進階搜尋

 
查詢範圍:「   」
顯示範圍:第筆 論文書目資料
顯示格式:全部欄位
共 20 筆
------------------------------------------------------------------------ 第 1 筆 ---------------------------------------------------------------------
系統識別號 U0026-0102201503131200
論文名稱(中文) 企業政商關係對環保與公共安全違法處分之影響
論文名稱(英文) The Impact of Corporate Political Connections on the Penalties for Environmental Violations and Public Safety
校院名稱 成功大學
系所名稱(中) 財務金融研究所碩士在職專班
系所名稱(英) Graduate Institute of Finance (on the job class)
學年度 103
學期 1
出版年 104
研究生(中文) 楊淋婷
學號 R87011370
學位類別 碩士
語文別 中文
口試日期 2014-01-28
論文頁數 51頁
口試委員 指導教授-楊朝旭
召集委員-蔡柳卿
口試委員-林軒竹
口試委員-陳政芳
關鍵字(中) 政商關係
企業社會責任
違法處分
關鍵字(英) Political Connections
Corporate Social Responsibility
Penalties
學科別分類
中文摘要 近幾年來,臺灣天災人禍不斷,2014年的高雄石化氣爆、餿水油事件、食安危機;2013年的日月光廢水污染、毒澱粉事件…等,搞得人心惶惶,喚起大眾對企業良知 (即企業社會責任) 的看重。
本研究採用2011年度臺灣證券交易所股票上市公司為研究對象,將企業董事會成員與高階管理階層過去或現在曾經在國有企業、中央政府或地方政府擔任具影響力之要職,或曾任立法委員、議員、縣市長等職務來定義該企業具有政商關係,探討企業之政商關係對環保與公共安全違法處分之間的關聯性。實證結果顯示政商關係與企業其因環境污染與違反公共安全而遭受處分兩者為負相關,符合門神效應,政商間透過檯面下之關說、利益掛勾等行為,可降低企業受罰;但在具有較高污染與違反公共安全風險之企業中,反而呈現正相關,顯示在高違法風險的情況下,具有政商關係之上市公司更容易受到社會大眾的放大檢視,或因其違法情節已見諸媒體,導致政府機關無法冒險徇私包庇,反而積極給予適當的處分。
英文摘要 In recent years, there are more and more disasters in Taiwan, like Kaohsiung gas explosion, dirty recycled waste oil events and food security crisis in 2014, ASE wastewater pollution tainted starch storms in 2013, and so on. Everyone is getting well aware of the importance of Corporate Social Responsibility.

In this study, I use the 2011 Taiwan Stock Exchange companies as the research samples to discuss about the impact of corporate political connections on the penalties for environmental violations and public safety. The member of Board of directors has the experience of government’s important position, Legislator, or councillor, and have at least one politician on company’s board of directors. Politicians are defined as mayor, county magistrate, in-service Legislator or councilor that may have influence on business activities. The result is the higher political connections, the penalties is lower. It meet our hypotheses, under-table lobbying and tunnelling through the political connections. However, in higher risk of illegal companies, They has have the positive correlation. It means that all public figures are closely watched by all and the medias. Regardless how carefully they behave, one misstep, small and otherwise, will invite merciless criticism. So they will enhance the reputation by penalties for environmental violations and public safety.
論文目次 第一章 緒論 1
第一節 研究動機與目的 1
第二節 研究架構與流程 3
第二章 文獻探討 6
第一節 企業社會責任相關文獻 6
第二節 政商關係相關文獻 10
第三節 政商關係與環保和公共安全違法處分之關連性 11
第三章 研究方法 13
第一節 實證模型設計 13
第二節 變數說明 14
第三節 資料來源及樣本選取 19
第四章 實證結果與分析 25
第一節 敘述性統計分析 25
第二節 相關係數分析 30
第三節 實證結果 35
第四節 額外分析測試 39
第五章 結論與建議 43
第一節 研究結論 43
第二節 研究限制 44
第三節 後續研究建議 45
參考文獻 46
參考文獻 壹、 中文文獻
丁仁方,王慶輝(2001),政府與企業-第二版,台北:空大出版,出版日期:2001-02-01
吳必然、賴衍輔(2006),企業社會責任概念的理論與實踐,證券櫃檯月刊122期,31-42
吳家慧(2014),政商關係與財務報表重編之關聯性,國立成功大學財務金融研究所碩士在職專班碩士論文
李馨蘋、莊宗憲(2007),公司治理機制與公司績效之實證研究,東吳經濟商學學報,第五十七期,1-27
周德宇(2007),政商關係-企業營運的助力?經濟發展的阻力?,臺灣民主季刊,第4卷第1期,187-194
洪雪卿、陳薇如、傅雁鈴(2013),影響企業社會責任績效之重要因素為何?,商管科技季刊,第14卷第4期,405-441
張琬喻(2005),政商網絡的建立必然使企業獲利嗎?,管理學報,第22卷第2期,155-172
黃宗昊(2004),台灣政商關係的演變:歷史制度論分析,問題與研究,第四十三卷第四期,35-72
楊舜涵(2013),政商關係、審計委員會與部門別報導品質之關聯,國立成功大學會計研究所碩士論文
葉銀華、邱顯比(1996),資本結構、股權結構與公司價值關聯性之實證研究:代理成本理論,台大管理論叢,第七卷第二期,57-90
劉美纓、丁碧慧、朱奐聿(2014),企業社會責任與公司治理、公司績效之關連性研究,科際整合管理研討會,2014第17屆(2014/06/22),17-30

貳、 英文文獻
Agrawal, A. and C. R.,Knoeber (1996). Firm Performance and Mechanisms to Control Agency Problems between Managers and Shareholders. The Journal of Financial and Quantitative Analysis, 31(3), 377-397
Aguilera, R. V., & Jackson, G. (2003). The cross-national diversity of corporate governance: Dimensions and determinants. Academy of Management Review, 28(3), 447-465
Abbott, L. J., Parker, S., & Peters, G. F. (2004). Audit committee characteristics and restatements. Auditing: A Journal of Practice & Theory, 23(1), 69-87
Bowen, H. (1953). Social Responsibilities of the Businessman. New York: Harper.
Beltratti, A. (2005). The complementarity between corporate governance and corporate social responsibility. The Geneva Papers, 30, 373-386.
Cornell B. and Shapiro A. C. (1987). Corporate Stakeholders and Corporate Finance. Financial Management, 16(1), 5-14.
Carroll, AB (1991). The pyramid of corporate social responsibility: Toward the moral management of organizational stakeholder. Business Horizons, 34(4), 39-48.
Eisenberg, T., Sundgren, S., & Wells, M. (1998). Larger board size and decreasing firm value in small firms. Journal of Financial Economics, 48(1), 35-54.
Fombrun, C. J., and M. Shanley. (1990). What’s in a name? reputation building and corporate strategy. Academy of Management Journal 33, 233-258.
Fan, P. H. and T. J. Wong (2002). Corporate Ownership Structure and the Information of Accounting Earnings in East Asia. Journal of Accounting and Economics, 33, 401-425.
Fan, J. P. H., Wong, T. J.,and Zhang, T. (2007). Politically connected CEOs,corporate governance, and Post-IPO performance of China's newly partially privatized firms. Journal of financial economics, 84(2), 330-357.
Guedhami, O., Pittman, J. A., & Saffar, W. (2014). Auditor choice in politically connected firms. Journal of Accounting Research, 52, 107–162.
Hudson, C., J. Jahera, and W. Lloyd (1992). Further Evidence on the Relationship Between Ownership and Performance. The Financial Review, 27, 227-239.
Hung, M., Wong, T. J. and Zhang T. (2012). Political considerations in the decision of Chinese SOEs to list in Hong Kong. Journal of Accounting and Economics, 53(1-2), 435-449.
Houston J., Liangliang Jiang, Chen Lin, and Yue Ma. (2014). Political Connections and the Cost of Bank Loan. Journal of Accounting Research, 52(1),193-243.
Jensen, M. C., & Meckling, W. H. (1976). Theory of the firm: Managerial behavior, agency costs and ownership structure. Journal of Financial Economics, 3, 305-360.
Jensen, M. C., & Ruback, R. S. (1983). The market for corporate control: The scientific evidence. Journal of Financial Economics, 11(1-4), 5-50.
Matsumura, E. M., Prakash, R., & Vera-Muñoz, S. C. (2014). Firm-value effects of carbon emissions and carbon disclosures. The Accounting Review, 89(2), 695-724.
Oswald, S. L. and Jahera Jr. (1991). The Influence of Ownership on Performance: An Empirical Study. Strategic Management Journal, 12, 218-228.
Porter, M. E., and C. Van der Linde. (1995). Green and competitive: Ending the stalemate. Harvard Business Review 73 (5), 120-134.
Preston L. E. and O'Bannon D. P.(1997). The Corporate Social-Financial Performance Relationship: A Typology and Analysis. Business and Society, 36(4), 419-429.
Ruf, B. M., Muralidhar, K., Brown, R. M., Janney, J. J., and Paul, K.( 2001). An empirical investigation of the relationship between change in corporate social performance and financial performance: A stakeholder theory perspective, Journal of Business Ethics, 32, 143-156.
Seifert B., Morris S. A. and Bartkus B. R. (2004). Having, Giving, and Getting: Slack Resources,Corporate Philanthropy, and Firm Financial Performance. Business Society, 43(2), 135-161.
Srinivasan, S. (2005). Consequences of financial reporting failure for outside directors:Evidence from accounting restatements and audit committee members. Journal of Accounting Research, 43(2), 291-334.
Shahin, A., & Zairi, M. (2007). Corporate governance as a critical element for driving excellence in corporate social responsibility. International Journal of Quality and Reliability Management, 24(7), 753-770.
Shen C. H., and Y. Chang. (2009). Ambition versus conscience, does corporate social responsibility pay off? the application of matching methods. Journal of Business Ethics 88, 133-153.
Vance, S. (1995). Inside or Outside Directors: Is There Really a Difference. Across The Board, 15-17.
Waddock S. A. and Graves S. B. (1997). The Corporate Social Performance–Financial performance Link. Strategic Management Journal, 18(4), 303-319
Wan, S. W. J. (2006). Defining corporate social responsibility. Journal of Public Affairs,6 (3-4), 176-184.
Yermack, D. (1996), Higher Market Valuation of Companies with a Small Board of Directors. Journal of Financial Economics, 40, 185-211.

------------------------------------------------------------------------ 第 2 筆 ---------------------------------------------------------------------
系統識別號 U0026-0107201401343800
論文名稱(中文) 臺灣桃園國際機場公司企業社會責任策略之研究
論文名稱(英文) Developing Corporate Social Responsibility Strategies for Taiwan’s Taoyuan International Airport
校院名稱 成功大學
系所名稱(中) 交通管理科學系
系所名稱(英) Department of Transportation & Communication Management Science
學年度 102
學期 2
出版年 103
研究生(中文) 趙文綺
學號 R56014141
學位類別 碩士
語文別 中文
口試日期 2014-06-03
論文頁數 150頁
口試委員 指導教授-張有恆
口試委員-徐村和
口試委員-鄭永祥
口試委員-陳昭宏
口試委員-陳方元
關鍵字(中) 機場策略
企業社會責任
價值鏈
鑽石模型
層級分析法
決策實驗室分析法
關鍵字(英) Airport Strategy
Corporate Social Responsibility
Strategy Development
Strategy Evaluation and Planning
學科別分類
中文摘要 企業社會責任之全球浪潮下,學者們與各式國際組織紛紛為企業社會責任進行績效評估、範疇規範及擬定衡量指標,各式文獻亦指出企業社會責任與財務績效、競爭優勢乃相輔相成。而社會大眾亦相信企業需對其股東負責外,於環境、員工、社區和其他利害關係人皆負有責任。
然桃園國際機場公司化已屆三年,尚未能積極貫徹企業化經營之精神,作為臺灣最主要之國際機場,應成為臺灣國際機場實施企業社會責任之領頭羊。此外鄰近之各標竿競爭機場,如新加坡樟宜機場、香港國際機場、韓國仁川機場皆積極實施企業社會責任或融入永續發展理念,並發布完整之報告書以及完整揭露相關資訊。
而過去研究較少探討機場之企業社會責任,因此本研究藉由文獻回顧、價值鏈與鑽石模型,以期提供一套具有競爭利益之機場公司企業社會責任實施目標並研擬其策略。並進一步透過專家問卷發放,佐以層級分析法(AHP)與決策實驗室分析法(DEMATEL),以相對重要性、因果關係、可行性/可達成性等多元面向,探究策略之執行優先次序。
綜整分析結果,本研究認為「落實企業化管理與強化董事會職能」,「專業教育訓練制度,以強化員工職能與工作態度」,之影響力相當深遠,將有助帶動其餘策略之推行,為機場公司最值得投入資源且優先執行之策略。故本研究實為桃園機場公司提供一較完善之企業社會責任架構、目標與策略,亦以專家評估,使桃園機場公司能更具競爭力,以達永續經營。
英文摘要 As the leading airport in Taiwan, Taoyuan International Airport (TIA) has been corporatized since 2010 and is yet to develop CSR strategies to fulfill its corporate citizenship and to enhance its competitiveness. The purpose of this paper is to help TIA develop sustainable CSR strategies with an effective implementation plan. Based on TIA’s CSR-related activities, 18 development strategies grouped into 5 CSR goals (corporate governance and finance, green airport and environmental management, service quality and social relationship, employee and working environment, and safety and security) are developed using the CSR value chain and diamond framework. The analytic hierarch process and decision-making trial and evaluation laboratory methods are used respectively to evaluate the relative importance, feasibility and achievability of these 18 strategies and to analyze their causal relationships via expert questionnaire surveys. The viewpoints of both internal and external experts are incorporated to determine an effective implementation plan. The result suggests that the CSR strategies in relation to airport safety and security, service quality and corporate governance are most significant and have a high implementation priority. This paper contributes to the airport industry and literature by proposing a new structured approach for developing, evaluating and planning CSR strategies.
論文目次 表目錄 iii
圖目錄 iv
第一章 緒論 1
1.1 研究背景與動機 1
1.2 研究目的 3
1.3 研究範圍與限制 3
1.4 研究方法 4
1.5 研究流程 5
第二章 文獻回顧 7
2.1 企業社會責任 7
2.1.1 企業社會責任之演進發展 7
2.1.2 企業社會責任之定義 9
2.1.3 企業社會責任之範疇與相關規範 12
2.2 機場實施企業社會責任之探討 19
2.2.1 競爭機場實施企業社會責任之概況 19
2.2.2 臺灣桃園國際機場公司實施企業社會責任之概況 32
2.2.3 小結 36
第三章 研究方法 37
3.1 企業競爭優勢分析法 37
3.1.1 價值鏈分析 37
3.1.2 鑽石模型 40
3.2 策略評估分析法 43
3.2.1 層級分析法(Analytic Hierarchy Process, AHP) 43
3.2.2 決策實驗室分析法(Decision Making Trial and Evaluation Laboratory, DEMATEL) 46
3.2.3 重要度與可行性/可達成性分析(Importance-Achievability Analysis) 49
第四章 桃園國際機場公司實施企業社會責任策略研擬 51
4.1 桃園國際機場公司企業社會責任影響分析 51
4.1.1 價值鏈:由內向外看(Looking inside out: value chain) 51
4.1.2 鑽石模型:由外向內看(Looking outside in: diamond framwork) 54
4.2 桃園國際機場公司企業社會責任策略目標構面與策略項目選定 56
4.2.1 企業社會責任策略構面 56
4.2.2 企業社會責任策略研擬 61
第五章 桃園國際機場公司企業社會責任策略之研究分析 66
5.1 層級分析(AHP)之相對重要性 67
5.2 決策實驗室分析法 (DEMATEL)之策略因果關係 75
5.3 結合AHP與DEMATEL 88
5.4 相對重要性、可行性、可達成性及相對貢獻度之整合分析 90
5.5 小結 104
第六章 結論與建議 105
6.1 結論 105
6.2 建議 109
6.3 研究限制與貢獻 111
參考文獻-英文 112
參考文獻-中文 117
參考文獻-網頁 118
附件一專家問卷(產業界) 119
附件二專家問卷(官學界) 135
參考文獻 參考文獻-英文
1.Airport Cooperative Research Program (2008). Strategic Planning in the Airport Industry. Transportation Research and Board Business Office, Washington, D.C.
2.Albers, S., Koch, B., & Ruff C. (2005). Strategic alliances between airlines and airports – theoretical assessment and practical evidence. Journal of Air Transport Management, 11, 48-58.
3.Annual Report of Changi Airport Group (2013). Changi Airport Group, Singapore.
4.Bernstein, A. (2000). Too much corporate power. Business Week, 11 September, 149.
5.Bodin, L., Gass, S. I. (2003). On teaching the analytic hierarchy process. Computers and Operations Research 30(10), 1487-1497.
6.Boli, J., & Hartsuiker, D. (2001). World culture and transnational corporations: sketch of a project. the International Conference on Effects of and Responses to Globalization, Istanbul.
7.Bowen, H. (1953). Social responsibilities of the businessman. New York: Harper.
8.Carroll, A.B. (1979). A three-dimensional conceptual model of corporate social performance. Academy of Management Review, 4, 497–505.
9.Carroll, A.B. (1991). The pyramid of corporate social responsibility: toward the moral management of organizational stakeholders. Business Horizons, July–August, 39–48.
10.Carroll, A.B. (1999). Corporate social responsibility: evolution of a definitional construct. Business and Society, 38, 268–295.
11.Carroll, A.B, & Buchholtz, A.K. (2009). Business and Society: Ethics and Stakeholder Management, 7th edn. Mason, OH: South-Western Cengage Learning.
12.Carroll, A.B, & Shabana, K. M. (2010). The business case for corporate social responsibility: a review of concepts, research and practice. International Journal of Management Reviews, 12(1), 85-105.
13.Chang, Y.H., & Wong, K.M. (2012). Human risk factors associated with runway incursions. Journal of Air Transport Management, 24, 25-30.
14.Chang, Y.H., Yeh, C.H., & Wang, S.Y. (2007). A survey and optimization-based evaluation of development strategies for the air cargo industry. International Jounal of Production Economics, 106, 550-562.
15.Chiu, Y.J., Chen, H.C., Tzeng, G.H, & Shyu, J.Z. (2006). Marketing strategy based on customer behaviour for the LCD-TV. International Journal of Management and Decision Making, 7(2), 143-165.
16.Chiu, Y.C., Sun, C.C., & Yen, H.Y. (2012). Evaluating the criteria for human resource for science and technology (HRST) based on an integrated fuzzy AHP and fuzzy DEMATEL approach. Applied Soft Computing, 12(1), 64-71.
17.Dahlsrud, A. (2008). How corporate social responsibility is defined: an analysis of 37 definitions. Corporate social responsibility and environmental management, 15(1), 1-13.
18.Davis, K. (1973). The case for and against business assumption of social responsibilities. Academy of Management Journal, June, 312–322.
19.Ferrell, O.C, Fraedrich, J., & Ferrell, L. (2008). Business ethics: Ethical decision making and cases: CengageBrain. com.
20.Fontela, E., & Gabus, A., (1976). The DEMATEL observe. Battelle Geneva Research Centre, Geneva, Switzerland.
21.Friedman, M. (1962). The social responsibility of business is to increase its profits. New York Times, September, 126.
22.Friedman, M. (1970). The social responsibility of business is to increase its profits. New York Times, September, 13.
23.Frederick, W.C. (2008). Corporate social responsibility: deep roots, flourishing growth, promising future. In Crane, A., McWilliams, A., Matten, D., Moon, J. and Siegel, D., The Oxford Handbook of Corporate Social Responsibility. Oxford: Oxford University Press, 522–531.
24.Gabus, A, & Fontela, E. (1973). Perceptions of the world problematique: Communication procedure, communicating with those bearing collective responsibility. Battelle Geneva Research Centre, Geneva, Switzerland.
25.Hayek, F.A. (1969). The corporation in a democratic society: in whose interest ought it and will it be run? In Ansoff, H. (ed.), Business Strategy. Harmondsworth: Penguin Books, 225.
26.Hay, R., & Gray, E. (1974). Social responsibilities of business managers. Academy of Management Journal, March, 135–143.
27.Huang, C.Y., Shyu, J.Z., & Tzeng, G.H. (2007). Reconfiguring the innovation policy portfolios for Taiwan’s SIP Mall industry. Technovation, 27, 744-765.
28.Jackson, K.T. (2004). Building Reputational Capital: Strategies for Integrity and Fair Play that Improve the Bottom Line. Oxford: Oxford University Press.
29.Khan, N. (2012). Analysis of Airport and Airline Relationship. ACI Asia-Pacific.
30.Knudsen, F.B. (2004). Defining Sustainability in the Aviation Sector. Brussell: EUROCONTROL Experimental Centre.
31.Kotler, P., & Lee, N. (2005). Corporate Social Responsibility: Doing the Most Good for Your Companyyou’re your Cause. Hoboken, NJ: Wiley.
32.Kurucz, E., Colbert, B., & Wheeler, D. (2008). The business case for corporate social responsibility. In Crane, A., McWilliams, A., Matten, D., Moon, J. and Siegel, D., The Oxford Handbook of Corporate Social Responsibility. Oxford: Oxford University Press, 83–112.
33.Laszlo, C. (2003). The Sustainable Company: How to Create Lasting Value through Social and Environmental Performance. Washington: Island Press.
34.Lee, M.P. (2008). A review of the theories of corporate social responsibility: its evolutionary path and the road ahead. International Journal of Management Reviews, 10, 53–73.
35.Levitt, T. (1958). The dangers of social responsibility. Harvard Business Review, September-October, 41-50.
36.Lin, Y.T., Yang, Y.H., Kang, J.S., & Yu, H.C. (2011). Using DEMATEL method to explore the core competences and causal effect of the IC design service company: An empirical case study. Expert Systems with Applications, 38, 6262-6268.
37.Martilla, J. A., & James, J.C. (1977). Importance-performance analysis. Journal of Marketing, 41(1), 77-79.
38.McGuire, J. (1963). Business and Society. New York: McGraw-Hill.
39.McWilliams, A., & Siegel, D.S. (2011). Creating and capturing value: strategic corporate social responsibility, resource-based theory, and sustainable competitive advantage. Journal of Management, 37(5), 1480-1495.
40.Murphy, P.E. (1978). An evolution: corporate social responsiveness. University of Michigan Business Review, November, 20–22.
41.Najmi, A. & Makui, A. (2010). Providing hierarchical approach for measuring supply chain performance using AHP and DEMATEL methodologies. International Journal of Industrial Engineering Computations, 1(2), 199-212.
42.Oum, T.H, Adler, N., & Yu, C. (2006). Privatization, corporatization, ownership forms and their effects on the performance of the world's major airports. Journal of Air Transport Management, 12(3), 109-121.
43.Porter, M.E. (1985). Competitive advantages: creating and sustaining superior performance. New York: Simon & Schuster Inc..
44.Porter, M.E. (1990). The Competitive Advantage of Nations. New York: Free Press.
45.Porter, M.E., & Kramer, M.R. (2006). Strategy and society: the link between competitive advantage and corporate social responsibility. Havard Business Review, December, 78-93.
46.Raut, R.D., Bhasin, H.V., & Kamble, S.S. (2011). Evaluation of supplier selection criteria by combination of AHP and fuzzy DEMATEL method. International Journal of Business Innovation and Research, 5(4), 359-392.
47.Rawson, R., & Hooper, P.D. (2012). The importance of stakeholder participation to sustainable airport master planning in the UK. Environmental Development, 2, 36-47.
48.Saaty, T.L. (1980). The Analytic Hierarchy Process-Planning, Priority Setting, Resource Allocation. New York: McGraw Hill.
49.Saaty, T. L. (1990). The Analytic Hierarchy Process, RWS Publication, USA.
50.Saaty, T. L., & K. P. Kearns. (1985). Analytical Planning. New York: Pegramon.
51.Safety Management, Annex 19 to the Comvention on International Civil Aviation (2013). Canada: International Civil Aviation Organization.
52.Sethi, S.P. (1975). Dimensions of corporate social performance: an analytic framework. California Management Review, Spring, 58–64.
53.Sexty, R.W. (2010). Canadian Business and Society: Ethics & Responsibilities: McGraw-Hill Ryerson.
54.Seyed-Hosseini, S.M., Safaei, N, & Asgharpour, M.J. (2006). Reprioritization of failures in a system failure mode and effects analysis by decision making trial and evaluation laboratory technique. Reliability Engineering & System Safety, 91(8), 872-881.
55.Skouloudis, A., Evangelinos, K., & Moraitis, S. (2012). Accountability and stakeholder engagement in the airport industry: An assessment of airports’ CSR reports. Journal of Air Transport Management, 18(1), 16-20.
56.Smith, A.D. (2007). Making the case for competitive advantage of corporate social responsibility. Business Strategy Series, 8(3), 186-195.
57.Sustainability Report (2013). Incheon International Airport Corporation. Incheon, Korea.
58.Sustainability Reporting Guidelines G4 (2013). Global Reporting Initiative.
59.Tsai, W.H., & Chou, W.C. (2009). Selecting management systems for sustainable development in SMEs: A novel hybrid model based on DEMATEL, ANP, and ZOGP. Expert Systems with Applications, 36, 1444-1458.
60.Tsai, W.H., & Hsu, J.L. (2008). Corporate social responsibility programs choice and costs assessment in the airline industry—A hybrid model. Journal of Air Transport Management, 14(4), 188-196.
61.Tzeng, G.H., Chiang, C.H., & Li, C.W. (2007). Evaluating intertwined effects in e-learning programs: A novel hybrid MCDM model based on factor analysis and DEMATEL. Expert systems with Applications, 32(4), 1028-1044.
62.Vale, B., & Vale, R.J.D. (1991). Towards a green architecture: six practical case studies: Riba Publications.
63.Vogel, D.J. (2005). Is there a market for virtue? The business case for corporate social responsibility. California Management Review, 47, 19–45.
64.Waddock, S. (2002). Leading Corporate Citizens: Vision, Values, Value-added. New York: McGraw-Hill.
65.Wu, H.H., Shieh, J.I., Li, Y., & Chen, H.K. (2010). A combination of AHP and DEMATEL in evaluating the criteria of employment service outreach program personnel. Information Technology Journal, 9, 569-575.
66.Wu, W.W., & Lee, Y.T. (2007). Developing global managers’ competencies using the fuzzy DEMATEL method. Expert Systems with Applications, 32(2), 499-507.
67.Yeh, C.H., & Chang, Y.H. (2009). Modeling subjective evaluation for fuzzy group multicriteria decision making. European Journal of Operational Research, 194, 464-473. 
參考文獻-中文
1.上海機場建設指揮部,「綠色機場-上海可持續發展探索」,上海:上海科學技術出版社,2010年。
2.交通部民用航空局,「民航運輸統計101年度資料」,台北市:交通部民用航空局,2012年。
3.交通部運輸研究所,「運輸政策白皮書」,台北市:交通部運輸研究所,2013年。
4.江玫芬,「桃園國際機場公司之營運發展策略探討」,國立成功大學交通管理科學系未出版碩士論文,2012年。
5.江振邦,「提升國際機場飛航空收入之商業特許經營方式研究」,國立成功大學交通管理科學系未出版碩士論文,2012年。
6.邵珮琪,「臺灣航空器事故模型分析暨機場安全管理系統績效評估」,國立成功大學交通管理科學系博士論文,2013年。
7.香港國際機場,「可持續發展報告書」,香港:香港國際機場,2012年。
8.桃園國際機場公司,「年度報告書」,桃園縣:桃園國際機場,2005至2012年。
9.桃園機場改善小組,「臺灣桃園國際機場經營管理改善報告」,桃園縣:桃園國際機場,2010年。
10.翁望回,「企業正當性之實證研究:社會責任的觀點」,國立政治大學企業管理研究所博士論文,1987年。
11.楊政衡,「國際機場服務品質評估之研究-以桃園國際機場為例」,國立成功大學交通管理科學系未出版碩士論文,2011年。
12.張有恆,「飛航安全管理」,台北市:華泰文化,2005年。
13.張有恆,「桃園、松山雙機場聯結-營運加分」,聯合報,2010年。
14.張紹勳,「模糊多準則評估法及統計」,台北市:五南圖書,2012年。
15.鄧振源,「計畫評估:方法與應用(二版)」,台中市:鼎茂經銷,2005年。
16.廖珣如,「臺灣發展商務航空策略之探討」,國立成功大學交通管理科學系未出版碩士論文,2013年。
17.蔡敦浩、方士杰,「策略管理」,台中市:滄海書局,2012年。
18.錢為家,「企業社會責任實務全書:第四代企業的價值驅動優勢」,台北市:商周出版,2009年。

參考文獻-網頁
1.Airports Council International, http://www.aci.aero/, 2013.10
2.BSR: The Business of a Better World, http://www.bsr.org/, 2013.10
3.Changi Airport Group, http://www.changiairportgroup.com/cag/html/the-group/sustainability/, 2013.11
4.Committee for Economic Development, http://www.ced.org/, 2013.10
5.CSR International, http://www.csrinternational.org/, 2013.09
6.European Commission, http://ec.europa.eu/enterprise/policies/sustainable-business/corporate-social-responsibility/, 2013.09
7.Incheon Airport, http://www.airport.kr/iiacms/pageWork.iia?_scode=C1402030101, 2013.10
8.Skytrax: http://www.airlinequality.com/, 2013.10
9.World Business Council for Sustainable Development: WBCSD, http://www.wbcsd.org/home.aspx, 2013.09
10.天下企業公民,http://issue.cw.com.tw/issue/csr/analysis.jsp, 2013.08
11.中華民國企業永續發展協會,http://www.bcsd.org.tw/domain_node/domaintool/203/322, 2013.11
12.交通部民用航空局,http://www.caa.gov.tw/big5/index.asp, 2013.09
13.香港國際機場企業社會責任網站,http://www.hongkongairport.com/chi/csr/, 2013,10
14.桃園縣環保局網站,http://aviation.tyepb.gov.tw/TYAN_WEB/Subsidize/Search.aspx, 2014.03
15.遠見雜誌企業社會責任獎,http://www.gvm.com.tw/2013CSR/, 2013.08
16.經濟部投資業務處企業社會責任網站,http://www.dois.moea.gov.tw/main.asp, 2013.11

------------------------------------------------------------------------ 第 3 筆 ---------------------------------------------------------------------
系統識別號 U0026-0107201415420200
論文名稱(中文) 環境不確定性下策略性採購、供應鏈敏捷性與組織績效關係之研究-以資訊電子業為例
論文名稱(英文) Environmental Uncertainty, Strategic Sourcing, Supply Chain Agility and Organizational Performance in the Information Technology Industry
校院名稱 成功大學
系所名稱(中) 交通管理科學系
系所名稱(英) Department of Transportation & Communication Management Science
學年度 102
學期 2
出版年 103
研究生(中文) 莊舒婷
學號 R56011305
學位類別 碩士
語文別 中文
口試日期 2014-06-13
論文頁數 99頁
口試委員 指導教授-林珮珺
共同指導教授-孫雅彥
口試委員-張瀞之
口試委員-林正章
關鍵字(中) 資訊電子業
策略性採購
供應鏈敏捷性
組織績效
環境不確定性
關鍵字(英) Information Technology Industry
Strategic Sourcing
Supply Chain Agility
Organizational Performance
Environmental Uncertainty
學科別分類
中文摘要 本研究以台灣資訊電子業為例,探討策略性採購、供應鏈敏捷性與組織績效間的影響關係,並以環境不確定性作為調節變數。經過民國102年12月至民國103年3月的問卷發放,共回收了163份有效樣本,透過結構方程模式(SEM)分析後,發現台灣資訊電子產業中策略性採購對供應鏈敏捷性有正向影響關係,供應鏈敏捷性對組織績效亦存在正向影響關係,然而策略性採購對於組織績效之研究假設並無得到顯著支持,但研究結果得知策略性採購可透過提升供應鏈敏捷性間接影響組織績效。另外,本研究透過階層迴歸進行調節效果分析,發現環境不確定性對於策略性採購與供應鏈敏捷性之影響中具有調節效果,環境不確定性對於供應鏈敏捷性與組織績效之影響中亦具有調節效果,但環境不確定性對策略性採購與組織績效之影響中不具有調節效果。最後根據本研究結果提出相關之建議,以供台灣資訊電子業者參考。
英文摘要 This study aims to evaluate the impact of strategic sourcing on supply chain agility and organizational performance in the information technology industry, and considering the moderating effects of environmental uncertainty. During four months of questionnaires distributed, a total of 163 valid samples were collected. A structural equation modeling (SEM) approach was used to test the research hypotheses. Result indicated that strategic sourcing had a positive effect on supply chain agility, and supply chain agility had a positive effect on organizational performance. The impact of strategic sourcing on organizational performance was not supported in this study, however, strategic sourcing had an indirect effect on organizational performance mediated by supply chain agility. Otherwise , this study used hierarchical regression analysis to analyze whether moderating effects existed or not. Result indicated that environmental uncertainty had a negative moderating effect between strategic sourcing and supply chain agility, and which had a positive moderating effect between supply chain agility and organizational performance. But environmental uncertainty didn’t exist moderating effect between strategic sourcing and organizational performance. Practical implications of the research findings for information technology companies were discussed.
論文目次 目錄 i
表目錄 iv
圖目錄vi
第一章 緒論1
1.1研究背景與動機1
1.2研究目的5
1.3研究範圍5
1.4研究流程5
第二章 文獻回顧8
2.1資訊電子業8
2.2策略性採購12
2.3供應鏈敏捷性17
2.4組織績效20
2.5環境不確定性23
第三章 研究方法27
3.1研究模式與假設27
3.2研究設計28
3.3資料分析方法與應用32
3.3.1敘述性統計分析32
3.3.2因素分析32
3.3.3信度與效度分析33
3.3.4變異數分析33
3.3.5結構方程模式34
3.3.6調節效果分析35
第四章 環境不確定性下策略性採購、供應鏈敏捷性與組織績效關係之分析37
4.1問卷回收結果與樣本結構分析37
4.1.1樣本結構分析38
4.2策略性採購、供應鏈敏捷性、組織績效與環境不確定性敘述性統計40
4.2.1策略性採購敘述性統計分析40
4.2.2供應鏈敏捷性敘述性統計分析42
4.2.3組織績效敘述性統計分析44
4.2.4環境不確定性敘述性統計分析44
4.3策略性採購、供應鏈敏捷性、組織績效與環境不確定性之信度分析46
4.4填答者特性與構面之變異數分析47
4.4.1填答者職位與各構面之變異數分析47
4.4.2公司營運型態與各構面之變異數分析48
4.4.3公司成立年數與各構面之變異數分析49
4.4.4公司營業額與各構面之變異數分析50
4.4.5公司規模與各構面之變異數分析52
4.5收斂效度與區別效度53
4.6結構方程式分析結果55
4.6.1結構方程模式分析與校估56
4.6.2中介效果驗證59
4.6.3策略性採購、供應鏈敏捷性與組織績效之因素SEM分析61
4.6.4不同企業規模之SEM分析66
4.7 調節效果68
第五章 結論與建議74
5.1結論74
5.2實務建議79
5.3研究貢獻81
5.4後續研究建議82
參考文獻83
一、中文部分83
二、英文部分84
三、網站部分94
附錄一 正式問卷95
參考文獻 一、中文部分
1.工商時報,「強化製造力的兩大決勝關鍵」,經營知識,民國94年。
2.天下雜誌,「隱型冠軍出列!」,第522期,民國102年。
3.王長青、鄭博化,「掌握先機~更智慧的供應鏈管理」,採購專欄,財團法人供應管理協會,民國100年。
4.吳萬益,「企業研究方法」,第四版,華泰書局,民國100年。
5.林震岩,「多變量分析:SPSS的操作與應用」,智勝文化,民國96年。
6.陳順宇,「多變量分析」,第四版,華泰書局,民國94年。
7.許振邦、中華採購供應管理協會,「採購與供應管理」,第三版,智勝文化,民國100年。
8.新紀元週刊,「地震衝擊日本產業供應鏈」,第221期,民國100年。
9.趙李英紀,「企業關係滿意、信任、與承諾交互影響以關係價值干擾因子探討─以科技公司與廠商連鎖性互動行銷為例」,第八屆知識社群國際研討會,民國101年。
10.聯合報,「台幣Q3勁升電子業匯損壓力大」,民102。
11.劉國棟,「電子產業,懂這些就夠了」,大是文化,民國95年。


二、英文部分
1.Agarwal, A., Shankar, R., & Tiwari, M. (2007). Modeling agility of supply chain. Industrial Marketing Management, 36(4), 443-457.
2.Anderson, M. G., & Katz, P. B. (1998). Strategic sourcing. International Journal of Logistics Management, The, 9(1), 1-13.
3.Aragon-Correa, J. A., & Sharma, S. (2003). A contingent resource-based view of proactive corporate environmental strategy. Academy of Management Review, 28(1), 71-88.
4.Banfield, E. (1999). Harnessing value in the supply chain: strategic sourcing in action:John Wiley & Sons.
5.Barragan, S., Cappellino, C., Dempsey, N., & Rothenberg, S. (2003). A framework for sourcing product development services. Supply Chain Management: An International Journal, 8(3), 271-280.
6.Boyle, E., Humphreys, P., & McIvor, R. (2008). Reducing supply chain environmental uncertainty through e-intermediation: An organisation theory perspective. International Journal of Production Economics, 114(1), 347-362.
7.Braunscheidel, M. J., & Suresh, N. C. (2009). The organizational antecedents of a firm’s supply chain agility for risk mitigation and response. Journal of Operations Management, 27(2), 119-140.
8.Brown, S. L. (1998). Competing on the edge: Strategy as structured chaos: Boston, Mass.: Harvard Business School Press.
9.Carr, A. S., & Pearson, J. N. (2002). The impact of purchasing and supplier involvement on strategic purchasing and its impact on firm’s performance. International Journal of Operations & Production Management, 22(9), 1032-1053.
10.Carr, A. S., & Smeltzer, L. R. (1997). An empirically based operational definition of strategic purchasing. European Journal of Purchasing & Supply Management, 3(4), 199-207.
11.Carroll, S. J., & Schneier, C. E. (1982). Performance Appraisal and Review Systems: The Identification, Measurement, and Development of Performance In Organizations: Scott, Foresman Glenview, IL.
12.Chan, T. C., & Chin, K.-S. (2007). Key success factors of strategic sourcing: an empirical study of the Hong Kong toy industry. Industrial Management & Data Systems, 107(9), 1391-1416.
13.Chen, J., & Guo, Z. (2013). Strategic sourcing in the presence of uncertain supply and retail competition.Production and Operations Management.
14.Chiang, C.-Y., Kocabasoglu-Hillmer, C., & Suresh, N. (2012). An empirical investigation of the impact of strategic sourcing and flexibility on firm's supply chain agility. International Journal of Operations & Production Management, 32(1), 49-78.
15.Chow, G., Heaver, T. D., & Henriksson, L. E. (1994). Logistics performance: definition and measurement. International Journal of Physical Distribution & Logistics Management, 24(1), 17-28.
16.Christopher, M. (2000). The agile supply chain: competing in volatile markets. Industrial Marketing Management, 29(1), 37-44.
17.Churchill Jr, G. A., & Iacobucci, D. (2009). Marketing Research: Methodological Foundations: Cengage Learning.
18.Cleveland, G., Schroeder, R. G., & Anderson, J. C. (1989). A Theory of Production Competence*. Decision Sciences, 20(4), 655-668.
19.Daft, R. L., Sormunen, J., & Parks, D. (1988). Chief executive scanning, environmental characteristics, and company performance: an empirical study. Strategic Management Journal, 9(2), 123-139.
20.Duncan, R. B. (1972). Characteristics of organizational environments and perceived environmental uncertainty. Administrative Science Quarterly, 17(3), 313-327.
21.Eshlaghy, A. T., Mashayekhi, A. N., Rajabzadeh, A., & Razavian, M. M. (2010). Applying path analysis method in defining effective factors in organisation agility. International Journal of Production Research, 48(6), 1765-1786.
22.Federgruen, A., & Yang, N. (2008). Selecting a portfolio of suppliers under demand and supply risks. Operations Research, 56(4), 916-936.
23.Freytag, P. V., & Kirk, L. (2003). Continuous strategic sourcing. Journal of Purchasing and Supply Management, 9(3), 135-150.
24.Fynes, B., De Búrca, S., & Marshall, D. (2004). Environmental uncertainty, supply chain relationship quality and performance. Journal of Purchasing and Supply Management, 10(4), 179-190.
25.Grant, R. M. (1991). The Resource-Based Theory of Competitive Advantage: Implications for Strategy Formulation: California Management Review, University of California.
26.Greaver, M. F. (1999). Strategic Outsourcing: A Structured Approach to Outsourcing Decisions and Initiatives: Amacom.
27.Hair, J. F. (2010). Multivariate Data Analysis: A Global Perspective-7/E: Prentice Hall.
28.Henry, D., Cooke, S., Buckley, P., Dumagan, J., Gill, G., Pastore, D., & LaPorte, S. The emerging digital economy II.
29.Humphreys, P., Lo, V., & McIvor, R. (2000). A decision support framework for strategic purchasing. Journal of Materials Processing Technology, 107(1), 353-362.
30.Ismail, H. S., & Sharifi, H. (2006). A balanced approach to building agile supply chains. International Journal of Physical Distribution & Logistics Management, 36(6), 431-444.
31.Jain, V., Benyoucef, L., & Deshmukh, S. (2008). What's the buzz about moving from ‘lean’to ‘agile’integrated supply chains? A fuzzy intelligent agent-based approach. International Journal of Production Research, 46(23), 6649-6677.
32.Johnson, D. W., & Johnson, F. P. (1991). Joining Together: Group Theory and Group Skills: Prentice-Hall, Inc.
33.Justin Tan, J., & Litsschert, R. J. (1994). Environment‐strategy relationship and its performance implications: An empirical study of the chinese electronics industry. Strategic Management Journal, 15(1), 1-20.
34.Kaplan, R. S., & Norton, D. P. (1996). Using the balanced scorecard as a strategic management system. Harvard business review, 74(1), 75-85.
35.Katayama, H., & Bennett, D. (1999). Agility, adaptability and leanness: a comparison of concepts and a study of practice. International Journal of Production Economics, 60-61, 43-51.
36.Khan, A., & Pillania, R. K. (2008). Strategic sourcing for supply chain agility and firms' performance: a study of Indian manufacturing sector. Management Decision, 46(10), 1508-1530.
37.Kim, S. W. (2006). Effects of supply chain management practices, integration and competition capability on performance. Supply Chain Management: An International Journal, 11(3), 241-248.
38.Kocabasoglu, C., & Suresh, N. C. (2006). Strategic sourcing: an empirical investigation of the concept and its practices in US manufacturing firms. Journal of Supply Chain Management, 42(2), 4-16.
39.Krause, D. R., Handfield, R. B., & Tyler, B. B. (2007). The relationships between supplier development, commitment, social capital accumulation and performance improvement. Journal of Operations Management, 25(2), 528-545.
40.Krishnan, R., Martin, X., & Noorderhaven, N. G. (2006). When does trust matter to alliance performance? Academy of Management Journal, 49(5), 894-917.
41.Kumar, S., Bragg, R. and Creinin, D. (2003). Managing supplier relationships, Quality Progress, 36(1), 9-16.
42.Lawson, B., Cousins, P. D., Handfield, R. B., & Petersen, K. J. (2009). Strategic purchasing, supply management practices and buyer performance improvement: an empirical study of UK manufacturing organisations. International Journal of Production Research, 47(10), 2649-2667.
43.Lee, H. L. (2004). The triple-A supply chain. Harvard Business Review, 82(10), 102-113.
44.Lee, P. K., Yeung, A. C., & Edwin Cheng, T. (2009). Supplier alliances and environmental uncertainty: an empirical study. International Journal of Production Economics, 120(1), 190-204.
45.Li, S., Ragu-Nathan, B., Ragu-Nathan, T., & Subba Rao, S. (2006). The impact of supply chain management practices on competitive advantage and organizational performance. Omega, 34(2), 107-124.
46.Li, X., Chung, C., Goldsby, T. J., & Holsapple, C. W. (2008). A unified model of supply chain agility: the work-design perspective. International Journal of Logistics Management, The, 19(3), 408-435.
47.Lin, C.-T., Chiu, H., & Chu, P.-Y. (2006). Agility index in the supply chain. International Journal of Production Economics, 100(2), 285-299.
48.Liu, G. J., Shah, R., & Babakus, E. (2012). When to Mass Customize: The Impact of Environmental Uncertainty*. Decision Sciences, 43(5), 851-887.
49.Mason, S. J., Cole, M. H., Ulrey, B. T., & Yan, L. (2002). Improving electronics manufacturing supply chain agility through outsourcing. International Journal of Physical Distribution & Logistics Management, 32(7), 610-620.
50.Melnyk, S., Lummus, R., Vokurka, R., & Sandor, J. (2009). Mapping the future of the strategic supply chaint: a Delphi study. International Journal of Production Research, 47(16), 4629-4653.
51.Miles, R. E., & Snow, C. C. (1984). Fit, failure and the hall of fame. California Management Review, 26(3), 10-28.
52.Milliken, F. J. (1987). Three types of perceived uncertainty about the environment: State, effect, and response uncertainty. Academy of Management Review, 12(1), 133-143.
53.Momme, J., & Hvolby, H.-H. (2002). An outsourcing framework: action research in the heavy industry sector. European Journal of Purchasing & Supply Management, 8(4), 185-196.
54.Merschmann, U., & Thonemann, U. W. (2011). Supply chain flexibility, uncertainty and firm performance: an empirical analysis of German manufacturing firms. International Journal of Production Economics, 130(1), 43-53.
55.Nagel, R. N., & Dove, R. (1991).21st Century Manufacturing Enterprise Strategy: An Industry-Led View:DIANE publishing.
56.Narasimhan, R., & Das, A. (1999). An empirical investigation of the contribution of strategic sourcing to manufacturing flexibilities and performance*. Decision Sciences, 30(3), 683-718.
57.Newkirk, H. E., & Lederer, A. L. (2006). The effectiveness of strategic information systems planning under environmental uncertainty. Information & Management, 43(4), 481-501.
58.Novack, R. A., & Simco, S. W. (1991). The industrial procurement process: a supply chain perspective. Journal of Business Logistics, 12(1), 145-167.
59.Overby, E., Bharadwaj, A., & Sambamurthy, V. (2006). Enterprise agility and the enabling role of information technology. European Journal of Information Systems, 15(2), 120-131.
60.Paulraj, A., & Chen, I. J. (2005). Strategic supply management and dyadic quality performance: a path analytical model.Journal of Supply Chain Management, 41(3), 4-18.
61.Prater, E., Biehl, M., & Smith, M. A. (2001). International supply chain agility-Tradeoffs between flexibility and uncertainty. International Journal of Operations & Production Management, 21(5/6), 823-839.
62.Quélin, B., & Duhamel, F. (2003). Bringing together strategic outsourcing and corporate strategy: Outsourcing motives and risks. European Management Journal, 21(5), 647-661.
63.Quayle, M. (2002). Purchasing in small firms. European Journal of Purchasing & Supply Management, 8(3), 151-159.
64.Robbins, S. P., & Coulter, M. (2002). Management, 7”'edition: Prentice Hall Inc., New Jersey.
65.Russell, R., & Taylor III, B. (2000). Operations Management. 3. Auflage, London.
66.Ryu, I., So, S., & Koo, C. (2009). The role of partnership in supply chain performance. Industrial Management & Data Systems, 109(4), 496-514.
67.Sislian, E., & Satir, A. (2000). Strategic sourcing: a framework and a case study.Journal of Supply Chain Management, 36(3), 4-11.
68.Smeltzer, L. R., Manship, J. A., & Rossetti, C. L. (2003). An Analysis of the Integration of Strategic Sourcing and Negotiation Planning. Journal of Supply Chain Management, 39(4), 16-25.
69.Spekman, R. E., Kamauff Jr, J. W., & Myhr, N. (1998). An empirical investigation into supply chain management: a perspective on partnerships. Supply Chain Management: An International Journal, 3(2), 53-67.
70.Stank, T. P., Keller, S. B., & Daugherty, P. J. (2001). Supply chain collaboration and logistical service performance. Journal of Business Logistics, 22(1), 29-48.
71.Su, Q., Song, Y.-t., Li, Z., & Dang, J.-x. (2008). The impact of supply chain relationship quality on cooperative strategy. Journal of Purchasing and Supply Management, 14(4), 263-272.
72.Swafford, P. M., Ghosh, S., & Murthy, N. (2008). Achieving supply chain agility through IT integration and flexibility. International Journal of Production Economics, 116(2), 288-297.
73.Talluri, S., & Narasimhan, R. (2004). A methodology for strategic sourcing. European Journal of Operational Research, 154(1), 236-250.
74.Tracey, M., Lim, J.-S., & Vonderembse, M. A. (2005). The impact of supply-chain management capabilities on business performance. Supply Chain Management: An International Journal, 10(3), 179-191.
75.Tseng, F.-M., Chiu, Y.-J., & Chen, J.-S. (2009). Measuring business performance in the high-tech manufacturing industry: a case study of Taiwan's large-sized TFT-LCD panel companies. Omega, 37(3), 686-697.
76.Venkatraman, N., & Ramanujam, V. (1986). Measurement of business performance in strategy research: a comparison of approaches. Academy of Management Review, 11(4), 801-814.
77.Verdu, A. J., Tamayo, I., & Ruiz-Moreno, A. (2012). The moderating effect of environmental uncertainty on the relationship between real options and technological innovation in high-tech firms. Technovation, 32(9), 579-590.
78.Vickery, S., Droge, C., Setia, P., & Sambamurthy, V. (2010). Supply chain information technologies and organisational initiatives: complementary versus independent effects on agility and firm performance. International Journal of Production Research, 48(23), 7025-7042.
79.Wang, L., Yeung, J. H. Y., & Zhang, M. (2011). The impact of trust and contract on innovation performance: The moderating role of environmental uncertainty. International Journal of Production Economics, 134(1), 114-122.
80.Wheel Wright, S. C. (1984). Manufacturing strategy: defining the missing link. Strategic Management Journal, 5(1), 77-91.
81.Wong, C. W., Lai, K.-h., & Ngai, E. (2009). The role of supplier operational adaptation on the performance of IT-enabled transport logistics under environmental uncertainty. International Journal of Production Economics, 122(1), 47-55.
82.Wong, C. Y., Boon-Itt, S., & Wong, C. W. (2011). The contingency effects of environmental uncertainty on the relationship between supply chain integration and operational performance. Journal of Operations Management, 29(6), 604-615.
83.Yeung, K., Lee, P.C.K., Yeung, A.C.L., & Cheng, T.C.E. (2013). Supplier partnership and cost performance:The moderating roles of specific investments and environmental uncertainty. International Journal of Production Economics, 144(2), 546-559.
84.Yu, Z., Yan, H., & Cheng, T. E. (2001). Benefits of information sharing with supply chain partnerships. Industrial Management & Data Systems, 101(3), 114-121.
85.Yusuf, Y., Gunasekaran, A., Adeleye, E., & Sivayoganathan, K. (2004). Agile supply chain capabilities: Determinants of competitive objectives. European Journal of Operational Research, 159(2), 379-392.
86.Yusuf, Y. Y., Gunasekaran, A., Musa, A., Dauda, M., El-Berishy, N., & Cang, S. (2012). A relational study of supply chain agility, competitiveness and business performance in the oil and gas industry. International Journal of Production Economics.
87.Yusuf, Y. Y., Sarhadi, M., & Gunasekaran, A. (1999). Agile manufacturing:: The drivers, concepts and attributes. International Journal of Production Economics, 62(1), 33-43.
88.Zeng, A. Z. (2003). Global sourcing: process and design for efficient management. Supply Chain Management: An International Journal, 8(4), 367-379.

