イリジウム錯体触媒を用いるカルボニル化合物の高効率分子変換反応

京都大学0048新制・課程博士博士(工学)甲第16042号工博第3365号新制||工||1508(附属図書館)28621京都大学大学院工学研究科物質エネルギー化学専攻(主査)教授 辻 康之, 教授 大江 浩一, 教授 村上 正浩学位規則第4条第1項該当Doctor of Philosophy (Engineering)Kyoto UniversityDFA

Risk of Drug-Induced Accidents and Injuries in Elderly Patients Treated with Specific Drugs Rather than Polypharmacy : Analyses of the Japanese Adverse Drug Event Report Database

One of the reasons the health care system requires long-term nursing care for elderly patients is the risk of falls and fractures. In this study, we sought to identify risk factors for drug-induced falls and fractures in elderly patients in Japan. Risk factors for drug-induced falls and fractures in the elderly were analyzed by searching for the Standardised Medical Dictionary for Regulatory Activities （MedDRA） query （SMQ） “accidents/injuries” in the Japanese Adverse Drug Event Report database （JADER）, as this SMQ was the most well suited for evaluating data on falls and fractures. For elderly patients in Japan, the risk factors for drug-induced accidents/injuries include age ≥ 70 years old, female sex, and treatment with specific drugs, but not polypharmacy. Among the risk factors with the 10 highest reporting odds ratios （RORs） were treatment with: anti-osteoporosis agents such as bisphosphonates （e.g., minodronic acid）, eldecalcitol and bazedoxifene; dementia therapeutic agents such as rivastigmine and memantine; antiparkinsonian agents such as entacapone and pramipexole; and neuropathic pain relievers such as pregabalin. Although various geriatric syndromes were generally caused by polypharmacy, it has been posited that individual medications such as those mentioned above have a more significant association with drug-induced accidents and injuries in the elderly than polypharmacy. These drugs should be used cautiously while considering drug interruption, dose reductions, and switching to alternative therapies with lower risks. An association between accidents/injuries and drugs targeting the central nervous system （such as hypnotics, sedatives, anxiolytics, and antidepressants） has previously been reported. However, in the present study, no elevated risks in association with triazolam, zopiclone, flunitrazepam, diazepam, rilmazafone, estazolam, etizolam, or paroxetine were detected. Using RORs for risk detection for drugs in the JADER database is accessible and useful, and enables sensitive risk detection

Investigation of Cell Migration and Invasion Using Real-time Cell Analysis, as well as the Association with Matrix Metalloproteinase-9 in Oral Squamous Cell Carcinomas

The recently developed technology of real-time cell analysis (RTCA) was designed to analyze cell migration and invasion in vitro. In this study, we investigated these cellular factors in oral squamous cell carcinomas (OSCCs) of the tongue and floor of the mouth with RTCA. We also examined the associated matrix metalloproteinases (MMPs) and integrins. We used the cell lines SCC-4 and SAS, which are human poorly differentiated OSCCs from the tongue, and HO-1-u-1, which are human poorly differentiated OSCCs from the floor of the mouth. Using RTCA, cell migration was assessed on fibronectin–coated CIM-Plates, and invasion was assessed on fibronectin- and matrigel-coated CIM-Plates. SCC-4 cells demonstrated a high ability for cell migration and invasion compared with SAS and HO-1-u-1 cells. The SCC-4 cells also expressed high levels of MMP-9 and integrin α1 mRNA compared with SAS and HO-1-u-1 cells. The MMP inhibitor Marimastat blocked migration and invasion of all OSCCs. The findings suggest that MMP-9 is associated with cell migration and invasion in OSCCs, and indicate that RTCA will be useful for analyzing the metastatic capability of OSCCs and developing more effective new drugs for this disease

Visceral Fat Accumulation is Associated with Oxidative Stress and Increased Matrix Metalloproteinase-9 Expression in Atherogenic Factor-overlapped Model Rats

Visceral fat accumulation in lifestyle-related diseases increases the risk of atherosclerosis. Matrix metalloproteinases (MMPs) play an important role in the progression of atherosclerosis. We examined atherogenic factor-overlapped model rats to clarify the relationships among visceral fat, oxidative stress, and MMPs. We used four groups of male, 11-month-old, spontaneously hypertensive hyperlipidemic rats (SHHRs) or Sprague-Dawley (SD) rats. Animals were fed either a diet of high fat and 30% sucrose solution (HFDS) or a normal diet (ND) ad libitum for 6 months. The visceral fat weight increased by approximately three fold in SHHR-HFDS compared to SHHR-ND. The oxidative stress marker in plasma and MMP-9 mRNA expression in white blood cells increased in SHHR-HFDS compared to the other groups. A correlation was determined between oxidative stress and visceral fat or MMP-9 mRNA in all rats. Lipid deposition and immunostaining of CD68 and MMP-9 were observed mainly in the intima of aorta in SHHR-HFDS, while tissue inhibitor of metalloproteinase-1 mRNA expression decreased in both SHHR groups. The findings suggested that increased oxidative stress due to the visceral fat accumulation induced MMP-9 expression and macrophage accumulation in the intima of aorta in lifestyle-related disease model rats

Significant Impact of Age on Mortality and Non-significant Impact of Age on Thrombosis and Major Bleeding in Patients with COVID-19: From the CLOT-COVID Study.

