京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21995号 / 医博第4509号 / 新制||医||1037(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 戸井 雅和, 教授 万代 昌紀, 教授 武藤 学 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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<p><strong>Background:</strong> Heart failure (HF) constitutes an important growing medical and economic problem with high prevalence and mortality. Prognosis assessment remains a challenge because of the dynamic nature of HF and the existence of some unexplained variation in outcomes. Our objective was to refine the process of prognostic assessment in current HF patients.</p> <p><strong>Methods:</strong> We conducted a systematic review to identify existing risk prediction models in ambulatory HF patients, a meta-analysis to identify mortality predictors in HF patients treated with an implantable cardioverter defibrillator (ICD), a retrospective cohort study to validate a new model, the HF Meta-Score, derived from the results of the meta-analysis and a cross-sectional and prospective cohort study to evaluate whether circulating progenitor cells (CPCs) are associated with functional capacity and mortality in ambulatory HF patients.</p> <p><strong>Results:</strong> We identified 20 risk prediction models in ambulatory HF patients; only five were externally validated showing limited discrimination and calibration. The two most validated models were derived from HF cohorts from the 1990s and reported limited performance in ICD patients. In a meta-analysis, we identified that age, baseline renal function, history of heart failure, chronic obstructive pulmonary disease, diabetes, peripheral vascular disease, left ventricular ejection fraction, NYHA class, atrial fibrillation, wide QRS and the occurrence of appropriate or inappropriate ICD shocks were independent mortality predictors. Some of these predictors were omitted in previously identified models. From the results of the meta-analysis, we developed the HF Meta-Score that showed better performance that an existing model. We observed that CPCs were independently associated with functional capacity and outcomes in ambulatory HF patients.</p> <p><strong>Conclusions:</strong> These results open many pathways to further refine the prognostic assessment in ambulatory HF patients. The HF Meta-Score is a promising score. The clinical utility of the HF Meta-Score and of the incorporation of new predictive factors, such as CPCs, needs to be tested.</p> / Doctor of Philosophy (PhD)

The analysis of potentially harmful biological particles is imperative for the mitigation of disease. As a result, there is a growing need for tools which can characterize, detect, and separate biological particles for the alleviation of a multitude of disease. One powerful technique for the analysis of cells is the use of dielectrophoresis (DEP) forces for the manipulation of particle movement. DEP is a particle transport phenomenon, induced by the presence of non-uniform electric fields. The dependence on intrinsic electrical properties of cells, have enabled DEP force to be utilized for numerous biological analyses. This thesis presents the investigation of breast cancer, pathogen, neuronal and glial cells and their DEP profiles. The drug response of various breast cancer cell lines when exposed to a variety of chemical stimuli were analyzed using shifts in their DEP profiles in relation to control groups. These results were supplemented with gene expression analysis to identify biophysical changes which could contribute to the DEP shifts. Additional experiments were conducted for the monitoring of pathogens. Live/dead bacteria mixtures were evaluated using an integrated system with DEP enrichment and impedance spectroscopy. Another application of DEP which was investigated was the separation of heterogeneous mixtures. Through the use of a novel microfluidic channel design, the separation of simulated circulating tumor cells (CTCs) from diluted blood and neuron cells from glial cells was demonstrated. The wide range of applications examined in this thesis highlights the versatility of DEP and the flexibility of the reported devices. / MS / Microscale technology can be utilized for the identification, characterization and sorting of biological material in a plethora of biomedical applications. One promising technique which is capable of cell manipulation is dielectrophoresis (DEP). DEP is a microscale force which causes particles to be attracted or repelled by specific geometries in microchannels. The DEP force is produced by the application of electric fields and can be utilized to analysis biological cell populations. This is because biological particles have unique electrical properties based on their cell morphology. Distinctions in their external protrusions and internal structures contribute to their electrical properties and can be identified in their DEP profiles. Based on this concept a variety of biomedical applications of DEP was explored. Chapter 2 and 3 describe the investigation of cells when exposed to various drugs. Drug induced responses were characterized based on their shifts in their DEP profiles. Chapter 4 presents the a rapid and low-cost live/dead assay for bacteria in aqueous samples through DEP and impedance spectroscopy. In chapter 5, the development of a DEP platform for cell sorting is reported. The wide range of biomedical applications which were explored demonstrate the useful nature of the DEP phenomenon.