三、網站部分
1.Digitimes:http://www.digitimes.com.tw/tw/dt/p360.asp?CnlID=10
2.工業技術研究院:https://www.itri.org.tw/chi/iek/p11.asp?RootNodeId=070&NavRootNodeId=0753&NodeId=07534&ArticleNBR=4374
3.台灣經濟研究院:http://tie.tier.org.tw/index.asp
4.恩汎理財網:http://symy04.pixnet.net/blog/category/210187
5.財政部統計處:http://www.mof.gov.tw/mp.asp?mp=62

------------------------------------------------------------------------ 第 4 筆 ---------------------------------------------------------------------
系統識別號 U0026-0109201511471800
論文名稱(中文) 耐力運動與熱量限制對於成年雄性大鼠之骨材料特性的影響
論文名稱(英文) The effects of endurance exercise and caloric restriction on bone material properties in adult male rats
校院名稱 成功大學
系所名稱(中) 體育健康與休閒研究所
系所名稱(英) Institute of Physical Education, Health & Leisure Studies
學年度 103
學期 2
出版年 104
研究生(中文) 蔡宗諺
學號 rb6021087
學位類別 碩士
語文別 中文
口試日期 2015-07-28
論文頁數 35頁
口試委員 口試委員-楊艾倫
口試委員-林麗娟
指導教授-黃滄海
關鍵字(中) 耐力運動
熱量限制
生物力學特性
關鍵字(英) endurance exercise
caloric restriction
biomechanical properties
學科別分類
中文摘要 肥胖已儼然成為先進國家日趨受到重視的公衛議題,伴隨著肥胖所衍生而來的相關疾病更形成健康上相當大的負擔,因此,體重控制成了文明人的重要課題之一,在各種調節體重的介入方法中,熱量限制 (caloric restriction, 以下簡稱CR) 和耐力運動 (endurance training) 是兩種相對健康且自然的方法。然而,減重過程所伴隨的骨質減小,卻又形成了另一健康上的隱憂。目的:本研究將探討熱量限制和耐力運動介入對雄性大鼠骨材料特性之影響。方法: 以週齡26週的SD雄性大鼠為實驗動物,依實驗設計分別給予熱量限制 (CR) 和耐力運動 (EXE) (訓練強度:16公尺/分鐘、60分鐘/天及5天/週介入),實驗分組分成CON (n=12)、CR20% (n=12)、CR40% (n=12)及EXE (n=12) 等四組。動物犧牲後所得之骨骼樣本,進行骨密度及骨骼組織維度之量測,並以三點壓斷儀器測量及分析股骨之材料特性;統計方法以One-way ANOVA及 One-way ANCOVA進行組間各變項之差異性分析 ( = .05)。結果:本研究發現熱量限制組及耐力運動組在實驗後體重皆顯著低於控制組 (p<0.05)。雖然所有骨密度、骨組織維度的量測以及生物力學特性在絕對值方面並未呈現組間差異,進一步以體重為共變量所進行的單因子共變數分析,亦未呈現組間差異,然而將所有量測值進一步除以體重之後,耐力運動組及飲食限制組在各項量測值均顯著大於控制組 (p<0.05)。
結論: 九週的耐力運動訓練以及飲食限制後,造成雄性大鼠運動體重的增加趨緩或下降,然而此一體重下降,並未對各項骨質量測參數造成負面影響,且相對於體重而言,耐力運動及飲食限制大鼠反而有較佳的骨密度、骨組織維度及生物力學強度。本研究結果是否能應用於人類,須進一步研究證實。
英文摘要 Objective: To investigate the effects of calorie restriction and endurance exercise on cortical bone mineral density and geometry in adult male rats. Method: forty-eight male Sprague Dawley rats at age of 26 weeks old (n=60) were randomly assigned to control (CON), 40% and 20% caloric restriction (CR40% and CR20%), endurance training (EXE) (n=12 for each group). The exercise intervention was consisted of a treadmill running training at speed of 16 m/min, 60 min/day and 5 days/week for nine weeks. After euthanasia, femoral bones were collected and subjected three-point-bending and micro CT scanning for densitometric and geometric analyses. In addition to one-way ANOVA, one-way ANCOVA was adopted with body weight included as covariate for comparing difference among groups (=0.05). Result: The CR40%, CR20% and EXE groups were significant lower in body mass as compared to the CON (p <0.05). One-way ANOVA and one-way ANCOVA showed no difference among groups in the absolute BMD and BMC. And, also, none of cross-sectional geometry measurements showed difference among groups. However, when indices further divided by the body mass, the CON showed relatively lower values in most indices of densitometry (relative total and cortical BMD and BMC) as well as relatively lower cross-sectional parameters in cortical bone (including: cross-sectional area, cortical thickness and moment of inertia, etc.) (p <0.05). Conclusion: Absolutely, rats subjected to endurance exercise and caloric restriction showed no different effects on cortical bone size, densitometry and biomechanical properties in adult male rats. However, the body weight reduction shown in exercise and CR groups made the bones of those animals relatively higher in cortical bone strength, size and density. Further studies need to verify whether the findings of the current study are applicable in clinical practice .
論文目次 目錄
摘要 II
Abstract III
謝誌 IX
第壹章、緒論 1
第一節、研究背景 1
第二節、研究目的 2
第三節、名詞操作型定義 2
第四節、研究重要性 3
第貳章、文獻探討 4
第一節、熱量限制對整體健康與骨組織生物力學特性之影響 4
一、熱量限制對於壽命之影響 4
二、熱量限制對於健康之影響 4
三、熱量限制在骨骼材料特性上之影響 5
第二節、耐力運動對整體健康與骨組織生物力學特性之影響 6
一、 耐力運動對於壽命之影響 6
二、 耐力運動對健康之影響 7
三、 耐力運動在骨骼材料特性在之影響 7
第三節、骨組織的材料力學測量方法 8
第四節、結語 9
第參章、研究方法 10
第一節、實驗動物 10
第二節、實驗設計 10
第三節、運動訓練設計 10
第五節、動物犧牲 11
第六節、分析方法 11
第七節、統計方法 13
第四章、研究結果 14
第一節、體重 14
第二節、骨密度 15
第三節、骨斷面幾何參數 16
第四節、骨骼材料力學特性 18
第伍章、討論 22
第一節、體重 22
第二節、骨密度 22
第三節、骨骼組織生物力學特性分析 24
第四節、共變量分析的結果 26
第五節、 結論與建議 27
參考文獻 28
參考文獻 Adami, P. E., Negro, A., Lala, N., & Martelletti, P. (2010). The role of physical activity in the prevention and treatment of chronic diseases. Clin Ter, 161(6), 537-541.
Akkus, O., Adar, F., & Schaffler, M. B. (2004). Age-related changes in physicochemical properties of mineral crystals are related to impaired mechanical function of cortical bone. Bone, 34(3), 443-453. doi: 10.1016/j.bone.2003.11.003
Attipoe, S., Park, J. Y., Fenty, N., Phares, D., & Brown, M. (2008). Oxidative stress levels are reduced in postmenopausal women with exercise training regardless of hormone replacement therapy status. J Women Aging, 20(1-2), 31-45. DOI: 10.1300/J074v20n01_04
Avenell, A., Richmond, P. R., Lean, M. E., & Reid, D. M. (1994). Bone loss associated with a high fibre weight reduction diet in postmenopausal women. Eur J Clin Nutr, 48(8), 561-566.
Bleicher, K., Cumming, R. G., Naganathan, V., Travison, T. G., Sambrook, P. N., Blyth, F. M., . . . Seibel, M. J. (2011). The role of fat and lean mass in bone loss in older men: findings from the CHAMP study. Bone, 49(6), 1299-1305. doi: 10.1016/j.bone.2011.08.026 doi:10.1016/j.bone.2011.08.026
Bodkin, N. L., Alexander, T. M., Ortmeyer, H. K., Johnson, E., & Hansen, B. C. (2003). Mortality and morbidity in laboratory-maintained Rhesus monkeys and effects of long-term dietary restriction. J Gerontol A Biol Sci Med Sci, 58(3), 212-219. doi: 10.1093/gerona/58.3.B212
Bodnar, M., Skalicky, M., Viidik, A., & Erben, R. G. (2012). Interaction between exercise, dietary restriction and age-related bone loss in a rodent model of male senile osteoporosis. Gerontology, 58(2), 139-149. doi: 10.1159/000329113
Booth, FW, & Laye, MJ. (2010). The future: genes, physical activity and health. Acta physiologica, 199(4), 549-556. doi: 10.1111/j.1748-1716.2010.02117.x
Bourrin, S., Palle, S., Pupier, R., Vico, L., & Alexandre, C. (1995). Effect of physical training on bone adaptation in three zones of the rat tibia. J Bone Miner Res, 10(11), 1745-1752. doi: 10.1002/jbmr.5650101118
Browner, W. S., Pressman, A. R., Nevitt, M. C., & Cummings, S. R. (1996). Mortality following fractures in older women. The study of osteoporotic fractures. Arch Intern Med, 156(14), 1521-1525. doi:10.1001/archinte.
Burrows, M., Nevill, A. M., Bird, S., & Simpson, D. (2003). Physiological factors associated with low bone mineral density in female endurance runners. Br J Sports Med, 37(1), 67-71. doi:10.1136/bjsm.37.1.67
Castelli, D. M., Hillman, C. H., Buck, S. M., & Erwin, H. E. (2007). Physical fitness and academic achievement in third- and fifth-grade students. J Sport Exerc Psychol, 29(2), 239-252.
Caviezel, F., Margonato, A., Slaviero, G., Bonetti, F., Vicedomini, G., Cattaneo, A. G., & Pozza, G. (1986). Early improvement of left ventricular function during caloric restriction in obesity. Int J Obes, 10(6), 421-426.
Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults--The Evidence Report. National Institutes of Health. (1998). Obes Res, 6 Suppl 2, 51S-209S.
Cole, S. R., Kawachi, I., Sesso, H. D., Paffenbarger, R. S., & Lee, I. M. (1999). Sense of exhaustion and coronary heart disease among college alumni. Am J Cardiol, 84(12), 1401-1405. doi:10.1016/S0002-9149(99)00585-8
Compston, J. E., Watts, N. B., Chapurlat, R., Cooper, C., Boonen, S., Greenspan, S., . . . Glow, Investigators. (2011). Obesity is not protective against fracture in postmenopausal women: GLOW. Am J Med, 124(11), 1043-1050. doi: 10.1016/j.amjmed.2011.06.013
Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. (1993). Am J Med, 94(6), 646-650.
Cooper, L. A., & Joy, E. A. (2005). Osteoporosis in a female cross-country runner with femoral neck stress fracture. Curr Sports Med Rep, 4(6), 321-322.
Diet, nutrition and the prevention of chronic diseases. (2003). World Health Organ Tech Rep Ser, 916, i-viii, 1-149, backcover.
Drolet, B., Simard, C., & Poirier, P. (2007). Impact of weight-loss medications on the cardiovascular system: focus on current and future anti-obesity drugs. Am J Cardiovasc Drugs, 7(4), 273-288.
Elefteriou, F., Ahn, J. D., Takeda, S., Starbuck, M., Yang, X., Liu, X., . . . Karsenty, G. (2005). Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature, 434(7032), 514-520. doi: 10.1038/nature03398
Ensrud, K. E., Fullman, R. L., Barrett-Connor, E., Cauley, J. A., Stefanick, M. L., Fink, H. A., . . . Osteoporotic Fractures in Men Study Research, Group. (2005). Voluntary weight reduction in older men increases hip bone loss: the osteoporotic fractures in men study. J Clin Endocrinol Metab, 90(4), 1998-2004. doi: 10.1210/jc.2004-1805
Felson, D. T., Zhang, Y., Hannan, M. T., & Anderson, J. J. (1993). Effects of weight and body mass index on bone mineral density in men and women: the Framingham study. J Bone Miner Res, 8(5), 567-573. doi: 10.1002/jbmr.5650080507
Flegal, K. M., Carroll, M. D., Ogden, C. L., & Johnson, C. L. (2002). Prevalence and trends in obesity among US adults, 1999-2000. JAMA, 288(14), 1723-1727. doi:10.1001/jama.288.14.1723.
Funk, J. R., Kerrigan, J. R., & Crandall, J. R. (2004). Dynamic bending tolerance and elastic-plastic material properties of the human femur. Annu Proc Assoc Adv Automot Med, 48, 215-233.
Goldberg, J. H., & Kiernan, M. (2005). Innovative techniques to address retention in a behavioral weight-loss trial. Health Educ Res, 20(4), 439-447. doi: 10.1093/her/cyg139
Hamrick, M. W., Ding, K. H., Ponnala, S., Ferrari, S. L., & Isales, C. M. (2008). Caloric restriction decreases cortical bone mass but spares trabecular bone in the mouse skeleton: implications for the regulation of bone mass by body weight. J Bone Miner Res, 23(6), 870-878. doi: 10.1359/jbmr.080213
Hart, K. J., Shaw, J. M., Vajda, E., Hegsted, M., & Miller, S. C. (2001). Swim-trained rats have greater bone mass, density, strength, and dynamics. J Appl Physiol (1985), 91(4), 1663-1668.
Hedley, A. A., Ogden, C. L., Johnson, C. L., Carroll, M. D., Curtin, L. R., & Flegal, K. M. (2004). Prevalence of overweight and obesity among US children, adolescents, and adults, 1999-2002. JAMA, 291(23), 2847-2850. doi: 10.1001/jama.291.23.2847
Helmrich, S. P., Ragland, D. R., Leung, R. W., & Paffenbarger, R. S., Jr. (1991). Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med, 325(3), 147-152. doi: 10.1056/NEJM199107183250302
Hu, Gang, Lakka, Timo A, Barengo, Noël C, & Tuomilehto, Jaakko. (2004). Physical activity in the prevention of type 2 diabetes. Kardiovaskuläre Medizin, 7, 384-405.
Huang, T. H., Chang, F. L., Lin, S. C., Liu, S. H., Hsieh, S. S., & Yang, R. S. (2008). Endurance treadmill running training benefits the biomaterial quality of bone in growing male Wistar rats. J Bone Miner Metab, 26(4), 350-357. doi: 10.1007/s00774-007-0831-3
Huang, T. H., Lin, S. C., Chang, F. L., Hsieh, S. S., Liu, S. H., & Yang, R. S. (2003). Effects of different exercise modes on mineralization, structure, and biomechanical properties of growing bone. J Appl Physiol (1985), 95(1), 300-307. doi: 10.1152/japplphysiol.01076.2002
Huang, T. H., Su, I. H., Lewis, J. L., Chang, M. S., Hsu, A. T., Perrone, C. E., & Ables, G. P. (2015). Effects of Methionine Restriction and Endurance Exercise on Bones of Ovariectomized Rats: A Study of Histomorphometry, Densitometry and Biomechanical Properties. J Appl Physiol (1985), jap 00395 02015. doi: 10.1152/japplphysiol.00395.2015
Hursting, S. D., Lavigne, J. A., Berrigan, D., Perkins, S. N., & Barrett, J. C. (2003). Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. Annu Rev Med, 54, 131-152. doi: 10.1146/annurev.med.54.101601.152156
Jiang, Yebin, Zhao, Jenny, Genant, Harry K, Dequeker, Jan, & Geusens, Piet. (1997). Long‐Term Changes in Bone Mineral and Biomechanical Properties of Vertebrae and Femur in Aging, Dietary Calcium Restricted, and/or Estrogen‐Deprived/‐Replaced Rats. Journal of Bone and Mineral Research, 12(5), 820-831. DOI: 10.1359/jbmr.1997.12.5.820
Joo, Y. I., Sone, T., Fukunaga, M., Lim, S. G., & Onodera, S. (2003). Effects of endurance exercise on three-dimensional trabecular bone microarchitecture in young growing rats. Bone, 33(4), 485-493. doi:10.1016/S8756-3282(03)00212-6
Kelley, G. A., & Kelley, K. S. (2006). Aerobic exercise and HDL2-C: a meta-analysis of randomized controlled trials. Atherosclerosis, 184(1), 207-215. doi: 10.1016/j.atherosclerosis.2005.04.005
Kemper, A. R., McNally, C., Pullins, C. A., Freeman, L. J., Duma, S. M., & Rouhana, S. M. (2007). The biomechanics of human ribs: material and structural properties from dynamic tension and bending tests. Stapp Car Crash J, 51, 235-273.
Krakowski, M., Czobor, P., & Citrome, L. (2009). Weight gain, metabolic parameters, and the impact of race in aggressive inpatients randomized to double-blind clozapine, olanzapine or haloperidol. Schizophr Res, 110(1-3), 95-102. doi: 10.1016/j.schres.2009.02.006
Lanza, I. R., Short, D. K., Short, K. R., Raghavakaimal, S., Basu, R., Joyner, M. J., . . . Nair, K. S. (2008). Endurance exercise as a countermeasure for aging. Diabetes, 57(11), 2933-2942. doi: 10.2337/db08-0349
Lavie, C. J., Milani, R. V., & Ventura, H. O. (2009). Obesity and cardiovascular disease: risk factor, paradox, and impact of weight loss. J Am Coll Cardiol, 53(21), 1925-1932. doi: 10.1016/j.jacc.2008.12.068
Lear, S. A., Pauly, R. P., & Birmingham, C. L. (1999). Body fat, caloric intake, and plasma leptin levels in women with anorexia nervosa. Int J Eat Disord, 26(3), 283-288. 10.1002/(SICI)1098-108X(199911)26:3<283::AID-EAT5>3.0.CO;2-K
Lee, CJ, Panemangalore, M, & Wilson, K. (1986). Effect of dietary energy restriction on bone mineral content of mature rats. Nutrition Research, 6(1), 51-59. doi:10.1016/S0271-5317(86)80199-3
Leon, A. S., Connett, J., Jacobs, D. R., Jr., & Rauramaa, R. (1987). Leisure-time physical activity levels and risk of coronary heart disease and death. The Multiple Risk Factor Intervention Trial. JAMA, 258(17), 2388-2395. doi:10.1001/jama.1987.03400170074026.
Li, F., Fisher, K. J., & Harmer, P. (2005). Prevalence of overweight and obesity in older U.S. adults: estimates from the 2003 Behavioral Risk Factor Surveillance System survey. J Am Geriatr Soc, 53(4), 737-739. doi: 10.1111/j.1532-5415.2005.53228_10.x
Linke, A., Adams, V., Schulze, P. C., Erbs, S., Gielen, S., Fiehn, E., . . . Hambrecht, R. (2005). Antioxidative effects of exercise training in patients with chronic heart failure: increase in radical scavenger enzyme activity in skeletal muscle. Circulation, 111(14), 1763-1770. doi: 10.1161/01.CIR.0000165503.08661.E5
Martyn-St James, M., & Carroll, S. (2006). High-intensity resistance training and postmenopausal bone loss: a meta-analysis. Osteoporos Int, 17(8), 1225-1240. doi: 10.1007/s00198-006-0083-4
Masoro, Edward J. (2002). Caloric Restriction: A Key to Understanding and Modulating Aging: A Key to Understanding and Modulating Aging: Elsevier.
Maswood, N., Young, J., Tilmont, E., Zhang, Z., Gash, D. M., Gerhardt, G. A., . . . Ingram, D. K. (2004). Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson's disease. Proc Natl Acad Sci U S A, 101(52), 18171-18176. doi: 10.1073/pnas.0405831102
Mattison, J. A., Lane, M. A., Roth, G. S., & Ingram, D. K. (2003). Calorie restriction in rhesus monkeys. Exp Gerontol, 38(1-2), 35-46. doi:10.1016/S0531-5565(02)00146-8

McCay, C. M. (1935). The effect of retarded growth upon the length of life span and upon the ultimate body size. J Nutr, 10(1), 63.
Meckling, K. A., Gauthier, M., Grubb, R., & Sanford, J. (2002). Effects of a hypocaloric, low-carbohydrate diet on weight loss, blood lipids, blood pressure, glucose tolerance, and body composition in free-living overweight women. Can J Physiol Pharmacol, 80(11), 1095-1105. doi: 10.1139/y02-140
Michels, K. B., & Ekbom, A. (2004). Caloric restriction and incidence of breast cancer. JAMA, 291(10), 1226-1230. doi: 10.1001/jama.291.10.1226
Molster, A. O. (1986). Biomechanical effects of intramedullary reaming and nailing on intact femora in rats. Clin Orthop Relat Res(202), 278-285.
Montgomery, E., Pennington, C., Isales, C. M., & Hamrick, M. W. (2005). Muscle-bone interactions in dystrophin-deficient and myostatin-deficient mice. Anat Rec A Discov Mol Cell Evol Biol, 286(1), 814-822. doi: 10.1002/ar.a.20224
Mosekilde, L., Thomsen, J. S., Orhii, P. B., & Kalu, D. N. (1998). Growth hormone increases vertebral and femoral bone strength in osteopenic, ovariectomized, aged rats in a dose-dependent and site-specific manner. Bone, 23(4), 343-352. doi:10.1016/S8756-3282(98)00107-0
Ndiaye, Biram, Prudhon, Claudine, Guillozo, Huguette, & Lemonnier, Daniel. (1992). Rat serum osteocalcin concentration is determined by food intake and not by inflammation. The Journal of nutrition, 122(9), 1870.
Nguyen, T. V., Sambrook, P. N., & Eisman, J. A. (1998). Bone loss, physical activity, and weight change in elderly women: the Dubbo Osteoporosis Epidemiology Study. J Bone Miner Res, 13(9), 1458-1467. doi: 10.1359/jbmr.1998.13.9.1458
Paffenbarger, R. S., Jr., Hyde, R. T., Wing, A. L., & Hsieh, C. C. (1986). Physical activity, all-cause mortality, and longevity of college alumni. N Engl J Med, 314(10), 605-613. doi: 10.1056/NEJM198603063141003 DOI: 10.1056/NEJM198603063141003
Pate, R. R., Pratt, M., Blair, S. N., Haskell, W. L., Macera, C. A., Bouchard, C., . . . et al. (1995). Physical activity and public health. A recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA, 273(5), 402-407. doi:10.1001/jama.1995.03520290054029.
Peck, WA, Burckhardt, P, Christiansen, C, Fleisch, HA, Genant, HK, Gennari, C, . . . Ogata, E. (1993). Consensus development conference-diagnosis, prophylaxis, and treatment of osteoporosis: Excerpta Medica Inc 245 WEST 17TH STREET, NEW YORK, NY 10011.
Pedersen, B. K., & Saltin, B. (2006). Evidence for prescribing exercise as therapy in chronic disease. Scand J Med Sci Sports, 16 Suppl 1, 3-63. doi: 10.1111/j.1600-0838.2006.00520.x
Pocock, N., Eisman, J., Gwinn, T., Sambrook, P., Kelly, P., Freund, J., & Yeates, M. (1989). Muscle strength, physical fitness, and weight but not age predict femoral neck bone mass. J Bone Miner Res, 4(3), 441-448. doi: 10.1002/jbmr.5650040320
Raeini-Sarjaz, M., Vanstone, C. A., Papamandjaris, A. A., Wykes, L. J., & Jones, P. J. (2001). Comparison of the effect of dietary fat restriction with that of energy restriction on human lipid metabolism. Am J Clin Nutr, 73(2), 262-267.
Raitakari, M., Ilvonen, T., Ahotupa, M., Lehtimaki, T., Harmoinen, A., Suominen, P., . . . Raitakari, O. T. (2004). Weight reduction with very-low-caloric diet and endothelial function in overweight adults: role of plasma glucose. Arterioscler Thromb Vasc Biol, 24(1), 124-128. doi: 10.1161/01.ATV.0000109749.11042.7c
Reid, I. R., Ames, R., Evans, M. C., Sharpe, S., Gamble, G., France, J. T., . . . Cundy, T. F. (1992). Determinants of total body and regional bone mineral density in normal postmenopausal women--a key role for fat mass. J Clin Endocrinol Metab, 75(1), 45-51. doi: 10.1210/jcem.75.1.1619030
Reimers, C. D., Knapp, G., & Reimers, A. K. (2012). Does physical activity increase life expectancy? A review of the literature. J Aging Res, 2012, 243958. doi: 10.1155/2012/243958
Ritz, E., Rychlik, I., Locatelli, F., & Halimi, S. (1999). End-stage renal failure in type 2 diabetes: A medical catastrophe of worldwide dimensions. Am J Kidney Dis, 34(5), 795-808. doi: 10.1016/S0272-6386(99)70035-1
Rosamond, W., Flegal, K., Friday, G., Furie, K., Go, A., Greenlund, K., . . . Stroke Statistics, Subcommittee. (2007). Heart disease and stroke statistics--2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 115(5), e69-171. doi: 10.1161/CIRCULATIONAHA.106.179918
Ross, R., Dagnone, D., Jones, P. J., Smith, H., Paddags, A., Hudson, R., & Janssen, I. (2000). Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men. A randomized, controlled trial. Ann Intern Med, 133(2), 92-103.
Ryan, A. S., Nicklas, B. J., & Dennis, K. E. (1998). Aerobic exercise maintains regional bone mineral density during weight loss in postmenopausal women. J Appl Physiol (1985), 84(4), 1305-1310.
Salamone, L. M., Cauley, J. A., Black, D. M., Simkin-Silverman, L., Lang, W., Gregg, E., . . . Wing, R. (1999). Effect of a lifestyle intervention on bone mineral density in premenopausal women: a randomized trial. Am J Clin Nutr, 70(1), 97-103.
Sanderson, J. P., Binkley, N., Roecker, E. B., Champ, J. E., Pugh, T. D., Aspnes, L., & Weindruch, R. (1997). Influence of fat intake and caloric restriction on bone in aging male rats. J Gerontol A Biol Sci Med Sci, 52(1), B20-25. doi: 10.1093/gerona/52A.1.B20
Slemenda, C. W., Hui, S. L., Longcope, C., Wellman, H., & Johnston, C. C., Jr. (1990). Predictors of bone mass in perimenopausal women. A prospective study of clinical data using photon absorptiometry. Ann Intern Med, 112(2), 96-101. doi:10.7326/0003-4819-112-2-96
Stern, J. S., Gades, M. D., Wheeldon, C. M., & Borchers, A. T. (2001). Calorie restriction in obesity: prevention of kidney disease in rodents. J Nutr, 131(3), 913S-917S.
Talbott, S. M., Cifuentes, M., Dunn, M. G., & Shapses, S. A. (2001). Energy restriction reduces bone density and biomechanical properties in aged female rats. J Nutr, 131(9), 2382-2387.
Taormina, G., & Mirisola, M. G. (2014). Calorie restriction in mammals and simple model organisms. Biomed Res Int, 2014, 308690. doi: 10.1155/2014/308690
van Baak, M. A., & Visscher, T. L. (2006). Public health success in recent decades may be in danger if lifestyles of the elderly are neglected. Am J Clin Nutr, 84(6), 1257-1258.
Villareal, D. T., Banks, M., Sinacore, D. R., Siener, C., & Klein, S. (2006). Effect of weight loss and exercise on frailty in obese older adults. Arch Intern Med, 166(8), 860-866. doi: 10.1001/archinte.166.8.860
Villareal, D. T., Chode, S., Parimi, N., Sinacore, D. R., Hilton, T., Armamento-Villareal, R., . . . Shah, K. (2011). Weight loss, exercise, or both and physical function in obese older adults. N Engl J Med, 364(13), 1218-1229. doi: 10.1056/NEJMoa1008234
Villareal, D. T., Fontana, L., Weiss, E. P., Racette, S. B., Steger-May, K., Schechtman, K. B., . . . Holloszy, J. O. (2006). Bone mineral density response to caloric restriction-induced weight loss or exercise-induced weight loss: a randomized controlled trial. Arch Intern Med, 166(22), 2502-2510. doi: 10.1001/archinte.166.22.2502
Weindruch, R. (1996). The retardation of aging by caloric restriction: studies in rodents and primates. Toxicol Pathol, 24(6), 742-745. doi: 10.1177/019262339602400618
Weindruch, R., & Sohal, R. S. (1997). Seminars in medicine of the Beth Israel Deaconess Medical Center. Caloric intake and aging. N Engl J Med, 337(14), 986-994. doi: 10.1056/NEJM199710023371407
Westerbeek, Z. W., Hepple, R. T., & Zernicke, R. F. (2008). Effects of aging and caloric restriction on bone structure and mechanical properties. J Gerontol A Biol Sci Med Sci, 63(11), 1131-1136.
Witham, M. D., & Avenell, A. (2010). Interventions to achieve long-term weight loss in obese older people: a systematic review and meta-analysis. Age Ageing, 39(2), 176-184. doi: 10.1093/ageing/afp251
蘇亦秀. (2013). 甲硫胺酸限制飲食與耐力運動對去卵巢大鼠骨骼之代謝, 組織型態與生物力學特性的影響. (未出版碩士論文), 國立成功大學, 台南市.


------------------------------------------------------------------------ 第 5 筆 ---------------------------------------------------------------------
系統識別號 U0026-0209201510091200
論文名稱(中文) 高鐵酸鉀前氧化對微囊藻細胞破壞及微囊藻毒素降解之影響
論文名稱(英文) Effect of Potassium Ferrate on Cell Integrity of Microcystis aeruginosa and Release and Degradation of Microcystins
校院名稱 成功大學
系所名稱(中) 環境工程學系
系所名稱(英) Department of Environmental Engineering
學年度 103
學期 2
出版年 104
研究生(中文) 林柏宏
學號 P56024136
學位類別 碩士
語文別 中文
口試日期 2015-07-13
論文頁數 103頁
口試委員 指導教授-林財富
口試委員-王根樹
口試委員-葉宣顯
口試委員-黃良銘
關鍵字(中) 前氧化
微囊藻毒素
細胞完整性
高鐵酸鉀氧化
關鍵字(英) Pre-oxidation
Microcystins
Cell integrity
Potassium ferrate
學科別分類
中文摘要 本研究主要探討高鐵酸鉀氧化微囊藻時,對其細胞完整性,及毒素釋出和降解之影響。實驗中以高鐵酸鉀作為氧化劑,並選擇具有產毒能力之銅綠微囊藻(Microcystis aeruginosa)進行氧化反應。實驗分為兩部分,第一部分以三種不同背景水(ASM培養基、仁義潭水及成功湖水)進行高鐵酸鉀氧化實驗,並檢測微囊藻細胞完整性和毒素之變化及模擬;第二部分則以高鐵酸鉀進行前氧化及混凝程序之串聯式實驗,探討高鐵酸鉀氧化過程生成之氫氧化鐵是否能提升後續混凝程序之細胞去除率。
研究中微囊藻細胞被高鐵酸鉀所破壞之程度,以細胞完整性來表示,利用螢光染劑SYTOX(SYTOX Green nucleic acid stain)搭配流式細胞儀(flow cytometer, FCM)進行分析,並以顯微鏡協助判定細胞完整之情形。本研究中選用之銅綠微囊藻主要代謝產物為微囊藻毒素,應用酵素連結免疫吸附法(Enzyme-Linked Immunosorbent Assay, ELISA)進行毒素之濃度分析。串聯式實驗中,將前氧化後之藻液導入瓶杯試驗進行混凝程序,並監測微囊藻細胞去除率。
研究發現高鐵酸鉀對微囊藻細胞之氧化反應容易受到背景水之溶解性物質(天然有機物)的影響。高濃度(5105 cells/mL)及低濃度(1105 cells/mL)之微囊藻細胞於仁義潭水中,以10 mg/L高鐵酸鉀氧化30-60分鐘後細胞開始裂解,並於180分鐘後全數破裂;成功湖水含有高濃度之溶解性天然有機物,可能與微囊藻細胞競爭氧化劑,而導致高劑量高鐵酸鉀(20 mg/L)僅23%的細胞破裂;而在ASM培養基中則未有細胞破裂的現象發生。代謝物方面,微囊藻毒素能快速被高鐵酸鉀降解,當細胞破裂後胞內毒素釋出水體立即被降解,未觀察到胞外毒素累積之現象,此外在反應過程中,發現微囊藻細胞未破裂的情況下胞內毒素有減少的現象。
在細胞破裂動力學模擬,發現藻體破裂有遲滯期的現象,因此使用Delayed Chick-Watson model及Modified Chick-Watson model進行模擬微囊藻細胞完整性之變化趨勢,模擬結果,以Modified Chick-Watson model進行模擬能適合敘述細胞完整性之變化。而微囊藻毒素釋出及降解趨勢模擬中,兩個模式皆能適當敘述高鐵酸鉀對微囊藻細胞破壞和代謝物釋出及降解之變化趨勢。
高鐵酸鉀進行前氧化及混凝程序之串聯式實驗中, pH值、背景水及高鐵酸鉀消耗量為影響因素之一,研究結果顯示pH值在偏鹼性的情況下能有好的細胞去除率。以低濃度微囊藻細胞(1105 cells/mL)進行探討,於前氧化結束後及未終止反應下,高鐵酸鉀消耗量高之背景水中,有20%的細胞去除率,而在低消耗量之背景水中,僅只有5%之細胞去除率。而在有終止反應的情況下,高鐵酸鉀劑量為10 mg/L能有42%細胞去除率,去除效率的差異可能與高鐵酸鉀氧化生成之氫氧化鐵含量有關。若在終止前氧化反應條件下,能協助混凝程序增加細胞去除之效果。
本研究說明水中之溶解性物質會影響氧化過程對細胞的破壞、胞內代謝物的釋出及降解過程。此外,初步以高鐵酸鉀進行前氧化反應,除了能有效去除胞外代謝物,更能協助混凝程序增加細胞去除之效果及減少混凝劑之添加量,對於藻類控制及水處理程序之應用可提供參考。
英文摘要 Cyanobacteria bloom is a common issue in potable water sources. Potassium ferrate (K2FeO4) is an effective oxidant that may be used as a pre-oxidant in water treatment processes. In addition, during the oxidation processes the Fe(VI) in ferrate will be reduced to Fe(III) or ferric hydroxide, further acting as a coagulant for the removal of cyanobacteria cells. Therefore, understanding the interaction between the ferrate based oxidant and cyanobacteria cells will provide a better basis for the application of this oxidant in water treatment processes. In this study, the impact of K2FeO4 on the cell viability of Microcystis aeruginosa and fate of the associated microcystins (MCs) in water was investigated. In addition, the potential of cyanobacteria removal in the pre-oxidation and followed coagulation system was assessed. In conducting the experiments, the parameters that may affect the oxidation and removal of cyanobacteria, such as pH, K2FeO4 residual and background water matrix were also evaluated in this study. Two Chick-Watson type models were used to describe the experimental data for cell integrity and MCs release and degradation. The results showed that water matrix could affect the rate of cell lysis caused by ferrate. In the experiment using RET reservoir water spiked with 1105 and 5105 cells/mL of M. aeruginosa, 10 mg/L of ferrate can effectively damage all the cells and degrade MCs in 3 hours, while for the experiment using water with higher organic matter and ions, CK lake water and ASM medium, only 23 and ~0% of cells were damaged at the same time scale, respectively, under application of 20 mg/L of ferrate. When cells were ruptured, MCs were found to release into water and degraded by ferrate quickly, leading to no accumulation of dissolved MCs in the water. The Chick-Watson type models were found to successfully simulate the change of cell integrity over time. The cell rupture models were further combined with kinetic model for MCs degradation for the simulation of MCs concentrations in the water. The MCs degradation model was found to predict the trend of observed MCs concentrations over time, suggesting that the model is reasonable.
論文目次 摘要 I
Extended Abstract III
致謝 VII
目錄 IX
圖目錄 XII
表目錄 XV