AIM: There is scarce data on the impact of age on clinical outcomes in patients with coronavirus disease 2019 (COVID-19). METHOD: The CLOT-COVID Study was a retrospective, multicenter cohort study enrolling 2894 consecutive hospitalized patients with COVID-19 among 16 centers in Japan from April 2021 to September 2021. We divided the entire cohort into five groups according to age strata; -19, 20-39, 40-59, 60-79, and 80- years. RESULTS: Most patients under 19 had mild COVID-19 on admission (99%), while older patients had more severe COVID-19. The incidence rates of clinical outcomes during hospitalization in patients aged ≤ 19, 20-39, 40-59, 60-79, and 80 ≥ years were 0.0%, 0.5%, 2.2%, 2.7%, and 1.5% for thrombosis; 0.0%, 1.2%, 1.5%, 3.4%, and 2.0% for major bleeding; and 0.0%, 0.4%, 2.0%, 12.1%, and 16.8% for all-cause death, respectively. In the stratified analysis according to COVID-19 severity on admission, the incidences of thrombosis were generally higher among patients with more severe status, although those were not significantly different among age strata in all sub-types of COVID-19 severity. However, the incidences of all-cause death were significantly higher with increasing age in all sub-types of COVID-19 severity. CONCLUSIONS: In the current large observational study of patients with COVID-19, the risk of mortality became markedly higher with increased age. However, the risks of thrombosis and major bleeding did not necessarily increase as age increases, which seemed to be consistent irrespective of COVID-19 severity on admission

The current status of thrombosis and anticoagulation therapy in patients with COVID-19 in Japan: From the CLOT-COVID study

BACKGROUND: Data on thrombosis and current real-world management strategies for anticoagulation therapy are scarce but important for understanding current issues and unmet needs of an optimal management of patients with coronavirus disease 2019 (COVID-19). METHOD: The CLOT-COVID Study (thrombosis and antiCoaguLatiOn Therapy in patients with COVID-19 in Japan Study: UMIN000045800) was a retrospective, multicenter cohort study enrolling consecutive hospitalized patients with COVID-19 among 16 centers in Japan from April 2021 to September 2021, and we tried to capture the status of the patients in the fourth and fifth waves of the COVID-19 infections in Japan. We enrolled consecutive hospitalized patients who were diagnosed with COVID-19 and had a positive polymerase chain reaction test obtained from the hospital databases. RESULTS: Among 2894 patients with COVID-19, 1245 (43%) received pharmacological thromboprophylaxis. The proportion of pharmacological thromboprophylaxis increased according to the severity of the COVID-19 in 9.8% with mild COVID-19, 61% with moderate COVID-19, and 97% with severe COVID-19. The types and doses of anticoagulants varied widely across the participating centers. During the hospitalization, 38 patients (1.3%) and 126 (4.4%) underwent ultrasound examinations for the lower extremities and contrast-enhanced computed tomography examinations, respectively, and 55 (1.9%) developed thrombosis, mostly venous thromboembolism (71%). The incidence of thrombosis increased according to the severity of the COVID-19 in 0.2% with mild COVID-19, 1.4% with moderate COVID-19, and 9.5% with severe COVID-19. Major bleeding occurred in 57 patients (2.0%) and 158 (5.5%) died, and 81% of them were due to respiratory failure from COVID-19 pneumonia. CONCLUSIONS: In the present large-scale observational study, pharmacological thromboprophylaxis for hospitalized patients with COVID-19 was common especially in patients with severe COVID-19, and management strategies varied widely across the participating centers. The overall incidence of thrombosis was substantially low with an increased incidence according to the severity of the COVID-19

Suppression of mitochondrial oxygen metabolism mediated by the transcription factor HIF-1 alleviates propofol-induced cell toxicity

A line of studies strongly suggest that the intravenous anesthetic, propofol, suppresses mitochondrial oxygen metabolism. It is also indicated that propofol induces the cell death in a reactive oxygen species (ROS)-dependent manner. Because hypoxia-inducible factor 1 (HIF-1) is a transcription factor which is involved in cellular metabolic reprogramming by modulating gene expressions of enzymes including glycolysis pathway and oxygen utilization of mitochondria, we examined the functional role of HIF-1 activity in propofol-induced cell death. The role of HIF-1 activity on oxygen and energy metabolisms and propofol-induced cell death and caspase activity was examined in renal cell-derived RCC4 cells: RCC4-EV cells which lack von Hippel-Lindau protein (VHL) protein expression and RCC4-VHL cells, which express exogenous VHL, and in neuronal SH-SY5Y cells. It was demonstrated that HIF-1 is involved in suppressing oxygen consumption and facilitating glycolysis in cells and that the resistance to propofol-induced cell death was established in a HIF-1 activation-dependent manner. It was also demonstrated that HIF-1 activation by treatment with HIFα-hydroxylase inhibitors such as n-propyl gallate and dimethyloxaloylglycine, alleviated the toxic effects of propofol. Thus, the resistance to propofol toxicity was conferred by HIF-1 activation by not only genetic deletion of VHL but also exposure to HIFα-hydroxylase inhibitors