. All five patients remain in molecular remission a median of 20 months post-transplant. Conclusion. Autologous SCT performed during molecular remission is a treatment option for pediatric patients with relapsed APL and may provide durable leukemia-free survival without the complications of allogeneic transplantation.

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第21457号 / 人健博第64号 / 新制||人健||5(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 古田 真里枝, 教授 若村 智子, 教授 万代 昌紀 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

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Several subspecies of Monardella villosa (California Coyote Mint) have been distinguished on the basis of leaf thickness, shape, and trichome characteristics, yet many intermediates are known. We investigated morphological differences in natural populations of two subspecies (M. v. subsp. villosa and M. v. subsp. franciscana) in the Scott Creek watershed, north of Davenport, in Santa Cruz County, CA. Monardella villosa subsp. franciscana grows in coastal scrub in gulches and ocean terraces whereas subsp. villosa grows at more protected inland sites. Morphological difference between subspecies may be adaptations to these different habitats. I grew plants in a common garden at Cal Poly, San Luis Obispo to determine if the morphological differences were genetically based. I also conducted a reciprocal transplant of the two subspecies between inland and coastal populations to determine if they are locally adapted. The morphological differences (leaf hair density and length as well as leaf base angle) between subspecies were maintained in the common garden, yet no patterns of local adaptation were observed in germination or survival of the subspecies in reciprocal transplants in the first year. However, Monardella is a perennial plant and fitness differences may exist in later life stages that I have not yet measured.

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