第一章 緒論 1
1-1 研究起源 1
1-2 研究目的 3
第二章 文獻回顧 4
2-1 藍綠菌及有害代謝物介紹 4
2-1-1 微囊藻毒素之來源與結構 7
2-1-2 微囊藻毒素之去除 10
2-2 氧化作用對藍綠菌代謝物釋出之影響 13
2-2-1 氧化機制對於藍綠菌體之破壞 13
2-2-2 高鐵酸鉀之特性與反應 14
2-2-3 高鐵酸鉀對微囊藻毒素之降解 18
2-2-4 高鐵酸鉀對藍綠菌之混凝作用 22
第三章 實驗設備與方法 23
3-1 藍綠菌培養 23
3-1-1 藍綠菌之來源 25
3-1-2 藍綠菌之培養方法 25
3-2 藍綠菌細胞計數 27
3-3 高鐵酸鉀純度標定及濃度分析 30
3-4 高鐵酸鉀氧化實驗 34
3-4-1 氧化實驗藻類樣品之準備 34
3-4-2 氧化實驗 35
3-5 前氧化及混凝程序之串聯式實驗 37
3-6 藍綠菌細胞完整性觀察 39
3-6-1 流式細胞儀 (Flow Cytometer, FCM) 39
3-7 微囊藻毒素分析 41
3-8 掃描式電子顯微鏡 44
3-9 非揮發溶解性有機碳(Non-purgable dissolved organic carbon, NPDOC) 46
第四章 結果與討論 47
4-1 細胞完整性檢測方法之可行性測試 47
4-1-1 螢光顯微鏡可行性之測試 47
4-1-2 流式細胞儀可行性之測試 48
4-1-3 高鐵酸鉀對細胞完整性觀察之影響 49
4-2 高鐵酸鉀之氧化結果 51
4-2-1 高鐵酸鉀與微囊藻於不同背景水之測試 51
4-2-2 以ASM培養基為背景水 55
4-2-3 以仁義潭水為背景水 59
4-2-4 以成功湖水為背景水 67
4-2-5 微囊藻細胞經氧化後SEM觀測之結果 70
4-2-6 不同背景水氧化結果之比較 74
4-3 微囊藻細胞完整性及微囊藻毒素降解模式推導與模擬 76
4-3-1 細胞完整性之動力學模擬 76
4-3-2 微囊藻毒素釋出及降解趨勢之模擬 81
4-4 前氧化與混凝程序之串聯式實驗 84
4-4-1 pH值對串聯式實驗之影響 84
4-4-2 串聯式實驗之藍綠菌去除率 86
第五章 結論與建議 93
5-1 結論 93
5-2 建議 95
參考文獻 96
參考文獻 Acero, J.L., Rodriguez, E. and Meriluoto, J. (2005) Kinetics of reactions between chlorine and the cyanobacterial toxins microcystins. Water Research 39(8), 1628-1638.
Ashitani, K., Hishida, Y. and Fujiwara, K. (1988) Behavior of musty odorous compounds during the process of water treatment. Water Science & Technology 20(8-9), 261-267.
Association, A.P.H., Association, A.W.W., Federation, W.P.C. and Federation, W.E. (1915) Standard methods for the examination of water and wastewater, American Public Health Association.
Binet, M. and Stauber, J. (2006) Rapid flow cytometric method for the assessment of toxic dinoflagellate cyst viability. Marine environmental research 62(4), 247-260.
Briand, J.-F., Jacquet, S., Bernard, C. and Humbert, J.-F. (2003) Health hazards for terrestrial vertebrates from toxic cyanobacteria in surface water ecosystems. Veterinary research 34(4), 361-377.
Caddick, S., Murtagh, L. and Weaving, R. (2000) Potassium ferrate on wet alumina: preparation and reactivity. Tetrahedron 56(47), 9365-9373.
Chen, J.-J. and Yeh, H.-H. (2005) The mechanisms of potassium permanganate on algae removal. Water Research 39(18), 4420-4428.
Chen, J.-J., Yeh, H.-H. and Tseng, I.-C. (2009) Effect of ozone and permanganate on algae coagulation removal–Pilot and bench scale tests. Chemosphere 74(6), 840-846.
Chow, C., House, J., Velzeboer, R., Drikas, M., Burch, M. and Steffensen, D. (1998) The effect of ferric chloride flocculation on cyanobacterial cells. Water Research 32(3), 808-814.
Chow, C.W., Drikas, M., House, J., Burch, M.D. and Velzeboer, R.M. (1999) The impact of conventional water treatment processes on cells of the cyanobacterium Microcystis aeruginosa. Water Research 33(15), 3253-3262.
Clasen, J., Mischke, U., Drikas, M. and Chow, C. (2000) An improved method for detecting electrophoretic mobility of algae during the destabilisation process of flocculation: flocculant demand of different species and the impact of DOC. Aqua 49, 89-101.
Daly, R.I., Ho, L. and Brookes, J.D. (2007) Effect of Chlorination on Microcystis aeruginosa Cell Integrity and Subsequent Microcystin Release and Degradation. Environmental Science & Technology 41(12), 4447-4453.
Dawson, R.M. (1998) the toxicology of microcystins. Toxicon 36(7), 953-962.
de la Cruz, A.A., Antoniou, M.G., Hiskia, A., Pelaez, M., Song, W., O'Shea, K.E., He, X. and Dionysiou, D.D. (2011) Can we effectively degrade microcystins?--Implications on human health. Anticancer Agents Med Chem 11(1), 19-37.
Delaude, L. and Laszlo, P. (1996) A Novel Oxidizing Reagent Based on Potassium Ferrate(VI)1. The Journal of Organic Chemistry 61(18), 6360-6370.
DeLuca, S., Chao, A. and Smallwood, C. (1983) Ames Test of Ferrate Treated Water. Journal of Environmental Engineering 109(5), 1159-1167.
Ding, J., Shi, H., Timmons, T. and Adams, C. (2010) Release and Removal of Microcystins from Microcystis during Oxidative-, Physical-, and UV-Based Disinfection. Journal of Environmental Engineering 136(1), 2-11.
Dittmann, E., Fewer, D.P. and Neilan, B.A. (2013) Cyanobacterial toxins: biosynthetic routes and evolutionary roots. FEMS microbiology reviews 37(1), 23-43.
Drábková, M., Admiraal, W. and Maršálek, B. (2007) Combined exposure to hydrogen peroxide and light selective effects on cyanobacteria, Green Algae, and diatoms. Environmental Science & Technology 41(1), 309-314.
Eng, Y.Y., Sharma, V.K. and Ray, A.K. (2006) Ferrate (VI): Green chemistry oxidant for degradation of cationic surfactant. Chemosphere 63(10), 1785-1790.
Ettel, V. and Vepřek-Šiška, J. (1969) Reaktionen sehr reiner substanzen V. Ferratzersetzung in alkalischer lösung. Collection of Czechoslovak Chemical Communications 34(8), 2182-2188.
Falconer, I.R. (2008) Cyanobacterial Harmful Algal Blooms: State of the Science and Research Needs, pp. 607-612, Springer.
Falconer, I.R. and Humpage, A.R. (2005) Health risk assessment of cyanobacterial (blue-green algal) toxins in drinking water. International Journal of Environmental Research and Public Health 2(1), 43-50.
Fan, J., Daly, R., Hobson, P., Ho, L. and Brookes, J. (2013) Impact of potassium permanganate on cyanobacterial cell integrity and toxin release and degradation. Chemosphere 92(5), 529-534.
Fan, J., Hobson, P., Ho, L., Daly, R. and Brookes, J. (2014) The effects of various control and water treatment processes on the membrane integrity and toxin fate of cyanobacteria. Journal of hazardous materials 264, 313-322.
Glaze, W.H., Schep, R., Chauncey, W., Ruth, E.C., Zarnoch, J.J., Aieta, E.M., Tate, C.H. and McGuire, M.J. (1990) Evaluating oxidants for the removal of model taste and odor compounds from a municipal water supply. Journal (American Water Works Association), 79-84.
Gof, H. and Murmann, R.K. (1971) Studies on the Mechanism of Isotopic Oxygen Exchange and Reduction of Ferrate (VI) Ion (FeO42 一). Journal of the American Chemical Society 93(23), 6058-6065.
Gregory, J. (2006) Particles in Water: Properties and Processes.
Gregory, R. and Zabel, T. (1990) Water Quality and Treatment: A Handbook of Community Water Supplies, American Water Works Association, McGraw-Hill, New York.
Heeb, M.B., Criquet, J., Zimmermann-Steffens, S.G. and von Gunten, U. (2014) Oxidative treatment of bromide-containing waters: Formation of bromine and its reactions with inorganic and organic compounds — A critical review. Water Research 48(0), 15-42.
Henderson, R., Parsons, S.A. and Jefferson, B. (2008) The impact of algal properties and pre-oxidation on solid–liquid separation of algae. Water Research 42(8), 1827-1845.
Hitzfeld, B.C., Höger, S.J. and Dietrich, D.R. (2000) Cyanobacterial toxins: removal during drinking water treatment, and human risk assessment. Environmental Health Perspectives 108(Suppl 1), 113-122.
Hoppe, M.L., Schlemper, E.O. and Murmann, R.K. (1982) Structure of dipotassium ferrate(VI). Acta Crystallographica Section B 38(8), 2237-2239.
Hsieh, W., Chang, D. and Lin, T. (2013) Occurrence and Removal of Earthy-Musty Odorants in Two Waterworks in Kinmen Island, Taiwan. Journal of Hazardous, Toxic, and Radioactive Waste 18(3), 04014012.
Huo, X., Chang, D.-W., Tseng, J.-H., Burch, M.D. and Lin, T.-F. (2015) Exposure of Microcystis aeruginosa to Hydrogen Peroxide under Light: Kinetic Modeling of Cell Rupture and Simultaneous Microcystin Degradation. Environmental Science & Technology 49(9), 5502-5510.
Ibelings, B.W., Backer, L.C., Kardinaal, W.E.A. and Chorus, I. (2014) Current approaches to cyanotoxin risk assessment and risk management around the globe. Harmful Algae 40(0), 63-74.
Jiang, J.-Q. (2015) The role of coagulation in water treatment. Current Opinion in Chemical Engineering 8, 36-44.
Jiang, J.-Q. and Lloyd, B. (2002a) Progress in the development and use of ferrate (VI) salt as an oxidant and coagulant for water and wastewater treatment. Water Research 36(6), 1397-1408.
Jiang, J.-Q. and Lloyd, B. (2002b) Progress in the development and use of ferrate(VI) salt as an oxidant and coagulant for water and wastewater treatment. Water Research 36(6), 1397-1408.
Jiang, J.-Q., Lloyd, B. and Grigore, L. (2001) Preparation and evaluation of potassium ferrate as an oxidant and coagulant for potable water treatment. Environmental Engineering Science 18(5), 323-328.
Jiang, J.-Q., Wang, S. and Panagoulopoulos, A. (2006) The exploration of potassium ferrate (VI) as a disinfectant/coagulant in water and wastewater treatment. Chemosphere 63(2), 212-219.
Jiang, W., Chen, L., Batchu, S.R., Gardinali, P.R., Jasa, L., Marsalek, B., Zboril, R., Dionysiou, D.D., O’Shea, K.E. and Sharma, V.K. (2014) Oxidation of microcystin-LR by ferrate (VI): kinetics, degradation pathways, and toxicity assessments. Environmental Science & Technology 48(20), 12164-12172.
Jochimsen, E.M., Carmichael, W.W., An, J., Cardo, D.M., Cookson, S.T., Holmes, C.E., Antunes, M.B., de Melo Filho, D.A., Lyra, T.M. and Barreto, V.S.T. (1998) Liver failure and death after exposure to microcystins at a hemodialysis center in Brazil. New England Journal of Medicine 338(13), 873-878.
Johnson, M.D. and Sharma, K.D. (1999) Kinetics and mechanism of the reduction of ferrate by one-electron reductants. Inorganica chimica acta 293(2), 229-233.
Jones, G., Minatol, W., Craig, K. and Naylor, R. (1993) Removal of low level cyanobacterial peptide toxins from drinking water using powdered and granular activated carbon and chlorination-Results of laboratory and pilot plant studies. Proc 15th AWWA Fed. Convert.(Aust) 2, 339-346.
Kaebernick, M. and Neilan, B.A. (2001) Ecological and molecular investigations of cyanotoxin production. FEMS Microbiology Ecology 35(1), 1-9.
Kozlowsky-Suzuki, B., Wilson, A.E. and Ferrão-Filho, A.d.S. (2012) Biomagnification or biodilution of microcystins in aquatic foodwebs? Meta-analyses of laboratory and field studies. Harmful Algae 18(0), 47-55.
Lam, A.K.Y., Prepas, E.E., Spink, D. and Hrudey, S.E. (1995) Chemical control of hepatotoxic phytoplankton blooms: Implications for human health. Water Research 29(8), 1845-1854.
Lee, D.G. and Gai, H. (1993) Kinetics and mechanism of the oxidation of alcohols by ferrate ion. Canadian Journal of Chemistry 71(9), 1394-1400.
Lee, Y., Kissner, R. and von Gunten, U. (2014) Reaction of Ferrate(VI) with ABTS and Self-Decay of Ferrate(VI): Kinetics and Mechanisms. Environmental Science & Technology 48(9), 5154-5162.
Li, C., Li, X. and Graham, N. (2005) A study of the preparation and reactivity of potassium ferrate. Chemosphere 61(4), 537-543.
Licht, S., Naschitz, V. and Ghosh, S. (2002) Silver Mediation of Fe(VI) Charge Transfer:  Activation of the K2FeO4 Super-iron Cathode. The Journal of Physical Chemistry B 106(23), 5947-5955.
Licht, S., Naschitz, V., Halperin, L., Halperin, N., Lin, L., Chen, J., Ghosh, S. and Liu, B. (2001) Analysis of ferrate(VI) compounds and super-iron Fe(VI) battery cathodes: FTIR, ICP, titrimetric, XRD, UV/VIS, and electrochemical characterization. Journal of Power Sources 101(2), 167-176.
Licht, S., Wang, B. and Ghosh, S. (1999) Energetic Iron(VI) Chemistry: The Super-Iron Battery. Science 285(5430), 1039-1042.
Lin, T., Chang, D., Lien, S., Tseng, Y., Chiu, Y. and Wang, Y. (2009) Effect of chlorination on the cell integrity of two noxious cyanobacteria and their releases of odorants. Journal of Water Supply: Research and Technology—AQUA 58(8), 539-551.
Luo, Z., Strouse, M., Jiang, J.Q. and Sharma, V.K. (2011) Methodologies for the analytical determination of ferrate(VI): a review. J Environ Sci Health A Tox Hazard Subst Environ Eng 46(5), 453-460.
Ma, J. and Liu, W. (2002a) Effectiveness and mechanism of potassium ferrate(VI) preoxidation for algae removal by coagulation. Water Research 36(4), 871-878.
Ma, J. and Liu, W. (2002b) Effectiveness of ferrate (VI) preoxidation in enhancing the coagulation of surface waters. Water Research 36(20), 4959-4962.
Ma, M., Liu, R., Liu, H. and Qu, J. (2012) Chlorination of Microcystis aeruginosa suspension: cell lysis, toxin release and degradation. Journal of hazardous materials 217, 279-285.
Maizels, M. and Budde, W.L. (2004) A LC/MS Method for the Determination of Cyanobacteria Toxins in Water. Analytical Chemistry 76(5), 1342-1351.
Marugán, J., van Grieken, R., Sordo, C. and Cruz, C. (2008) Kinetics of the photocatalytic disinfection of Escherichia coli suspensions. Applied Catalysis B: Environmental 82(1), 27-36.
Mauclaire, L., Schürmann, A. and Mermillod-Blondin, F. (2006) Influence of hydraulic conductivity on communities of microorganisms and invertebrates in porous media: a case study in drinking water slow sand filters. Aquatic Sciences 68(1), 100-108.
Merel, S., Villarín, M.C., Chung, K. and Snyder, S. (2013) Spatial and thematic distribution of research on cyanotoxins. Toxicon 76(0), 118-131.
Montiel, A. and Welte, B. (1998) Preozonation coupled with flotation filtration: successful removal of algae. Water science and technology 37(2), 65-73.
Newcombe, G., Chorus, I., Falconer, I. and Lin, T.-F. (2012) Cyanobacteria: impacts of climate change on occurrence, toxicity and water quality management. Water Research 46(5), 1347-1348.
Newcombe, G., House, J., Ho, L., Baker, P. and Burch, M. (2010) Management strategies for cyanobacteria (blue-green algae): a guide for water utilities, WQRA.
Norcross, B.E., Lewis, W.C., Gai, H., Noureldin, N.A. and Lee, D.G. (1997) The oxidation of secondary alcohols by potassium tetraoxoferrate(VI). Canadian Journal of Chemistry 75(2), 129-139.
Pantelić, D., Svirčev, Z., Simeunović, J., Vidović, M. and Trajković, I. (2013) Cyanotoxins: Characteristics, production and degradation routes in drinking water treatment with reference to the situation in Serbia. Chemosphere 91(4), 421-441.
Plummer, J. and Edzwald, J. (2002) Effects of chlorine and ozone on algal cell properties and removal of algae by coagulation. Aqua 51, 307-318.
Schreyer, J.M., Thompson, G.W. and Ockerman, L.T. (1950) Oxidation of Chromium(III) with Potassium Ferrate(VI). Analytical Chemistry 22(11), 1426-1427.
Schroyer, J.M. and Ockerman, L.T. (1951) Stability of Ferrate(VI) Ion in Aqueous Solution. Analytical Chemistry 23(9), 1312-1314.
Sharma, V., Graham, N.D., Li, X.-Z. and Yuan, B.-L. (2010) Ferrate(VI) enhanced photocatalytic oxidation of pollutants in aqueous TiO2 suspensions. Environmental Science and Pollution Research 17(2), 453-461.
Sharma, V., Kazama, F., Jiangyong, H. and Ray, A. (2005) Ferrates (iron (VI) and iron (V)): Environmentally friendly oxidants and disinfectants. J Water Health 3, 45-58.
Sharma, V.K. (2002) Potassium ferrate(VI): an environmentally friendly oxidant. Advances in Environmental Research 6(2), 143-156.
Sharma, V.K., Triantis, T.M., Antoniou, M.G., He, X., Pelaez, M., Han, C., Song, W., O’Shea, K.E., de la Cruz, A.A., Kaloudis, T., Hiskia, A. and Dionysiou, D.D. (2012) Destruction of microcystins by conventional and advanced oxidation processes: A review. Separation and Purification Technology 91(0), 3-17.
Sharma, V.K., Zboril, R. and Varma, R.S. (2015) Ferrates: Greener Oxidants with Multimodal Action in Water Treatment Technologies. Accounts of Chemical Research 48(2), 182-191.
Sivonen, K. (1990) Effects of light, temperature, nitrate, orthophosphate, and bacteria on growth of and hepatotoxin production by Oscillatoria agardhii strains. Applied and Environmental Microbiology 56(9), 2658-2666.
Smith, V.H., Tilman, G.D. and Nekola, J.C. (1999) Eutrophication: impacts of excess nutrient inputs on freshwater, marine, and terrestrial ecosystems. Environmental pollution 100(1), 179-196.
Song, W., De La Cruz, A.A., Rein, K. and O'Shea, K.E. (2006) Ultrasonically induced degradation of microcystin-LR and-RR: Identification of products, effect of pH, formation and destruction of peroxides. Environmental Science & Technology 40(12), 3941-3946.
Song, W., Xu, T., Cooper, W.J., Dionysiou, D.D., Cruz, A.A.d.l. and O ‘Shea, K.E. (2009) Radiolysis studies on the destruction of microcystin-LR in aqueous solution by hydroxyl radicals. Environmental Science & Technology 43(5), 1487-1492.
Steynberg, M., Pieterse, A. and Geldenhuys, J. (1996) Improved coagulation and filtration of algae as a result of morphological and behavioural changes due to pre-oxidation. Aqua 45(6), 292-298.
Teixeira, M.R. and Rosa, M.J. (2006) Comparing dissolved air flotation and conventional sedimentation to remove cyanobacterial cells of Microcystis aeruginosa: Part I: The key operating conditions. Separation and Purification Technology 52(1), 84-94.
Thompson, G.W., Ockerman, L.T. and Schreyer, J.M. (1951) Preparation and Purification of Potassium Ferrate. VI. Journal of the American Chemical Society 73(3), 1379-1381.
Unluturk, S., Atılgan, M.R., Baysal, A.H. and Unluturk, M.S. (2010) Modeling inactivation kinetics of liquid egg white exposed to UV-C irradiation. International journal of food microbiology 142(3), 341-347.
USEPA (2001) Creating a Cyanotoxin Target List for the Unregulated Contaminant Monitoring Rule.
USEPA, J. (1999) Alternative disinfectants and oxidants guidance manual.
van Apeldoorn, M.E., van Egmond, H.P., Speijers, G.J.A. and Bakker, G.J.I. (2007) Toxins of cyanobacteria. Molecular Nutrition & Food Research 51(1), 7-60.
Velzeboer, R., Drikas, M., Donati, C., Burch, M. and Steffensen, D. (1995) Release of geosmin by Anabaena circinalis following treatment with aluminium sulphate. Water science and technology 31(11), 187-194.
Wagner, W., Gump, J. and Hart, E. (1952) Factors affecting stability of aqueous potassium ferrate (VI) solutions. Analytical Chemistry 24(9), 1497-1498.
Westrick, J., Szlag, D., Southwell, B. and Sinclair, J. (2010) A review of cyanobacteria and cyanotoxins removal/inactivation in drinking water treatment. Analytical and Bioanalytical Chemistry 397(5), 1705-1714.
Xing, H., Yuan, B., Wang, Y. and Qu, J. (2002) PHOTOCATALYTIC DETOXIFICATION OF MICROCYSTINS COMBINED WITH FERRATE PRETREATMENT. Journal of Environmental Science and Health, Part A 37(4), 641-649.
Yuan, B.-L., Qu, J.-H. and Fu, M.-L. (2002) Removal of cyanobacterial microcystin-LR by ferrate oxidation–coagulation. Toxicon 40(8), 1129-1134.
Yuan, B., Li, Y., Huang, X., Liu, H. and Qu, J. (2006) Fe(VI)-assisted photocatalytic degradating of microcystin-LR using titanium dioxide. Journal of Photochemistry and Photobiology A: Chemistry 178(1), 106-111.
Zamyadi, A., Fan, Y., Daly, R.I. and Prévost, M. (2013) Chlorination of Microcystis aeruginosa: Toxin release and oxidation, cellular chlorine demand and disinfection by-products formation. Water Research 47(3), 1080-1090.
Zamyadi, A., MacLeod, S.L., Fan, Y., McQuaid, N., Dorner, S., Sauvé, S. and Prévost, M. (2012) Toxic cyanobacterial breakthrough and accumulation in a drinking water plant: A monitoring and treatment challenge. Water Research 46(5), 1511-1523.
Zhou, S., Shao, Y., Gao, N., Zhu, S., Li, L., Deng, J. and Zhu, M. (2014) Removal of Microcystis aeruginosa by potassium ferrate (VI): Impacts on cells integrity, intracellular organic matter release and disinfection by-products formation. Chemical Engineering Journal 251(0), 304-309.
邱宜亭 (2009) 高錳酸鉀對三種藍綠菌破壞及其代謝物釋出之研究. 國立成功大學環境工程學系碩士論文.
游惇蓉 (2014) 過氧化氫在光催化系統下對魚腥藻之破壞及其代謝物釋出降解之研究. 國立成功大學環境工程學系碩士論文.
饒拉 (2013) 氯對團聚微囊藻細胞破壞及其代謝物釋出及降解之研究. 國立成功大學環境工程學系碩士論文.

------------------------------------------------------------------------ 第 6 筆 ---------------------------------------------------------------------
系統識別號 U0026-0209201511032700
論文名稱(中文) 建構大型運動賽會之品質成本指標-以全國大專院校運動會為例
論文名稱(英文) The Study of Construction the Quality Cost of Multiple Sport Event – Application in Taiwan National Intercollegiate Athletic Games
校院名稱 成功大學
系所名稱(中) 體育健康與休閒研究所
系所名稱(英) Institute of Physical Education, Health & Leisure Studies
學年度 103
學期 2
出版年 104
研究生(中文) 洪舜陞
學號 RB6021134
學位類別 碩士
語文別 英文
口試日期 2015-07-27
論文頁數 123頁
口試委員 指導教授-馬上鈞
共同指導教授-黃賢哲
口試委員-蔣任翔
召集委員-馬上閔
關鍵字(中) 大型綜合性運動賽會
全國大專院校運動會
品質成本
關鍵字(英) major multiple sport event
National Intercollegiate Athletic Games
quality cost
學科別分類
中文摘要 近年來隨著政治經濟及社會的進步,台灣已成功的申辦過許多大型的體育賽事,如2009年世界運動會、2009年聽障奧運會,以及2017年台北世界大學運動會的主辦權。舉辦大型的綜合性運動賽事,不僅可以替主辦單位吸引外界的目光,而且還可以替當地帶來人潮及經濟的成長。如何在有限的經費辦理出高品質的運動賽會往往是現今的主辦單位所會面臨的課題。
品質成本是現代企業界為了衡量和提高產品或品質而發展出來的一種以品質為核心的管理系統,品質成本的特性為它可以提升全面性的品質並降低失敗成本發生的機率進而減少失敗成本的花費。故本研究的主要目的為建構出大型綜合性運動賽會的品質成本指標、定義及各層級之權重,並以全國大專院校運動會為範本進行研究。本研究採用主題式訪談過去曾舉辦全國大專院校運動會之專家,得出品質成本在大型運動賽會之定義,接著透過德爾菲及AHP層級分析法得出大型運動賽會中品質成本之組成及各層級重要度之排序。
本研究結果發現,在大型運動賽會中導入品質成本之概念是可行的。在預防成本、鑑定成本、內部失敗成本及外部失敗成本中以預防成本被認為是評估大型運動賽會品質成本之最重要因子。在預防成本中又以「賽會場地設施之保養及更新」及「開閉幕典禮規劃」最為重要;在鑑定成本中以「正式與預備賽程安排」最為重要;在內部失敗成本當中以「決策錯誤」最為重要;在外部失敗成本當中以「對參賽職員抱怨處理」最為重要。研究結果冀望能提供未來有興趣辦理大型綜合性運動賽會之主辦單位做一個參考。
英文摘要 Hosting major sport event has been a tactic to the region and government to catch the eyes of people and medias. However hosting major multiple sport event can get some positive impacts such as improving tourism revenues, makes governments subsidize the construction, it often creates the economic deficit in those regions. In addition to this reason, to make a high quality event is very important, too. So in this study would construct the concept of quality cost in sport event (i.e., National Intercollegiate Athletic Games). Quality cost is a way to control the conference (prevention and appraisal cost) and non-conference cost (internal and external failure cost) in event, when we can reduce the non-conformance cost in event, the quality of sport event can be promoted undoubtedly. The purpose of this study is to clearly define the quality cost in sport event and measure the weights of quality cost criteria in hosting a major sporting event.
The research methods in this study are a literature review, a thematic analysis in depth interview, the Delphi Technique, and the Analytical Hierarchy Process. The data were processed using Microsoft Excel 2010 and Power Choice 2.0. We found the prevention cost was the most important components in quality cost of sport event. In every hierarchies of quality cost in sport event, “Update and maintain the facility”, “The planning of opening and closing ceremony”, “Set up the standard of operation process”, “Wrong decision making”, and “The complaint of players” should be mainly noticed.
論文目次 Table of Contents

摘要………………………………………………………………………………Ι
Abstract…………………………………………………………………………… II
誌謝…………………………………………………………………………III
Chapter One:Introduction…………………………………………………………… 1
1.1 Introduction…………………………………………………………………1
1.2 The Purpose of this Study………………………………………………… 4
1.3 The Significance of this Study……………………………………………4
1.4 Scope of this Study………………………………………………………5
Chapter Two:Literature Review……………………………………………………6
2.1 Sport events………………………………………………………………6
2.2 National Intercollegiate Athletic Games…………………………………..16
2.3 Quality Cost……………………………………………………………19
2.4 Conclusion………………………………………………………………29
Chapter Three:Methodology……………………………………………………… 31
3.1 Conceptual Framework & Research Process…………………………….. 31
3.2 Selection of Participants…………………………………………………. 34
3.3 Research Methods…………………………………………………………34
3.4 Measurement Tools & Data Analysi………………………………………38
Chapter Four:Results……………………………………………………………….41
4.1 The Application of Quality Cost to the National Intercollegiate Athletic Games……………………………………………………………………..41
4.2 The process of Delphi Method…………………………………………….51
4.3 The Findings of Statistics…………………………………………………57
Chapter Five:Discussion, Suggestion and Limitation………………………………68
5.1 Discussions………………………………………………………………..68
5.2 Practical Implications……………………………………………………..73
5.3 Suggestions and Limitations………………………………………………76
Reference …………………………………………………………………………….77
Appendix……………………………………………………………………………..84
參考文獻 中文文獻:
中華民國98年全國大專校院運動會報告書。 國立臺灣師範大學,台北市。
中華民國99年全國大專校院運動會報告書。 國立體育大學,桃園市。
中華民國100年全國大專校院運動會報告書。 國立中興大學,台中市。
中華民國101年全國大專校院運動會報告書。 義守大學,高雄市。
中華民國102年全國大專校院運動會報告書。 國立宜蘭大學,宜蘭縣。
中華民國103年全國大專院校運動會報告書。 國立雲林科技大學,雲林縣。
中華民國行政院 (2013)。2017臺北世界大學運動會籌辦計畫書。 取自: 中華民國行政院官網網址 http://www.ey.gov.tw/Upload/RelFile/27/704784/09ba542c-83ae-477c-ae1f-5eb574a97800.pdf
江建良 (2000)。 服務業服務品質管理模式之建構:顧客滿意觀點。 (未出版之碩士論文)。 國立空中大學,台北市。
伊藤嘉博 (2010)。 重視環境的品質成本管理。 台北市: 財團法人中衛發展中心。
李至斌 (2002)。 九十一年全國運動會游泳比賽賽程時間之探討。(未出版之碩士論文) 國立臺灣師範大學,台北市。
林慈恩 (2014)。 2009年臺北聽障奧林匹克運動會文化創意促銷活動之研究。(未出版之碩士論文) 國立台北教育大學,台北市。
翁振益、周瑛琦 (2006)。 決策分析方法與應用。 台北市: 華泰文化事業股份有限公司。
曾瑞程 (2009)。 2009年全國大專校院運動會參賽選手體驗價值之研究。 運動休閒管理學報,,6(2),,108-125。
葉公鼎 (2013)。 大型運動賽會經營管理。 台北市: 華都文化。
劉照金、葉公鼎 (2003)。 91年度全國大專運動賽會期間外地參與者之消費對高雄地區的經濟影響評估。 台灣體育運動管理學報, 2,14-30。
廖翊誠 (2012)。臺灣國際大型運動賽會永續指標之研究。(未出版之碩士論文)。國立成功大學,台南市。
饒淑芳 (2011)。探討供應商評選準則之品質成本觀點。(未出版之碩士論文)。國立高雄應用科技大學,高雄市。

英文文獻:
Aoieong, R. T., Tang, S. L., & Ahmed, S. M. (2002). A process approach in measuring quality costs of construction projects: model development. Construction Management and Economics, 20(2), 179-192.
Alderman, H., & Lavy, V. (1996). Household responses to public health services: Cost and quality tradeoffs. World Bank Research Observer, 11(1), 3-22.
Baido, H. N. (1999). Cost of Quality: A Measurement Tool for Continuous Improvement. California State University, Dominguez Hills.
Bhushan, N., & Rai, K. (2004). Strategic decision making: Applying the Analytic Hierarchy.
Campanella, J. (1999). Principle of Quality Costs - Principles, Implementation, and Use: ASQC Quality Press.
Carson, J. K. (1986). Quality costing - a practical approach. International Journal of Quality & Reliability Management, 3(1), 54-67.
Carr, L.P. (1992). Applying cost of quality in service business. Sloan Management Review, 33(4).
Clark. (2005). Major Sport Event: The Guid. London.
Crosby, P. B. (1979). Quilty is free. New York, NY.: McGraw-Hill.
Dale, B. G., & Plunkett, J. J. (1988). Quality-related costing: findings from an industry-based research study. Engineering Management International, 4(4), 247-257.
Dale, B. G., & Plunkett, J. J. (1995). Quality Costing (Second Edition ed.): Champman & Hall.
Dalkey, N. C., & Helmer, O. (1963). An experimental application of the Delphi method to the use of experts. Management science, 9, 458-467.
Deming, W. E. (1986). Massachusetts Institute of Technology. Cambridge: Massachusetts Institute of Technology.
Deming, W. E. (1986). Out Of Crisis: Quality, Productivity and Competitive Position. Cambridege, M.A.: Combridege University Press.
Donovan, M. E. (1998). The Economic Benefits of a Sporting Event to a Community Springfield College.
Feigenbaum, A. V. (1956). Total Quality Control. Havard Business Review, 34(6).
Fry, F. L., Stoner, C. R., & Hattwick, R. E. (2001). Business an Integrative Approach. Boston: McGraw-Hill.
Getz, D. (1991). Special Events Defining the Product. 125-137.
Getz, D. (1998). Trends, strategies, and issues in sport-event tourism. Sport Marketing Quarterly, 7(2), 8-13.
Getz, D. (2003). Sport event tourism, development and marketing. In S. Hudson (Ed.), . New York: Hayworth Hospitality Press.
Glyptis, S. (1991). Countryside Recreation. Harlow: Longman.
Gratton, C., & Taylor, P. (2000). Economics of Sport and Recreation. London: E. & F.N.
Hall, C. M. (1992). Hallmark Tourist Events: Impacts, Management and Planing. London: Belhaven Press.
Houce, L., Hill, J., Oxford. (2009). Strategic Sports Event Management. Burlinton: Elsevier Ltd.
Howard, D. R., & Crompton, J. L. (2004). Tactics used by sports organizations in the United States to increase ticket sales. Managing Leisure, 9, 87-95.
Ishizaka, A. L., A. (2009). Analytic Hierarchy Process and Expert Choice: benefits and limitations. Or Insight, 22(4), 201-220.
Israeli, A., & Fisher, B. (1995). Cutting quality costs. Quality Progress, 46-48.
Jago, L. &Shaw, R. (1998). Special events: a conceptual and differential framwork. Festival Management and Event Tourisam, 5(1/2), 21-32.
Johnson, R. D., & Kleiner, B. H. (1993). Does higher quality mean high cost? International Journal of Quality & Reliability Management, 10(4), 86-100.
Juran, J. M. (1974). Quality Control Handbook. New York: McGraw-Hill.
Juran, J. M. (1988). Quality Control Handbook (Fouth Edition ed.). New York: McGrew Hill.
Juran, J. M., & Gryna. (1970). Quality Planning and Analysis. New York: McGrew Hill.
Kazaz, A., Birgonul, M. T., & Ulubeyli, S. (2005). Cost-based analysis of quality in developing countries: a case study of building projects. Building and Environment, 40(10), 1356-1365.
Kelly, S. W., & Turley, L. W. (2001). Consumer perceptions of service quality attributes at sporting events. Journal of Business Research, 54, 161-166.
Ko, Y. J., & Pastore, D. L. (2005). A hierarchical model of service quality for the recreational sport industry. Sport Marketing Quarterly, 14, 84-97.
Markedonov, S. (2014). The 2014 Sochi Olympics: A Patchwork of Challenges: Rowman & Littlefield.
Morse, W. J., Roth, H., & Poston, K. (1987). Measureing, Planning and Controlling Quality Costs. National Association and Accountants.
Preuss, H. (2004). The Economic of Staging the Olympics: A Comparison of the Games 1972-2008. Cheltenham: Edward Elga.
Preuss, H., & Solberg, H. A. (2007). Attraction major sporting events: The role of local residents. European Sport Management Quarterly, 6(4), 391-411.
Roche, M. (2000). Mega-events and Modernity: Olympics and Expos in the Growth of Glable Culture. London: Routledge.
Satty, T. (1977). A scaling method for priorities in hierarchical structures. Journal of Mathematical Psychology, 15(3), 234-281.
Scamuzzi, S. (2006). Winter Olympic Games 2006 in Turin: the rising weight of public opinion. The Winter Games in the Scope of Olympic Research, 8, 343-357.
Schiffauerova, A., & Thomson, V. (2006). A review of research on cost of quality models and best practices. International Journal of Quality and Reliability Management, 23(4).
Searle, G. (2002). Uncertain Legacy: Sydney's Olympic Stadiums. European Planning Studies, 10(7), 845-860.
Shilbury, D. (1994). Delivering quality service in professional sport. Sport Marketing Quarterly, 3(1), 29-35.
Short, J. R., Benton, L. M., Luce, W. B., & Walton, J. (1993). Reconstructing the image of an industrial city. Annals of the Association of American Geographers, 83(2), 207-224.
Stone Fish, L., & Busby, D. M. (1996). The Delphi method. In D.H. Sprenkle & S.M. Moon (Eds.), Global Reporting Initiate (2012). Amsterdam: Global Reporting Initiate.
Theodorakis, N. D., & Alexandris, K. (2008). Can service quality predict spectators' behavioral intentions in professional soccer? , 13(3-4), 162-178.
Valavi, D. G., & Pramod, V. R. (2014). A hybrid fuzzy MCDM approach to maintenance Quality Function Deployment. Decision Science Letters, 4(2015), 97-108.
Wakefield, K. L., Blodgett, J. G., & Sloan, H. J. (1996). Measurement and management of the sport scape. Journal of Sport Management, 10, 15-31.
Westerbeek, H., Shilbury, D., & Deane, J. (1995). The Australian sports system, its history and an organisational overview. European Journal for Sport Management, 2(1), 42-58.


