ベイズ流意思決定と頻度論との関係

【学位授与の要件】中央大学学位規則第4条第1項【論文審査委員主査】小西　貞則　（中央大学理工学部教授）【論文審査委員副査】松山　登喜夫（中央大学理工学部教授）、酒折　文武（中央大学理工学部准教授）、大橋　靖雄（中央大学理工学部教授）、鎌倉　稔成（中央大学理工学部教授）、清水　邦夫（統計数理研究所特命教授）博士（理学）中央大

Coagulation potential of immobilised factor VIII in flow-dependent fibrin generation on platelet surfaces.

Coagulation factor VIII (FVIII) plays an essential role in haemostasis. To date, physiologic activity of FVIII circulating in the bloodstream (S-FVIII) is evaluated by classic coagulation assays. However, the functional relevance of FVIII (-von Willebrand factor complex) immobilised on thrombogenic surfaces (I-FVIII) remains unclear. We used an in vitro perfusion chamber system to evaluate the function of I-FVIII in the process of mural thrombus formation under whole blood flow conditions. In perfusion of either control or synthetic haemophilic blood, the intra-thrombus fibrin generation on platelet surfaces significantly increased as a function of I-FVIII, independent of S-FVIII, under high shear rate conditions. This I-FVIII effect was unvarying regardless of anti-FVIII inhibitor levels in synthetic haemophilic blood. Thus, our results illustrate coagulation potentials of immobilised clotting factors, distinct from those in the bloodstream, under physiologic flow conditions and may give a clue for novel therapeutic approaches for haemophilic patients with anti-FVIII inhibitors.博士（医学）・甲第602号・平成25年7月22日The definitive version is available at " http://dx.doi.org/10.1160/TH13-02-0159

全血流動下でのフォンビルブランド因子依存性血栓形成における組織因子の機能特性

Von Willebrand factor (VWF) plays an important role in mediating platelet adhesion and aggregation under high shear rate conditions. Such platelet aggregates are strengthened by fibrin-network formation triggered by tissue factor (TF). However, little is known about the role of TF in VWF-dependent thrombus formation under blood flow conditions. We evaluated TF in thrombus formation on immobilized VWF under whole blood flow conditions in an in vitro perfusion chamber system. Surface-immobilized TF amplified intra-thrombus fibrin generation significantly under both low and high shear flow conditions, while TF in sample blood showed no appreciable effects. Furthermore, immobilized TF enhanced VWF-dependent platelet adhesion and aggregation significantly under high shear rates. Neutrophil cathepsin G and elastase increased significantly intra-thrombus fibrin deposition on immobilized VWF–TF complex, suggesting the involvement of leukocyte inflammatory responses in VWF/TF-dependent mural thrombogenesis under these flow conditions. These results reveal a functional link between VWF and TF under whole blood flow conditions, in which surface-immobilized TF and VWF mutually contribute to mural thrombus formation, which is essential for normal hemostasis. By contrast, TF circulating in blood may be involved in systemic hypercoagulability, as seen in sepsis caused by severe microbial infection, in which neutrophil inflammatory responses may be active.博士（医学）・乙第1388号・平成28年11月24日© The Japanese Society of Hematology 2016The original publication is available at www.springerlink.comThe final publication is available at Springer via http://dx.doi.org/10.1007/s12185-016-2086-

Green Process of Three-Component Prostaglandin Synthesis and Rapid ¹¹C Labelings for Short-Lived PET Tracers: Highly Polished C-Couplings Revolutionizing Advances in Bio- and Medical Sciences

General synthesis of prostaglandins (PGs) has been accomplished based on a one-pot three-component coupling using a combination of organocopper or organozincate conjugate addition to 4-hydroxy-2-cyclopentenone followed by trapping of resulting enolate with an organic halide. Based on the use of this synthetic methodology, biologically significant PG derivatives including ent-Δ7-PGA1, 15SAPNIC ([3H]APNIC), and 15R–TIC have also been synthesized. Ultimately, organozincate conjugate addition combined with the enolate trapping by an organic triflate results in practical green three-component coupling comprising the use of stoichiometric amounts of three components (enone, α- and ω-side chains in a nearly 1:1:1 ratio) without using HMPA and heavy metals. General methodology for introducing short-lived 11C and 18F radionuclides into carbon frameworks has been established by developing rapid C-[11C]methylation and C-[18F]fluoromethylation using Pd0-mediated rapid cross-coupling between [11C]methyl iodide and an organotributylstannane or organoboronate; or [18F]fluoromethyl bromide and organoboronate, respectively, allowing the synthesis of a wide variety of biologically significant and disease-oriented PET probes such as 15R-[11C]TIC. Moreover, PdII-mediated rapid C-[11C]carbonylation using [11C]CO and organoboronate at ambient temperature under atmospheric pressure using conventional helium carrier gas has been explored. Further, C-[11C]carboxylation has been promoted using [11C]CO2 and organoboronate with RhI catalyst under atmospheric pressure

Characteristics of hospital differences in missing of clinical laboratory test results in a multi-hospital observational database contributing to MID-NET® in Japan

Background: In Japan, a multiple-hospital observational database system, the Medical Information Database Network (MID-NET®), was launched for post-marketing drug safety assessments. These assessments will be based on datasets with missing laboratory results. The characteristics of missing data considering hospital differences have not been evaluated. We assessed the missing proportion and the association between missingness and a factor through case studies using a database system, a part of MID-NET®. Methods: Seven scenarios using laboratory results before the prescription of the assessed drug as baseline covariates and data from 10 hospitals of Tokushukai Medical Group were used. The missing proportion and the association between missingness and patient background were investigated per hospital. The associations were assessed using the log of adjusted odds ratio (log-aOR). Additionally, an ad hoc survey was conducted to explore other factors affecting the missingness. Results: For some laboratory tests, missing proportions varied among hospitals, such as 7.4-44.4% of alkaline phosphatase (ALP) and 8.1-31.2% of triglyceride (TG) among statin users. The association between missingness and affecting factors also differed among hospitals for some factors; example, the log-aOR of hospitalization associated with missingness of TG was -0.41 (95% CI, -1.06 to 0.24) in hospital 3 and 1.84 (95% CI, 1.34 to 2.34) in hospital 4. In the ad hoc survey focusing on ALP, hospital-dependent differences in the ordering system settings were observed. Conclusions: Hospital differences in missing data appeared in some laboratory tests in our multi-hospital observational database, which could be attributed to the affecting factors, including the patient background