------------------------------------------------------------------------ 第 7 筆 ---------------------------------------------------------------------
系統識別號 U0026-0302201510402200
論文名稱(中文) 電感式比壓器與斷路器極間電容鐵共振抑制及氧化鋅避雷器預防維護方法之研究
論文名稱(英文) A Study of Ferroresonance Suppression for Potential Transformers with Circuit Breaker Grading Capacitances and Predictive Maintenance for ZnO Arresters
校院名稱 成功大學
系所名稱(中) 電機工程學系
系所名稱(英) Department of Electrical Engineering
學年度 103
學期 1
出版年 104
研究生(中文) 謝建賢
學號 N28951243
學位類別 博士
語文別 英文
口試日期 2015-01-23
論文頁數 56頁
口試委員 召集委員-劉志文
口試委員-張文恭
口試委員-魏忠必
口試委員-張簡樂仁
指導教授-黃世杰
關鍵字(中) 鐵磁共振
斷路器極間電容
避雷器
洩漏電流
預防維護
關鍵字(英) Ferroresonance
grading capacitance
arresters
leakage current
predictive maintenance
學科別分類
中文摘要 於廣大且複雜之電力供電網路中,相關電業人員常藉由調控相關補償設備及裝設斷路器與相關保護設備,以確保電力系統之安全運轉。惟各電力設備恐因結構差異或運轉特性不同,將產生足以危害系統運轉風險,例如比壓器運轉時,易與系統裝設之電容元件或斷路器極間電容產生鐵磁共振,致使系統產生過電壓與過電流,導致變壓器高壓側線圈過熱、比壓器鐵心飽和及相關設備絕緣破壞,實際匯流排比壓器鐵共振並曾發生於氣體絕緣變電所,故如何有效抑制鐵磁共振及縝密評估引發鐵磁共振發生之原因,確已成為重要電力運轉問題之一。
此外,相關電力工程人員為抑制鐵磁共振所產生之過電壓,常於系統中加裝氧化鋅避雷器,用以抑制電壓突波,然由於避雷器劣化,致使避雷器元件產生洩漏電流,卻易造成避雷器運轉過熱,進而縮短避雷器使用壽命。又因氧化鋅避雷器常將多節氧化鋅予以串聯組合,而每節氧化鋅之老化程度並不相同,若僅偵測避雷器之總洩漏電流量,仍難準確判斷避雷器元件異常位置,故如何於現有量測環境中,正確有效判斷避雷器故障位置,亦已躍為重要電力工程研究問題。
有鑑於此,本論文整體研究目標,不僅在於評估系統運轉引發鐵磁共振原因,同時致力研創偵測鐵磁共振及其抑制方法,此外並輔以電阻性洩漏電流量測技術及溫度量測技術精進,進而加入新穎數學演算技術之開發,俾有助於提升氧化鋅避雷器之預測保養能力。本論文將所提之各項方法,均經由軟體模擬及實際系統加以驗證,同時與其他診斷方法相互比較,而由測試結果可知,本論文所提之診斷技術已可有效偵測與抑制鐵磁共振,並可協助避雷器之預測保養,確有助於降低輸電風險及提升電網運轉安全。
英文摘要 To ensure a safe operation in a complex power network, utility engineers often regulate certain compensation equipment and install protection devices to increase the power system security. However, because of distinctive features of each power equipments, there exists a possibility of risk, hence damaging the power grid. For example, the operation of potential transformer is easy to generate a ferroresonance with capacitive elements or circuit breaker grading capacitance so as to result in overvoltage and overcurrent, bringing in the overheat of transformer coils, the saturation of iron cores, and the insulation breakdown of equipment. A real case of bus PT ferroresonance was observed in a gas-insulated substation. Therefore, the study on the generation of ferroresonce as well as a systematic way of suppressing such nuisances has become one of important topics in power system operations.
Next, in order for restricting the overvoltage caused by the ferroresonance, the ZnO arresters are often used against surge overvoltages. Yet, the increased leakage current due to the degradation of a metal oxide arrester would result in overheating, largely shortening the operation life of arresters. Moreover, since the arresters are often formed by several sections of zinc oxides where the level of degradation at each section is different, the detection of overall leakage current would be insufficient to identify the location of faulted section. A method of justifying the faulted location of an arrester is being deemed as one of important topic in power engineering studies.
In view of aforementioned problems, this dissertation is devoted to developing a method of ferroresonance detection and suppression, by which the reason of ferrresonance occurrence can be evaluated and the suppression of this event is investigated as well. In addition, the leakage current and temperature measurement techniques are integrated with a new mathematical algorithm to increase the predictive maintenance capability of ZnO arresters. These proposed methods are evaluated through software simulations and field validations. The test results confirm the feasibility of the proposed methods for the detection and mitigation of ferroresonance as well as for the maintenance improvement of arresters, benefitting the reduction of transmission risks and the increment of grid operation safety.
論文目次 摘要 II
Abstract IV
誌 謝 VI
Contents VII
List of Tables X
List of Figures XI
Symbols and Abbreviations XII
Chapter 1 Introduction 1
1.1 Background and Motivation 1
1.2 Literature Survey 2
1.3 Contribution of This Dissertation 4
1.4 Organization of This Dissertation 4
Chapter 2 Problem Description 7
2.1 Introduction 7
2.2 Ferroresonance Problems 7
2.3 Discrimination Problems of Zinc Oxide Arresters 8
Chapter 3 Development of Ferroresonance Suppression for Potential Transformer with Circuit Breaker Grading Capacitance 10
3.1 Introduction 10
3.2 Overview of Ferroresonance 11
3.3 Investigation of Ferroresonance in 161kV Substation 12
3.3.1 Expressions of Ferroresonance 13
3.3.2 Analytical Approach with EMTP/ATP Simulation 14
3.3.2.1 Bus PT with CB Grading Capacitor Ferroresonance Analysis 17
3.3.2.2 Ferroresonance Suppression Performance Analysis 19
3.3.2.3 Relation of Driving Force Factor Analysis 21
3.4 Ferroresonance Suppression 22
3.4.1 Proposed Method 23
3.4.2 Suppression Device 24
3.4.3 Application of Suppression Device 26
3.5 Summary 28
Chapter 4 Application of Regression Method to Enhance ZnO Arrester Predictive Maintenance 29
4.1 Introduction 29
4.2 Overview of ZnO Arrester Diagnosis 29
4.2.1 Resistive Leakage Current Monitoring System 30
4.2.2 Infrared Imaging Diagnosis 31
4.3 Regression Method Algorithm 32
4.3.1 Regression Model Development 33
4.3.2 Computation of Regression Model 35
4.4 Application of the Proposed Method 36
4.4.1 Regression Method Testing 38
4.4.2 Comparisons with Others Methods 39
4.5 Summary 42
Chapter 5 Conclusions 43
5.1 Conclusions 43
5.2 Future Study 44
References 46
Biography 55
List of Publications 56
參考文獻 [1] J. Glover, M. Sarma, and T. Overbye, Power System Analysis and Design, Fourth Edition, Thomson Learning, 2008.
[2] Z. N. Stojanovic and Z. M. Stojkovic, “Evaluation of MOSA condition using leakage current method,” International Journal of Electric Power and Energy Systems, Vol. 52, November 2013, pp. 87-95.
[3] J. Wisniewski, E. Anderson, and J. Karolak, “Search for network parameters preventing ferroresonance occurrence,” International Conference on Electrical Power Quality and Utilization, Barcelona, Spain, October 2007, pp. 1-6.
[4] V. C. Nikolaidis, I. Milis, and G. Rizopoulos, “Transient phenomena analysis and protection evaluation in an industrial power system,” IEEE Transactions on Power Delivery, Vol. 27, No. 1, January 2012, pp. 300-308.
[5] H. L. Li, S. L. Ho, and W. N. Fu, “Application of multi-stage diagonally-implicit runge-kutta algorithm totransient magnetic field computation using finite element method,” IEEE Transactions on Magnetics, Vol. 48, No. 2, February 2012, pp. 279-282.
[6] M. Zhu, Q. Cao, and L. Zhao, “Study and analysis of a novel runge–kutta high-order finite-difference time-domain method,” IET Microwaves, Antennas & Propagation, Vol. 8, No. 12, March 2014, pp. 951-958.
[7] A. Rezaei-Zare, R. Iravani, M. Sanaye-Pasand, H. Mohseni, and S. Farhangi, “An accurate current transformer model based on preisach theory for the analysis of electromagnetic transients,” IEEE Transactions on Power Delivery, Vol. 23, No. 1, January 2008, pp. 233-242.
[8] A. Rezaei-Zare, M. Sanaye-Pasand, H. Mohseni, S. Farhangi, and R. Iravani, “Analysis of ferroresonance modes in power transformers using preisach-type hysteretic magnetizing inductance,” IEEE Transactions on Power Delivery, Vol. 22, No. 2, April 2007, pp. 919-928.
[9] D. A. N. Jacobson, P. W. Lehn, and R. W. Menzies, “Stability domain calculations of period-1 ferroresonance in a non-linear resonant circuit,” IEEE Transactions on Power Delivery, Vol. 17, No. 3, July 2002, pp. 865-871.
[10] A. Rezaei-Zare, R. Iravani, and M. Sanaye-Pasand, “An accurate hysteresis model for ferroresonance analysis of a transformer,” IEEE Transactions on Power Delivery, Vol. 23, No. 3, July 2008, pp. 1448-1456.
[11] C. A. Charalambous, Z. D. Wang, P. Jarman, and J. P. Sturgess, “Frequency domain analysis of a power transformer experiencing sustained ferroresonance,” IET Generation, Transmission & Distribution, Vol. 5, No. 6, 2011, pp. 640–649.
[12] S. L. Ho, X. Zhang, and W. N. Fu, “Extension of time-domain finite element method to nonlinear frequency-sweeping problems,” IEEE Transactions on Magnetics, Vol. 49, No. 5, May 2013, pp. 1781-1784.
[13] G. R. S. Lira, and E. G. Costa “MOSA monitoring technique based on analysis of total leakage current,” IEEE Transactions on Power Delivery, Vol. 28, No. 2, April 2013, pp.1057-1062.
[14] T. Zhao, Q. Li, and J. Qian, “Investigation on digital algorithm for on-line Monitoring and diagnostics of metal oxide surge arrester based on an accurate model,” IEEE Transaction on Power Delivery, Vol. 20, No. 2, April 2005, pp.751-756.
[15] H. Zhu and M. R. Raghuver, “Influence of representation model and voltage harmonics on metal oxide surge arrester diagnostics,” IEEE Transactions on Power Delivery, Vol. 16, No. 4, October 2001, pp. 599-603.
[16] Z. Xu, L. Zhao, A. Ding, and F. Lü, “A current orthogonality method to extract resistive leakage current of MOSA,” IEEE Transactions on Reliability, Vol. 28, No. 1, January 2013, pp. 93-101.
[17] K. Weyand, “Compensation of the temperature coefficient of magnetic field coils,” IEEE Transactions on Instrumention and Measurement, Vol. 54, No. 2, April 2005, pp. 713-717.
[18] K. Korendo and M. Florkowski, “Thermography based diagnostic of power equipment,” Power Engineering Journal, Vol. 15, No. 1, February 2001, pp. 33-42.
[19] L. Wu, S. Liu, and Y. Wu, “ Infrared imaging detection of water permeation on field large-scale rock relics,” IEEE Transactions on Geoscience and Remote Sensing, Vol. 49, No. 1, January 2011, pp. 581-590.
[20] H. Li and Y. Fan, “Impact of breaker operations on ferroresonance in power systems,” International Conference on Electronic Measurement and Instruments, China, July 2007, pp. 680-682.
[21] S. J. Huang and C. H. Hsieh, “Relation analysis for ferroresonance of bus potential transformerand circuit breaker grading capacitance,” International Journal of Electric Power and Energy Systems, Vol. 51, March 2013, pp. 61-70.
[22] M. Davarpanah, M. Sanaye-Pasand, and F. B. Ajaei, “CCVT failure due to improper design of auxiliary voltage transformers,” IEEE Transactions on Power Delivery, Vol. 27, No. 1, January 2012, pp. 391-400.
[23] Z. Ma, C. A. Bliss, A. R. Penfold, A. F. W. Harris, and S. B. Tennakoon, “An investigation of transient overvoltage generation when switching high voltage shunt reactors by SF6 Circuit Breaker,” IEEE Transactions on Power Delivery, Vol. 13, No. 2, April 1998, pp.472-478.
[24] D. Giordano, N. Banu, E. Barbisio, O. Bottauscio, M. Chiampi, and G. Crotti, “Ferroresonance analysis in LCR circuits including rapidly solidified alloy cores,” IEEE Transactions on Magnetics, Vol. 45, No. 9, September 2009, pp. 3243-3250.
[25] Z. Emin, B. A. T. A. Zahawi, and Y. K. Tong, “Voltage transformer ferroresonance in 275 kV substation,” Proceedings of the 11th International Symposium on High-Voltage Engineering, London, England, August 1999, pp. 283-286.
[26] A. H. A. Bakar, N. A. Rahim, and M. K. M. Zambri, “Analysis of lightning-caused ferroresonance in capacitive voltage transformer (CVT),” International Journal of Electrical Power and Energy Systems, Vol. 33, No. 9, November 2011, pp. 1536-1541.
[27] K. H. Tseng and P. Y. Cheng, “Mitigating 161 kV electromagnetic potential transformers’ ferroresonance with damping reactors in a gas-insulated switchgear,” IET Generation Transmition Distribution, Vol. 5, No. 4, 2011, pp. 479-488.
[28] W. Piaseeki, M. Florkowski, M. Fulczyk, P. Mahonen, and W. Nowak, “Mitigating ferroresonance in voltage transformers in ungrounded MV networks,” IEEE Transactions on Power Delivery, Vol. 22, No. 4, October 2007, pp. 2362-2369.
[29] L. Yung, S. Wei, Q. Rui, and J. Yang, “A systematical method for suppressing ferroresonance at neutral-grounded substations,” IEEE Transactions on Power Delivery, Vol. 18, No. 3, July 2003, pp. 1009-1014.
[30] J. A. Martinez-Velasco and B. A. Mork, “Transformer modeling for low- and mid- frequency transients- A review,” IEEE Transactions on Power Delivery, Vol. 20, No. 2, April 2005, pp. 1625-1632.
[31] K. Milicevic and Zia Emin, “Initiation of characteristic ferroresonance states based on flux reflection model,” IEEE Transactions on Circuits and Systems–II: Express briefs, Vol. 60, No. 1, January 2013, pp51-55.
[32] S. Jazebi, A. Farazmand, B. P. Murali, and F. de León, “A comparative study on and equivalent models for the analysis of transformer ferroresonance,” IEEE Transactions on Power Delivery, Vol. 28, No. 1, January 2013, pp. 526-528.
[33] K. Milicevic and Z. Emin, “Impact of initial conditions on the initiation of ferroresonance,” International Journal of Electrical Power and Energy Systems, Vol. 31, No. 4, May 2009, pp. 146-152.
[34] B. Zahawi, Z. Emin, and Y. K. Tong, “Chaos in ferroresonant wound voltage transformers: Effect of core losses and universal circuit behavior,” IEE Proceedings- Science, Measurement and Technology, Vol. 145, No. 1, January 1998, pp. 39-43.
[35] M. Sanaye-Pasand, A. Rezaei-Zare, H. Mohseni, S. Farhangi, and R. Iravani, “Comparison of performance of various ferroresonance suppressing methods in inductive and capacitive voltage transformers,” IEEE Power India Conference, New Delhi, India, June 2006, pp. 1-8.
[36] Alternative Transients Program (ATP)- Rule Book, Canadian/American EMTP User Group, 1987-1998.
[37] J. A. Martinez, R. Walling, B. A. MOrk, J. Martin-Arnedo, and D. Durbak, “Parameter determination for modeling system transients—Part III: Transformer,” IEEE Transactions on Power Delivery, Vol. 20, No. 3, July 2005, pp. 2051-2062.
[38] A. Rezaei-Zare and R. Iravani, “On the transformer core dynamic behavior during electromagnetic transients,” IEEE Transactions on Power Delivery, Vol. 25, No. 3, July 2010, pp. 1606-1618.
[39] A. Rezaei-Zare, R. Iravani, and M. Sanaye-Pasand, “Impacts of transformer core hysteresis formation on stability domain of ferroresonance modes,” IEEE Transactions on Power Delivery, Vol. 22, No. 2, April 2009, pp. 177-186.
[40] M. V. Escudero, I. Dudurych, and M. A. Redfern, “Characterization of ferroresonance mode in HV substation with CB grading capacitors,” International Conference on Power Systems Transients, Montreal, Canada, June 2005, pp. 141-146.
[41] Y. Li, W. Shi, and F. Li, “Novel analytical solution to fundamental ferroresonance- Part II: criterion and elimination,” IEEE Transactions on Power Delivery, Vol. 21, No. 2, April 2006, pp. 794-800.
[42] P. S. Moses, M. A. S. Masoum, and H. A. Toliyat, “Dynamic modeling of three-phase asymmetric power transformers with magnetic hysteresis: No-load and inrush conditions,” IEEE Transactions on Energy Conversion, Vol. 25, No. 4, December 2010, pp.1040-1047.
[43] A. Greenwood, Electrical Transients in Power Systems, John Wiley Publishing Company, Second Edition, 1991.
[44] X. Yan, Y. Wen, and X. Yi, “Study on the resistive leakage current characteristic of MOV surge arresters,” IEEE PES Transmission and Distribution Conference and Exhibition, Tokyo, Japan, Vol.2, October 2002, pp. 683-687.
[45] S. J. Huang and C. H. Hsieh, “A Method to Enhance the Predictive Maintenance of ZnO Arresters in Energy Systems,” International Journal of Electric Power and Energy Systems, Vol. 62, November 2014, pp. 183-188.
[46] J. E. Freund, Modern Elementary Statistics, Prentice Hall, New Jersey, USA, 2007.
[47] Z. N. Stojanovic and Z. M. Stojkovic, “Evaluation of MOSA condition using leakage current method,” Electrical Power and Energy Systems, Vol. 52, November 2013, pp. 87-95
[48] V. Hinrichsen, G. Scholl, M. Schubert, and T. Ostertag, “Online monitoring of high-voltage metal-oxide surge arresters by wireless passive surface acoustic wave (SAW) temperature sensors,” International Symposium on High Voltage Engineering, London, England, August 1999, pp. 238-241.
[49] K. P. Mardira and T. K. Saha, “Mordern electrical diagnostics for metal oxide surge arresters,” IEEE Transactions on Power Delivery, Vol. 16, No. 4, October 2001, pp.1-5.
[50] C. Heinrich and V. Hinrichsen, “Diagnostics and monitoring of metal-oxide surge arresters in high-voltage networks comparison of existing and newly developed procedures,” IEEE Transactions on Power Delivery, Vol. 16, No. 1, January 2001, pp. 138-143.
[51] S. Boggs and H. Andoh, “A statistical approach to prediction of zno arrester element characteristics,” IEEE Transactions on Power Delivery, Vol. 16, No. 4, Octorber 2001, pp. 604-610.
[52] Z. Zhong, S. A. Boggs, T. Imai, and S. Nishiwaki, “Computation of arrester thermal stability,” IEEE Transactions on Power Delivery, Vol. 25, No. 3, July 2010, pp. 1526-1529.
[53] F. R. Stockum, “Simulation of the nonlinear thermal behavior of metal oxide surge arresters using a hybrid finite difference and empirical model,” IEEE Transactions on Power Delivery, Vol. 9, No.1, January 1994, pp. 306-313.
[54] He. J, Zeng. R, Chen. S, and Tu. Y, “Thermal characteristics of high voltage whole-solid-insulated polymeric ZnO surge arrester,” IEEE Transactions on Power Delivery, Vol. 18, No. 4, October 2003, pp. 1221-1227.
[55] J. Li, C. Sun, W. Sima, Q Yang, and J. Hu “Contamination level prediction of insulators based on the characteristics of leakage current,” IEEE Transactions on Power Delivery, Vol. 25, No.1, January 2010, pp. 417-424.
[56] E. T. W. Neto, E. G. da Costa, and M. Maia, “Artificial neural networks used for ZnO arresters diagnosis,” IEEE Transactions on Power Delivery, Vol. 24, No. 3, July 2009, pp. 1390-1395.
[57] A. G. Kanashiro, M. Z. Jr, P. F. Obase, and W. R. Bacega, “Diagnostic of silicon carbide surgge arresters using leakage current measuremennt,” IEEE Latin Ammerica Transactions, Vol. 9, No. 5, September 2011, pp. 761- 766.
[58] N. Bashir and H. Ahmad, “Odd harmonics and third to fifth harmonic ratios of leakage currents as diagnostic tools to study the ageing of glass insulators,” IEEE Transactions on Dielectrics and Electrical Insulation, Vol. 17, No. 3, June 2010, pp.819-832.
[59] C. A. L. Almeida, A. P. Braga, S. Nascimento, V. Paiva, H. J. A. Martins, R. Torres, and W. M. Caminhas, “Intelligent thermographic diagnostic applied to surge arresters: A new approach,” IEEE Transactions on Power Delivery, Vol. 24, No. 2, April 2009, pp. 751-757.
[60] K. Chrzan and W. Koehler, “Diagnostics of high-voltage metal-oxide surge arresters procedure errors,” International Symposium on High Voltage Engineering, London, England, August 1999, pp. 385-388.
[61] N. Zhou, J. W. Pierre, and D. Trudnowski, “A stepwise regression method for estimating dominant electromechanical modes,” IEEE Transactions on Power Delivery, Vol. 27, No. 2, May 2012, pp. 1051-1059.
[62] M. J. Flynn, S. Sarkani, and T. A. Mazzuchi, “Regression analysis of automatic measurement systems,” IEEE Transactions on Instrumentation and Measurement, Vol. 58, No.10, October 2009, pp. 3373-3379.
[63] P. Valsalal, S. Usa, and K. Udayakumar “Response of metal oxide arrester in gas-insulated substation and method to improve its dynamic characteristics,” IET Science, Measurement and Technology, Vol. 6, No. 4, February 2012, pp. 222-228.
[64] K. Korendo, M. Florkowski, “Thermography based diagnostic of power equipment,” Power Engineering Journal, February 2001, pp. 33-42.

------------------------------------------------------------------------ 第 8 筆 ---------------------------------------------------------------------
系統識別號 U0026-0302201517081100
論文名稱(中文) 探討冷誘導核醣核酸結合蛋白在低溫對抗MPP+毒性的神經保護作用中所扮演之角色
論文名稱(英文) The role of cold-inducible RNA binding protein in the neuroprotection of hypothermia against MPP+ toxicity
校院名稱 成功大學
系所名稱(中) 生理學研究所
系所名稱(英) Department of Physiology
學年度 103
學期 1
出版年 104
研究生(中文) 謝嘉芸
學號 s36014083
學位類別 碩士
語文別 英文
口試日期 2015-01-20
論文頁數 60頁
口試委員 指導教授-莊季瑛
口試委員-蔣輯武
口試委員-楊尚訓
口試委員-陳珮君
關鍵字(中) 低溫
CIRBP
Nrf2
MPP+
神經保護
關鍵字(英) hypothermia
CIRBP
Nrf2
MPP+
neuroprotection
學科別分類
中文摘要 低溫治療目前已經被認為是一個具有潛力去阻止廣泛腦損傷的治療方式。我們之前的研究以人類神經母細胞瘤細胞株 (SK-N-SH cell line) 在低溫 (32C) 處理後發現,細胞株會大量的表達冷所誘導的核糖核酸結合蛋白(cold-inducible RNA binding protein, CIRBP),這個大量表達的蛋白在低溫下所扮演的功能,目前為止還不是很清楚。因此,我們想要探討冷誘導核糖核酸結合蛋白在低溫對抗MPP+毒性的神經保護作用當中所扮演的角色。MPP+是一個粒線體中呼吸鏈上複合體I (complex I) 的抑制劑,此藥物可以廣泛且選擇性的造成多巴胺神經的死亡,因此是一種常被用來模擬帕金森氏症的藥物。首先,我們發現SK-N-SH 細胞株暴露在低溫下24 h 可以顯著的降低內源性及MPP+所誘導H2O2產生,接著,低溫可以顯著降低細胞死亡率以及增加細胞的存活率。文獻已指出,轉錄因子-Nrf2,可以被氧化壓力活化,並促進下游抗氧化酵素的轉錄,包含-穀氨醯半胱氨酸合成酶 (-GCS)、第一型血紅素氧化酶 (HO-1) 及NAD(P)H對苯二酮脫氫酶 (NQO1),進而去抑制氧化壓力,達到細胞保護的作用。我們探討Nrf2抗氧化系統是否涉及低溫誘導保護作用機制,在低溫暴露下,依序會提高下列mRNA分子或蛋白的表現:1 h下,細胞核中Nrf2蛋白及HO-1 mRNA表現; 6 h, -GCSc 蛋白及 HO-1 mRNA表現; 12 h, HO-1 mRNA表現; 12 h-48 h, RBM3 mRNA表現; 24 h會提高 -GCSc蛋白表現; 24-48 h會提高CIRBP mRNA表現。低溫處理也抑制MPP+所誘導CIRBP、 -GCSc及RBM3 (another cold-inducible protein) mRNA下降以及HO-1及NQO-1 mRNA上升。低溫還可以避免MPP+誘導ARE啟動子活性下降。接著,我們分別將pEGFP-N1融合蛋白及pLKO.AS3w.puro vectors 插入一段人類全長cirbp 基因去大量表達CIRBP。我們發現轉染cirbp-EGFP 融合蛋白質體或共同轉染 cirbp/puromycin plasmid 以及 ARE-pGL3 plasmid,顯著降低MPP+誘導細胞死亡,然而單獨轉染cirbp/puromycin plasmid卻沒有保護作用,並且會誘發H2O2含量增高。另外,大量表達CIRBP在MPP+誘導Nrf2所調控抗氧化酵素的改變以及對神經細胞的保護作用中,並沒有像低溫處理一樣明顯。我們繼續探討這樣不同的結果是否是因為CIRBP表達在細胞中不同位置所造成的影響。利用免疫螢光染色及表達cirbp-EGFP 融合蛋白的實驗中,我們發現不管細胞處於低溫或大量表達CIRBP或MPP+處理之下,都可以看到細胞核的CIRBP表現量高於細胞質。這樣的結果暗示,CIRBP在低溫誘導的神經保護作用機制當中,只扮演了部分的角色。
英文摘要 Hypothermia has a promising therapeutic advantage in the prevention of a broad range of brain damages. Our preliminary results showed that human SK-N-SH neuroblastoma cells cultured in cold condition (32C) significantly upregulated the cold-inducible RNA binding protein (CIRBP) expression. However, the function of CIRBP upregulation under cold exposure is unclear. Herein, we investigated the role of CIRBP in cold exposure-induced neuroprotection against 1-methyl-4-phenylpyridinium (MPP+) toxicity. MPP+ is an inhibitor of mitochondrial complex I and widely used to selectively induced dopaminergic neuron death as a model of Parkinson’s disease. Firstly, we found that cold exposure for 24 h significantly reduced endogenous and MPP+-induced H2O2 production, and subsequently prevented neuron death 48 h after MPP+ treatment. Because it has been reported that transcription factor of nuclear factor erythroid 2-related factor 2 (Nrf2) is activated by oxidative stress and up-regulates the downstream antioxidant enzymes, including -glutamylcysteine synthetase (-GCS), NAD(P)H dehydrogenase quinone 1 (NQO-1), and heme oxygenase-1 (HO-1) to protect cells from oxidative insult, we investigated the involvement of Nrf2 antioxidant system in cold exposure-induced neuroprotection. Results from time-course study revealed that cold exposure induced upregulation of nuclear Nrf2 protein and HO-1 mRNA (1 h), -GCS protein and HO-1 mRNA (6 h), HO-1 (12 h) and RBM3 (12-48 h) mRNA, and -GCS protein (24 h) and CIRBP mRNA and protein (24-48 h) expression. Cold exposure prevented MPP+-induced downregulation of CIRBP and-GCS and RNA binding motif 3 (RBM3, another cold-inducible protein), as well as upregulation of HO-1 and NQO-1 mRNA expression. Cold exposure can block MPP+-induced decrease in ARE promoter activity. CIRBP overexpression using cirbp-EGFP fusion protein plasmid or cotransfection cirbp/puromycin plasmid with ARE-pGL3 plasmid, but not transfection of cirbp/puromycin plasmid only, significantly reduced MPP+-induced neuron death, though a significant increase in H2O2 level was found. However, the effect of CIRBP overexpression on MPP+-induced changes in the expression of Nrf2-regulated antioxidant enzymes and its neuroprotective effect was less pronounced than that under cold exposure. We considered and examined whether the disparity was caused by the different distribution of CIRBP in cells. Results from immunocytochemistry and overexpression of cirbp-EGFP fusion protein studies showed that higher CIRBP expression was found in the nucleus than in the cytosol after MPP+ treatment and also in both cold exposure and CIRBP overexpression. These results imply that CIRBP plays partial role in cold exposure-induced neuroprotection.
論文目次 Contents
中文摘要 1
Abstract 3
謝辭 5
Contents 7
Introduction 11
Parkinson’s disease (PD) 11
Clinical characteristics and pathological feature of Parkinson’s disease (PD) 11
MPTP/MPP+-induced parkinsonian model 12
Nrf2-regulated antioxidant defense system 12
The role of Nrf2 in neurodegenerative disease 13
Therapeutic hypothermia 14
Clinical application 14
Mechanisms underlying hypothermia-induced neuroprotection 14
Cold-inducible RNA binding protein (CIRBP) 15
Discovery of cold shock protein 15
The neuroprotective effect of CIRBP 16
The relationship between CIRBP and inflammatory 16
Research rationale and hypothesis 18
Specific aims 18
Materials and Methods 19
Chemicals and antibodies 19
Cell culture 19
3-[4, 5-Dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay 19
Propidium iodide (PI) staining 20
Determination of intracellular H2O2 level 20
Total RNA extraction 21
Reverse transcription-polymerase chain reaction (RT-PCR) 21
Isolation of nuclear extracts 22
Western blot analysis 23
Immunocytochemistry 23
Cloning of full length human CIRBP 24
Expression of the EGFP-CIRBP fusion protein 25
Transfection of FL-hCIRBP 25
Reporter assay 25
Statistical analysis 26
Results 27
Cold exposure prevents MPP+-induced cell death and H2O2 production 27
Cold exposure upregulates the expression of CIRBP and Nrf2-regulated antioxidant enzymes 27
Cold exposure prevents the effect of MPP+ on CIRBP, RBM3, and Nrf2-regulated gene expression 28
CIRBP overexpression prevents the MPP+-induced cell death, but induces a significant increase in H2O2 level 28
CIRBP translocates from the cytosol to the nucleus in cold exposure and CIRBP overexpression 30
Discussion 31
Summary of our major findings 31
Brain temperature in Parkinson’s disease 31
The role of CIRBP on hypothermia against MPP+ toxicity 32
The role of CIRBP under various stresses 33
The effect of Nrf2-regulated antioxidant enzymes on hypothermia after MPP+ treatment 35
Conclusion 37
References 38
Figure contents 44
Figure 1 Protocol for cold exposure. 44
Figure 2 Cold exposure prevents MPP+-induced cell death and H2O2 production. 45
Figure 3 Cold exposure induces upregulation of CIRBP, HO-1 and RBM3 mRNA expression. 46
Figure 4 Cold exposure induces increase in Nrf2, CIRBP, HO-1, and -GCSc protein expression. 48
Figure 5 Cold exposure prevents MPP+-induced decrease in ARE promoter activity. 49
Figure 6 Cold exposure inhibits MPP+-induced upregulation of HO-1 and NQO-1, and downregulation of CIRBP, -GCSc, and RBM3 mRNA expression. 50
Figure 7 CIRBP overexpression induces H2O2 production and did not prevent MPP+-induced cell death. 52
Figure 8 CIRBP overexpression did not mimic the effect of cold exposure on MPP+-induced gene expression. 53
Figure 9 CIRBP overexpression prevents MPP+-induced decrease in ARE promoter activity. 55
Figure 10 CIRBP overexpression prevents MPP+-induced cell death, but induces H2O2 production. 56
Figure 11 Cold exposure and MPP+ induces CIRBP translocation to nucleus 57
Figure 12 CIRBP overexpression also induces CIRBP translocation to nucleus. 58
Figure 13 Overexpression of cirbp-EGFP fusion protein prevents basal and MPP+-induced cell death. 59
Figure 14 Overexpression of cirbp-EGFP fusion protein represents CIRBP translocation to nucleus. 60
參考文獻 References

1 Steece-Collier, K., Maries, E. & Kordower, J. H. Etiology of Parkinson's disease: Genetics and environment revisited. Proceedings of the National Academy of Sciences of the United States of America 99, 13972-13974, doi:10.1073/pnas.242594999 (2002).
2 Lee, H. J., Bae, E. J. & Lee, S. J. Extracellular alpha--synuclein-a novel and crucial factor in Lewy body diseases. Nature reviews. Neurology 10, 92-98, doi:10.1038/nrneurol.2013.275 (2014).
3 Vekrellis, K., Xilouri, M., Emmanouilidou, E., Rideout, H. J. & Stefanis, L. Pathological roles of alpha-synuclein in neurological disorders. The Lancet. Neurology 10, 1015-1025, doi:10.1016/s1474-4422(11)70213-7 (2011).
4 Fitzmaurice, P. S. et al. Nigral glutathione deficiency is not specific for idiopathic Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society 18, 969-976, doi:10.1002/mds.10486 (2003).
5 Schapira, A. H. et al. Mitochondrial complex I deficiency in Parkinson's disease. Journal of neurochemistry 54, 823-827 (1990).
6 Javitch, J. A., D'Amato, R. J., Strittmatter, S. M. & Snyder, S. H. Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proceedings of the National Academy of Sciences of the United States of America 82, 2173-2177 (1985).
7 Cui, M. et al. The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway. Proceedings of the National Academy of Sciences of the United States of America 106, 8043-8048, doi:10.1073/pnas.0900358106 (2009).
8 Blesa, J., Phani, S., Jackson-Lewis, V. & Przedborski, S. Classic and new animal models of Parkinson's disease. Journal of biomedicine & biotechnology 2012, 845618, doi:10.1155/2012/845618 (2012).
9 Kopin, I. J. & Markey, S. P. MPTP toxicity: implications for research in Parkinson's disease. Annual review of neuroscience 11, 81-96, doi:10.1146/annurev.ne.11.030188.000501 (1988).
10 Thimmulappa RK et al. Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. Antioxid Redox Signal 9(11), 1963-1970 (2007).
11 Sharma, R. et al. Role of 4-hydroxynonenal in chemopreventive activities of sulforaphane. Free radical biology & medicine 52, 2177-2185, doi:10.1016/j.freeradbiomed.2012.04.012 (2012).
12 Zhang, D. D. & Hannink, M. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Molecular and cellular biology 23, 8137-8151 (2003).
13 Kim, H. J. & Vaziri, N. D. Contribution of impaired Nrf2-Keap1 pathway to oxidative stress and inflammation in chronic renal failure. American journal of physiology. Renal physiology 298, F662-671, doi:10.1152/ajprenal.00421.2009 (2010).
14 Ishii, T. et al. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. The Journal of biological chemistry 275, 16023-16029 (2000).
15 Clark, J. & Simon, D. K. Transcribe to survive: transcriptional control of antioxidant defense programs for neuroprotection in Parkinson's disease. Antioxidants & redox signaling 11, 509-528, doi:10.1089/ars.2008.2241 (2009).
16 van Muiswinkel, F. L. et al. Expression of NAD(P)H:quinone oxidoreductase in the normal and Parkinsonian substantia nigra. Neurobiology of aging 25, 1253-1262, doi:10.1016/j.neurobiolaging.2003.12.010 (2004).
17 Schipper, H. M. Heme oxygenase expression in human central nervous system disorders. Free radical biology & medicine 37, 1995-2011, doi:10.1016/j.freeradbiomed.2004.09.015 (2004).
18 Jakel, R. J., Townsend, J. A., Kraft, A. D. & Johnson, J. A. Nrf2-mediated protection against 6-hydroxydopamine. Brain research 1144, 192-201, doi:10.1016/j.brainres.2007.01.131 (2007).
19 Chen, P. C. et al. Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte. Proceedings of the National Academy of Sciences of the United States of America 106, 2933-2938, doi:10.1073/pnas.0813361106 (2009).
20 Xu, L., Yenari, M. A., Steinberg, G. K. & Giffard, R. G. Mild hypothermia reduces apoptosis of mouse neurons in vitro early in the cascade. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 22, 21-28, doi:10.1097/00004647-200201000-00003 (2002).
21 Polderman, K. H. Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet 371, 1955-1969, doi:10.1016/s0140-6736(08)60837-5 (2008).
22 Holzer, M. Targeted temperature management for comatose survivors of cardiac arrest. The New England journal of medicine 363, 1256-1264, doi:10.1056/NEJMct1002402 (2010).
23 Yenari, M., Kitagawa, K., Lyden, P. & Perez-Pinzon, M. Metabolic downregulation: a key to successful neuroprotection? Stroke; a journal of cerebral circulation 39, 2910-2917, doi:10.1161/strokeaha.108.514471 (2008).
24 Tissier, R. et al. Mild hypothermia reduces per-ischemic reactive oxygen species production and preserves mitochondrial respiratory complexes. Resuscitation 84, 249-255, doi:10.1016/j.resuscitation.2012.06.030 (2013).
25 Yenari, M. A. & Han, H. S. Neuroprotective mechanisms of hypothermia in brain ischaemia. Nature reviews. Neuroscience 13, 267-278, doi:10.1038/nrn3174 (2012).
26 Deng, H., Han, H. S., Cheng, D., Sun, G. H. & Yenari, M. A. Mild hypothermia inhibits inflammation after experimental stroke and brain inflammation. Stroke; a journal of cerebral circulation 34, 2495-2501, doi:10.1161/01.str.0000091269.67384.e7 (2003).
27 Xiong, M., Yang, Y., Chen, G. Q. & Zhou, W. H. Post-ischemic hypothermia for 24h in P7 rats rescues hippocampal neuron: association with decreased astrocyte activation and inflammatory cytokine expression. Brain research bulletin 79, 351-357, doi:10.1016/j.brainresbull.2009.03.011 (2009).
28 Feng, J. F. et al. Effect of therapeutic mild hypothermia on the genomics of the hippocampus after moderate traumatic brain injury in rats. Neurosurgery 67, 730-742, doi:10.1227/01.neu.0000378023.81727.6e (2010).
29 Nishiyama, H. et al. A glycine-rich RNA-binding protein mediating cold-inducible suppression of mammalian cell growth. J Cell Biol. 137, 899-908 (1997).
30 Yu, X. X. et al. Characterization of novel UCP5/BMCP1 isoforms and differential regulation of UCP4 and UCP5 expression through dietary or temperature manipulation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 14, 1611-1618 (2000).
31 Hofmann, S., Cherkasova, V., Bankhead, P., Bukau, B. & Stoecklin, G. Translation suppression promotes stress granule formation and cell survival in response to cold shock. Molecular biology of the cell 23, 3786-3800, doi:10.1091/mbc.E12-04-0296 (2012).
32 Nishiyama, H. et al. A glycine-rich RNA-binding protein mediating cold-inducible suppression of mammalian cell growth. The Journal of cell biology 137, 899-908 (1997).
33 Derry, J. M., Kerns, J. A. & Francke, U. RBM3, a novel human gene in Xp11.23 with a putative RNA-binding domain. Human molecular genetics 4, 2307-2311 (1995).
34 Tong, G. et al. Effects of moderate and deep hypothermia on RNA-binding proteins RBM3 and CIRP expressions in murine hippocampal brain slices. Brain research 1504, 74-84, doi:10.1016/j.brainres.2013.01.041 (2013).
35 Lunde, B. M., Moore, C. & Varani, G. RNA-binding proteins: modular design for efficient function. Nature reviews. Molecular cell biology 8, 479-490, doi:10.1038/nrm2178 (2007).
36 Yang, R., Weber, D. J. & Carrier, F. Post-transcriptional regulation of thioredoxin by the stress inducible heterogenous ribonucleoprotein A18. Nucleic acids research 34, 1224-1236, doi:10.1093/nar/gkj519 (2006).
37 De Leeuw, F. et al. The cold-inducible RNA-binding protein migrates from the nucleus to cytoplasmic stress granules by a methylation-dependent mechanism and acts as a translational repressor. Experimental cell research 313, 4130-4144, doi:10.1016/j.yexcr.2007.09.017 (2007).
38 Wilusz, J., Feig, D. I. & Shenk, T. The C proteins of heterogeneous nuclear ribonucleoprotein complexes interact with RNA sequences downstream of polyadenylation cleavage sites. Molecular and cellular biology 8, 4477-4483 (1988).
39 Al-Fageeh, M. B. & Smales, C. M. Cold-inducible RNA binding protein (CIRP) expression is modulated by alternative mRNAs. RNA (New York, N.Y.) 15, 1164-1176, doi:10.1261/rna.1179109 (2009).
40 Sumitomo, Y. et al. Identification of a novel enhancer that binds Sp1 and contributes to induction of cold-inducible RNA-binding protein (cirp) expression in mammalian cells. BMC biotechnology 12, 72, doi:10.1186/1472-6750-12-72 (2012).
41 Li, S., Zhang, Z., Xue, J., Liu, A. & Zhang, H. Cold-inducible RNA binding protein inhibits H(2)O(2)-induced apoptosis in rat cortical neurons. Brain research 1441, 47-52, doi:10.1016/j.brainres.2011.12.053 (2012).
42 Saito, K. et al. Moderate low temperature preserves the stemness of neural stem cells and suppresses apoptosis of the cells via activation of the cold-inducible RNA binding protein. Brain research 1358, 20-29, doi:10.1016/j.brainres.2010.08.048 (2010).
43 Brochu, C. et al. NF-kappaB-dependent role for cold-inducible RNA binding protein in regulating interleukin 1beta. PloS one 8, e57426, doi:10.1371/journal.pone.0057426 (2013).
44 Zhou, M., Yang, W. L., Ji, Y., Qiang, X. & Wang, P. Cold-inducible RNA-binding protein mediates neuroinflammation in cerebral ischemia. Biochimica et biophysica acta 1840, 2253-2261, doi:10.1016/j.bbagen.2014.02.027 (2014).
45 Qiang, X. et al. Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nature medicine 19, 1489-1495, doi:10.1038/nm.3368 (2013).
46 Matsui, T., Yoshida, Y., Yanagihara, M. & Suenaga, H. Hypothermia at 35 degrees C reduces the time-dependent microglial production of pro-inflammatory and anti-inflammatory factors that mediate neuronal cell death. Neurocritical care 20, 301-310, doi:10.1007/s12028-013-9911-5 (2014).
47 Kiyatkin, E. A. Brain temperature homeostasis: physiological fluctuations and pathological shifts. Frontiers in bioscience (Landmark edition) 15, 73-92 (2010).
48 Rango, M., Arighi, A., Bonifati, C. & Bresolin, N. Increased brain temperature in Parkinson’s disease. NeuroReport 23, 129-133, doi:10.1097/WNR.0b013e32834e8fac (2012).
49 Ye, Q., Zhang, X., Huang, B., Zhu, Y. & Chen, X. Astaxanthin suppresses MPP(+)-induced oxidative damage in PC12 cells through a Sp1/NR1 signaling pathway. Marine drugs 11, 1019-1034, doi:10.3390/md11041019 (2013).
50 Yang, C. & Carrier, F. The UV-inducible RNA-binding protein A18 (A18 hnRNP) plays a protective role in the genotoxic stress response. The Journal of biological chemistry 276, 47277-47284, doi:10.1074/jbc.M105396200 (2001).
51 Xu, Z. et al. Selective alterations of transcription factors in MPP+-induced neurotoxicity in PC12 cells. Neurotoxicology 26, 729-737, doi:10.1016/j.neuro.2004.12.008 (2005).
52 Aoki, K., Ishii, Y., Matsumoto, K. & Tsujimoto, M. Methylation of Xenopus CIRP2 regulates its arginine- and glycine-rich region-mediated nucleocytoplasmic distribution. Nucleic acids research 30, 5182-5192 (2002).
53 Tsou, Y. H. et al. Treadmill exercise activates Nrf2 antioxidant system to protect the nigrostriatal dopaminergic neurons from MPP(+) toxicity. Experimental neurology 263, 50-62, doi:10.1016/j.expneurol.2014.09.021 (2015).
54 Alam, J. & Cook, J. L. How many transcription factors does it take to turn on the heme oxygenase-1 gene? American journal of respiratory cell and molecular biology 36, 166-174, doi:10.1165/rcmb.2006-0340TR (2007).
55 Cherry, A. D. & Piantadosi, C. A. Regulation of mitochondrial biogenesis and its intersection with inflammatory responses. Antioxidants & redox signaling, doi:10.1089/ars.2014.6200 (2015).
56 Stocker, R. & Perrella, M. A. Heme oxygenase-1: a novel drug target for atherosclerotic diseases? Circulation 114, 2178-2189, doi:10.1161/circulationaha.105.598698 (2006).
57 Schipper, H. M., Liberman, A. & Stopa, E. G. Neural heme oxygenase-1 expression in idiopathic Parkinson's disease. Experimental neurology 150, 60-68, doi:10.1006/exnr.1997.6752 (1998).
58 Jaiswal, A. K. Regulation of genes encoding NAD(P)H:quinone oxidoreductases. Free radical biology & medicine 29, 254-262 (2000).
59 Tobon-Velasco, J. C. et al. 6-OHDA-induced apoptosis and mitochondrial dysfunction are mediated by early modulation of intracellular signals and interaction of Nrf2 and NF-kappaB factors. Toxicology 304, 109-119, doi:10.1016/j.tox.2012.12.011 (2013).


------------------------------------------------------------------------ 第 9 筆 ---------------------------------------------------------------------
系統識別號 U0026-0307201515194400
論文名稱(中文) 代理成本與內部稽核主管異動關係之探討
論文名稱(英文) The association between Agency Cost and the Turnover of Internal Audit Manager
校院名稱 成功大學
系所名稱(中) 財務金融研究所碩士在職專班
系所名稱(英) Graduate Institute of Finance (on the job class)
學年度 103
學期 2
出版年 104
研究生(中文) 林玉萍
學號 R87011443
學位類別 碩士
語文別 中文
口試日期 2015-07-02
論文頁數 56頁
口試委員 指導教授-林囿成
口試委員-黃華瑋
口試委員-陳政芳
關鍵字(中) 代理理論
代理成本
內部稽核
內部稽核主管異動
公司治理
關鍵字(英) agency theory
agency cost
internal audit
turnover of internal audit manager
corporate governance
學科別分類
中文摘要 摘要
本文將探討代理成本與內部稽核主管異動之關聯性,並進一步探討內部人持股及外部審計單位與其之相關性。以2009年至2013年臺灣上市及上櫃公司為樣本,並參考Singh and Davidson Ⅲ (2003)及Ang, Cole and Lin (2000)以營業費用率及資產週轉率衡量代理成本,主要採用Logit迴歸模式進行實證分析。經實證結果發現在控制其他內部稽核主管異動因素,內部稽核主管的異動與代理成本、股權結構、與公司治理相關之經理人異動、及更換會計師事務所,具有顯著相關。
關鍵字:代理理論、代理成本、內部稽核、內部稽核主管異動、公司治理
英文摘要 SUMMARY
This paper is examines the relation between agency costs and the turnover of internal audit manager (henceforth IAM), and further explore whether firm attributes, such as managerial ownership, and dual chairman/CEO structure, external audit firm switching, influence that relationship. In reference to Singh and Davidson Ⅲ(2003) and Ang, Cole and Lin(2000), this paper use the operating expense ratio and asset turnover ratio as the proxies for agency costs. By using Logit regression analysis, this study finds that the turnover of IAM is not only significantly correlation with agency costs but also managerial ownership. Furthermore the results show that the corporate governance factors, like external audit firm switch and turnover of the mangers, are positively associated with IAM turnover.
Keyword: agency theory, agency cost, internal audit, turnover of internal audit manager, corporate governance
論文目次 目錄
第一章、緒論 1
第一節 研究動機 2
第二節 研究目的 3
第三節 研究流程 4
第二章、相關規範及文獻探討 5
第一節 內部稽核制度規範與發展 5
第二節 內部稽核相關文獻 10
第三節 股權結構與代理成本相關文獻 13
第四節 高階主管異動相關文獻 15
第五節 公司治理相關文獻 17
第三章、研究方法 21
第一節 假說發展 21
第二節 實證模型設計 23
第三節 變數說明 24
第四節 資料來源及樣本選取 30
第四章、實證結果與分析 34
第一節 敘述統計分析 34
第二節 實證結果 42
第三節 額外測試 45
第五章 結論與建議 48
第一節 結論 48
第二節 研究限制及建議 49
參考資料 50

圖表目錄
圖目錄
圖1:研究流程 4
圖2:立場聲明書-三道防線模式、基本角色及特性 6
圖3:公司治理、內部控制與內部稽核的關聯性 8
圖4:內部稽核的角色 10
圖5:專業-組織衝突、工作滿意度及內部稽核人員異動的關係圖 13
圖6:良好公司治理之內外部機制 18
圖7:我國公司治理藍圖計劃項目 20

表目錄
表1:變數定義表 23
表2:樣本選取 30
表3-1:異動次數分析表-內部稽核主管 31
表3-2:異動次數分析表-董事長 31
表3-3:異動次數分析表-總經理 31
表3-4:異動次數分析表-財務主管 32
表3-5:異動次數分析表-發言人 32
表4:樣本產業年度分佈狀況表 33
表5:分群統計內部稽核主管異動次數 37
表6:敘述統計量 38
表7:Pearson相關係數矩陣 40
表8:Logit迴歸分析結果(一) 43
表9:Logit迴歸分析結果(二) 44
表10:Logit迴歸分析結果(三) 46

參考文獻 中文部分
內部稽核執業準則公報,1995,中華民國內部稽核協會
內部稽核實務守則,2011,中華民國內部稽核協會
安侯建業會計師事務所,2014,2014年舞弊及不當行為問卷調查報告
國際專業實務架構,2013,林炳滄、陳錦烽譯,中華民國內部稽核協會出版
審計準則公報第25號,1993,內部稽核工作之採用,中華民國會計研究發展基金會
李佳玲、葉穎蓉與何晉滄,2005,績效、公司治理與高階管理者離職關係之實證研究,中山管理評論,第13 卷第1 期:75-106。
李建然、許書偉、湯麗芬,2008,內部稽核品質與財務報表品質之關聯性,輔仁管理評論,第15卷第3期(9月):33-62
林有志、邱炳雲、高茂峰,2008,更換經理人對公司經營績效之影響,會計與公司治理,第5卷第2期(12月):1-28
林宛瑩、鄭桂蕙,2011,內部稽核需求的決定因素,Taiwan Accounting Review,(7)2:188-217
林宛瑩、陳錦烽等,2012,內部稽核與代理成本,行政院國家科學委員會專題研究計劃部分公開資料
林柄滄,2013,內部稽核理論與實務,第六版,中華民國內部稽核協會
林嬋娟、張哲嘉,2009,董監事異常變動、家族企業與企業舞弊之關聯性,會計評論,第48期(1月):1-33
林穎芬,1998,台灣上市公司控管機制之研究-探討家族與非家族企業高階主管薪酬與離職的控管效果,國立中山大學企業管理研究所博士論文
林穎芬、祝道松與洪晨桓,2006,經濟附加價值與總經理更替之探討,當代會計,第7卷第1期(6月):103-134。
林慧珠,1995,內部稽核在企業組織內角色定位之研究,國立台灣大學會計研究所碩士論文
柯思豪,2009,內部稽核單位規模影響因素之研究,國立政治大學會計研究所碩士論文
俞海琴、周本鄂,1994,台灣地區上市公司董監事、關係人持股比率和公司Tobin’s Q 關係之研究,管理評論,第13卷第1期(1月):79-98
洪裕琨,2003,企業內部稽核人員離職傾向之研究,國立政治大學行政管理研究所碩士論文
洪榮華、陳香如、柯璟瑩,2005,從代理理論的角度探討董事會特性、股權結構與負債之關聯性,管理與系統,第2卷第4期(10月):33-53
唐大鈞,2001,工作價值與工作特性影響我國內部稽核人員投入與離職傾向的探討,國立中山大學人力資源研究所碩士論文
陳美華,洪世炳(2005),公司治理、股權結構與公司績效關係之實證研究,企業管理學報,65,129~153
許永聲、陳信吉、陳琬菁,2013,董事會特性與盈餘管理之選擇行為,會計評論,第57期(7月):39-72
黃心怡,1988,我國企業內部稽核功能發揮影響因素之研究,東吳大學會計研究所碩士論文
黃旭輝,2006,經理人異動與股東財富效果,管理評論,第25卷第1期(1月):23-45
溫育芳、楊鈞棠,2012,公司治理與舉債融資在降低代理問題替代性之探討,台灣銀行季刊,第63卷第2期:108-130
楊朝旭、蔡柳卿,2003,總經理更換與相對績效評估,人力資源管理學報,第3卷第1期:63-80
蔡柳卿、邵佩雯、楊怡芳,2008,公司治理對代理成本與無形資產之影響,中華管理評論國際學報,第11卷第4期(11月):1-32
蔡柳卿、陳慧慧,2006,公司治理對總經理更換-公司績效敏感性之影響:台灣上市公司之證據,管理研究學報,第6卷第2期(7月):273-305
薛敏正、林嬋娟、林秀鳳,2008,董事會特性與財務報表重編,Chiao Da Mangerment Review,第28卷第2期: 73-103
韓慧玲,1994,影響內部稽核績效因素之研究:以上市公司製造業為例,國立中央大學企業管理研究所碩士論文
戴錦周、郭佩文,2006,高階管理者更迭的因素及其對公司績效的影響,台中技術學院學報,第7 期第2 卷(7 月):47-68
簡俱揚、陳玉梅,2009,產業審計專家與獨立董監事對新發行公司債資金成本的影響,當代會計,10,99-130

英文部分
Abbott, L. J., Y. Park, and S. Parker. 2000. The effects of audit committee activity and independence on corporate fraud. Managerial Finance 26 (November):55-67.
Abdel-Khalik, A. R. 1993. Why Do Private Companies Demand Auditing? A Case for Organizational Loss of Control. Journal of Accounting, Auditing and Finance 8 Winter):31-52.
Adams, M.B. 1994. Agency Theory and the Internal Audit. Managerial Auditing Journal 9(8):8-12.
Adrian Harrell, Eugene Chewning and Martin Taylar, 1986. Organization-professional conflict and the job satisfaction and turnover intentions of internal auditors , A journal of Practice and Theory Vol. 5, No.2 Spring 1986:109-121.
Agrawal, A., & Knoeber, C. R. 1996. Firm Performance and Mechanisms to Control Agency Problems between Managers and Shareholders. Journal of Financial and Quantitative Analysis, 377-397.
Anderson, D., J. R. Francis, and D. J. Stokes., 1993. Auditing, Directorsships and the Demand for Monitoring. Journal of Accounting and Public Policy 12(Month):335-375.
Ang, J.S., R.A. Cole, and J.W. Lin., 2000. Agnecy Cost and Ownership Structure. TheJournal of Finance 55 (February): 81-106.
Aranya, N., Pollock, J., and Amemnic, J. 1981. An examination of professional commitment in public accounting. Accounting Organizations and Society, 6(4), 271-280.
Baliga, B. R., Moyer, N. C., and Rao, R. S., 1996. CEO duality and firm performance: What’s the fuss? Strategic Management Journal, 17, 41-53.
Beasley, M. S. 1996. An empirical analysis of the relation between the board of directors composition and financial statement fraud. The accounting Review 71(October):443-465.
Berle, A., and Means, G. C. 1932. The modern corporation and private property. New York: MacMillan.
Booth J.R., M.M. Cornett, and H.Tehranian..2002. Boards of directors, ownership, and regulation. Journal of Banking & Finance 26 (October): 1973-1996.
Brickley, J., and James, C., 1987. The takeover market, corporate board compensation, and ownership structure. Journal of Law and Economics, 30, 161-180.
Brickley, J. A., Coles, L., and Terry, R. L. 1994. Outside directors and the adoption of poison pills. Journal of Financial Economics, 35, 371-390.
Brown, C. M. 1982. Administrative succession and organizational performance: The succession effect. Administrative Science Quarterly, 27(March): 1-16.
Carcello, J.V., D. R. Hermanson, and K. Raghunandan. 2005a. Factors Associated with U.S.Public Companies' Investment in Internal Auditing. Accounting Horizons 19 (June):69-367.
Carcello, J.V., D.R. Hermanson, and K. Raghunandan. 2005b. Changes in Internal Auditing during the time of the major US accounting scandals, International Journal of Auditing 9(2): 117-127.
Carey, P., R. Simnett, and G. Tanewski. 2000. Voluntary demand for internal and external auditing by family business. Auditing 19 (Supplement): 37-61.
Chadwick, W., "Tough Questions, Tougher Answers", Internal Auditor, Vol. 52(6), 1995, pp.63-65.
Cohen, J., G. Krisnamoorthy, and A.M. Wright. 2002. Corporate governance and the auditprocess. Contemporary Accounting Research 19(4): 573-594.
Cosh, A. and A. Hughes. 1997. Executive remuneration, executive dismissal and institutional shareholdings. International Journal of Industrial Organization, 15(July):469-492.
Dahya, J., J. J. McConnell and N. G. Travlos. 2002. The Cadbury Committee, corporate performance, and top management turnover. The Journal of Finance, 57(February): 461-483.
DeAngelo, L. E. 1981. Auditor Size and Auditor Quality. Journal of Accounting and Economics:183-199.
Dechow, P. M., Sloan, R., and Sweeney, A. (1996), “Causes and Consequences of Earnings Manipulation: An Analysis of Firms Subject to Enforcement Actions by the SEC,” Contemporary Accounting Research, 13(1), 1-36.
DeFond, M. L.1992.The Association Between Changes in Client Firm Agency Costs and Auditor Switching. Auditing 11 (Spring): 16-31.
Denis, D. J., & Denis, D. K. (1995). Performance changes following top management dismissals. Journal of Finance, 50(4), 1029-1057.
Dopuch, N. and D. Simunic. 1982. Competition in Auditing :An Assessment. Fourth Symposium on Auditing Research:401-450.
Ettredge, M., and M. Reed. 2000. An Examination of Substitution among Monitoring Devices: The Case of Internal and External Audit. Review of Quantitative Finance and Accounting 15 (July): 57-80.
Engel, E., R. M. Hayes, and X. Wang. 2001. Relative usefulness of firm performance measure in CEO turnover decision. Unpublished manuscript, University of Chicago.
Fama, E. F. ,1980, Agency Problems and the Theory of the Firm, Journal of Political Economy, 88:2, 288-307.
Fame, E. F. and Jensen, M. C., 1983. Separation of Ownership and Control, Journal of Law and Economics, 26:2, 301-326.
Farrell, K. A., and D. A. Whidbee. 2002. The impact of forced CEO turnover on committee structure. Journal of Managerial Issues, 14(Spring): 49-67.
Felix Jr., W. L., A. A. Gramling, and M. J. Maletta. 2001. The contribution of internal audit as a determinant of external audit fees and factors influencing this contribution. Journal of Accounting Research 39(3): 513-534.
Francis, J. R., and E.R. Wilson, 1988. Auditor Changes: A Joint Test of Theory Relating to Agency Costs and Auditor Differentiation. Accounting Review 63 (October): 663-682.
Fuerst, O., and Kang, S. H. 2000. Corporate governance, expected operation performance, and pricing. Working Paper (Yale School of Management, New Haven).
Gamson, W. A. and N. A. Scotch. 1964. Scapegoating in baseball. American Journal of Sociology, 70(July): 69-72.
Goodwin, J. 2003, The Relationship between the audit committee and the internal audit function: evidence Australia and New Zealand. International Journal of Auditing 7(September): 263-278.
Goodwin-Stewart, J., and P. Kent. 2004. The incentives of Australian companies to utilize executive stock option plans. Corporate Ownership and Control 1 (2): 137-149.
Grusky, O. 1963. Managerial succession and organizational effectiveness. American Journal of Sociology, 69(July): 21-31.
Harrell, L. W., Elston, R. A., Scott, T M-, Wilkinson, M. T.,1986. A significant new systemic disease of net-pen reared chmook salmon (Oncorhynchus tshawytscha) brood stock. Aquaculture 55: 249-262.
Hill, C. W. L. and S. A. Snell. 1989. Effects of ownership structure and control on corporate productivity. Academy of Management Journal, 32(March): 25-46.
Hirschman, A. O. 1970. Exit, voice and loyalty response to decling in firms, organizations. Journal of Financial Economics, 20: 317-346.
Hotchkiss, E. S. 1995. Postbankruptcy performance and management turnover. Journal of Finance, 50(March): 3–21.
Huson, M. R., P. H. Malatesta and R. Parrino. 2004. Managerial succession and firm performance. Journal of Financial Economics, 74(November): 237-275.
Huson, M. R., R. Parrino and L. T. Starks. 2001. Internal monitoring mechanisms and CEO turnover: A long-term perspective. The Journal of Finance, 56(December):2265-2297
James, D. R., and M. Soref. 1981. Profit constraints on managerial autonomy: Managerial theory and the unmaking of the corporate president. American Sociological Review, 46(December): 1-18.
James, L. K., "The Effects of Internal Audit Structure on Perceived Financial Statement Fraud Prevention", Accounting Horizons, Vol. 17(4), 2003, pp.315-327.
Jensen, M, C. and W. H. Meckling, 1976. Theory of the firm: Managerial Behavior, Agency Costs and Ownership Structure, Journal of Financial Economics, 3:4, 305-360.
Jensen, M, C. and R. S.Ruback, 1983. The Market for Corporate Control: The Scientific Evidence, Journal of Financial Economics, 11:1-4, 5-50.
Jensen, M, C., 1986. Agency Cost of Free Flow, Corporate Finance, and Takeover, The American Economic Review, 76:2, 223-329.
Jensen, M. C. (1993), “The Modern Industrial Revolution, Exit, and the Failure of the Internal Control System,” Journal of Finance, 48(3), 831-880.
Johnson, W. B., and T. Lys., 1990. The Market for Audit Service: Evidence from Voluntary Auditor Change. Journal of Accounting and Economics, (January):281-308.
Kalbers, L., "Audit Committees and Internal Auditors", Internal Auditor, December 1992, pp.37-44.
Kao, L. and Chen, A. (2004), “The Effects of Board Characteristics on Earnings Management,” Corporate Ownership & Control, 1(3), 96-107.
Kesner I. F. and D.R. Dalton. 1987. Composition and CEO duality in boards of directors: an international perspective. Journal of International Business Studies 18 (September):3-42.
Khorana, A. (2001). Performance changes following top management turnover: evidence from open-end mutual funds. Journal of Financial and Quantitative Analysis, 36(3), 371-393.
Kinney, W., "Research Opportunities in Internal Control Quality and Quality Assurance", Auditing, Vol. 19(supplement), 2000, pp.83-90.
Klein, A. (2002b), “Audit Committee, Board of Director Characteristics, and Earnings Management,” Journal of Accounting and Economics, 33(3), 375-400.
Kosnik, R. D., 1990. Effects of board demography and directors’ incentives on corporate green-mail decisions. Academy of Management Journal, 33, 129-150.
Linda Lee Larson, 2004. Internal auditor and job stress, Managerial Auditing Journal, 19(9), 1119-1130.
McMullen, D. A., 1996. Audit committee performance: An investigation of the consequences associated with audit committee. Auditting: A Journal of Practice and Theory 16(Spring): 87-103.
Morck, R., A. Shleifer and R. W. Vishny, 1988. Managerment Ownership and Market Valuation: An Empirical Analysis, Journal of Financial Economics, 20, 295-315.
Ng, Y. M. 2005. An empirical study on the relationship between ownership and performance in a family-based corporate environment. Journal of Accounting, Auditing and Finance, 20(Spring): 121-146.
Parrino, R., R. Sias, and L. Starks. 2003. Voting with their feet: Institutional ownership changes around forced CEO turnover. Journal of Financial Economics, 68(April):3-46.
Patton, A., and Baker, J. C. 1987. Why won’t directors rock the boat. Harvard Business Review, 65(6), 10-18.
Raghunandan, K., W. J. Read, and D. V. Rama. 2001. Audit Committee Composition, "Gray Directors," and Interaction with Internal Auditing. Accounting Horizons 15 (June):105-118.
Sarens, G.. B. 2007. The Agency Model as a Predictor of the Size of Internal Audit Function in Belgian Companies. Working Paper, Gent University.
Sawyer, L.B. 1988, Sawyer’s Internal Auditing, The Institute of Internal Auditors, Altamonte Springs, FL.
Scarbrough, D. P.; and D. V. Rama, and K. Raghunandan. 1998. Audit Committee Composition and Interaction with Internal Auditing: Canadian Evidence. Accounting Horizons 12 (May): 51-62.
Shleifer, A. and Vishny, R., 1977. A survey of Coporate Governance, Journal of Finance, 52:2, 773-783.
Stiglitz, J. E. 1985. Credit markets and the control of capital. Journal of Money, Credit and Banking, 17(May): 133-152.
Singh, M., and Davidson, W. III. 2003. Agency costs, ownership structure and corporate governance mechanisms. Journal of Banking and Finance, 27(5), 793.
Stocks, Kevin D;Albrecht, W Steve;Howe, Keith R;Schueler, Dennis R 1988. What Makes An Effective Internal Audit Department? The Internal Auditor; 45, 2; ProQuest Central:45-49.
Teoh, S. H. 1992. Auditor Independence, Dismissal Threats, and the Market Reaction to Auditor Switches. Journal of Accounting Research (Spring):7-34.
Titman, S., & Trueman, B. 1986. Information Quality and the Valuation of New Issues. Journal of Accounting and Economics,2, 159- 172.
Wallace, W. A., and R. W. Kreutzfeldt. 1991. Distinctive characteristics of entities with an internal audit department and the association of the quality of such departments with errors. Contemporary Accounting Research 7 (2): 485–512.
Watts, R. L., & Zimmerman, J. L. 1986. Positive Accounting Theory.Englewood Cliffs, NJ: Prentice Hall.
Xie, B., Davidson III, W. N., and Dadalt, P. J. (2003), “Earnings Management and Corporate Governance: The Role of the Board and the Audit Committee,” Journal of Corporate Finance, 9(3), 295-316.
Yermack 1996. Higher market valuation of companies with a small board of directors. Journal of Financial Economics, 40(2), 185-211.
Zahra, S. A. and J. A. Pearce. 1989. Boards of directors and corporate financial performance: A review and integrative model. Journal of Management, 15(June):291-334.

------------------------------------------------------------------------ 第 10 筆 ---------------------------------------------------------------------
系統識別號 U0026-0308201516183400
論文名稱(中文) 非線性方法用於第二心音分析及其在臨床診療上之應用
論文名稱(英文) Nonlinear Methods for Analyzing Second Heart Sounds and Applications in Clinical Diagnosis
校院名稱 成功大學
系所名稱(中) 電機工程學系
系所名稱(英) Department of Electrical Engineering
學年度 103
學期 2
出版年 104
研究生(中文) 蕭巴馬
學號 N28007044
學位類別 博士
語文別 英文
口試日期 2015-06-17
論文頁數 94頁
口試委員 指導教授-王駿發
口試委員-羅錦興
口試委員-吳宗憲
口試委員-陳璽煌
口試委員-王家慶
召集委員-黃錦煌
關鍵字(中) 第二心音
希爾伯特振動分解
心音分析
關鍵字(英) Second Heart Sound
Hilbert Vibration Decomposition
Heart Sound Analysis
學科別分類
中文摘要 第二心音 (S2s) 是一個具有不同頻率聽覺振動的短脈衝且其包含兩個成分,稱為主動脈 (aortic, A2) 和肺動脈 (pulmonic, P2) 的閉合聲音。S2 的臨床評估已被認定為 “心臟聽診的關鍵”。A2s 和 P2s 之間的延遲在醫學術語上被稱為分裂 (split),其攜帶著重要的臨床線索。此外,其他參數如 S2s (即 A2s, P2s, 和分裂) 的持續時間和 A2s 和 P2s 的瞬時頻率能量 (EIF) 也可以提供重要的臨床線索。但是,由於 A2–P2 之間的重疊及 P2 的低能量模型導致分裂偵測的問題是難解的。就此而言,有可能將 S3 (第三心音) 誤判為一個帶有 “固定分裂” 問題的不正常的 S2。在文獻中,先前研究僅注重經驗上的分裂量測,其是基於 S2s時頻表示 (TFR) 的目視檢查,而兩個不可或缺的議題 A2–P2 重疊及 S2s 的低能量模型則被
忽略。此外,S2s、A2s和 P2s的持續時間並沒有被利用。而且,該方法無法提供任何基於S2s 分析的診斷原則。更進一步地說,S3 和不正常 S2s (特別是 “固定分裂” 問題) 之間的誤判議題並沒有被解決。前述所提之議題在此博士論文中透過發展基於非線性訊號處理的方法被處理,其中包含非線性訊號分解、瞬時頻率估計和非線性時頻局部化。據此,發展的方法可以非常有效率的應付這兩個嚴重的議題 — A2s 和 P2s 之間的重疊以及 P2s 的低能量模型。本博士論文以三個主要的部份達到這些目標。
在敘述方法之前,與發展方法有關的所有理論會被個別的闡明。在那之後,發展方法包括方法、實驗、結果和討論會在接下來的章節中被詳盡的說明。在第一個部分,基於稱為希爾伯特振動分解 (Hilbert vibration decomposition, HVD) 的非線性訊號分解,發展的方法可以定量的測量 S2s 的分裂。HVD 將 S2 拆解為一定數量的分量同時完整地保存相位資訊。接下來,透過使用平滑式魏格納 - 韋立分佈 (smoothed pseudo Wigner-Ville distribution, SPWVD) 和重新分配方法將 A2s 和 P2s 局部化。最後,A2s 和 P2s 的時間索引的均值之間的差異被用來計算分裂。實驗結果顯示分裂的均值 ± 標準差 (SD) 是 34.7±46ms。此方法能有效率的測量分裂,即使當 A2–P2 重疊 ≤ 20 ms 及 P2 對 A2 的正規化峰值時間比是低的 (≥0.22)。
在第二部分,發展方法透過識別 A2s 和 P2s 的起始和結束位置可以測量持續時間、分裂和瞬時頻率的能量。與 A2s–P2s 的持續時間和 IFs 的能量 (EIFs) 有關的診斷也會被檢驗。發展方法精確地指示以識別出正常/不正常的 S2s 同時包含 S2 分裂的類型。此方法的特點是基於 Hilbert 轉換的 IF 估計和基於 SPWVD 重新分配的局部化技術。結果顯示 A2s和 P2s 的持續時間之 mean ± SD 分別為 46.7±2.5 ms 和 41.8±2.4 ms。A2s 和 P2s 的 EIFs 之mean ± SD 分別為 13.8±2.4 和 10.5±1.7。
第三部分發展了 S3 偵測,其可以解決 S3 和帶有 “固定分裂” 的不正常 S2 之間的誤判問題。發展方法基於非線性訊號分解和時頻局部化來偵測 S3。S3 基於位置的資訊被識別並透過測量 S2-S3 之間的時間延遲來確定。結果分析顯示此方法可以正確地偵測 S3s,即使當 S3s 的正規化時間能量和頻率分別 > 0.15 和 > 35 Hz。最後,在結論中提出了限制和未來的展望。
英文摘要 The second heart sounds (S2s) are a short burst of auditory vibration of varying frequencies and it includes two components, called aortic (A2) and pulmonic (P2) closure sounds. The clinical evaluations of the S2s have been recognized as “key to auscultation to the heart.” The delay between the A2s and P2s is called split in medical term, which carries significant clinical clues. Besides, the other parameters such as duration of the S2s (i.e., A2s, P2s and split) and energy of instantaneous frequencies (EIF) of the A2s and P2s can provide significant clinical clues. However, the detection of split is obscured due to overlap between A2–P2 and low energy model of the P2. In this regard, there is a chance of misreading the S3 (third heart sounds) as an abnormal S2 with “fixed split” problem. In literature, the previous works were focused only the measurement of the split empirically based on the visual inspections of the time-frequency representation (TFR) of the S2s only and two vital issues A2–P2 overlap and low energy model of P2s were ignored. Besides, the durations of the S2s, A2s, and P2s were not taken into account. Moreover, the methods could not provide any diagnostic principle based on the analysis of the S2s. Furthermore, the misreading issue between the S3 and abnormal S2s (especially “fixed split” problem) was not addressed. The aforementioned issues were handled in this dissertation by developing methods based on nonlinear signal processing which include nonlinear signal decomposition, instantaneous frequency estimation, and nonlinear time-frequency localization. In accordance, the developed methods could tackle the two serious issues of the S2s — Overlap between A2s and the P2s and low energy model of P2s very efficiently. This dissertation achieves these goals in three main parts.

Before describing the methods all the theories concerned with the developed methods are enlightened in particulars. After that, the developed methods are explained including methods, experiments, results and discussions in subsequent chapters with full details. In the first part, the developed method can measure the split of the S2s quantitatively based on nonlinear signal decomposition called Hilbert vibration decomposition (HVD). The HVD decomposes the S2 into certain number of components while preserving the phase information intact. Further, A2s and P2s are localized by using smoothed pseudo Wigner-Ville distribution (SPWVD) followed by reassignment method. Finally, the split is calculated by taking the differences between the means of time indices of A2s and P2s. The result shows that the mean ± standard deviations (SD) of the split is 34.7±46 ms. The method measures the split efficiently, even when A2–P2 overlap is ≤ 20ms and the normalized peak temporal ratio of P2 to A2 is low (≥0.22).

In the second part, the developed method can measure the duration, splits, and energy of instantaneous frequency by identifying start and end positions of the A2s and P2s. The diagnosis related to duration and energy of IFs (EIFs) of A2s-P2s is also examined. The developed method explicitly guides to distinguish the normal/abnormal S2s including the types of S2 splits. The method is characterized by Hilbert transform-based IF estimation as well as the localization technique based on the reassignment of SPWVD. The results show that the mean ± SD of the duration of A2s and P2s are 46.7±2.5ms and 41.8±2.4ms, respectively for normal subjects. The mean ± SD of the EIFs of A2s and P2s are 13.8±2.4 and 10.5±1.7, respectively.


The third part, the detection of the S3 has been developed which could solve the misreading problem between the S3 and the abnormal S2 with ‘fixed split’ problem. The developed method detects the S3 based on nonlinear single decomposition and time-frequency localization. Based on the positional information, the S3 is distinguished and confirmed by measuring time delay between S2–S3. The result analysis shows that the method can detect the S3s correctly, even when normalized temporal energy and frequency of S3s are > 0.15, and > 35 Hz respectively. Finally the conclusions are drawn mentioning the limitation followed by future scopes.
論文目次 Abstract (in English)………………………………………………………… i
Abstract (in Chinese) ……………………………………………………… iii
Acknowledgement ……………………………………………………………… v
List of Figures ……………………………………………………………… vi
List of Tables ………………………………………………………………… ix
Chapter 1. Introduction.......................................... 1
1.1 Preliminaries on Heart Sounds................................ 1
1.2 Second Heart Sound (S2)...................................... 3
1.2.1 Auscultation of the S2..................................... 3
1.2.2 Clinical Significance of the S2............................ 4
1.2.3 Physical Characteristics of the S2 ........................ 5
1.3 Literature Review............................................ 5
1.4 Motivation................................................... 7
1.5 Objectives .................................................. 8
1.5.1 Objective 1 ............................................... 9
1.5.2 Objective 2 ............................................... 9
1.5.3 Objective 3 ............................................... 9
1.6 Outline of the Dissertation.................................. 9
Chapter 2. Background Theory..................................... 10
2.1 Introduction................................................. 10
2.2 Estimation of Instantaneous Frequency (IF)................... 10
2.2.1 Hilbert Transform.......................................... 11
2.2.2 Analytic Signal Representation............................. 12
2.2.3 Estimation of IF using Analytic Signal Representation...... 13
2.3 Hilbert Vibration Decomposition (HVD)........................ 14
2.3.1 Extraction of Envelop and Instantaneous Frequency.......... 16
2.3.2 Synchronous Detection ..................................... 17
2.3.3 Subtraction of the Synchronous largest Component........... 19
2.3.4 An Example of HVD Method .................................. 19

2.4 Smoothed Pseudo-Wigner-Ville Distribution (SPWVD)............ 20
2.5 Reassignment of Time-Frequency Distribution.................. 23
Chapter 3. Quantitative Measurement of Split..................... 27
3.1 Introduction................................................. 27
3.2 System Overview.............................................. 29
3.3 Proposed Method ............................................. 30
3.3.1 Signal Decomposition ...................................... 30
3.3.2 Localization............................................... 32
3.3.3 Calculation of Split ...................................... 33
3.4 Experiments ................................................. 34
3.4.1 Data Set................................................... 34
3.4.2 Experimental Environment................................... 36
3.5 Results and Discussions...................................... 36
3.6 Conclusions.................................................. 43
Chapter 1. Duration and IF Estimation............................ 45
4.1 Introduction................................................. 45
4.2 System Overview.............................................. 47
4.3 Proposed Method ............................................. 48
4.3.1 Instantaneous Frequency Estimation......................... 48
4.3.2 Time-frequency Localization ............................... 49
4.3.3 Calculation of the Duration, Energy of IFs, and Splits..... 52
4.4 Experiments ................................................. 55
4.4.1 Data Set................................................... 55
4.4.2 Experimental Environment .................................. 56
4.5 Results and Discussions...................................... 57
4.5.1 Normal Case................................................ 57
4.5.2 Abnormal Case.............................................. 58
4.5.3 Effectiveness Analysis for Split Detection ................ 61
4.6 Conclusions.................................................. 62
Chapter 5. Third Heart Sound Detection .......................... 63
5.1 Introduction................................................. 63

5.2 System Overview.............................................. 65
5.2.1 Decomposition ............................................. 66
5.2.2 Localization............................................... 67
5.2.3 Detection of S3s........................................... 70
5.3 Experiments ................................................. 70
5.3.1 Data Set................................................... 70
5.3.2 Experimental Environment................................... 72
5.4 Results and Discussions...................................... 73
5.4.1 Data Analysis ............................................. 73
5.4.2 Analysis for Detection Accuracy ........................... 76
5.5 Conclusions.................................................. 78
Chapter 6. Conclusions and Future Work .......................... 79
6.1 Introduction................................................. 79
6.2 Principle Contributions...................................... 80
6.2.1 Study 1 ................................................... 80
6.2.2 Study 2 ................................................... 80
6.2.3 Study 3 ................................................... 81
6.3 Limitations.................................................. 82
6.3.1 Clinical Validation ....................................... 82
6.3.2 Computational Cost......................................... 82
6.3.3 Chaos in Heart Sound....................................... 82
6.4 Future Work.................................................. 82
6.4.1 Intelligent Stethoscope ................................... 83
6.4.2 Automatic Heart Monitoring................................. 83
6.4.3 Hardware Implementation.................................... 83
Bibliography .................................................... 84
Appendix A....................................................... 91
Appendix B....................................................... 92
Publication List ................................................ 93
Awards........................................................... 94
Curriculum Vitae ................................................ 94
參考文獻 [1] H. Walker, D. Hall, and W. Hurst, (3rd Ed) Clinical Methods: The History, Physical, and Laboratory Examinations, H. Walker, D. Hall, and W. Hurst, eds., 3rd Ed., Boston: Butterworth, pp. 122–125, 1990.
[2] M. E. Silverman, Chapter 24: The Third Heart Sound" Clinical Methods: The History, Physical, and Laboratory Examinations, H. Walker, D. Hall, and W. Hurst, eds., 3rd Ed., Boston: Butterworth, pp. 126–128, 1990.
[3] E. S. Williams, Chapter 25: The Fourth Heart Sound" Clinical Methods: The History, Physical, and Laboratory Examinations, H. Walker, D. Hall, and W. Hurst, eds., 3rd Ed., Boston: Butterworth, pp. 129–130, 1990.
[4] G. M. Marcus, I. L. Gerber, B. H. McKeown, J. C. Vessey, M. V. Jordan, M. Huddleston, C. E. McCulloch, E. Foster, K. Chatterjee, A. D. Michaels, “Association between phonocardiographic third and fourth heart sounds and objective measures of left ventricular function,” The Journal of the American Medical Association, vol. 293, no. 18, pp. 2238–2244, May 2005.
[5] N. J. Mehta and I. A. Khan, “Third heart sound: genesis and clinical importance,” International Journal of Cardiology, vol. 97, no. 2, pp. 183–186, Nov. 2004.
[6] L. Durand, and P. Pibarot, “Digital signal processing of the phonocardiogram: review of the most recent advancements,” Critical Review in Biomedical Engineering., vol. 23, no. 3–4, pp. 163-219, Dec. 1995.
[7] J. Felner, Chapter 23: The Second Heart Sound" Clinical Methods: The History, Physical, and Laboratory Examinations, H. Walker, D. Hall, and W. Hurst, eds., 3rd Ed., Boston: Butterworth, pp. 122–125, 1990.
[8] A. Shaver, R. Salerni, and P. S. Reddy, “Normal and abnormal heart sounds in cardiac diagnosis part I: systolic sounds,” Current Problems in Cardiology, vol. 10, no. 3, pp. 1–68, Mar. 1985.
[9] J. Xu, L. Durand, and P. Pibarot, “Nonlinear transient chirp signal modeling of the aortic and pulmonary components of the second heart sound,” IEEE Transactions on Biomedical Engineering, vol. 47, no. 10, pp. 1328–1335, Oct. 2000.
[10] S. Debbal, and F. Reguig, “Analysis and study of the variation of splitting in the second heartbeat sound of wavelet transform,” Journal of Medical Engineering and Technology, vol. 30, no. 5, pp. 298–305, Oct. 2006.
[11] T. Leung, P. White, J. Cook, W. Collis, E. Brown, and A. Salmon., “Analysis of the Second Heart Sound for Diagnosis of Paediatric Heart Disease,” in IEE Proceedings in Science, Measurement and Technology, vol. 145, no. 6, pp. 285–290, Nov. 1998.
[12] A. Djebbari, and F. Reguig, “Detection of the Valvular Split Within the Second Heart Sound Using the Reassigned Smoothed Pseudo Wigner-Ville Distribution,” Biomedical Engineering Online, vol. 12, no. 1, pp. 37, Apr. 2013.
[13] S. Debbal and F. Reguig, “Analysis of the Second Heart Sound Using Continuous Wavelet Transform,” Journal of Medical Engineering and Technology, vol. 28, no. 4, pp. 151–156, Aug. 2004.
[14] Rangayyan, Rangraj M., and Richard J. Lehner. “Phonocardiogram signal analysis: a review” Critical Reviews in Biomedical Engineering, vol. 15, no. 3, pp. 211–236, Sep. 1986.
[15] M. Chizner, “Cardiac Auscultation: Rediscovering the Lost Art,” Current Problems in Cardiology, vol. 33, no. 7, pp. 326–408, Jul. 2008.
[16] L. M. Douglas., D. P. Zipes, P. Libby, and R. O. Bonow, Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, Elsevier Health Sciences, 2014.
[17] T. Reed, N. Reed, and P. Fritzson, “Heart sound analysis for symptom detection and computer-aided diagnosis,” Simulation, Modeling, Practice, and Theory, vol. 12, no. 2, pp. 129–146, May 2004.
[18] J. J. Lee, S. M. Lee, I. Y. Kim, H. K. Min, and S. H. Hong “Comparison Between Short Time Fourier and Wavelet Transform for Feature Extraction of Heart Sound,” IEEE International Conferences Proceedings IEEE Region 10 (TENCON 99), Cheju Island South Korea, Dec. 1999, vol. 2, pp. 1547-1550.
[19] B. Ergen, and Y. Tatar, “Optimal Continuous Wavelet Analysis of Periodogram Signals,” IJCI Proceedings International Conference on Signal Processing, vol. 1, pp. 188-192, Sep. 2003.
[20] P. Vikhe, S. Hamde, and N. Nehe, “Wavelet Transform Based Abnormality Analysis of Heart Sound,” in International Conference in Advance Computing, Control, Telecommunication, &Technology (ACT'09), Trivandrum, India, Dec. 2009, pp. 367-371.
[21] J. Xu, L. Durand, and P. Pibarot, “Extraction of the aortic and pulmonary components of the second heart sound using a nonlinear transient chirp signal model,” IEEE Transactions on Biomedical Engineering, vol. 48, no. 3, pp. 277–283, Mar. 2001.
[22] A. Djebbari, and F. Reguig, “Smoothed Pseudo Wigner-Ville Distribution of Normal and Aortic Stenosis Heart Sounds,” Journal of Mechanics in Medicine and Biology, vol. 5, no. 3, pp. 415-428, Sep. 2005.
[23] I. Yildirim, and R. Ansari, “A Robust Method to Estimate Time Split in Second Heart Sound Using Instantaneous Frequency Analysis,” in Annual International Conference in Engineering in Medicine and Biology Society, Lyon, France, Aug. 2007, pp. 1855-1858.
[24] F. Auger, and P. Flandrin, “Improving the Readability of Time-Frequency and Time-Scale Representations by the Reassignment Method,” IEEE Transactions on Signal Process., vol. 43, no. 5, pp. 1068-1089, Aug. 1995.
[25] F. Auger, and P. Flandrin, “Generalization of the Reassignment Method to All Bilinear Time-Frequency and Time-Scale Representations,” in IEEE International Conference in Acoustics, Speech and Signal Process. (ICASSP'94), Adelaide, Australia,, Apr. 1994, vol. 4, pp. 317-320.
[26] B. Popov, G. Sierra, L. Durand, J. Xu, P. Pibarot, R. Agarwal, and V. Lanzo, “Automated extraction of aortic and pulmonary components of the second heart sound for the estimation of pulmonary artery pressure,” in IEEE International Conference of Engineering in Medicine and Biology Society (EMBS 2004), San Francisco, USA, Sep. 2004, vol. 1, pp. 921–924.
[27] C. Ahlstrom, O. Liljefeldt, P. Hult, and P. Ask, “Heart sound cancellation from lung sound recordings using recurrence time statistics and nonlinear prediction,” IEEE Signal Processing Letter, vol. 12, no. 12, pp. 812–815, Dec. 2005.
[28] H. Tang, J. Gao, and Y. Park, “Heart valve closure timing intervals in response to left ventricular blood pressure,” Journal of Biomedical Science and Engineering, vol. 6, no. 1, pp. 65–75, Jan. 2013.
[29] M. Segaier, O. Lilja, S. Lukkarinen, L. Sornmo, R. Sepponen, and E. Pesonen, “Computer-based detection and analysis of heart sound and murmur,” Annals of Biomedical Engineering, vol. 33, no. 7, pp. 937–942, Jul. 2005.
[30] G. Andria, M. Savino, and A. Trotta, “Application of Wigner-Ville distribution to measurements on transient signals,” IEEE Transaction on Instrumentation and Measurement, vol. 43, no. 2, pp. 187–193, Apr. 1994.
[31] L. Stankovic, “Time-frequency distributions with complex argument,” IEEE Transaction on Signal Processing, vol. 50, no. 3, pp. 475–486, Mar. 2002.
[32] R. M. Rangayyan, Biomedical signal analysis: IEEE Standards Office, 2001.
[33] D. Vakman and L. Vaĭnshteĭn, Amplitude, phase, frequency—Fundamental Concepts of Oscillation Theory, Soviet Physics Uspekhi, vol. 20, pp. 1002, 1977.
[34] D. Vakman, “New high precision frequency measurement,” Measurement Science and Technology, vol. 11, no. 10, pp. 1493–1497, 2000.
[35] L. Sun, M. Shen, and F. H. Chan, “A method for estimating the instantaneous frequency of non-stationary heart sound signals,” in International Conference on Neural Network and Signal Processing, Nanjing, China, Dec. 2003, vol. 1, pp. 798–801.
[36] S. L. Hahn, Hilbert transforms in signal processing, Artech House, 1996.
[37] F. W. King Hilbert Transforms, volume 125 of Encyclopedia Of Mathematics And Its Applications, ed: Cambridge University Press, 2009.
[38] M. Feldman, Hilbert Transform Application in Mechanical Vibration. 1st Ed., UK: John Wiley & Sons Ltd., 2011.
[39] M. Feldman, “Hilbert Transform in Vibration Analysis,” Mechanical Systems and Signal Processing, vol. 25, no. 3, pp. 735-802, 2011.
[40] R. N. Bracewell and R. Bracewell, The Fourier Transform and Its Applications, vol. 31999: McGraw-Hill New York, 1986.
[41] P. J. Schreier and L. L. Scharf, Statistical signal processing of complex-valued data: the theory of improper and noncircular signals: Cambridge University Press, 2010.
[42] D. Vakman, Signals Oscillations and Waves: A Modern Approach. Boston, USA: Artech House, 1998.
[43] R. G. Lyons, Understanding Digital Signal Processing. Pearson Education, 2010.
[44] R. Lyons, “Quadrature Signals: Complex, But Not Complicated” URL: http://www. dspguru. com/info/tutor/quadsig. htm, 2000.
[45] M. Feldman, “Non-linear System Vibration Analysis Using Hilbert Transform-I. Free Vibration Analysis Method ‘FREEVIB’,” Mechanical Systems and Signal Processing, vol. 8, no. 2, pp. 119-127, 1994.
[46] N. E. Huang, Z. Shen, S. R. Long, M. C. Wu, H. H. Shih, Q. Zheng, N. C. Yen, C. C. Tung, and H. H. Liu.,“The Empirical Mode Decomposition and the Hilbert Spectrum for Nonlinear and Nonstationary Time Series Analysis,” in Proceedings of the Royal Society of London, Series A: Mathematical, Physical and Engineering Sciences, vol. 454, no. 1971, pp. 903-995, Mar. 1998.
[47] B. Boashash, “Estimating and Interpreting the Instantaneous Frequency of a Signal. I. Fundamentals,” IEEE Proceedings, vol. 80, no. 4, pp. 520-538, Apr. 1992.
[48] M. Feldman, “Theoretical analysis and comparison of the Hilbert transform decomposition methods,” Mechanical Systems and Signal Processing, vol. 22, no. 3, pp. 509–519, Oct. 2008.
[49] W. M. Hartmann, Signals, Sound, and Sensation: Springer, 1997.
[50] G. R. Blackwell, The electronic packaging handbook: CRC Press, 2002
[51] B. Ergena, Y. Tatara, and H. O. Gulcur, “Time-frequency analysis of phonocardiogram signals using wavelet transform: A comparative study,” Computer Methods in Biomechanics and Biomedical Engineering, vol. 15, no. 4, pp. 371–381, Jun. 2011.
[52] S Qian and D. Chen, “Joint time-frequency analysis,” IEEE Signal Processing Magazine, vol. 16, no. 2, pp. 52-67, 1999.
[53] B. Boashash, Time Frequency Analysis, 1st Ed., UK: Elsevier Ltd., 2003.
[54] L. Stankovic, M. Dakovic, and T. Thayaparan, Time-Frequency Signal Analysis with Applications. Boston, USA: Artech House, 2013.
[55] F. Hlawatsch and F. Auger, Time-Frequency Analysis: Concepts and Methods. vol. 36, Hoboken, NJ: John Wiley & Sons, 2010.
[56] P. Flandrin, F. Auger, and E. Mottin, “Time-frequency reassignment: from principles to algorithms,” in Applications in Time-Frequency Signal Processing, vol. 5, A. Suppappola, Ed. Boca Raton: CRC Press LLC, 2003, pp. 179–203.
[57] Q. Zhu, Y. Wang, and G. Shen, “Research and Comparison of Time-frequency Techniques for Nonstationary Signals,” Journal of Computers, vol. 7, no. 4, pp. 954-958, Apr. 2012.
[58] B. Reyes S. Charleston-Villalobos, R. Gonzalez-Camarena, and T. Aljama-Corrales, “Time Frequency Representations for Second Heart Sound Analysis,” IEEE International Conference of Engineering in Medicine and Biology Society, Vancouver, Canada, Aug. 2008, pp. 3616-3619.
[59] Z. Zhidong, Z. Zhijin, and C. Yuquan, “Time-Frequency Analysis of Heart Sound Based on HHT [Hilbert-Huang Transform],” International Conference on Communications, Circuits and Systems, vol. 2, May 2005.
[60] L. Liu, L. Liu, H. Wang; Y. Wang, T. Tao; and X. Wu., “Feature Analysis of Heart Sound Based on the Improved Hilbert-Huang Transform,” IEEE International Conference of Computer Science and Information Technology, Chengdu, China Jul. 2010, vol. 6, pp. 378-381.
[61] Y. L. Tseng, P. Y. Ko, and F. S. Jaw, “Detection of the third and fourth heart sounds using Hilbert-Huang transform,” Biomedical Engineering Online, vol. 11, no. 1, pp. 1–13, Aug. 2012.
[62] J. Chen H. L. Hou, L. C. Luo, and Y. Cheng, “Automatic Identification Method for the First and Second Heart Sound Based on Double-Threshold,” Jisuanji Gongcheng Computer Engineering., vol. 38, no. 16, pp. 174-177, Aug. 2012.
[63] P. Flandrin, G. Rilling, and P. Goncalves, “Empirical Mode Decomposition as a Filter Bank,” IEEE Signal Processing. Letter, vol. 11, no. 2, pp. 112-114, Jan. 2004.
[64] M. Feldman, “Time-Varying Vibration Decomposition and Analysis Based on the Hilbert Transform,” Journal of Sound Vibration, vol. 295, no. 3, pp. 518-530, Aug. 2006.
[65] F. Auger, P. Flandrin, P. Goncalves, and O. Lemoine. (1999, Jan.). Time-frequency toolbox for Matlab. [Online]. Available: http://tftb.nongnu.org/.
[66] S. M. Debbal and F. Bereksi-Reguig, “Time-frequency analysis of the first and the second heartbeat sounds,” Applied Mathematics and Computation, vol. 184, no. 2, pp. 1041–1052, Jan. 2007
[67] L. Angrisani and M. D'Arco, “A measurement method based on a modified version of the chirplet transform for instantaneous frequency estimation,” IEEE Transactions on Instrumentation and Measurement, vol. 51, no. 4, pp. 704–711, Aug. 2002.
[68] Z. Peng, G. Meng, F. Chu, Z. Lang, W. Zhang, and Y. Yang, “Polynomial chirplet transform with application to instantaneous frequency estimation,” IEEE Transactions on Instrumentation and Measurement, vol. 60, no. 9, pp. 3222–3229, Sep. 2011.
[69] L. Angrisani, M. D'Arco, R. Moriello, and M. Vadursi, “On the use of the warblet transform for instantaneous frequency estimation,” IEEE Transactions on Instrumentation and Measurement, vol. 54, no. 4, pp. 1374–1380, Aug. 2005.
[70] A. Carlosena, C. Macua, and M. Zivanovic, “Instrument for the measurement of the instantaneous frequency,” IEEE Transactions on Instrumentation and Measurement, vol. 49, no. 4, pp. 783–789, Aug. 2000.
[71] N. Tse, J. Y. Chan, W. Lau, and L. Lai, “Hybrid wavelet and hilbert transform with frequency-shifting decomposition for power quality analysis,” IEEE Transactions on Instrumentation and Measurement, vol. 61, no. 12, pp. 3225–3233, Dec. 2012.
[72] E. Hermanowicz, M. Rojewskia, G. Cainb, and A. Tarczynskic, “On an instantaneous frequency estimator with FIR filters having maximally flat frequency response error magnitude,” Signal Processing, vol. 81, no. 7, pp. 1491–1501, Jul. 2001.
[73] D. Vakman, “Computer measuring of frequency stability and the analytic signal,” IEEE Transactions on Instrumentation and Measurement, vol. 43, no. 4, pp. 668–671, Aug. 1994.
[74] S. Engelberg and E. Chalom, “Measuring the spectral content of a signal: an introduction [instrumentation notes],” IEEE Instrumentation and Measurement Magazine, vol. 13, no. 6, pp. 34–38, Dec. 2010.
[75] P. Hao, W. Zanji, and C. Jianye, “A measuring method of the single-phase AC frequency, phase, and reactive power based on the Hilbert filtering,” IEEE Transactions on Instrumentation and Measurement, vol. 56, no. 3, pp. 918–923, Jul. 2007.
[76] M. Caciotta, S. Giarnetti, F. Leccese, and Z. Leonowicz, “Detection of short transients and interruptions using the Hilbert transform,” in XIX IMEKO World Congress of Fundamental Application and Metrology, Lisbon, Portugal, Sep. 2009, pp. 913–916.
[77] C. Minge, “Design of Equiripple Linear-Phase FIR Filters Using MATLAB,” in International Conference of Control Automation and System Engineering (CASE), Singapore, Jul. 2011, pp. 1–4.
[78] V. Nigam and R. Priemer, “A dynamic method to estimate the time split between the A2 and P2 components of the S2 heart sound,” Physiological Measurement, vol. 27, no. 7, pp. 553–567, Jul. 2006.
[79] F. Auger, P. Flandrin, Y. Lin, S. McLaughlin, S. Meignen, T. Oberlin, and H. Wu, “Time-frequency reassignment and synchrosqueezing: an overview,” IEEE Signal Processing Magazine, vol. 30, no. 6, pp. 32–41, Nov. 2013.
[80] K. Fitz and S. Fulop. (2009, Mar. 18). “A unified theory of time-frequency reassignment,” [Online]. Available: http://arxiv.org/pdf/0903.3080v1.pdf.
[81] A. Dennis, A. Michaels, P. Arand, and D. Ventura, “Noninvasive diagnosis of pulmonary hypertension using heart sound analysis,” Computers in Biology and Medicine, vol. 40, no. 9, pp. 758–764, Sep. 2010.
[82] Heart Sounds Podcast Series, Texas Heart® Institute. (2011, Dec. 6). [Online]. Available: http://www.texasheart.org/Education/CME/explore/events/eventdetail_6456.cfm.
[83] P. Hult, T. Fjällbrant, K. Hildén, U. Dahlström, B. Wranne, and P. Ask, “Detection of the third heart sound using a tailored wavelet approach: method verification,” Medical and Biological Engineering and Computing, vol. 43, no. 2, pp. 212–217, Apr. 2005.
[84] M. Johnston, S. P. Collins, and A. B. Storrow, “The third heart sound for diagnosis of acute heart failure,” Current Heart Failure Reports, vol. 4, no. 3, pp. 164–169, Mar. 2008.
[85] C. E. Lok, C. D. Morgan, and N. Ranganathan, “The accuracy and interobserver agreement in detecting the gallop sounds’ by cardiac auscultation,” CHEST Journal, vol. 114, no. 5, pp. 1283–1288, Nov. 1998.
[86] R. Patel, D. Bushnell, and P. Sobotka, “Implications of an audible third heart sound in evaluating cardiac function,” Western Journal of Medicine, vol. 158, no. 6, pp. 606–609, Jun. 1993.
[87] C. Ahlstrom, P. Hult, and P. Ask, “Detection of the 3rd heart sound using recurrence time statistics,” in IEEE International Conference in Acoustic, Speech and Signal Processing (ICASSP), Toulouse, France, May 2006, vol. 2, pp. 1040–1043.
[88] J. Wynne, “The clinical meaning of the third heart sound,” American Journal of Medicine, vol. 111, no. 2, pp. 157–158, Aug. 2001.
[89] C. M. Tribouilloy, M. E. Sarano, D. Mohty, R. A. Horn, K. R. Bailey, J. B. Seward, A. M. Weissler, and A. J. Tajik, “Pathophysiologic determinants of third heart sounds: a prospective clinical and doppler echocardiographic study,” American Journal of Medicine, vol. 111, no. 2, pp. 96–102, Aug. 2001.
[90] G. Marcus, J. Vessey, M. V. Jordan, M. Huddleston, B. McKeown, I. L. Gerber, E.Foster, K. Chatterjee, C. E. McCulloch, and A. D. Michaels, “Relationship between accurate auscultation of a clinically useful third heart sound and level of experience,” Archives of Internal Medicine, vol. 166, no. 6, pp. 617–622, Mar. 2006.
[91] G. Livanos, N. Ranganathan, and J. Jiang, “Heart sound analysis using the S transform,” in Conference of Computers in Cardiology, Cambridge, UK, Sep. 2000, pp. 587–590.
[92] E. Sejdic and J. Jin, “Comparative study of three time-frequency representations with applications to a novel correlation method,” in IEEE International Conferences in Acoustic Speech and Signal Process. (ICASSP), Montreal, Canada, May 2004, vol. 2, pp. 633–636.
[93] P. Hult, T. Fjällbrant, B. Wranne, and P. Ask, “Detection of the third heart sound using a tailored wavelet approach,” Medical and Biological Engineering and Computing, vol. 42, no. 2, pp. 253–258, Mar. 2004.
[94] D. Kumar, P. Carvalho, M. Antunes, J. Henriques, A. S. Melo, R. Schmidt, and J. Habetha, “Third heart sound detection using wavelet transform-simplicity filter,” in IEEE International Conference of Engineering in Medicine and Biology Society(EMBS), Lyon, France, Aug. 2007, pp. 1277–1281.
[95] N. E. Huang and Z. Wu, “A review on Hilbert-Huang transform: Method and its applications to geophysical studies,” Reviews of Geophysics, vol. 46, no. 2, pp. 1–23, Jun. 2008.
[96] S. Barma, B. W. Chen, K. L. Man, and J. F. Wang, “Quantitative Measurement of Split of the Second Heart Sound (S2),” IEEE/ACM Transactions on Computational Biology and Bioinformatics, vol. PP, pp. 1-1, (Early Access)

------------------------------------------------------------------------ 第 11 筆 ---------------------------------------------------------------------
系統識別號 U0026-0309201502061500
論文名稱(中文) 製備具力學非等向性之聚丙三醇癸二酸酯薄膜應用於血管組織工程
論文名稱(英文) Fabrication of a mechanically anisotropic poly(glycerol sebacate) membrane for vascular tissue engineering
校院名稱 成功大學
系所名稱(中) 生物醫學工程學系
系所名稱(英) Department of BioMedical Engineering
學年度 103
學期 2
出版年 104
研究生(中文) 許祺農
學號 p86021168
學位類別 碩士
語文別 中文
口試日期 2015-07-22
論文頁數 32頁
口試委員 指導教授-胡晉嘉
口試委員-林睿哲
口試委員-張志涵
口試委員-陳文正
關鍵字(中) 聚乙烯醇
圓柱形孔洞
電紡絲
聚(甘油癸二酸)
彈性體
機械性質
凹槽
管狀支架
關鍵字(英) poly(glycerol sebacate)
poly(vinyl alcohol)
anisotropic membrane
channel
mechanical properties
學科別分類
中文摘要 聚丙三醇癸二酸酯(PGS)在軟組織工程上是一種很有前途的彈性體。因為PGS成纖維型態過程複雜、較困難耗時,但還是有人使PGS成纖維型態,正因為製程困難,所以在這研究中推出一個做法,是用一種比較容易電紡的材料,選用PVA做電紡材料來當作犧牲支架,再加入PGS溶液,讓PGS溶液包覆在PVA纖維的外面,犧牲掉PVA後,做成具有圓柱形孔洞(channel)微結構的PGS薄膜且具有纖維大小的孔洞。因為PGS是熱固性彈性體,在真空烘箱中固化溫度和時間為120℃/130℃、24/48小時,以增加最終材料的交聯程度。PGS包覆在PVA纖維的外側,加水以洗去PVA纖維,使薄膜微結構變為圓柱形孔洞(channel)結構,它類似於電紡纖維排列。PGS薄膜的機械性質隨著圓柱形孔洞(channel)微結構在特定方向的排列而可以被調整。該薄膜必須能夠製成特定方向排列的結構,其機械性質可以透過固化條件和特定方向微結構來進行調整。為了評估薄膜的機械性質,我們在製造各種固化條件下的PGS薄膜並具有凹槽(groove)微結構。微結構和測試條件,其中包括固化條件是有影響其機械性質。PGS薄膜隨著固化時間增長和固化溫度增加,導致楊氏係數增加和斷裂應變下降。藉由調控PVA纖維方向性,讓PGS薄膜也具有方向性,依據管狀支架製備方法,我們藉著包捆具有方向性的PGS薄膜,做出有夾角(30度、60度)的管狀支架,拿去做管狀機械測試,其軸與纖維夾角越大,則環向彈性模數越大。支架為組織工程中一大要素,提供適合細胞生長之微結構,其中用電紡絲製作出來的支架,其纖維排列方向也會影響細胞生長的型態。所以預期PGS薄膜表面的凹槽(groove)微結構方向排列也要能導引細胞的分布,使細胞做生長排列,以滿足組織工程的要求。在本研究中,我們的目標是做一個PGS薄膜,其薄膜具有圓柱形孔洞(channel)的微結構,類似於纖維排列的薄膜,隨著圓柱形孔洞(channel)的特定方向排列,其可調整 PGS薄膜的機械性質,使其PGS薄膜具有非等向性的特性。
英文摘要 Poly(glycerol sebacate) (PGS) is an attractive biodegradable elastomer for engineering soft tissues. PGS, however, is mechanically isotropic, which limits its applications as many soft tissues have anisotropic behaviors in the body. Electrospinning has been used to make mechanically anisotropic membranes. Because electrospinning thermosetting polymer such as PGS is challenging, anisotropic membranes made of PGS electrospun fibers are not easy to achieve. In this study, we aimed at fabricate a mechanically anisotropic PGS membrane with the use of sacrificial fibers. First, electrospun poly(vinyl alcohol) (PVA) membranes were prepared. The PVA fibrous membrane was then embeded in PGS prepolymer. The resulting composite membrane was then cured in a vaccum oven at 120oC or 130oC for 1 or 2 days. Finally, PVA fibers were removed by water, leaving numerous fiber-like voids in the PGS matrix. We found that the mechanical properties of the membrane depended on curing temperature and reaction time. Increasing curing temperature and reaction time led to a increased Young's modulus and a decreased elongation at break of the PGS membrane. In particular, by employing electrospun PVA membranes containing aligned fibers, mechanically anisotropic PGS membrane was achieved. Tubular structure was formed by wrapping the PGS membranes with axisymmetric fiber-like voids. The compliance of the tubular construct was found to be dependent on the pitch angle of the helical structure.
論文目次 中文摘要 II
Extended Abstract III
誌謝 IX
圖目錄 XI
第一章 緒論 1
1-1 前言 1
1-2 單軸電紡聚(乙烯醇)(PVA)纖維薄膜 1
1-3 聚丙三醇癸二酸酯(PGS)的應用 1
1-4 研究動機與目的(PGS電紡纖維的困難) 2
1-5 物性分析-SEM、AFM、ATR-FTIR、孔隙率、單軸拉伸測試、管狀支架機械測試 3
第二章 材料與方法 4
2-1 材料 4
2-2 方法 4
2-2-1 單軸電紡絲操作(隨機排列、高度排列纖維薄膜) 4
2-2-2 合成PGS prepolymer 5
2-2-3 製備、分析薄膜 5
2-2-4 SEM 5
2-2-5 AFM 6
2-2-6 ATR-FTIR 6
2-2-7 測量孔隙率 6
2-2-8 單軸拉伸測試 7
2-2-9 管狀壓 7
第三章 實驗結果 9
3-1 薄膜物性分析(厚度、黏度、孔隙率、SEM、AFM、ATR-FTIR) 9
3-2 機械性質分析 15
3-2-1單軸拉伸測試(量測薄膜機械強度) 15
3-2-2客製管狀力學量測系統 19
第四章 討論 24
4-1 薄膜物性分析(厚度、黏度、孔隙率、SEM、AFM、ATR-FTIR) 24
4-2 單軸拉伸力學分析 24
4-3 管狀支架力學分析 25
4-4 實驗限制與未來展望 25
第五章 結論 27
參考文獻 28
參考文獻 [1] F. Y., et al. (2012). "Gradient nanofibrous chitosan/poly epsilon-caprolactone scaffolds as extracellular microenvironments for vascular tissue engineering." Biomaterials 33(3): 762-770.

[2] Hu, J. J., et al. (2012). "Construction and characterization of an electrospun tubular scaffold for small-diameter tissue-engineered vascular grafts: A scaffold membrane approach." Journal of the Mechanical Behavior of Biomedical Materials 13: 140-155.

[3]Isayama, N., et al. (2014). "Histological maturation of vascular smooth muscle cells in in situ tissue-engineered vasculature." Biomaterials 35(11): 3589-3595.

[4]Bourget, J. M., et al. (2012). "Human fibroblast-derived ECM as a scaffold for vascular tissue engineering." Biomaterials 33(36): 9205-9213.

[5] Koski, A., et al. (2004). "Effect of molecular weight on fibrous PVA produced by electrospinning." Materials Letters 58(3-4): 493-497.

[6]Zeytuncu, B., et al. (2014). "Preparation and Characterization of UV-Cured Hybrid Polyvinyl Alcohol Nanofiber Membranes by
Electrospinning." Materials Research-Ibero-American Journal of Materials 17(3): 565-569.

[7]Gao, Q., et al. (2013). "Hydrophilic non-wovens made of cross-linked fully-hydrolyzed poly(vinyl alcohol) electrospun nanofibers." Polymer 54(1): 120-126.

[8]Mitsak, A. G., et al. (2012). "Mechanical characterization and non-linear elastic modeling of poly(glycerol sebacate) for soft tissue engineering." Journal of the Mechanical Behavior of Biomedical Materials 11: 3-15.

[9] Wang, Y. D., et al. (2002). "A tough biodegradable elastomer." Nature Biotechnology 20(6): 602-606.

[10]Gao, J., et al. (2006). "Macroporous elastomeric scaffolds with extensive micropores for soft tissue engineering." Tissue Engineering 12(4): 917-925.

[11]Wang, Y. D., et al. (2003). "In vivo degradation characteristics of poly(glycerol sebacate)." Journal of Biomedical Materials Research Part A 66A(1): 192-197.

[12]Sundback, C. A., et al. (2005). "Biocompatibility analysis of poly(glycerol sebacate) as a nerve guide material." Biomaterials 26(27): 5454-5464.

[13]Motlagh, D., et al. (2006). "Hernocompatibility evaluation of poly(glycerol-sebacate) in vitro for vascular tissue engineering." Biomaterials 27(24): 4315-4324.

[14]Bettinger, C. J., et al. (2006). "Micro fabrication of poly (glycerol-sebacate) for contact guidance applications." Biomaterials 27(12): 2558-2565.

[15]Bettinger, C. J., et al. (2006). "Three-dimensional microfluidic tissue-engineering scaffolds using a flexible biodegradable polymer." Advanced Materials 18(2): 165-+.

[16]Vunjak-Novakovic, G., et al. (2006). "Cardiac tissue engineering: effects of bioreactor flow environment on tissue constructs." Journal of Chemical Technology and Biotechnology 81(4): 485-490.

[17]Xu, B., et al. (2015). "Fabrication, mechanical properties and cytocompatibility of elastomeric nanofibrous mats of poly(glycerol sebacate)." European Polymer Journal 64: 79-92.

[18]Xu, B., et al. (2013). "Non-linear elasticity of core/shell spun PGS/PLLA fibres and their effect on cell proliferation." Biomaterials 34(27): 6306-6317.

[19]Jeffries, E. M., et al. (2015). "Highly elastic and suturable electrospun poly(glycerol sebacate) fibrous scaffolds." Acta Biomaterialia 18: 30-39.

[20]Sant, S., et al. (2013). "Effect of biodegradation and de novo matrix synthesis on the mechanical properties of valvular interstitial cell-seeded polyglycerol sebacate-polycaprolactone scaffolds." Acta Biomaterialia 9(4): 5963-5973.

[21]Kharaziha, M., et al. (2013). "PGS:Gelatin nanofibrous scaffolds with tunable mechanical and structural properties for engineering cardiac tissues." Biomaterials 34(27): 6355-6366.

[22] Choolani, M., et al. (2007). "FastFISH: technique for ultrarapid fluorescence in situ hybridization on uncultured amniocytes yielding results within 2 h of amniocentesis." Molecular Human Reproduction 13(5-6): 355-359.

[23] Wang, Y. D., et al. (2002). "A tough biodegradable elastomer." Nature Biotechnology 20(6): 602-606.

[24]LeBlon, C. E., et al. (2013). "In vitro comparative biodegradation analysis of salt-leached porous polymer scaffolds." Journal of Applied Polymer Science 128(5): 2701-2712.

[25]Frydrych, M. and B. Q. Chen (2013). "Large three-dimensional poly(glycerol sebacate)-based scaffolds - a freeze-drying preparation approach." Journal of Materials Chemistry B 1(48): 6650-6661.

[26]Zeytuncu, B., et al. (2014). "Preparation and Characterization of UV-Cured Hybrid Polyvinyl Alcohol Nanofiber Membranes by Electrospinning." Materials Research-Ibero-American Journal of Materials 17(3): 565-569.

[27]Zeytuncu, B., et al. (2014). "Preparation and Characterization of UV-Cured Hybrid Polyvinyl Alcohol Nanofiber Membranes by Electrospinning." Materials Research-Ibero-American Journal of Materials 17(3): 565-569.

[28]Chen, Q. Z., et al. (2011). "Manipulation of mechanical compliance of elastomeric PGS by incorporation of halloysite nanotubes for soft tissue engineering applications." Journal of the Mechanical Behavior of Biomedical Materials 4(8): 1805-1818.

[29]Kemppainen, J. M. and S. J. Hollister (2010). "Tailoring the mechanical properties of 3D-designed poly(glycerol sebacate) scaffolds for cartilage applications." Journal of Biomedical Materials Research Part A 94A(1): 9-18.

[30] Chen, Q. Z., et al. (2008). "Characterisation of a soft elastomer poly(glycerol sebacate) designed to match the mechanical properties of myocardial tissue." Biomaterials 29(1): 47-57.

[31]Liu, Q. Y., et al. (2007). "Structure and properties of thermoplastic poly(glycerol sebacate) elastomers originating from prepolymers with different molecular weights." Journal of Applied Polymer Science 104(2): 1131-1137.

[32] Jaafar, I. H., et al. (2010). "Spectroscopic evaluation, thermal, and thermomechanical characterization of poly(glycerol-sebacate) with variations in curing temperatures and durations." Journal of Materials Science 45(9): 2525-2529.

[33]Sundback, C. A., et al. (2005). "Biocompatibility analysis of poly(glycerol sebacate) as a nerve guide material." Biomaterials 26(27): 5454-5464.

[34]Yamaguchi, S. (1992). "Analysis of Stress-Strain Curves at Fast and Slow Velocities of Loading Invitro in the Transverse Section of the Rat Incisor Periodontal-Ligament Following the Administration of Beta-Aminopropionitrile." Archives of Oral Biology 37(6): 439-444.

[35]Komatsu, K. and M. Chiba (1993). "The Effect of Velocity of Loading on the Biomechanical Responses of the Periodontal-Ligament in Transverse Sections of the Rat Molar Invitro." Archives of Oral Biology 38(5): 369-375.

[36]Lee, M. C. and R. C. Haut (1992). "Strain Rate Effects on Tensile Failure Properties of the Common Carotid-Artery and Jugular Veins of Ferrets." Journal of Biomechanics 25(8): 925-927.

[37]Zong, X. H., et al. (2002). "Structure and process relationship of electrospun bioabsorbable nanofiber membranes." Polymer 43(16): 4403-4412.

[38]Crapo, P. M., et al. (2008). "Seamless tubular poly(glycerol sebacate) scaffolds: High-yield fabrication and potential applications." Journal of Biomedical Materials Research Part A 86A(2): 354-363.

[39]Gao, J., et al. (2007). "Poly(glycerol sebacate) supports the proliferation and phenotypic protein expression of primary baboon vascular cells." Journal of Biomedical Materials Research Part A 83A(4): 1070-1075.

[40]Lee, K. W., et al. (2011). "Substantial expression of mature elastin in arterial constructs." Proceedings of the National Academy of Sciences of the United States of America 108(7): 2705-2710.

[41]Crapo, P. M. and Y. D. Wang (2010). "Physiologic compliance in engineered small-diameter arterial constructs based on an elastomeric substrate." Biomaterials 31(7): 1626-1635.

[42] Sant, S., et al. (2011). "Hybrid PGS-PCL microfibrous scaffolds with improved mechanical and biological properties." Journal of Tissue Engineering and Regenerative Medicine 5(4): 283-291.

[43] Sarkar, S., et al. (2005). "Vascular tissue engineering: microtextured scaffold templates to control organization of vascular smooth muscle cells and extracellular matrix." Acta Biomaterialia 1(1): 93-100.



------------------------------------------------------------------------ 第 12 筆 ---------------------------------------------------------------------
系統識別號 U0026-0408201501335800
論文名稱(中文) 運用實證為基礎之整合性藥物效益風險決策分析-以Statins類降血脂藥物為例
論文名稱(英文) Balancing Benefit and Risk to Select an Optimal Drug among a Series of Alternatives for Patients:An Evidence-Based Assessment of Statins
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 103
學期 2
出版年 104
研究生(中文) 謝幸㚬
學號 S66024034
學位類別 碩士
語文別 中文
口試日期 2015-06-25
論文頁數 209頁
口試委員 指導教授-徐之昇
口試委員-高淑敏
口試委員-高雅慧
口試委員-吳至行
召集委員-劉亞明
關鍵字(中) Statins 類降血脂藥
效益風險評估
療效
安全性
處方率
關鍵字(英) statins
multi-criteria decision analysis
benefit-risk assessment
drug utilization
學科別分類
中文摘要 背景:心血管疾病名列許多已開發國家死因排行的第一名,而高膽固醇是心血管疾病的重要危險因子之一,目前最常被用來治療高膽固醇血症的藥品為statin類降血脂藥物,雖然過去已有許多文獻確立statin類藥物的療效與安全性,然而,statin類降血脂藥物效益及風險的綜合性評估研究卻非常缺乏。

目的:本研究利用多準則決策分析方法,在同時考量藥物的效益及風險下,整合性地量化評估不同statin類降血脂藥物在一般血脂異常病患之療效與安全性。另外統計台灣於2002年至2011年間各statins及不同強度statins類藥物處方比率隨年份之變化趨勢,並針對有無特定臨床事件疾病史之新使用statins族群,探討statins類藥物處方比率之差異,呼應前半部決策分析結果進行討論。

方法:本研究利用多準則決策分析法(multiple criteria decision analysis, MCDA)評估atorvastatin、fluvastatin、lovastatin、pravastatin、rosuvastatin、simvastatin等六種statin。MCDA模型中包含五項評估準則,包括重大冠狀動脈事件之預防、重大腦血管事件之預防、肌痛或相關肌肉病變之風險、肝臟酵素上升之風險及新發生糖尿病之風險;其中,前兩項屬效益面評估準則,後三項屬風險面評估準則。藉由文獻回顧,本研究整理出各類statin在不同準則之間的表現能力及分數,並利用蒐集健康生活品質相關文獻及問卷設計與執行,分別收集代表病患以及南部某醫學中心醫師之偏好與意見,作為各準則權重分配之依據,最後,綜合各種statin於不同準則的表現分數及權重,為各類statin計算出總和分數,此外,本研究也進行了敏感度分析以評估準則權重的變化是否會影響研究結果。台灣每年度statins類使用族群之各statin處方比率統計部份,則透過2001-2011年之健保資料庫中百萬抽樣歸人檔資料進行分析。

結果:本研究結果顯示,不論是依據病患或醫師之立場評估所決定的準則權重,於所有statins中,fluvastatin有最高的總和分數(病患部分與醫師部分各得62.0分、54.9分),次高者為simvastatin (53.9分、54.6分),atorvastatin (53.1分、52.8分)與pravastatin (52.7分、53.8分)排名第三或四,而lovastatin (52.5分、52.2分)及rosuvastatin (51.9分、52.8分)之分數最低,整體而言,除病患部分評估結果中fluvastatin擁有顯著較高之分數,其他statins之間分數差距不大。以準則權重作為調整變數的敏感度分析結果發現,病患部分評估結果中,fluvastatin仍然擁有最高的總和分數,而其他statins的排名可能因準則權重之變動而有所變化;醫師部分評估結果則顯示fluvastatin的分數易受重大冠狀動脈事件及肝酵素上升等兩準則權重之變動而改變,反觀simvastatin的分數變化較不受準則權重變動之影響。在台灣各statin處方比率部份,研究期間以atorvastatin之處方比率為最高,而自2006年開始,強效statins如:rosuvastatin與simvastatin之處方比率有明顯的成長,在2010年後在處方占率上分別位居第二與第三。統計不同強度之statins處方趨勢,可觀察到低強度statins處方率隨年份下降,中高強度statins處方率則隨年份有明顯的成長。而在特定臨床事件疾病史的次族群分析部分,有冠狀動脈阻塞事件或腦血管事件疾病史的族群較無病史的患者有更高(>10%)的比例開立較強效的statins,包括atorvastatin及rosuvastatin,此開方情形在研究期間呈現一致之趨勢,亦可由發生特定臨床事件之族群有較高比例被開立中高強度之statins觀察而知。其他特定疾病史有無的次族群分析中則較無明顯藥物處方差異。

結論:本研究以statin類藥物為例,率先利用MCDA法之分析作為協助藥物在臨床上處方的決策參考,評估過程涵蓋病患或醫師兩方對不同準則之間的重要性評估,結果顯示,綜合考量藥物的效益與風險下,fluvastatin及simvastatin對一般血脂異常患者可作為較佳的藥物選擇。實際統計台灣本土之statins處方比率,可發現處方趨勢偏向以藥物療效為主,且曾經發生過重大心血管阻塞事件之患者有較高比例被開立強效之statins。
英文摘要 This study aims to synthetically evaluate the efficacy and safety of statins in general population and to investigate trends in use of statins among statin-users in Taiwan from 2002 to 2011 (10 years). We applied multi-criteria decision analysis (MCDA) methods to quantitatively assess different statins and made explicit the preferences and trade-offs between multiple criteria for patients and physicians, respectively. Criteria being assessed include benefits (prevention of major coronary events, and prevention of major cerebrovascular events) and risks (risk of myalgia/myopathy, risk of liver injury, and risk of incident diabetes) of statins. As for use of statins in Taiwan, the “Longitudinal Health Insurance dataset” derived from the National Health Insurance Research Database (NHIRD) was used for calculating prescribing rates of statins. Results form MCDA analysis suggested that fluvastatin might be preferred over other statins for general population. In Taiwan, atorvastatin has been the most commonly used statin (30-40% of market share by prescription volume) during the study period. Simvastatin and rosuvastatin also shared substantial prescription volume in recent years. Among statin new-users, patients with history of coronary or cerebrovascular events were more likely to be prescribed high-intensity statins (atorvastatin and rosuvastatin) than those without history of these events. To conclude, this study suggested use of fluvastatin based on risk-benefit balance of statins. However, prescription volume of statins in Taiwan indicated tendency towards drug efficacy.
論文目次 目錄
中文摘要 I
Extended Abstract IV
表目錄 XIII
圖目錄 XV
附件目錄 XVII
縮寫與全文對照表 XVIII

第一篇、Statin類降血脂藥物之治療決策分析與藥物利用趨勢分析 1
第1章 研究背景 1
第2章 研究目的與重要性 4
2.1 研究目的 4
2.2 研究重要性 5
第3章 文獻回顧 6
3.1 心血管疾病與高膽固醇 6
3.1.1 心血管疾病之簡介 6
3.1.2 高膽固醇與心血管疾病的關係 8
3.1.3 高膽固醇之流行病學 9
3.1.4 高膽固醇之簡介與治療 10
3.2 Statin類降血脂藥 14
3.2.1 Statin類降血脂藥物簡介 14
3.2.2 Statin類藥物之降血脂效果 15
3.2.3 Statin類降血脂藥物於心血管疾病之預防效果 18
3.2.4 Statin類降血脂藥物之安全性 27
3.3 醫療效益風險評估 (benefit-risk assessment of medicines) 30
3.3.1 醫療效益風險評估之緣起與簡介 30
3.3.2 醫療效益風險評估之類型與方法 32
3.3.3 運用效益風險評估於醫療決策分析 36
3.4 多準則決策分析 (multiple-criteria decision analysis, MCDA) 38
3.4.1 多準則決策分析法之簡介 38
3.4.2 運用多準則決策分析法於醫藥品評估 38
3.4.3 多準則決策分析模型應用於藥品決策之分析步驟 41
3.4.4 多準則決策分析模型之優勢與限制 45
3.5 層級分析法 (analytical hierarchy process, AHP) 47
3.5.1 層級分析法之簡介 47
3.5.2 層級分析法之目的與假設 48
3.5.3 層級分析法之分析步驟 49
3.5.4 層級分析法之應用 50
3.6 Statin類藥物利用 51
3.6.1 藥物利用研究 51
3.6.2 statin類藥物利用分析 52
3.6.3 國內statin類之藥物利用分析 54
3.7 文獻回顧總結 57
第4章 研究方法 58
4.1 研究架構與類型 58
4.2 MCDA:Statins類藥物多準則決策分析 59
4.2.1 建立決策內容 Establish the decision context 59
4.2.2 確立評估品項 Identify the options to be appraised 60
4.2.3 確立決策目標及評估準則 Identify objectives and criteria 60
4.2.4 評估不同準則之下各品項之表現 Assess the expected performance of each option against the criteria (‘scoring’) 63
4.2.5 為各評估準則設定權重 Assign weights for each criterion 69
4.3 台灣statins類藥物利用趨勢 72
4.3.1 研究設計 72
4.3.2 研究變項與操作定義 77
4.4 統計方法 80
4.4.1 統計軟體 80
4.4.2 資料分析 80
第5章 研究結果 81
5.1 MCDA:Statins類藥物多準則決策分析 81
5.1.1 計算各品項之加權總分 Calculate overall weighted scores 81
5.1.2 敏感性分析 Sensitivity analysis 86
5.2 台灣statins類藥物利用趨勢 89
5.2.1 每年度statins類藥物使用者(all users)之降血脂藥物處方比率趨勢 89
5.2.2 特定疾病史之statins類新使用者其第一筆statins處方分析 105
第6章 研究討論 128
6.1 MCDA:Statins類藥物多準則決策分析 128
6.1.1 研究之貢獻 128
6.1.2 研究結果之討論 128
6.1.3 多準則決策分析法之應用可能性 135
6.2 台灣statins類藥物利用趨勢 138
6.2.1 Statins類藥物使用者之人口特性 138
6.2.2 每年度statins類藥物使用者之各statin處方比率趨勢 138
6.2.3 特定疾病史之statins類新使用者處方分析 141
6.3 綜合討論 144
6.4 研究之限制 148
6.5 未來研究方向 149
第7章 結論與建議 150

第二篇、臨床藥事服務:Statins類藥物處方品質探討-著重潛在藥物交互作用之處方評估 151
第1章 緣起 151
第2章 目的與方法 157
2.1 研究目的 157
2.2 研究方法 157
第3章 結果 158
3.1 Statin類藥物基本處方量 158
3.2 潛在Statin類藥物交互作用之處方比例 159
3.3 常見Statin類藥物交互作用中之併用藥物 160
第4章 討論 164
第5章 未來建議 172

參考文獻 174
參考文獻 1. WHO | The top 10 causes of death. 2015; http://www.who.int/mediacentre/factsheets/fs310/en/# Accessed 29 Apr. , 2015.
2. Castelli WP. Cholesterol and lipids in the risk of coronary artery disease--the Framingham Heart Study. Canadian Journal of Cardiology. 1988;4 Suppl A:5a-10a.
3. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. The Journal of the American Medical Association. 1999;282(24):2340-2346.
4. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97(18):1837-1847.
5. WHO | Global status report on noncommunicable diseases 2010 - Description of the global burden of NCDs, their risk factors and determinants. WHO;2011. 978 92 4 156422 9.
6. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation. 2001;104(22):2746-2753.
7. Ito MK. Dyslipidemia: management using optimal lipid-lowering therapy. Annals of Pharmacotherapy. 2012;46(10):1368-1381.
8. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1-45.
9. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364(9435):685-696.
10. Kearney PM, Blackwell L, Collins R, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371(9607):117-125.
11. Afilalo J, Duque G, Steele R, Jukema JW, de Craen AJ, Eisenberg MJ. Statins for secondary prevention in elderly patients: a hierarchical bayesian meta-analysis. Journal of the American College of Cardiology. 2008;51(1):37-45.
12. Deedwania P, Stone PH, Bairey Merz CN, et al. Effects of intensive versus moderate lipid-lowering therapy on myocardial ischemia in older patients with coronary heart disease: results of the Study Assessing Goals in the Elderly (SAGE). Circulation. 2007;115(6):700-707.
13. Aronow WS. Lipid-lowering therapy in older persons. Archives of Medical Science. 2015;11(1):43-56.
14. Brugts JJ, Yetgin T, Hoeks SE, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. British Medical Journal. 2009;338:b2376.
15. Mills EJ, Rachlis B, Wu P, Devereaux PJ, Arora P, Perri D. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. Journal of the American College of Cardiology. 2008;52(22):1769-1781.
16. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews. 2013;1:Cd004816.
17. McKenney JM. Pharmacologic characteristics of statins. Clinical cardiology. 2003;26(4 Suppl 3):Iii32-38.
18. Vaughan CJ, Gotto AM, Jr. Update on statins: 2003. Circulation. 2004;110(7):886-892.
19. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267-1278.
20. Naci H, Brugts JJ, Fleurence R, Ades AE. Dose-comparative effects of different statins on serum lipid levels: a network meta-analysis of 256,827 individuals in 181 randomized controlled trials. European journal of preventive cardiology. 2013;20(4):658-670.
21. Delahoy PJ, Magliano DJ, Webb K, Grobler M, Liew D. The relationship between reduction in low-density lipoprotein cholesterol by statins and reduction in risk of cardiovascular outcomes: an updated meta-analysis. Clinical therapeutics. 2009;31(2):236-244.
22. Valuck RJ, Williams SA, MacArthur M, et al. A retrospective cohort study of correlates of response to pharmacologic therapy for hyperlipidemia in members of a managed care organization. Clinical therapeutics. 2003;25(11):2936-2957.
23. Harley CR, Gandhi S, Blasetto J, Heien H, Sasane R, Nelson SP. Low-density lipoprotein cholesterol (LDL-C) levels and LDL-C goal attainment among elderly patients treated with rosuvastatin compared with other statins in routine clinical practice. The American journal of geriatric pharmacotherapy. 2007;5(3):185-194.
24. Meyer JW, Schultz JS, O'Donnell JC, Patel PA, Sasane RM. Patterns and effectiveness of lipid-lowering therapies in a managed care environment. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2005;8(5):601-612.
25. Mahley RW BT. Drug therapy for hypercholesterolemia and dyslipidemia. In: Hardman JG LL, Gilman AG, eds., ed. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 10th ed. ed. New York: McGraw Hill; 2001:971-1002.
26. Finegold JA, Manisty CH, Goldacre B, Barron AJ, Francis DP. What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice. European journal of preventive cardiology. 2014;21(4):464-474.
27. Silva MA, Swanson AC, Gandhi PJ, Tataronis GR. Statin-related adverse events: a meta-analysis. Clinical therapeutics. 2006;28(1):26-35.
28. Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions. Circulation. 2004;109(23 Suppl 1):Iii50-57.
29. Macedo AF, Taylor FC, Casas JP, Adler A, Prieto-Merino D, Ebrahim S. Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis. BMC medicine. 2014;12:51.
30. Furberg CD, Pitt B. Withdrawal of cerivastatin from the world market. Current controlled trials in cardiovascular medicine. 2001;2(5):205-207.
31. Tobert JA. Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nature Reviews Drug Discovery. 2003;2(7):517-526.
32. Naci H, van Valkenhoef G, Higgins JP, Fleurence R, Ades AE. Evidence-based prescribing: combining network meta-analysis with multicriteria decision analysis to choose among multiple drugs. Circulation. Cardiovascular quality and outcomes. 2014;7(5):787-792.
33. Szucs TD. Pharmaco-economic aspects of lipid-lowering therapy: is it worth the price? European heart journal. 1998;19 Suppl M:M22-28.
34. van Hout BA, Simoons ML. Cost-effectiveness of HMG coenzyme reductase inhibitors; whom to treat? European heart journal. 2001;22(9):751-761.
35. Morrison A, Glassberg H. Determinants of the cost-effectiveness of statins. Journal of Managed Care Pharmacy. 2003;9(6):544-551.
36. Franco OH, Peeters A, Looman CW, Bonneux L. Cost effectiveness of statins in coronary heart disease. Journal of epidemiology and community health. 2005;59(11):927-933.
37. Ohsfeldt RL, Gandhi SK, Fox KM, Stacy TA, McKenney JM. Effectiveness and cost-effectiveness of rosuvastatin, atorvastatin, and simvastatin among high-risk patients in usual clinical practice. American Journal of Managed Care. 2006;12(15 Suppl):S412-423.
38. Ray S, Jindal AK, Sengupta S, Sinha S. Statins: Can we advocate them for primary prevention of heart disease? Medical Journal Armed Forces India. 2014;70(3):270-273.
39. Mussen F, Salek S, Walker S. A quantitative approach to benefit-risk assessment of medicines - part 1: the development of a new model using multi-criteria decision analysis. Pharmacoepidemiology and drug safety. 2007;16 Suppl 1:S2-s15.
40. Dolan JG. Multi-criteria clinical decision support: A primer on the use of multiple criteria decision making methods to promote evidence-based, patient-centered healthcare. The patient. 2010;3(4):229-248.
41. WHO. Definition of cardiovascular diseases. 2015; http://www.who.int/mediacentre/factsheets/fs317/en/. Accessed April 3, 2015.
42. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics--2013 update: a report from the American Heart Association. Circulation. 2013;127(1):e6-e245.
43. AISBL EHN. European Cardiovascular Disease Statistics 2012. 2012; http://www.ehnheart.org/cvd-statistics.html. Accessed Febuary 21, 2015.
44. 民國103年主要死因分析. In: 衛生福利部統計處, ed. 台灣: 衛生福利部統計處; 民104.
45. 台灣血脂異常防治共識-血脂異常預防及診療臨床指引. 第一版 ed. 臺北市: 中華民國血脂及動脈硬化學會; 2009.
46. Gaziano TA GJ. Epidemiology of Cardiovascular Disease. In: Kasper D FA, Hauser S, Longo D, Jameson J, Loscalzo J. eds., ed. Harrison's Principles of Internal Medicine 19e. Vol 19e. New York, NY: McGraw-Hill; 2015.
47. Ueshima H, Sekikawa A, Miura K, et al. Cardiovascular disease and risk factors in Asia: a selected review. Circulation. 2008;118(25):2702-2709.
48. Strasser T. Reflections on Cardiovascular Diseases. Interdisciplinary Science Reviews. 1978;3(3):225-230.
49. WHO. Prevention of cardiovascular disease (CVDs). 2015; http://www.who.int/cardiovascular_diseases/guidelines/Pocket_GL_information/en/. Accessed March 8, 2015.
50. Ebrahim S, Taylor F, Ward K, Beswick A, Burke M, Davey Smith G. Multiple risk factor interventions for primary prevention of coronary heart disease. Cochrane Database of Systematic Reviews. 2011(1):Cd001561.
51. Goff DC, Jr., Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S49-73.
52. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2):227-239.
53. Law MR, Wald NJ. An ecological study of serum cholesterol and ischaemic heart disease between 1950 and 1990. The European Journal of Clinical Nutrition. 1994;48(5):305-325.
54. Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? British Medical Journal. 1994;308(6925):367-372.
55. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):7-22.
56. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. The New England journal of medicine. 2005;352(14):1425-1435.
57. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. British Medical Journal. 2003;326(7404):1423.
58. WHO. Global health risks: mortality and burden of disease attributable to selected major risks. Geneva: World Health Organization;2009.
59. Lee Y, Lin RS, Sung FC, et al. Chin-Shan Community Cardiovascular Cohort in Taiwan-baseline data and five-year follow-up morbidity and mortality. Journal of clinical epidemiology. 2000;53(8):838-846.
60. 孫建安等. 2007年台灣地區高血壓、高血糖、高血脂之追蹤調查研究專輯. In: 衛生福利部國民健康署, ed. 台灣: 衛生福利部國民健康署; 2007.
61. 陳建仁等. 2007年台灣地區高血壓、高血糖、高血脂盛行率調查報告. In: 行政院衛生署國民健康局, ed. 台灣台北: 行政院衛生署國民健康局; 民國92年11月:頁89.
62. 潘文涵等. 2005 - 2008 台灣國民營養健康狀況變遷調查結果. In: 衛生福利部食品藥物管理署, ed. 台灣: 衛生福利部食品藥物管理署; 2011:40.
63. 丁彥伶. 健保三高用藥品質改善. In: 行政院衛生福利部中央健康保險署, ed. 台灣: 行政院衛生福利部中央健康保險署; 民103.
64. Kasper D FA, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine. 19e. ed. New York, NY: McGraw-Hill; 2015.
65. TP. B. Chapter 31. Drug Therapy for Hypercholesterolemia and Dyslipidemia. In: Brunton LL CB, Knollmann BC. eds., ed. Goodman & Gilman's The Pharmacological Basis of Therapeutics. New York, NY: McGraw-Hill; 2011.
66. Lipid Modification: Cardiovascular Risk Assessment and the Modification of Blood Lipids for the Primary and Secondary Prevention of Cardiovascular Disease. London: National Clinical Guideline Centre, 2014.; 2014.
67. Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). European heart journal. 2011;32(14):1769-1818.
68. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681.
69. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143-3421.
70. O'Riordan M. New Cholesterol Guidelines Abandon LDL Targets. November 14, 2013; http://www.medscape.com/viewarticle/814152#vp_2.
71. D'Agostino RB, Sr., Ansell BJ, Mora S, Krumholz HM. Clinical decisions. The guidelines battle on starting statins. The New England journal of medicine. 2014;370(17):1652-1658.
72. Keaney JF, Jr., Curfman GD, Jarcho JA. A pragmatic view of the new cholesterol treatment guidelines. The New England journal of medicine. 2014;370(3):275-278.
73. New guidelines in USA: 2013 ACC/AHA Guidelines on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk. [press release]. Gothenburg SWEDEN: European Atherosclerosis Society 2013.
74. Ray KK, Kastelein JJP, Matthijs Boekholdt S, et al. The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. European heart journal. 2014.
75. Alberts AW, Chen J, Kuron G, et al. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proceedings of the National Academy of Sciences of the United States of America. 1980;77(7):3957-3961.
76. Taylor FC, Huffman M, Ebrahim S. Statin therapy for primary prevention of cardiovascular disease. The Journal of the American Medical Association. 2013;310(22):2451-2452.
77. Simons J. "The $10 billion pill". Fortune magazine2003.
78. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986;232(4746):34-47.
79. Ginsberg HN, Le NA, Short MP, Ramakrishnan R, Desnick RJ. Suppression of apolipoprotein B production during treatment of cholesteryl ester storage disease with lovastatin. Implications for regulation of apolipoprotein B synthesis. The Journal of Clinical Investigation. 1987;80(6):1692-1697.
80. Grundy SM. Consensus statement: Role of therapy with "statins" in patients with hypertriglyceridemia. American Journal of Cardiology. 1998;81(4A):1B-6B.
81. Bakker-Arkema RG, Davidson MH, Goldstein RJ, et al. Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. The Journal of the American Medical Association. 1996;275(2):128-133.
82. Stein EA, Lane M, Laskarzewski P. Comparison of statins in hypertriglyceridemia. American Journal of Cardiology. 1998;81(4A):66B-69B.
83. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation. 2000;101(2):207-213.
84. Smith MEB, Lee NJ, Haney E, Carson S. Drug Class Review: HMG-CoA Reductase Inhibitors (Statins) and Fixed-dose Combination Products Containing a Statin: Final Report Update 5. Portland OR: Oregon Health & Science University, Portland, Oregon.; 2009.
85. Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). American Journal of Cardiology. 1998;81(5):582-587.
86. Kapur NK, Musunuru K. Clinical efficacy and safety of statins in managing cardiovascular risk. Journal of Vascular Health and Risk Management. 2008;4(2):341-353.
87. Davidson MH. Efficacy of simvastatin and ezetimibe in treating hypercholesterolemia. Journal of the American College of Cardiology. 2003;42(2):398-399.
88. Roberts WC. The rule of 5 and the rule of 7 in lipid-lowering by statin drugs. American Journal of Cardiology. 1997;80(1):106-107.
89. Kim HS, Wu Y, Lin SJ, et al. Current status of cholesterol goal attainment after statin therapy among patients with hypercholesterolemia in Asian countries and region: the Return on Expenditure Achieved for Lipid Therapy in Asia (REALITY-Asia) study. Current Medical Research & Opinion. 2008;24(7):1951-1963.
90. Paragh G, Mark L, Zamolyi K, Pados G, Ofner P. Lipid-modifying therapy and attainment of cholesterol goals in Hungary: the return on expenditure achieved for lipid therapy (REALITY) study. Clinical drug investigation. 2007;27(9):647-660.
91. Pearson TA, Laurora I, Chu H, Kafonek S. The lipid treatment assessment project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Archives of internal medicine. 2000;160(4):459-467.
92. Santos RD, Waters DD, Tarasenko L, et al. Low- and high-density lipoprotein cholesterol goal attainment in dyslipidemic women: The Lipid Treatment Assessment Project (L-TAP) 2. American heart journal. 2009;158(5):860-866.
93. Waters DD, Brotons C, Chiang C-W, et al. Lipid treatment assessment project 2 a multinational survey to evaluate the proportion of patients achieving low-density lipoprotein cholesterol goals. Circulation. 2009;120(1):28-34.
94. Organization WH. Pocket guidelines for assessment and management of CVD risk. Prevention of cardiovascular disease (CVDs) 2007; http://www.who.int/cardiovascular_diseases/guidelines/Pocket_GL_information/en/. Accessed April 2015.
95. Mills EJ, O'Regan C, Eyawo O, et al. Intensive statin therapy compared with moderate dosing for prevention of cardiovascular events: a meta-analysis of >40 000 patients. European heart journal. 2011;32(11):1409-1415.
96. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. The New England journal of medicine. 2004;350(15):1495-1504.
97. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. The Journal of the American Medical Association. 2004;292(11):1307-1316.
98. Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. The Journal of the American Medical Association. 2005;294(19):2437-2445.
99. Armitage J, Bowman L, Wallendszus K, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010;376(9753):1658-1669.
100. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. The New England journal of medicine. 1997;336(3):153-162.
101. Serruys PW, de Feyter P, Macaya C, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. The Journal of the American Medical Association. 2002;287(24):3215-3222.
102. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. The New England journal of medicine. 2007;357(22):2248-2261.
103. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344(8934):1383-1389.
104. Koren MJ, Hunninghake DB. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the alliance study. Journal of the American College of Cardiology. 2004;44(9):1772-1779.
105. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. The New England journal of medicine. 1996;335(14):1001-1009.
106. Results of the low-dose (20 mg) pravastatin GISSI Prevenzione trial in 4271 patients with recent myocardial infarction: do stopped trials contribute to overall knowledge? GISSI Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico). Italian Heart Journal. 2000;1(12):810-820.
107. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. The New England journal of medicine. 1998;339(19):1349-1357.
108. Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. The New England journal of medicine. 2011;365(22):2078-2087.
109. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581-590.
110. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. The New England journal of medicine. 1995;333(20):1301-1307.
111. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). The Journal of the American Medical Association. 2002;288(23):2998-3007.
112. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. The Journal of the American Medical Association. 1998;279(20):1615-1622.
113. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361(9364):1149-1158.
114. Holdaas H, Fellstrom B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet. 2003;361(9374):2024-2031.
115. Nakamura H, Arakawa K, Itakura H, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet. 2006;368(9542):1155-1163.
116. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. The New England journal of medicine. 2008;359(21):2195-2207.
117. Black DM. A general assessment of the safety of HMG CoA reductase inhibitors (statins). Current Atherosclerosis Reports. 2002;4(1):34-41.
118. Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA reductase inhibitors. Annals of Pharmacotherapy. 2001;35(9):1096-1107.
119. Wolfe SM. Dangers of rosuvastatin identified before and after FDA approval. Lancet. 2004;363(9427):2189-2190.
120. Mora S, Ridker PM. Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)--can C-reactive protein be used to target statin therapy in primary prevention? American Journal of Cardiology. 2006;97(2A):33A-41A.
121. Information P. Lescol®/Lescol® XL (fluvastatin sodium). New Jersey: Novartis Pharmaceuticals Corporation; 2012.
122. Information P. PRAVACHOL® (pravastatin sodium). Princeton, New Jersey 08543 USA: Bristol-Myers Squibb Company; 2012.
123. Information P. LIVALO® (pitavastatin). Kowa Pharmaceuticals America, Inc.; 2013.
124. Information P. CRESTOR (rosuvastatin calcium). Wilmington, DE 19850 AstraZeneca Pharmaceuticals LP; 2014.
125. Information P. LIPITOR® (atorvastatin calcium) NY: Pfizer Inc. Parke-Davis; 2015.
126. Information P. ZOCOR (simvastatin). Cramlington, Northumberland, UK: Merck & Co., Inc.; 2015.
127. Law M, Rudnicka AR. Statin safety: a systematic review. American Journal of Cardiology. 2006;97(8a):52c-60c.
128. Alberton M, Wu P, Druyts E, Briel M, Mills EJ. Adverse events associated with individual statin treatments for cardiovascular disease: an indirect comparison meta-analysis. Quarterly Journal of Medicine. 2012;105(2):145-157.
129. Jacobson TA. NLA Task Force on Statin Safety--2014 update. Journal of clinical lipidology. 2014;8(3 Suppl):S1-4.
130. Chou R, Aronson N, Atkins D, et al. AHRQ series paper 4: assessing harms when comparing medical interventions: AHRQ and the effective health-care program. Journal of clinical epidemiology. 2010;63(5):502-512.
131. Vandenbroucke JP. What is the best evidence for determining harms of medical treatment? Canadian Medical Association Journal. 2006;174(5):645-646.
132. Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. British Medical Journal. 2010;340:c2197.
133. Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet. 2005;365(9458):475-481.
134. Merck Resolves Previously Disclosed Seven-Year Investigation Led by U.S. Attorney’s Office for the District of Massachusetts Related to Vioxx® [press release]. Merck Sharp & Dohme Corp.Tuesday, November 22, 2011.
135. WILLMAN D. The Rise and Fall of the Killer Drug Rezulin. Los Angeles Times. June 04, June 04, 2000;SUNDAY REPORT.
136. Willman D. FDA's Approval and Delay in Withdrawing Rezulin Probed. Los Angeles Times. August 16, 2000;Investigative Reporting.
137. FDA US. Drug Safety and Risk Management Advisory Committee Charter. Advisory Committees http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/ucm094886.htm. Accessed May 23, 2015.
138. Guidance for Industry - Premarketing Risk Assessment. In: (CDER) CfDEaR, (CBER) CfBEaR, eds: U.S. Department of Health and Human Services Food and Drug Administration; 2005.
139. Guidance for Industry - Development and Use of Risk Minimization Action Plans. In: (CDER) CfDEaR, (CBER) CfBEaR, eds: U.S. Department of Health and Human Services Food and Drug Administration; 2005.
140. Guidance for Industry - Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment. In: (CDER) CfDEaR, (CBER) CfBEaR, eds: U.S. Department of Health and Human Services Food and Drug Administration; 2005.
141. Food and Drug Administration Amendments Act (FDAAA) of 2007. U.S. Food and Drug Administration; 2007.
142. Enhancing Benefit-Risk Assessment in Regulatory Decision-Making. U.S. Food and Drug Administration; 2013.
143. Structured Approach to Benefit-Risk Assessment in Drug Regulatory Decision-Making. U.S. Food and Drug Administration; 2013.
144. Guo JJ, Pandey S, Doyle J, Bian B, Lis Y, Raisch DW. A review of quantitative risk-benefit methodologies for assessing drug safety and efficacy-report of the ISPOR risk-benefit management working group. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2010;13(5):657-666.
145. Benefit-risk methodology. Supporting research http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/document_listing/document_listing_000314.jsp. Accessed May 23, 2015.
146. Kahneman D. Maps of Bounded Rationality: A Perspective on Judgment and Choice. December 8, 2002; http://www.nobelprize.org/nobel_prizes/economic-sciences/laureates/2002/kahnemann-lecture.pdf. Accessed May 23, 2015.
147. Is quantitative benefit-risk modelling of drugs desirable or possible? Drug Discovery Today: Technologies. 2011;8(1):e1-e42.
148. Reflection paper on benefit-risk assessment methods in the context of the evaluation of marketing authorisation applications of products for human use. In: Use TCfMPfH, ed: European Medicines Agency 2008:13.
149. IV CWG. Benefit-Risk Balance for Marketed Drugs: Evaluating Safety Signals. Geneva: The Council for International Organizations of Medical Sciences; 1998.
150. Holden WL. Benefit-risk analysis : a brief review and proposed quantitative approaches. Drug safety. 2003;26(12):853-862.
151. Mt-Isa S, Hallgreen CE, Wang N, et al. Balancing benefit and risk of medicines: a systematic review and classification of available methodologies. Pharmacoepidemiology and drug safety. 2014;23(7):667-678.
152. Consortium tP. Review of methodologies for benefit and risk assessment of medication Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium 2013.
153. Work package 3 report: Field tests In: Evaluation HMDa, ed: European Medicines Agency; 2011.
154. Work package 2 report: Applicability of current tools and processes for regulatory benefit-risk assessment. In: Evaluation HMDa, ed: European Medicines Agency; 2010.
155. Belton V ST. Multiple criteria decision analysis: an integrated approach. 1st ed. Boston/Dordrecht/London: Kluwer Academic Publishers; 2002.
156. Marsh K, Dolan P, Kempster J, Lugon M. Prioritizing investments in public health: a multi-criteria decision analysis. Journal of Public Health. 2013;35(3):460-466.
157. Marsh K, Lanitis T, Neasham D, Orfanos P, Caro J. Assessing the value of healthcare interventions using multi-criteria decision analysis: a review of the literature. PharmacoEconomics. 2014;32(4):345-365.
158. Adunlin G DV, Xiao H. Application of multicriteria decision analysis in health care: a systematic review and bibliometric analysis. Health Expect. 2014.
159. Dolan JG, Boohaker E, Allison J, Imperiale TF. Patients' preferences and priorities regarding colorectal cancer screening. Medical Decision Making. 2013;33(1):59-70.
160. Diaz-Ledezma C, Lichstein PM, Dolan JG, Parvizi J. Diagnosis of periprosthetic joint infection in Medicare patients: multicriteria decision analysis. Clinical Orthopaedics and Related Research. 2014;472(11):3275-3284.
161. Johnson SR, Naden RP, Fransen J, et al. Multicriteria decision analysis methods with 1000Minds for developing systemic sclerosis classification criteria. Journal of clinical epidemiology. 2014;67(6):706-714.
162. Hsu JC, Tang DH, Lu CY. Risk-benefit assessment of oral phosphodiesterase type 5 inhibitors for treatment of erectile dysfunction: a multiple criteria decision analysis. International Journal of Clinical Practice. 2015;69(4):436-443.
163. Aenishaenslin C, Hongoh V, Cisse HD, et al. Multi-criteria decision analysis as an innovative approach to managing zoonoses: results from a study on Lyme disease in Canada. BMC Public Health. 2013;13:897.
164. Ramli A, Aljunid SM, Sulong S, Md Yusof FA. National Drug Formulary review of statin therapeutic group using the multiattribute scoring tool. Journal of Therapeutics and Clinical Risk Management. 2013;9:491-504.
165. Tervonen T, Naci H, van Valkenhoef G, et al. Applying Multiple Criteria Decision Analysis to Comparative Benefit-Risk Assessment: Choosing Among Statins in Primary Prevention. Medical Decision Making. 2015.
166. Hsu JC, Hsieh CY, Yang YHK, Lu CY. Net Clinical Benefit of Oral Anticoagulants: A Multiple Criteria Decision Analysis. PloS one. 2015;10(4).
167. Grof A. [Allocating resources for cancer control--resolving multicriteria decision-making using the analytic hierarchy process]. Magyar onkologia. 2007;51(3):197-208.
168. Sussex J, Rollet P, Garau M, Schmitt C, Kent A, Hutchings A. A pilot study of multicriteria decision analysis for valuing orphan medicines. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2013;16(8):1163-1169.
169. Nutt DJ, King LA, Phillips LD. Drug harms in the UK: a multicriteria decision analysis. Lancet. 2010;376(9752):1558-1565.
170. Ritrovato M, Faggiano FC, Tedesco G, Derrico P. Decision-Oriented Health Technology Assessment: One Step Forward in Supporting the Decision-Making Process in Hospitals. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2015;18(4):505-511.
171. Tony M, Wagner M, Khoury H, et al. Bridging health technology assessment (HTA) with multicriteria decision analyses (MCDA): field testing of the EVIDEM framework for coverage decisions by a public payer in Canada. BMC Health Services Research. 2011;11:329.
172. Goetghebeur MM, Wagner M, Khoury H, Levitt RJ, Erickson LJ, Rindress D. Evidence and Value: Impact on DEcisionMaking--the EVIDEM framework and potential applications. BMC Health Services Research. 2008;8:270.
173. Youngkong S, Tromp N, Chitama D. The EVIDEM framework and its usefulness for priority setting across a broad range of health interventions. Cost Effectiveness and Resource Allocation. 2011;9:8.
174. P. A. Risk benefit assessment. . Pharmaceutical Physician. 2001;12:12–17.
175. LL. M. Risk/Benefit Assessment: The “Greased Pig” of Drug Development. Drug Information Journal. 1993 27(4):1011-1020.
176. Diaby V, Goeree R. How to use multi-criteria decision analysis methods for reimbursement decision-making in healthcare: a step-by-step guide. Expert review of pharmacoeconomics & outcomes research. 2014;14(1):81-99.
177. Edwards W. Social utilities. The Engineering Economist Summer Symposium Series. 1971;6:119-129.
178. Edwards W. How to use multiattribute utility measurement for social decisionmaking. IEEE Transactions on Systems, Man, and Cybernetics. 1977;SMC-7(5):326-340.
179. Edwards W, Barron FH. SMARTS and SMARTER: Improved Simple Methods for Multiattribute Utility Measurement. Organizational Behavior and Human Decision Processes. 1994;60(3):306-325.
180. Filip Mussen SS, Stuart Walker. Benefit-Risk Appraisal of Medicines. John Wiley & Sons, Ltd; 2009.
181. Merkin BG. Group Choice. NY: John Wiley & Sons; 1979.
182. Saaty TL. The Analytical Hierarchy Process. NY: McGraw-Hill Book Co.; 1980.
183. Simon H. Theories of Bounded Rationality. In: Radner CBRaR, ed. Decision and Organization. Amsterdam: North-Holland; 1972:161-176.
184. Whyte L. Hierarchical Structures. New York: American Elsevier; 1969.
185. Stevens SS. On the Theory of Scales of Measurement. Science. 1946;103(2684):677-680.
186. 鄧振源. 多準則決策分析:方法與應用. 鼎茂; 2012.
187. Ernest H. Forman SIG. The Analytic Hierarchy Process: An Exposition. Operations Research. 2001;49(4):469-486.
188. Vidal L-A, Marle F, Bocquet J-C. Using a Delphi process and the Analytic Hierarchy Process (AHP) to evaluate the complexity of projects. Expert Systems with Applications. 2011;38(5):5388-5405.
189. Hsu Y-L, Lee C-H, Kreng VB. The application of Fuzzy Delphi Method and Fuzzy AHP in lubricant regenerative technology selection. Expert Systems with Applications. 2010;37(1):419-425.
190. Hsu JC, Hsieh CY, Yang YH, Lu CY. Net clinical benefit of oral anticoagulants: a multiple criteria decision analysis. PloS one. 2015;10(4):e0124806.
191. 陳義分、陳映君、林學茂、楊展耀、林亮宗. 利用多目標模糊理論建立旅遊服務業之績效評估模式 修平學報. 民國九十九年九月;第二十一期:115-130
192. WHO. Introduction to Drug Utilization Research. In: WHO, ed2003.
193. Salas M. Drug Utilization Studies. Paper presented at: ISPE Mid-Year Meeting2012; Miami, Florida.
194. Walley T, Folino-Gallo P, Stephens P, Van Ganse E. Trends in prescribing and utilization of statins and other lipid lowering drugs across Europe 1997-2003. British journal of clinical pharmacology. 2005;60(5):543-551.
195. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). The Journal of the American Medical Association. 2001;285(19):2486-2497.
196. Praveen KG AK. Drug Utilization and Evaluation of Hmg-co a Reductase Inhibitors in Tertiary Care Teaching Hospital. Indian Journal of Pharmacy Practice. 2013;6(4):56-63.
197. Stagnitti MN. Trends in Statins Utilization and Expenditures for the U.S. Civilian Noninstitutionalized Population, 2000 and 2005 Agency for Healthcare Research and Quality;May 2008
198. DeWilde S, Carey IM, Bremner SA, Richards N, Hilton SR, Cook DG. Evolution of statin prescribing 1994-2001: a case of agism but not of sexism? Heart (British Cardiac Society). 2003;89(4):417-421.
199. Ferrajolo C, Arcoraci V, Sullo MG, et al. Pattern of statin use in southern italian primary care: can prescription databases be used for monitoring long-term adherence to the treatment? PloS one. 2014;9(7):e102146.
200. Svensson E, Nielsen RB, Hasvold P, Aarskog P, Thomsen RW. Statin prescription patterns, adherence, and attainment of cholesterol treatment goals in routine clinical care: a Danish population-based study. Journal of clinical epidemiology. 2015;7:213-223.
201. Omar MA, Wilson JP. FDA adverse event reports on statin-associated rhabdomyolysis. Annals of Pharmacotherapy. 2002;36(2):288-295.
202. Huskamp HA, Deverka PA, Epstein AM, Epstein RS, McGuigan KA, Frank RG. The effect of incentive-based formularies on prescription-drug utilization and spending. The New England journal of medicine. 2003;349(23):2224-2232.
203. Stockl KM, Tjioe D, Gong S, Stroup J, Harada AS, Lew HC. Effect of an intervention to increase statin use in medicare members who qualified for a medication therapy management program. Journal of Managed Care Pharmacy. 2008;14(6):532-540.
204. Simpson RJ, Jr., Signorovitch J, Birnbaum H, et al. Cardiovascular and economic outcomes after initiation of lipid-lowering therapy with atorvastatin vs simvastatin in an employed population. Mayo Clinic proceedings. 2009;84(12):1065-1072.
205. Foody JM, Joyce AT, Rudolph AE, Liu LZ, Benner JS. Cardiovascular outcomes among patients newly initiating atorvastatin or simvastatin therapy: a large database analysis of managed care plans in the United States. Clinical therapeutics. 2008;30(1):195-205.
206. Tzeng-Ji Chen S-JL, Liang-Kung Chen, Shinn-Jang Hwang, Li-Fang Chou. Prevalence of Antilipemic Drug Use in Taiwan: Analysis of a Sampling Cohort within the National Health Insurance. Journal of the Chinese Medical Association. 2003;66:39-45.
207. 林美汝. 台灣地區血脂異常用藥之流行病學研究: 藥學研究所碩士在職專班, 高雄醫學大學; 2005.
208. 翁德昌. Statins類降血脂藥品處方型態分析及療效可替換性評估: 臨床藥學研究所, 成功大學; 2007.
209. Chiang CW, Chiu HF, Chen CY, Wu HL, Yang CY. Trends in the use of lipid-lowering drugs by outpatients with diabetes in Taiwan, 1997-2003. Pharmacoepidemiology and drug safety. 2008;17(1):62-69.
210. Yi-Chun Lin C-CY, Ying-Ju Chen, Wei-Chien Peng, Chung-Yi Li, Chii-Min Hwu. Utilization of statins and aspirin among patients with diabetes and hyperlipidemia: Taiwan, 1998–2006. Journal of the Chinese Medical Association 75 (2012) 567 e 572. 2012;75:567-572.
211. Chin-Feng Hsuan T-LL, Hsiu-Ling Chang, Wei-Kung Tseng, and Chau-Chung Wu. A Retrospective Study of Statin Use and Its Effectiveness in Taiwanese. Acta Cardiologica Sinica. 2009;25:18-25.
212. 張秀玲. 某教學醫院高血脂初級與次級預防患者Statin類藥品使用回溯性分析研究: 藥學研究所碩士在職專班, 高雄醫學大學; 2006.
213. 吳珮君. 高風險病人Statin類降血脂藥品順從性與其心血管疾病再發生率之相關性: 臨床藥學研究所, 國立成功大學; 2008.
214. Informatics IIfH. TOP 20 GLOBAL THERAPY AREAS 2014. England and Wales: IMS Health MIDAS;2014.
215. Informatics IIfH. The Global Use of Medicines: Outlook Through 2016. USA: IMS Institute for Healthcare Informatics;2012.
216. 張翠芬. 健保大支出 三高藥費逾300億. 中國時報2010.
217. Micromedex® 2.0, (electronic version). 2015; http://www.micromedexsolutions.com/. Accessed April 30, 2015.
218. Information P. MEVACOR® (lovastatin). Ontario, Canada Merck & Co., Inc.; 2014.
219. Saaty TL. Fundamentals of Decision Making. Pittsburgh, PA.: RWS Publications; 1994.
220. Naci H, Brugts JJ, Fleurence R, Tsoi B, Toor H, Ades AE. Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trials. European journal of preventive cardiology. 2013;20(4):641-657.
221. Naci H, Brugts JJ, Fleurence R, Ades AE. Comparative effects of statins on major cerebrovascular events: a multiple-treatments meta-analysis of placebo-controlled and active-comparator trials. Quarterly Journal of Medicine. 2013;106(4):299-306.
222. Naci H, Brugts J, Ades T. Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246 955 participants from 135 randomized, controlled trials. Circulation. Cardiovascular quality and outcomes. 2013;6(4):390-399.
223. Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM. Risk of incident diabetes among patients treated with statins: population based study. British Medical Journal. 2013;346:f2610.
224. Jonathan J Deeks JPHaDGA. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 ed: The Cochrane Collaboration; 2011.
225. Chinn S. A simple method for converting an odds ratio to effect size for use in meta-analysis. Statistics in Medicine. 2000;19(22):3127-3131.
226. DJ. F. Statistical Method in Biological Assay. 3rd ed: Charles Grin: London and High Wycombe; 1978.
227. Wilson DB. Calculating Effect-Sizes. The Campbell Collaboration; 2011:15.
228. Tengs TO, Wallace A. One thousand health-related quality-of-life estimates. Medical care. 2000;38(6):583-637.
229. Nyman JA, Barleen NA, Dowd BE, Russell DW, Coons SJ, Sullivan PW. Quality-of-life weights for the US population: self-reported health status and priority health conditions, by demographic characteristics. Medical care. 2007;45(7):618-628.
230. Gandhi SK, Jensen MM, Fox KM, Smolen L, Olsson AG, Paulsson T. Cost-effectiveness of rosuvastatin in comparison with generic atorvastatin and simvastatin in a Swedish population at high risk of cardiovascular events. Journal of ClinicoEconomics and Outcomes Research. 2012;4:1-11.
231. Ohsfeldt RL, Gandhi SK, Smolen LJ, et al. Cost effectiveness of rosuvastatin in patients at risk of cardiovascular disease based on findings from the JUPITER trial. Journal of medical economics. 2010;13(3):428-437.
232. Tengs TO, Lin TH. A meta-analysis of quality-of-life estimates for stroke. PharmacoEconomics. 2003;21(3):191-200.
233. Pignone M, Earnshaw S, Tice JA, Pletcher MJ. Aspirin, statins, or both drugs for the primary prevention of coronary heart disease events in men: a cost-utility analysis. Annals of internal medicine. 2006;144(5):326-336.
234. Slejko JF, Page RL, 2nd, Sullivan PW. Cost-effectiveness of statin therapy for vascular event prevention in adults with elevated C-reactive protein: implications of JUPITER. Current Medical Research & Opinion. 2010;26(10):2485-2497.
235. Kashani A, Phillips CO, Foody JM, et al. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation. 2006;114(25):2788-2797.
236. Younossi ZM, Boparai N, McCormick M, Price LL, Guyatt G. Assessment of utilities and health-related quality of life in patients with chronic liver disease. The American journal of gastroenterology. 2001;96(2):579-583.
237. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735-742.
238. 全民健保保險研究資料庫. 承保抽樣歸人檔. 2015; http://nhird.nhri.org.tw/date_cohort.htm#top. Accessed December 23, 2015.
239. 衛生福利部中央健康保險署. 2001年ICD-9-CM疾病碼一覽表. 疾病分類代碼及範圍 2001; http://www.nhi.gov.tw/webdata/webdata.aspx?menu=18&menu_id=703&webdata_id=1008. Accessed December 23, 2015.
240. 衛生福利部中央健康保險署. 健保用藥品項104年03月壓縮總檔. 藥材專區-用藥品項 2015; http://www.nhi.gov.tw/webdata/webdata.aspx?menu=21&menu_id=713&webdata_id=873. Accessed March 1, 2015.
241. 全民健保保險研究資料庫. 譯碼簿. 2015; http://nhird.nhri.org.tw/date_02.htm. Accessed October, 2015.
242. Rosenson RS, Kent ST, Brown TM, et al. Underutilization of high-intensity statin therapy after hospitalization for coronary heart disease. Journal of the American College of Cardiology. 2015;65(3):270-277.
243. 鄭靜蘭. 選擇性第二型環氧酶抑制劑與傳統非類固醇抗發炎劑於栓塞性中風老年患者之藥物流行病學研究: 藥學生物科技研究所, 成功大學; 2010.
244. 吳家雯. 全民健康保險研究資料庫HMG-CoAReductaseInhibitors處方型態及用藥安全性分析:自藥品交互作用觀點探討, 臺灣大學; 2005.
245. Lo Re V, 3rd, Haynes K, Goldberg D, et al. Validity of diagnostic codes to identify cases of severe acute liver injury in the US Food and Drug Administration's Mini-Sentinel Distributed Database. Pharmacoepidemiology and drug safety. 2013;22(8):861-872.
246. Chen GL, Hsiao FY, Dong YH, Shen LJ, Wu FL. Statins and the risk of liver injury: a population-based case-control study. Pharmacoepidemiology and drug safety. 2014;23(7):719-725.
247. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. The Journal of the American Medical Association. 2003;289(13):1681-1690.
248. FDA. Zocor (simvastatin): increased risk of muscle injury with high doses. U.S. Food and Drug Administration; 03/19/2010.
249. 邵文逸. 間接比較各種隨機分派臨床試驗之治療效果 ─ 一種擴大利用實證資料的分析方法. 中華民國九十八年十一月.
250. Mitchell AP, Simpson RJ. Statin cost effectiveness in primary prevention: a systematic review of the recent cost-effectiveness literature in the United States. BMC research notes. 2012;5:373.
251. Lazar LD, Pletcher MJ, Coxson PG, Bibbins-Domingo K, Goldman L. Cost-effectiveness of statin therapy for primary prevention in a low-cost statin era. Circulation. 2011;124(2):146-153.
252. 李玟瑾 溫譚羅. 於同類藥品中選最符合成本效益之藥品來治療取代:以Statins為例. 臺灣臨床藥學雜誌. 2011;19(1):11-33.
253. Medicine CfE-B. Oxford Centre for Evidence-based Medicine – Levels of Evidence. Critically Appraising the Evidence 2009; http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/. Accessed June 29, 2015.
254. Sackett DL SS, Richardson WS, et al. Evidence-based medicine: how to practice and teach EBM. 2nd ed. Edinburgh: Churchill Livingstone; 2000.
255. Barron FH, Barrett BE. Decision Quality Using Ranked Attribute Weights. Management Science. 1996;42(11):1515-1523.
256. 莊其穆. 臨床醫師如何閱讀統合分析(Meta-analysis)的論文. 臺灣醫界. 2011;52(2):18.
257. 譚延輝. 新藥如何以價值來核價. In: 醫藥科技評估組 財, ed: 財團法人醫藥品查驗中心; 2009.
258. Goetghebeur MM, Wagner M, Khoury H, Levitt RJ, Erickson LJ, Rindress D. Bridging health technology assessment (HTA) and efficient health care decision making with multicriteria decision analysis (MCDA): applying the EVIDEM framework to medicines appraisal. Medical Decision Making. 2012;32(2):376-388.
259. Doctor discussion is key for cholesterol treatment [press release]. November 30th, 2013 2013.
260. 食品藥物管理局 行. 2005-2008 國人血脂異常之狀況. 台灣營養健康狀況變遷調查 2010; http://nahsit.nhri.org.tw/node/18. Accessed Novenber, 2014.
261. Statistics. NCfH. Health, United States, 2010: With Special Feature on Death and Dying. In: Prevention CfDCa, ed. Washington, DC 20402: U.S. Department of Health and Human Services; 2011.
262. 冠脂妥膜衣錠20毫克. 西藥、醫療器材、化粧品許可證查詢 2015; http://www.fda.gov.tw/MLMS/(S(ouzva145a01yomy2npobqv45))/H0001D.aspx?Type=Lic&LicId=02024129. Accessed May 25, 2015.
263. 張超群. 醫師用藥行為的因素分析─以南部(嘉南高屏)各醫療院所執業中之醫師為例: 高階公共政策碩士班, 國立中山大學; 2013.
264. Smith SC, Jr., Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113(19):2363-2372.
265. Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). American Journal of Cardiology. 2003;92(2):152-160.
266. Haffner SM. Management of dyslipidemia in adults with diabetes. Diabetes Care. 2003;26 Suppl 1:S83-86.
267. Liu YM, Yang YH, Hsieh CR. Financial incentives and physicians' prescription decisions on the choice between brand-name and generic drugs: evidence from Taiwan. Journal of Health Economics. 2009;28(2):341-349.
268. Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. The Lancet Neurology. 2009;8(5):453-463.
269. Amarenco P, Labreuche J, Lavallee P, Touboul PJ. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke. 2004;35(12):2902-2909.
270. Amarenco P, Bogousslavsky J, Callahan A, 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. The New England journal of medicine. 2006;355(6):549-559.
271. 洪乙禎. 醫師處方行為之影響因素研究. 行政院國家科學委員會;2009.
272. 周銘正. 從SID模式探討台灣某外國藥廠供給活動對中部醫學中心與區域醫院的醫師處方行為影響之研究: 高階經理人碩士在職專班, 中興大學; 2008.
273. Applbaum K. Pharmaceutical Marketing and the Invention of the Medical Consumer. PLoS Medicine. 2006;3(4):e189.
274. Cardarelli R, Licciardone JC, Taylor LG. A cross-sectional evidence-based review of pharmaceutical promotional marketing brochures and their underlying studies: is what they tell us important and true? BMC family practice. 2006;7:13.
275. Overgaard AB, Hojsted J, Hansen R, Moller-Sonnergaard J, Christrup LL. Patients' evaluation of shape, size and colour of solid dosage forms. Pharmacy World and Science. 2001;23(5):185-188.
276. Steven Yoder JR, Charlotte Miller, Jason Hansell, Kamlesh Oza. Physical Appearance Preferences for Oral Solid Dosage Formulations. Paper presented at: American Association of Pharmaceutical Scientists (AAPS) 2014; San Diego.
277. Roumie CL, Elasy TA, Wallston KA, et al. Clinical inertia: a common barrier to changing provider prescribing behavior. The Joint Commission Journal on Quality and Patient Safety. 2007;33(5):277-285.
278. Tompkins R, Schwartzbard A, Gianos E, Fisher E, Weintraub H. A current approach to statin intolerance. Clinical Pharmacology & Therapeutics. 2014;96(1):74-80.
279. Fernandez G, Spatz ES, Jablecki C, Phillips PS. Statin myopathy: a common dilemma not reflected in clinical trials. Cleveland Clinic journal of medicine. 2011;78(6):393-403.
280. Maningat P, Breslow JL. Needed: pragmatic clinical trials for statin-intolerant patients. The New England journal of medicine. 2011;365(24):2250-2251.
281. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. The Journal of the American Medical Association. 2002;288(4):462-467.
282. Pasternak RC, Smith SC, Jr., Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Journal of the American College of Cardiology. 2002;40(3):567-572.
283. Armitage J. The safety of statins in clinical practice. Lancet. 2007;370(9601):1781-1790.
284. Shek A, Ferrill MJ. Statin-fibrate combination therapy. Annals of Pharmacotherapy. 2001;35(7-8):908-917.
285. Tachibana-Iimori R, Tabara Y, Kusuhara H, et al. Effect of genetic polymorphism of OATP-C (SLCO1B1) on lipid-lowering response to HMG-CoA reductase inhibitors. Drug metabolism and pharmacokinetics. 2004;19(5):375-380.
286. Ballantyne CM, Corsini A, Davidson MH, et al. Risk for myopathy with statin therapy in high-risk patients. Archives of internal medicine. 2003;163(5):553-564.
287. Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacology & therapeutics. 1999;84(3):413-428.
288. Tobert JA. Efficacy and long-term adverse effect pattern of lovastatin. American Journal of Cardiology. 1988;62(15):28j-34j.
289. Neuvonen PJ NM, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clinical Pharmacology & Therapeutics. 2006;80(6):565-581.
290. Shitara Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacology & therapeutics. 2006;112(1):71-105.
291. Ose L. Pitavastatin: a distinctive lipid-lowering drug. Clinical Lipidology. 2010;5(3):309-323.
292. Administration USFaD. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Drug Interactions & Labeling 2015; http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm. Accessed April 2015, 2015.
293. Susan E. Schober PDMDC, M.S.P.H.; David A. Lacher, M.D.; and Rosemarie Hirsch, M.D., M.P.H.,, Surveys DoHaNE. Prevalence of high serum total cholesterol by age and sex, United States, 2005-2006. 2007.
294. Guiding principles for the care of older adults with multimorbidity: an approach for clinicians: American Geriatrics Society Expert Panel on the Care of Older Adults with Multimorbidity. Journal of the American Geriatrics Society. 2012;60(10):E1-e25.
295. Hajjar ER, Cafiero AC, Hanlon JT. Polypharmacy in elderly patients. The American journal of geriatric pharmacotherapy. 2007;5(4):345-351.
296. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacology & therapeutics. 2013;138(1):103-141.
297. Williams D FJ. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clinical Pharmacokinetics. 2002;41(5):343-370.
298. Ratz Bravo AE, Tchambaz L, Krahenbuhl-Melcher A, Hess L, Schlienger RG, Krahenbuhl S. Prevalence of potentially severe drug-drug interactions in ambulatory patients with dyslipidaemia receiving HMG-CoA reductase inhibitor therapy. Drug safety. 2005;28(3):263-275.
299. 成大醫院藥劑部. 成大醫院藥劑部藥品查詢系統. 2015; http://140.116.253.135/NewHomePage/index.asp, 2015.
300. Tatro DS. Drug Interaction Facts 2012: The Authority on Drug Interactions. Lippincott Williams & Wilkins; 2011.
301. Methodology WCCfDS. ATC/DDD Index 2015. 2015; http://www.whocc.no/atc_ddd_index/. Accessed May 12, 2015.
302. Bakhai A, Rigney U, Hollis S, Emmas C. Co-administration of statins with cytochrome P450 3A4 inhibitors in a UK primary care population. Pharmacoepidemiology and drug safety. 2012;21(5):485-493.
303. Heerey A, Barry M, Ryan M, Kelly A. The potential for drug interactions with statin therapy in Ireland. Irish Journal of Medical Science. 2000;169(3):176-179.
304. 吳家雯. 全民健康保險研究資料庫HMG-CoAReductaseInhibitors處方型態及用藥安全性分析:自藥品交互作用觀點探討: 臨床藥學研究所, 臺灣大學; 2005.
305. 江品儀. Statins引起藥物不良反應之評估:分析其發生率及合併潛在交互作用藥物之影響: 藥學研究所, 國防醫學院; 2010.
306. Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361(9374):2005-2016.
307. Study of the Effectiveness of Additional Reductions in C, Homocysteine Collaborative G. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12 064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010;376(9753):1658-1669.
308. 許郁笙 沈, 李春璟, 蘇淑薰 電腦醫囑系統中藥物交互作用之篩選與用藥品質之相關性評估. 臺灣臨床藥學雜誌. 2011;19(1):1-10.
309. 建立健保雲端藥歷 提升用藥品質 [press release]. 衛生福利部中央健康保險署2013.
310. 王嘉珍、李炳鈺. Statins類藥物不良反應通報案例分析. Vol 27: 財團法人藥害救濟基金會 全國藥物不良反應通報中心; 2009:9-16.

------------------------------------------------------------------------ 第 13 筆 ---------------------------------------------------------------------
系統識別號 U0026-0412201408085300
論文名稱(中文) 上消化道癌症中 RUNX3 及 Pin1 對 β-catenin/cyclin D1 的調控
論文名稱(英文) RUNX3 And Pin1 Regulate β-catenin/cyclin D1 in Cancers of Upper Digestive Tract
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 103
學期 1
出版年 103
研究生(中文) 林逢嘉
學號 S98971055
學位類別 博士
語文別 英文
口試日期 2014-11-28
論文頁數 100頁
口試委員 召集委員-王憶卿
口試委員-劉校生
口試委員-林進清
口試委員-陳尚文
指導教授-許博翔
指導教授-呂佩融
關鍵字(中) RUNX3
Pin1
Akt1
β-catenin
cyclin D1
胃癌
食道鱗狀細胞癌
關鍵字(英) RUNX3
Pin1
Akt1
β-catenin
cyclin D1
gastric cancer
esophageal squamous cell carcinoma
學科別分類
中文摘要 癌症是重要的人類健康問題,胃癌及食道鱗狀細胞癌是常見且致命的疾病。雖然整合運用了各種的治療方式,多數病人依然死於疾病或治療引起的副作用,為了改善現有的及發展新穎的診斷與治療癌症的方式,癌症致病機轉必須更清楚地被研究。
RUNX3是癌症抑制基因,它的抑癌作用最早是在胃癌中被確認,在大約八成的胃癌中RUNX3會有低表現或失去功用的情形。雖然RUNX3已知會透過調控許多分子的表現或作用而抑制胃癌的生成,但是其機轉仍未被透徹地瞭解。所以我的博士論文研究胃癌中RUNX3對β-catenin/ cyclin D1的調控,RUNX3被發現會抑制Akt1的轉錄並降低Akt1的表現量,進而促使β-catenin被分解及cyclin D1的低表現,結果顯示在胃癌中RUNX3的失去功能會促使癌化的進行,其機轉包括Akt1/ β-catenin/ cyclin D1訊息途徑的活化。
β-catenin與cyclin D1也都是Pin1基質,而Pin1已被證實會藉由調控許多抑癌或致癌分子而促使癌症的生成。所以我的博士論文研究食道鱗狀細胞癌中RUNX3對β-catenin與cyclin D1的調控,以細胞株的實驗證明了將Pin1的表現量降低會抑制 β-catenin與cyclin D1的表現量及食道鱗狀細胞癌的生成,也確認在接受手術治療的食道鱗狀細胞癌病患中,Pin1的高表現量與不良預後有相關性,上述結果顯示Pin1會透過β-catenin與cyclin D1而增進食道鱗狀細胞癌惡性度。
綜言之,β-catenin與cyclin D1在胃癌中會被RUNX3抑制,而在食道鱗狀細胞癌中會被Pin1正相關地調控,我的博士論文讓上消化道癌症的致病機轉更清楚地被了解,期望對未來癌症診療業務的改進與發展有所助益。
英文摘要 Cancer is one of major health issues. Gastric cancer and esophageal squamous cell carcinoma (ESCC) are common and fatal malignancy. Despite multi-modality therapies, most patients eventually die from the disease or treatment-related complications. More comprehensive investigations of carcinogenesis and tumor progression are necessary for developing novel diagnostic and therapeutic strategies for these cancers.
RUNX3 is recognized as a tumor suppressor. The tumor suppressive functions of RUNX3 were first reported in gastric epithelial cells. RUNX3 was inactivated by gene silencing or protein mislocalization in more than 80% of gastric cancers. Although restoration of RUNX3 in gastric cancer cells could inhibit tumorigenesis through regulating several target genes, the mechanisms were not clearly understood. The role of RUNX3 in regulating β-catenin and cyclin D1 in gastric cancer was studied in my thesis. RUNX3 repressed Akt1 expression through transcriptional inhibition. Two RUNX3-binding sites on Akt1 promoter were identified. The inhibition of Akt1 facilitated β-catenin degradation followed by cyclin D1 downregulation. The data suggested loss of RUNX3 in gastric cancer promoted tumorigenesis through Akt1/β-catenin/cyclin D1 signaling pathway.
β-catenin and cyclin D1 are well known substrates of Pin1 which is a peptidyl-prolyl isomerase and promotes oncogenesis by regulating multiple oncogenic signaling at various levels. Pin1/β-catenin/cyclin D1 signaling pathway in ESCC was investigated. The experimental evidences were provided that Pin1 knockdown inhibited expression of β-catenin/cyclin D1 and tumorigenesis of ESCC cells. The inhibited tumorigenesis in cells with Pin1 knockdown was partially recovered by cyclin D1 restoration. In addition, high Pin1 expression was correlated with poor prognosis of ESCC patients. The results supported that Pin1 may promote ESCC aggressiveness through β-catenin and cyclin D.
In summary, β-catenin and cyclin D1 are repressed by tumor suppressor RUNX3 but positively regulated by Pin1 in cancers of upper digestive tract. The results of my thesis can help people understand carcinogenic mechanisms and provide rationales for developing novel target therapy of cancer in the future.
論文目次 TABLE OF CONTENTS
Abstract in Chinese II
Abstract in English III-IV
Acknowledgement V
Table of Contents VI-VIII
Table Contents IX
Figure Contents X-XII
Chapter One: Introduction 1
1.1 Cancer 2
1.2 Gastric cancer 2
1.3 Esophageal squamous cell carcinoma 3
1.4 β-catenin 4
1.5 Cyclin D1 4
1.6 RUNX3 5
1.7 Protein interacting with NIMA (never in mitosis A)-1 (Pin1) 6
1.8 The goal and specific aims 8
Chapter Two: Materials and Methods 9
2.1 Cell lines and cell culture 10
2.2 Patients and clinical specimens 10
2.3 Generation of recombinant plasmids 10
2.4 Gene transfection 11
2.5 Western blot analysis 11
2.6 RNA extraction and reverse transcription-polymerase chain reaction 12
2.7 Cell proliferation assay 13
2.8 Colony formation assay 13
2.9 Xenograft tumor growth 13
2.10 Luciferase reporter assay 13
2.11 Immunohistochemistry analysis 14
2.12 Flow cytometry analysis 15
2.13 Human phospho-kinase array 15
2.14 Quantitative real-time polymerase chain reaction 15
2.15 Chromatin immunoprecipitation assay 16
2.16 Immunofluorescence studies 17
2.17 Degradation assay 17
2.18 Statistical analysis 17
Chapter Three: Results 19
3.1 Loss of RUNX3 activates the Akt1/bcatenin/cyclin D1 signaling pathway that promotes tumorigenesis in gastric cancer 20
3.1.1 Restoration of RUNX3 caused cell cycle arrest and inhibited cell proliferation 20
3.1.2 RUNX3 directly repressed Akt1 transcription 21
3.1.3 RUNX3 attenuated the Akt1/-catenin/cyclin D1 signaling pathway 23
3.1.4 RUNX3 reduced -catenin nuclear localization, transactivation and protein stability 24
3.1.5 Restoration of cyclin D1 reversed RUNX3-mediated cell growth inhibition and cell cycle arrest 26
3.2 Pin1 positively affects tumorigenesis of esophageal squamous cell carcinoma and correlates with poor survival of patients 27
3.2.1 Pin1 knockdown inhibites proliferation, clonogenicity and tumorigenesis of ESCC 27
3.2.2 Pin1 upregulation was identified in clinical ESCC specimens and correlated with poor prognosis of patients 27
3.2.3 β-catenin and cyclin D1 were positively regulated by Pin1 28
Chapter Four: Discussion and Conclusion 30
Chapter Five: Tables and Figures 42
Chapter Six: References 87
Theses-related Publications 97
Curriculum Vitae 98
參考文獻 Bao L, Kimzey A, Sauter G, Sowadski JM, Lu KP, Wang DG: Prevalent overexpression of prolyl isomerase Pin1 in human cancers. Am J Pathol. 2004; 164: 1727-37.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME: Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999; 96: 857-68.
Bureau of Health Promotion, Department of Health and Welfare, R.O.C. (Taiwan). Cancer registry annual report, 2011. 2014.
Chang TL, Ito K, Ko TK, Liu Q, Salto-Tellez M, Yeoh KG, Fukamachi H, Ito Y: Claudin-1 has tumor suppressive activity and is a direct target of RUNX3 in gastric epithelial cells. Gastroenterology. 2010; 138: 255-65.
Chuang LS, Ito Y: RUNX3 is multifunctional in carcinogenesis of multiple solid tumors. Oncogene. 2010; 29: 2605-15.
Cinar B, Fang PK, Lutchman M, Di Vizio D, Adam RM, Pavlova N, Rubin MA, Yelick PC, Freeman MR: The pro-apoptotic kinase Mst1 and its caspase cleavage products are direct inhibitors of Akt1. EMBO J. 2007; 26: 4523-34.
Clements WM, Wang J, Sarnaik A, Kim OJ, MacDonald J, Fenoglio-Preiser C, Groden J, Lowy AM: beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res. 2002; 62: 3503-6.
Clevers H: Wnt/beta-catenin signaling in development and disease. Cell. 2006; 127: 469-80.
Czito BG, Denittis AS, Willett CG: Esophageal cancer. In Perez CA and Brady LW. eds. Principles and Practice of Radiation Oncology. 5th ed. Philadelphia: Lippincott Co. 1131-1153, 2008.
Dihlmann S, Kloor M, Fallsehr C, von Knebel Doeberitz M: Regulation of AKT1 expression by beta-catenin/Tcf/Lef signaling in colorectal cancer cells. Carcinogenesis. 2005; 26: 1503-12.
Du K, Tsichlis PN: Regulation of the Akt kinase by interacting proteins. Oncogene. 2005; 24: 7401-9.
Durst KL, Hiebert SW: Role of RUNX family members in transcriptional repression and gene silencing. Oncogene. 2004; 23: 4220-4.
Ebert MP, Fei G, Kahmann S, Müller O, Yu J, Sung JJ, Malfertheiner P: Increased beta-catenin mRNA levels and mutational alterations of the APC and beta-catenin gene are present in intestinal-type gastric cancer. Carcinogenesis. 2002; 23: 87-91.
Fenoglio-Preiser CM, Noffsinger AE, Belli J, Stemmermann GN: Pathologic and phenotypic features of gastric cancer. Semin Oncol. 1996; 23: 292-306.
Fischer G, Aumuller T: Regulation of peptide bond cis/transisomerization by enzyme catalysis and its implication in physiological processes. Rev Physiol Biochem Pharmacol. 2003; 148: 105–50.
Fujii S, Ito K, Ito Y, Ochiai A: Enhancer of zeste homologue 2 (EZH2) down-regulates RUNX3 by increasing histone H3 methylation. J Biol Chem. 2008; 283: 17324–32.
Fukuchi M, Fukai Y, Kimura H, Sohda M, Miyazaki T, Nakajima M, Masuda N, Tsukada K, Kato H, Kuwano H: Prolyl isomerase Pin1 expression predicts prognosis in patients with esophageal squamous cell carcinoma and correlates with cyclin D1 expression. Int J Oncol. 2006; 29: 329-34.
Gao YB, Chen ZL, Li JG, Hu XD, Shi XJ, Sun ZM, Zhang F, Zhao ZR, Li ZT, Liu ZY, Zhao YD, Sun J, Zhou CC, Yao R, Wang SY, Wang P, Sun N, Zhang BH, Dong JS, Yu Y, Luo M, Feng XL, Shi SS, Zhou F, Tan FW, Qiu B, Li N, Shao K, Zhang LJ, Zhang LJ, Xue Q, Gao SG, He J: Genetic landscape of esophageal squamous cell carcinoma. Nat Genet. 2014 doi: 10.1038/ng.3076. [Epub ahead of print]
Gebski V, Burmeister B, Smithers BM, Foo K, Zalcberg J, Simes J; Australasian Gastro-Intestinal Trials Group: Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol. 2007; 8: 226-34.
Gunderson LL, Sosin H: Adenocarcinoma of the stomach: areas of failure in a re-operation series (second or symptomatic look) clinicopathologic correlation and implications for adjuvant therapy. Int J Radiat Oncol Biol Phys. 1982; 8: 1-11.
Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell. 2011; 144: 646-74.
Hong L, Han Y, Zhang H, Li M, Gong T, Sun L, Wu K, Zhao Q, Fan D: The prognostic and chemotherapeutic value of miR-296 in esophageal squamous cell carcinoma. Ann Surg. 2010; 251: 1056-63.
Hsu PI, Hsieh HL, Lee J, Lin LF, Chen HC, Lu PJ, Hsiao M: Loss of RUNX3 expression correlates with differentiation, nodal metastasis, and poor prognosis of gastric cancer. Ann Surg Oncol. 2009; 16: 1686-94.
Ito K, Lim AC, Salto-Tellez M, Motoda L, Osato M, Chuang LS, Lee CW, Voon DC, Koo JK, Wang H, Fukamachi H, Ito Y: RUNX3 attenuates β-catenin/T cell factors in intestinal tumorigenesis. Cancer Cell 2008; 14: 226-37.
Ito Y: RUNX genes in development and cancer: regulation of viral gene expression and the discovery of RUNX family genes. Adv Cancer Res. 2008; 99: 33-76.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011; 61: 69-90.
Jin H, Jiang J, Sun L, Zheng F, Wu C, Peng L, Zhao Y, Wu X: The prolyl isomerase Pin1 is overexpressed in human esophageal cancer. Oncol Lett. 2011; 2: 1191-6.
Jin YH, Jeon EJ, Li QL, Lee YH, Choi JK, Kim WJ, Lee KY, Bae SC: Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation. J Biol Chem. 2004; 279: 29409-17.
Kahn M: Can we safely target the WNT pathway? Nat Rev Drug Discov. 2014; 13: 513-32.
Kamangar F, Chow WH, Abnet CC, Dawsey SM: Environmental causes of esophageal cancer. Gastroenterol Clin North Am. 2009; 38: 27-57.
Kim JH, Choi JK, Cinghu S, Jang JW, Lee YS, Li YH, Goh YM, Chi XZ, Lee KS, Wee H, Bae SC: Jab1/CSN5 induces the cytoplasmic localization and degradation of RUNX3. J Cell Biochem. 2009; 107: 557-65.
Kim S, Koga T, Isobe M, Kern BE, Yokochi T, Chin YE, Karsenty G, Taniguchi T, Takayanagi H: Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation. Genes Dev. 2003; 17: 1979-91.
Kordes S, van Berge Henegouwen MI, Hulshof MC, Bergman JJ, van der Vliet HJ, Kapiteijn E, van Laarhoven HW, Richel DJ, Klinkenbijl JH, Meijer SL, Wilmink JW: Preoperative Chemoradiation Therapy in Combination With Panitumumab for Patients With Resectable Esophageal Cancer: The PACT Study. Int J Radiat Oncol Biol Phys. 2014; 90: 190-6.
Lee KH, Lin FC, Hsu TI, Lin JT, Guo JH, Tsai CH, Lee YC, Lee YC, Chen CL, Hsiao M, Lu PJ: MicroRNA-296-5p (miR-296-5p) functions as a tumor suppressor in prostate cancer by directly targeting Pin1. Biochim Biophys Acta. 2014; 1843: 2055-66.
Lee SH, Kim J, Kim WH, Lee YM: Hypoxic silencing of tumor suppressor RUNX3 by histone modification in gastric cancer cells. Oncogene. 2009; 28: 184–94.
Li QL, Ito K, Sakakura C, Fukamachi H, Inoue Ki, Chi XZ, Lee KY, Nomura S, Lee CW, Han SB, Kim HM, Kim WJ, Yamamoto H, Yamashita N, Yano T, Ikeda T, Itohara S, Inazawa J, Abe T, Hagiwara A, Yamagishi H, Ooe A, Kaneda A, Sugimura T, Ushijima T, Bae SC, Ito Y: Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell. 2002; 109: 113-24.
Li T, Lu YY, Zhao XD, Guo HQ, Liu CH, Li H, Zhou L, Han YN, Wu KC, Nie YZ, Shi YQ, Fan DM: MicroRNA-296-5p increases proliferation in gastric cancer through repression of Caudal-related homeobox 1. Oncogene. 2014; 33: 783-93.
Li VS, Wong CW, Chan TL, Chan AS, Zhao W, Chu KM, So S, Chen X, Yuen ST, Leung SY: Mutations of PIK3CA in gastric adenocarcinoma. BMC Cancer. 2005; 5: 29.
Liou YC, Ryo A, Huang HK, Lu PJ, Bronson R, Fujimori F, Uchida T, Hunter T, Lu KP: Loss of Pin1 function in the mouse causes phenotypes resembling cyclin D1-null phenotypes. Proc Natl Acad Sci USA 2002; 99: 1335-40.
Liou YC, Zhou XZ, Lu KP: Prolyl isomerase Pin1 as a molecular switch to determine the fate of phosphoproteins. Trends Biochem Sci. 2011; 36: 501-14.
Lu KP, Zhou XZ: The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol. 2007; 8: 904-16.
Lu PJ, Zhou XZ, Shen M, Lu KP: Function of WW domains as phosphoserine- or phosphothreonine-binding modules. Science. 1999; 283: 1325-8.
Maira SM, Galetic I, Brazil DP, Kaech S, Ingley E, Thelen M, Hemmings BA: Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane. Science. 2001; 294: 374-80.
Malumbres M, Barbacid M: Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009; 9: 153-66.
Misra UK, Pizzo SV: Upregulation of AKT1 protein expression in forskolin- stimulated macrophage: evidence from ChIP analysis that CREB binds to and activates the AKT1 promoter. J Cell Biochem. 2007; 100: 1022-33.
McLean MH, El-Omar EM: Genetics of gastric cancer. Nat Rev Gastroenterol Hepatol. 2014 Aug 19. doi: 10.1038/nrgastro.2014.143. [Epub ahead of print]
Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL: Cyclin D as a therapeutic target in cancer. Nat Rev Cancer. 2011; 11: 558-72.
National Comprehensive Cancer Network. Gastric cancer: NCCN Clinical Practice Guidelines in Oncology. Version 2. 2013.
Nicole Tsang YH, Wu XW, Lim JS, Wee Ong C, Salto-Tellez M, Ito K, Ito Y, Chen LF: Prolyl isomerase Pin1 downregulates tumor suppressor RUNX3 in breast cancer. Oncogene. 2013; 32: 1488-96.
Ogawa S, Satake M, Ikuta K. Physical and functional interactions between STAT5 and Runx transcription factors. J Biochem. 2008; 143: 695-709.
Oki E, Baba H, Tokunaga E, Nakamura T, Ueda N, Futatsugi M, Mashino K, Yamamoto M, Ikebe M, Kakeji Y, Maehara Y: Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int J Cancer. 2005; 117: 376-80.
Ono H, Sakoda H, Fujishiro M, Anai M, Kushiyama A, Fukushima Y, Katagiri H, Ogihara T, Oka Y, Kamata H, Horike N, Uchijima Y, Kurihara H, Asano T: Carboxy-terminal modulator protein induces Akt phosphorylation and activation, thereby enhancing antiapoptotic, glycogen synthetic, and glucose uptake pathways. Am J Physiol Cell Physiol. 2007; 293: C1576-1585.
Osaki M, Oshimura M, Ito H: PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis. 2004; 9: 667-76.
Park S, Kim D, Kaneko S, Szewczyk KM, Nicosia SV, Yu H, Jove R, Cheng JQ: Molecular cloning and characterization of the human AKT1 promoter uncovers its up-regulation by the Src/Stat3 pathway. J Biol Chem. 2005; 280: 38932–41.
Pestell RG: New roles of cyclin D1. Am J Pathol. 2013; 1831: 3-9.
Pradeep A, Sharma C, Sathyanarayana P, Albanese C, Fleming JV, Wang TC, Wolfe MM, Baker KM, Pestell RG, Rana B: Gastrin-mediated activation of cyclin D1 transcription involves beta-catenin and CREB pathways in gastric cancer cells. Oncogene. 2004; 23: 3689-99.
Remy I, Montmarquette A, Michnick SW: PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3. Nat Cell Biol. 2004; 6: 358-65.
Ryo A, Nakamura N, Wulf G, Liou YC, Lu KP: Pin1 regulates turnover and subcellular localization of β-catenin by inhibiting its interaction with APC. Nat Cell Biol. 2001; 3: 793–801.
Sakakura C, Miyagawa K, Fukuda KI, Nakashima S, Yoshikawa T, Kin S, Nakase Y, Ida H, Yazumi S, Yamagishi H, Okanoue T, Chiba T, Ito K, Hagiwara A, Ito Y: Frequent silencing of RUNX3 in esophageal squamous cell carcinomas is associated with radioresistance and poor prognosis. Oncogene 2007; 26: 5927–38.
Samatar AA, Wang L, Mirza A, Koseoglu S, Liu S, Kumar CC: Transforming growth factor-beta 2 is a transcriptional target for Akt/protein kinase B via forkhead transcription factor. J Biol Chem. 2002; 277: 28118-26.
Savi F, Forno I, Faversani A, Luciani A, Caldiera S, Gatti S, Foa P, Ricca D, Bulfamante G, Vaira V, Bosari S: miR-296/Scribble axis is deregulated in human breast cancer and miR-296 restoration reduces tumour growth in vivo. Clin Sci (Lond). 2014; 127: 233-42.
Sherr CJ, Roberts JM: Living with or without cyclins and cyclin-dependent kinases. Genes Dev. 2004; 18: 2699–711.
Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, Barbour A, Gebski V; Australasian Gastro-Intestinal Trials Group: Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol. 2011; 12: 681-92.
Song S, Mazurek N, Liu C, Sun Y, Ding QQ, Liu K, Hung MC, Bresalier RS: Galectin-3 mediates nuclear beta-catenin accumulation and Wnt signaling in human colon cancer cells by regulation of glycogen synthase kinase-3beta activity. Cancer Res. 2009; 69: 1343–9.
Soung YH, Lee JW, Nam SW, Lee JY, Yoo NJ, Lee SH: Mutational analysis of AKT1, AKT2 and AKT3 genes in common human carcinomas. Oncology. 2006; 70: 285-9.
Spigel DR, Greco FA, Meluch AA, Lane CM, Farley C, Gray JR, Clark BL, Burris HA 3rd, Hainsworth JD: Phase I/II trial of preoperative oxaliplatin, docetaxel, and capecitabine with concurrent radiation therapy in localized carcinoma of the esophagus or gastroesophageal junction. J Clin Oncol. 2010; 28: 2213-9.
Stock M, Otto F: Gene deregulation in gastric cancer. Gene. 2005; 360: 1-19.
Subramaniam MM, Chan JY, Yeoh KG, Quek T, Ito K, Salto-Tellez M: Molecular pathology of RUNX3 in human carcinogenesis. Biochim Biophys Acta. 2009; 1796: 315-31.
Tonomoto Y, Tachibana M, Dhar DK, Onoda T, Hata K, Ohnuma H, Tanaka T, Nagasue N: Differential expression of RUNX genes in human esophageal squamous cell carcinoma: downregulation of RUNX3 worsens patient prognosis. Oncology. 2007; 73: 436-56.
van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, Cuesta MA, Blaisse RJ, Busch OR, ten Kate FJ, Creemers GJ, Punt CJ, Plukker JT, Verheul HM, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJ, Rozema T, Biermann K, Beukema JC, Piet AH, van Rij CM, Reinders JG, Tilanus HW, van der Gaast A; CROSS Group: Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012; 366: 2074-84.
Wei D, Gong W, Oh SC, Li Q, Kim WD, Wang L, Le X, Yao J, Wu TT, Huang S, Xie K: Loss of RUNX3 expression significantly affects the clinical outcome of gastric cancer patients and its restoration causes drastic suppression of tumor growth and metastasis. Cancer Res. 2005; 65: 4809-16.
Würdinger T, Tannous BA, Saydam O, Skog J, Grau S, Soutschek J, Weissleder R, Breakefield XO, Krichevsky AM: miR-296 regulates growth factor receptor overexpression in angiogenic endothelial cells. Cancer Cell. 2008; 14: 382-93.
Xing X, Wang J, Xing LX, Li YH, Yan X, Zhang XH: Involvement of MAPK and PI3K signaling pathway in sterigmatocystin-induced G2 phase arrest in human gastric epithelium cells. Mol Nutr Food Res. 2011; 55: 749–60.
Xu XC: Risk factors and gene expression in esophageal cancer. Methods Mol Biol. 2009; 471: 335-60.
Yamamura Y, Lee WL, Inoue K, Ida H, Ito Y: RUNX3 cooperates with FoxO3a to induce apoptosis in gastric cancer cells. J Biol Chem. 2006; 281: 5267-76.
Yeh ES, Means AR: PIN1, the cell cycle and cancer. Nat Rev Cancer. 2007; 7: 381-8.
Ziros PG, Georgakopoulos T, Habeos I, Basdra EK, Papavassiliou AG: Growth hormone attenuates the transcriptional activity of Runx2 by facilitating its physical association with Stat3beta. J Bone Miner Res. 2004; 19: 1892-904.

------------------------------------------------------------------------ 第 14 筆 ---------------------------------------------------------------------
系統識別號 U0026-0412201412585700
論文名稱(中文) 適用於三維晶片以矩陣摺積技術為主之電子系統層級高效溫度模擬器
論文名稱(英文) A highly effective transient thermal simulator using matrix convolution at Electronic System Level for three-dimensional integrated circuits
校院名稱 成功大學
系所名稱(中) 電機工程學系
系所名稱(英) Department of Electrical Engineering
學年度 103
學期 1
出版年 103
研究生(中文) 蘇鈺雄
學號 N26004870
學位類別 碩士
語文別 英文
口試日期 2014-11-24
論文頁數 48頁
口試委員 指導教授-邱瀝毅
口試委員-陳中和
口試委員-雷曉方
關鍵字(中) 溫度模擬器
矩陣摺積
三維晶片
暫態分析
關鍵字(英) thermal simulator
matrix convolution
three-dimensional integrated circuits
transient analysis
power blurring
學科別分類
中文摘要 隨著整體製程的微縮以及系統上對功能要求的提高,在晶片上的功率消耗與隨之而來的熱也不斷地增加。半導體晶片對熱的忍受度是有限的,若有過度的熱在晶片上會導致系統功能故障、可靠度降低、壽命減短、消耗功率增加等副作用。單純只依靠封裝技術散熱會增加晶片的成本百分之二十至八十不等。因此在設計時必須要利用溫度模擬器來考量晶片的受熱狀況。一個好的溫度模擬器必須盡量滿足模型建構快、可重複使用模型、支援不同系統架構與封裝、執行速度快等各種條件。另外對於現今運作頻率越來越高的晶片,傳統上所使用的穩態分析已經不足以反映現實環境在時間與空間上的快速變化。為了解決以上所提的各種問題,本論文致力於打造一個以矩陣摺積技術為主之高效溫度模擬器,支援最新的三維晶片設計技術與暫態分析,並在電子系統層級上實作以期與更多相關技術與平台連結。
英文摘要 As technology shrinks and performance requirement raises, power consumption creates great amount of heat. Excessive heat causes function failure, reliability downgrade and other side effects. Chip cost increases by 20~80% if only package and assembly are considered for maintaining normal temperature under severe thermal circumstances. Thermal-aware designs require thermal simulators to accurately predict temperature distribution on chip before tapeout. An ideal thermal simulator builds models fast and efficiently, support different architecture and package with short execution time. Nevertheless, faster operational frequency made traditional steady-state analysis inadequate for simulating real world circumstances. This work devoted to build a highly effective transient thermal simulator using matrix convolution at Electronic System Level. Proposed simulator applies thermal-aware transient power blurring algorithm save 99% of execution time against ANSYS ICEPAK with only 4% error and extend power blurring to three-dimension analysis.
論文目次 摘 要 i
Abstract ii
誌 謝 iii
Contents iv
List of Tables vii
List of Figures viii
Chapter 1 Introduction 1
1.1 Motivation 1
1.2 Background 3
1.2.1 Thermal simulators 3
1.2.2 Early thermal evaluation 5
1.2.3 Supporting different architecture 5
1.2.4 Collaboration with other models 5
1.2.5 Transient / Steady-state analysis 6
1.3 Problem description 6
1.4 Contributions 7
1.5 Organization of thesis 7
Chapter 2 Related Works 8
2.1 Thermal models 8
2.1.1 Finite Difference Method/Finite Element Method 8
2.1.2 Thermal RC 10
2.2 Matrix convolution based technique 11
2.2.1 Power blurring 11
2.2.2 Convolution by Image 12
2.2.3 Intrinsic error 13
2.2.4 Temperature variation 14
2.2.5 Look-up table based method 15
2.3 Three-dimensional integrated circuits 15
2.3.1 Multiple active layers 16
2.3.2 Through Silicon Via (TSV) 16
Chapter 3 Proposed Method 18
3.1 Problem description 18
3.2 Mask construction 19
3.3 Transient analysis 20
3.4 Convolution 21
3.5 Thermal related issues 21
3.5.1 Conduction 22
3.5.2 Convection 22
3.6 3D issue 22
3.7 Algorithm of the simulator 23
3.8 Pseudo code of the thermal simulator 25
Chapter 4 Experimental Results and Analysis 27
4.1 General experimental setup 27
4.1.1 Test cases 27
4.1.2 Meshing conditions 28
4.1.3 Error calculation 29
4.2 Transient analysis 29
4.2.1 Experimental environment and setup 30
4.2.2 Validation flow 30
4.2.3 Transient simulation 30
4.3 Conduction analysis 32
4.3.1 Experimental environment and setup 32
4.3.2 Validation flow 32
4.3.3 Conduction effect 32
4.4 Convection analysis 33
4.4.1 Experimental environment and setup 34
4.4.2 Mask adaption for different temperature 34
4.5 Transient analysis 35
4.5.1 Experimental environment and setup 35
4.5.2 Error analysis 35
4.6 3D simulation 36
4.6.1 Experimental environment and setup 36
4.6.2 Stacked structure 37
4.7 Mask size analysis 38
4.7.1 Experimental environment and setup 38
4.7.2 Mask size trade-off 38
4.8 Speed analysis and memory analysis 40
4.8.1 Experimental environment and setup 40
4.8.2 Speed analysis 41
4.8.3 Memory usage analysis 41
Chapter 5 Conclusion and Future Works 43
5.1 Conclusion of this work 43
5.2 Future works 43
5.2.1 Real world validation 43
5.2.2 Radiation effect 44
5.2.3 Fast matrix convolution 44
5.2.4 Three-dimensional ICs 44
References 45
個人簡歷 48
參考文獻 [1] K. L. Wang, K. Galatsis, R. Ostroumov, A. Khitun, Z. Zhao, and S. Han, "Nanoarchitectonics for heterogeneous integrated nanosystems," Proceedings of the IEEE, vol. 96, pp. 212-229, Feb. 2008.
[2] K. Dae Hyun, K. Athikulwongse, M. Healy, M. Hossain, J. Moongon, I. Khorosh, et al., "3D-MAPS: 3D Massively parallel processor with stacked memory," in Proc. Int. Solid-State Circuits Conference Digest of Technical Papers (ISSCC), pp. 188-190, Feb. 2012.
[3] S. Pateras, "3D-IC Testing with the Mentor Graphics Tessent Platform," Silicon Test and Yield Analysis, Oct. 2011.
[4] S. A. Alqaffas, “Front end planning may take time, but will save you big time in the end”, [Online], Available: http://www.isa.org/InTechTemplate.cfm?Section=Communitie
s2&template=/TaggedPage/DetailDisplay.cfm&ContentID=64736
[5] H. Wei, K. Skadron, S. Gurumurthi, R. J. Ribando, and M. R. Stan, "Differentiating the roles of IR measurement and simulation for power and temperature-aware design," IEEE Int. Symp. Performance Analysis of Systems and Software (ISPASS), pp. 1-10, 2009.
[6] K. Skadron, M. R. Stan, H. Wei, S. Velusamy, K. Sankaranarayanan, and D. Tarjan, "Temperature-aware microarchitecture," in Proc. Int. Symp. Computer Architecture, pp. 2-13, 2003.
[7] M. Pedram and S. Nazarian, "Thermal Modeling, Analysis, and Management in VLSI Circuits: Principles and Methods," Proceedings of the IEEE, vol. 94, pp. 1487-1501, 2006.
[8] K. Skadron, T. Abdelzaher, and M. R. Stan, "Control-theoretic techniques and thermal-RC modeling for accurate and localized dynamic thermal management," in Proc . Int. Symp. High-Performance Computer Architecture(HPCA), pp. 17-28, 2002.
[9] H. Wei, M. R. Stan, K. Skadron, K. Sankaranarayanan, S. Ghosh, and S. Velusamy, "Compact thermal modeling for temperature-aware design," in Proc. Design Automation Conference, pp. 878-883, 2004.
[10] K. Sankaranarayanan, S. Velusamy, M. Stan and K. Skadron, "A Case for Thermal-Aware Floorplanning at the Microarchitectural Level," J. Instruction-Level Parallelism, vol. 7, Oct. 2005.
[11] H. Wei, K. Sankaranarayanan, K. Skadron, R. J. Ribando, and M. R. Stan, "Accurate, Pre-RTL Temperature-Aware Design Using a Parameterized, Geometric Thermal Model," IEEE Trans. Computer, vol. 57, pp. 1277-1288, 2008.
[12] A. Ziabari and A. Shakouri, "Fast thermal simulations of vertically integrated circuits (3D ICs) including thermal vias," IEEE Intersociety Conference on Thermal and Thermomechanical Phenomena in Electronic Systems (ITHERM), pp. 588-596, 2012.
[13] Y. Z. T. Kemper, Zhixi Bian and Ali Shakouri, "Ultrafast Temperature Profile Calculation In IC Chips," in International Workshop on Thermal Investigation of ICs and Systems (THERMINIC), Sep. 2006.
[14] A. Ziabari, E. K. Ardestani, J. Renau, and A. Shakouri, "Fast thermal simulators for architecture level integrated circuit design," in Proc. Symp. Semiconductor Thermal Measurement and Management (SEMI-THERM), pp. 70-75, 2011.
[15] S. Melamed, T. Thorolfsson, T. R. Harris, S. Priyadarshi, P. Franzon, M. B. Steer, et al., "Junction-Level Thermal Analysis of 3-D Integrated Circuits Using High Definition Power Blurring," IEEE Trans. Computer-Aided Design of Integrated Circuits and Systems, vol. 31, pp. 676-689, 2012.
[16] P. Chi-Wen, L. Yu-Min, H. Pei-Yu, Y. Chi-Ping, L. Chang-Tzu, L. Chia-Hsin, et al., "I-LUTSim: An iterative look-up table based thermal simulator for 3-D ICs," in Proc. Asia and South Pacific Design Automation Conference (ASP-DAC), pp. 151-156, 2013.
[17] Y. Yonghong, G. Zhenyu, Z. Changyun, R. P. Dick, and S. Li, "ISAC: Integrated Space-and-Time-Adaptive Chip-Package Thermal Analysis," IEEE Trans. Computer-Aided Design of Integrated Circuits and Systems, vol. 26, pp. 86-99, 2007.
[18] J.H. Park, V. M. Hériz, A. Shakouri, and S.-M. Kang, "Ultra Fast Calculation of Temperature Profiles of VLSI ICs in Thermal Packages Considering Parameter Variations," in Proc. Int. Symp. Microelectronics(IMAPS), 2007.
[19] C. Lih-Yih, L. Liang-Ying, C. Zhao-Hong, S. Yu-Hsiung, Y. Jen-Chieh, C. Yi-Fan, et al., "System thermal analysis of 3D IC on ESL virtual platform," in Int. SoC Design Conference (ISOCC), pp. 394-397, 2013.
[20] C. J. Glassbrenner and G. A. Slack, “Thermal Conductivity of Silicon and Germanium from 3°K to the Melting Point,” Physical Review, pp.1058-1069, Dec. 1964.
[21] P. Flubacher, A. J. Leadbetter, and J. A. Morrison,” The heat capacity of pure silicon and germanium and properties of their vibrational frequency spectra,” Philosophical Magazine, vol. 4, pp.273-294, 1959.
[22] ANSYS ICEPAK13.0.2, [Online], Available: http://www.ansys.com
[23] G. E. Moore, "Cramming more components onto integrated circuits,” Electronics Magazine, pp. 114-117, Apr. 1965
[24] M.W. Wu, [Online], Available: http://phys.thu.edu.tw/~mengwen/UniversityPhy
sics/Halliday-problem/Note-physics-CH18.pdf
[25] W. G. Simon,"Transistor Count and Moore's Law", [Online], Available: http://en.wikipedia.org/wiki/Moore%27s_law
[26] Y.M. Lee, T.H. Wu, P.Y. Huang, and C.P. Yang, "NUMANA: A hybrid numerical and analytical thermal simulator for 3-D ICs," in Design, Automation & Test in Europe Conference & Exhibition (DATE), pp. 1379-1384, 2013.
[27] P. J. Hyoung, W. Xi, A. Shakouri, and K. Sung-Mo, "Fast Computation of Temperature Profiles of VLSI ICs with High Spatial Resolution," in Semiconductor Thermal Measurement and Management Symposium (SEMITHERM), pp. 50-54, 2008.
[28] P. J. Hyoung, S. Sangho, J. Christofferson, A. Shakouri, and K. Sung-Mo, "Experimental validation of the power blurring method," in Semiconductor Thermal Measurement and Management Symposium (SEMITHERM), pp. 240-244, 2010.
[29] V. M. Heriz, P. Je-Hyoung, T. Kemper, K. Sung-Mo, and A. Shakouri, "Method of images for the fast calculation of temperature distributions in packaged VLSI chips," in Int. Workshop on Thermal Investigation of ICs and Systems(THERMINIC), pp. 18-25, 2007.
[30] A.Ziabari, Z.Bian, and A. Shakouri, "Adaptive Power Blurring Techniques to Calculate IC Temperature Profile under Large Temperature Variations," in Proc. International Symposium on Microelectronics (IMAPS), 2010.
[31] D. Hua, W. Wei, Q. Zhiliang, T. Chi-Ying, and L. Liangzhen, "Thermal modeling of three-dimensional integrated circuits considering the thermal removal capability of different TSVs," in Proc. Asia Symposium Quality Electronic Design (ASQED), pp. 1-7, 2011.
[32] D. Oh, C. C. P. Chen, and Y. H. Hu, "Efficient Thermal Simulation for 3-D IC With Thermal Through-Silicon Vias," IEEE Trans. Computer-Aided Design of Integrated Circuits and Systems, vol. 31, pp. 1767-1771, Nov. 2012.
[33] Z. H. Chen, “Thermal-Aware ESL Virtual Platform for Multi-Processor Systems with Voltage and Frequency Scaling,” M.S. dissertation, Department of Electrical Engineering, National Cheng-Jung University, Tainan, Taiwan, July. 2012.
[34] P. E. Weng, "Architecture-aware instruction-based power model considering voltage and frequency scaling for ESL virtual platforms," M.S. dissertation, Department of Electrical Engineering, National Cheng-Jung University, Tainan, Taiwan, July. 2012.

------------------------------------------------------------------------ 第 15 筆 ---------------------------------------------------------------------
系統識別號 U0026-0508201520311000
論文名稱(中文) 腦幹核區的G蛋白偶合受體經二聚體化後會促使高血壓的形成
論文名稱(英文) GPCR-Dimerization in Brainstem Nuclei Contributes to the Development of Hypertension
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 103
學期 2
出版年 104
研究生(中文) 孫國清
學號 S98971063
學位類別 博士
語文別 英文
口試日期 2015-06-05
論文頁數 136頁
口試委員 指導教授-曾清俊
共同指導教授-呂佩融
口試委員-張雅雯
召集委員-蕭宏昇
口試委員-劉秉彥
口試委員-何文譽
關鍵字(中) 嗎啡受體
血壓
異源二聚體
孤立束核
一氧化氮
關鍵字(英) mu opioid receptors
blood pressure
heterodimer
nucleus tractus solitarii
nitric oxide
學科別分類
中文摘要 在生物體內中樞神經系統的延腦孤立束核,已知會有嗎啡接受器、內生性嗎啡前驅物,前腦啡黑細胞促素皮促素(pro-opiomelanocortin,POMC),及腦啡肽原(pro-enkephalin)的高度表現。這暗示,除了廣為人所熟知的止痛效果外,嗎啡可能有鲜為人知的心血管調控作用。相關研究指出,mu型嗎啡作用在孤立束核所造成的升血壓效果,會有劑量依賴(dose-dependent)的現象;即當劑量增加時其血壓也呈比例的增加。但其中詳細的分子作用機轉目前仍不清楚。在周邊感壓反射的主要投射中樞,孤立束核上,會有多種參與調控自主神經活性的神經傳導物質以及相關的接受器,這包含了同屬於抑制型G蛋白偶合受體的mu型嗎啡接受器以及alpha2a型腎上腺素接受器。先前活體外的實驗已證實mu型嗎啡接受器會與alpha2a型腎上腺素接受器形成所謂的異源二聚體 (heterodimer)。活化/抑制異源二聚體,會產生異於單一接受器的藥理學反應。相關的後續活體外研究指出:當mu型嗎啡接受器與alpha2a型腎上腺素接受器形成異源二聚體後,會造成alpha2a型腎上腺素接受器活性的減低。而許多研究已證實,中樞神經系統中的alpha2a型腎上腺素接受器活性降低,是造成血壓上升的原因之一。因此,我們假設中樞性高血壓的形成,有可能是在孤立束核上,mu型嗎啡接受器與alpha2a型腎上腺素接受器形成異源二聚體後,所造成alpha2a型腎上腺素接受器降血壓功能的活性降低所導致的。因此,首先,分別在正常血壓大鼠以及在高血壓大鼠的孤立束核上,先利用免疫螢光染色法去證實,mu型嗎啡接受器會與alpha2a型腎上腺素接受器有共同區域化現象(colocalization)。接著,再利用免疫共同沉澱法去證實,mu型嗎啡接受器會與alpha2a型腎上腺素接受器有相互作用(interaction)的現象。最後,再透過原位鄰位連接分析(in situ proximity ligation assay),直接去證實在孤立束核上,mu型嗎啡接受器確實會與alpha2a型腎上腺素接受器形成異源二聚體。接下來利用正常血壓大鼠,透過在孤立束核給予mu型嗎啡專一型作用劑(DAMGO)顯微注射,證實mu型嗎啡作用劑除了會造成血壓的上升外,還會誘使mu型嗎啡接受器與alpha2a型腎上腺素接受器異源二聚體的形成與異常的增加。相對的,在正常血壓大鼠孤立束核上,給予alpha2a型腎上腺素專一型作用劑(guanfacine)顯微注射,則並不會造成異源二聚體的形成。誘導異源二聚體形成與異常增加的mu型嗎啡專一型作用劑,在正常血壓大鼠孤立束核,顯微注射所造成血壓的上升,會合併相對應的一氧化氮產生減少。而這樣的現象,也可以在異源二聚體異常增多的高血壓大鼠孤立束上,觀察到相同的血壓上升,所呼應一氧化氮相對的減少。這樣的結果暗示著:原本用以透過一氧化氮生成增加,來降低血壓的alpha2a型腎上腺素接受器,在不管是內生性或是外因性所造成異位二聚體形成增加後,其alpha2a型腎上腺素接受器的活性確實是下降的。
依據上述的結果證實,在孤立束核中,異常增加的內生性mu型嗎啡會誘導mu型嗎啡接受器/alpha2a型腎上腺素接受器的異源二聚體形成增加,進而造成依賴一氧化氮生成來調控血壓的alpha2a型腎上腺素接受器活性的下降,因而造成高血壓的形成。
英文摘要 μ-Opioid receptors (μORs), pro-opiomelanocortin, and pro-enkephalin are highly expressed in the nucleus tractus solitarii (NTS). μ-Opioid agonists in the NTS cause dose-dependent increases in blood pressure (BP). However, the molecular mechanisms of this process remain unclear. Previous studies have revealed that the μORs heterodimerise with the α2A-adrenergic receptors (α2A-ARs) in vitro. We hypothesised that α2A-ARs lose their depressor effect when components of μOR/α2A-AR heterodimers in the NTS. Immunofluorescence staining revealed the colocalization of α2A-ARs and μORs in NTS neurons. A coimmunoprecipitation study also revealed an interaction between α2A-ARs and μORs. An in situ proximity ligation assay confirmed that μOR/α2A-AR heterodimers were present in the NTS. More endogenous endomorphin-1 and μOR/α2A-AR heterodimers were found in the NTS of hypertensive rats than in those of normotensive rats. Microinjection of the μOR agonist [D-Ala2, MePhe4, Gly5-ol]-enkephalin (DAMGO) into the NTS of normotensive rats promoted μOR/α2A-AR heterodimer-formations and BP elevation; however, the α2A-AR agonist guanfacine did not have the same effect. The nitric oxide (NO)-dependent BP-lowering effect of α2A-ARs was blunted as a result of greater μOR/α2A-AR heterodimer-formations in the NTS of hypertensive rats and DAMGO-treated normotensive rats. Our results suggest that inappropriate increases in endogenous μ-opioids in the NTS induce μOR/α2A-AR heterodimer-formations and reduce the NO-dependent depressor effect of α2A-ARs. Therefore, this process contributes to the pathogenesis of hypertension.
論文目次 目錄
摘要...............I
Abstract...............III誌謝..............IV
List of abbreviation.. ...........VI
目錄..............IX
List of figures ............XIII
List of tables.............XVII
Chapter 1
Introduction....01
Blood pressure regulation...........01
The nucleus of the solitary tract and Hypertension .......05
The role of NO in hypertension..........09
Effects of α2A-AR in central nerve system.......12
Effects of μOR in central nerve system........16
G protein-coupled receptor...........20
Functional consequences of heterodimerization......23
Altered heterodimerization leading to clinical disorder.....26
The implication of interaction of μOR and α2A-AR in the pathogenesis of hypertension.............30
Hypothesis and specific aims..........34
To confirm the heterodimerization of μORs and α2A-ARs in the NTS..34
To study the association of μORs/α2A-ARs heterodimers-formation and BP..35
To study the causes of μOR/α2A-AR heterodimer-formation in the NTS..36
To confirm the pathogenetic role of μOR/α2A-AR heterodimer- formation in the NTS on hypertension development........37
To investigate the mechanisms of μOR/α2A-AR heterodimer-mediated hypertension.............37
Chapter 2
Materials and methods.....39
Animals..............39
Intra-NTS microinjection...........39
Co-immunoprecipitation assay.........40
Immunofluorescence staining.........41
Fluorescence in situ α2A-AR and μOR proximity ligation assay....42
Measurement of NO in the NTS..........43
Immunoblotting analysis..........43
Statistical analysis............44
Results......45
μORs form heterodimers with α2A-ARs in the NTS.......45
Increases in μOR/α2A-AR heterodimers in the NTSs of hypertensive rats..48
Increases in endomorphin-1 in the NTSs of hypertensive rats.....52
Excessive μOR ligands induce heterodimer formations in the NTS....55
Microinjecting the μOR agonist DAMGO into the NTS of normotensive rats promoted μOR/α2A-AR heterodimer-formations......55
Endomorphin-1 blocking by the μOR antagonist CTAP reduced the number of μOR/α2A-AR heterodimers.....,.....58
μOR/α2A-AR heterodimer-formation is the cause rather than a consequence of hypertension.............61
Microinjecting the μOR agonist DAMGO into the NTS of WKY rats elevated BP as well as increased the number of μOR/α2A-AR heterodimers....61
μOR/α2A-AR heterodimer-formation is the cause rather than a consequence of hypertension.............64
CTAP pretreatment reduced the DAMGO-induced μOR/α2A-AR heterodimer-
formation and the BP-elevating effect........64
Intra-NTS CTAP microinjection markedly reduced BP and μOR/α2A-AR heterodimers in hypertensive SHRs.........67
Reducing BP in hypertensive rats had no effect on the number of μOR/α2A-AR heterodimers in the NTS..........70
Elevating BP in normotensive rats had no effect on the number of μOR/α2A-AR heterodimers in the NTS..........73
μOR/α2A-AR heterodimer-formation impaires the NO-dependent depressor effect of α2A-ARs in the NTS............76
The BP regulation of α2A-AR in the NTS is the NO-dependent depressor effect..76
The BP-lowering effect of α2A-ARs in the NTS is significantly attenuated in heterodimer-associated hypertension.........79
μOR/α2A-AR heterodimer-associated α2A-AR dysfunction is caused by the reduction of NO in the NTS...........82
DDAH1 provides a possible link between the pressor responses of the α2A-AR and μOR heterodimers and NO/NOS..........85
Discussion..............88
Chapter 3
Future perspectives............108
Conclusion.............112
References.............113
Publications lists.............135
參考文獻 Abboud FM (2010). The Walter B. Cannon Memorial Award Lecture, 2009. Physiology in perspective: The wisdom of the body. In search of autonomic balance: the good, the bad, and the ugly. Am J Physiol Regul Integr Comp Physiol 298: R1449-1467.

AbdAlla S, Lother H, el Massiery A, Quitterer U (2001). Increased AT(1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness. Nat Med 7: 1003-1009.

Aicher SA, Goldberg A, Sharma S, Pickel VM (2000). mu-opioid receptors are present in vagal afferents and their dendritic targets in the medial nucleus tractus solitarius. J Comp Neurol 422: 181-190.

Al-Hasani R, Bruchas MR (2011). Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology 115: 1363-1381.

Altman JD, Trendelenburg AU, MacMillan L, Bernstein D, Limbird L, Starke K, et al. (1999). Abnormal regulation of the sympathetic nervous system in alpha2A-adrenergic receptor knockout mice. Mol Pharmacol 56: 154-161.

Andrew PJ, Mayer B (1999). Enzymatic function of nitric oxide synthases. Cardiovasc Res 43: 521-531.

Arakawa K, De Jong W, Mulder AH, Versteeg DH (1991). The electrically stimulated release of [3H]noradrenaline from nucleus tractus solitarii slices in vitro is modulated via mu-opioid receptors. Eur J Pharmacol 192: 311-316.

Arvidsson U, Riedl M, Chakrabarti S, Lee JH, Nakano AH, Dado RJ, et al. (1995). Distribution and targeting of a mu-opioid receptor (MOR1) in brain and spinal cord. J Neurosci 15: 3328-3341.

Atweh SF, Kuhar MJ (1977). Autoradiographic localization of opiate receptors in rat brain. II. The brain stem. Brain Res 129: 1-12.

Bai M (2004). Dimerization of G-protein-coupled receptors: roles in signal transduction. Cell Signal 16: 175-186.

Barki-Harrington L, Luttrell LM, Rockman HA (2003). Dual inhibition of beta-adrenergic and angiotensin II receptors by a single antagonist: a functional role for receptor-receptor interaction in vivo. Circulation 108: 1611-1618.

Barnes PJ (2006). Receptor heterodimerization: a new level of cross-talk. J Clin Invest 116: 1210-1212.

Barron BA (1999). Opioid peptides and the heart. Cardiovasc Res 43: 13-16.

Benarroch EE (2008). The arterial baroreflex: functional organization and involvement in neurologic disease. Neurology 71: 1733-1738.

Berg KA, Patwardhan AM, Akopian AN (2012). Receptor and channel heteromers as pain targets. Pharmaceuticals (Basel) 5: 249-278.

Berg KA, Rowan MP, Sanchez TA, Silva M, Patwardhan AM, Milam SB, et al. (2011). Regulation of kappa-opioid receptor signaling in peripheral sensory neurons in vitro and in vivo. J Pharmacol Exp Ther 338: 92-99.

Bhuiyan ME, Waki H, Gouraud SS, Takagishi M, Cui H, Yamazaki T, et al. (2009). Complex cardiovascular actions of alpha-adrenergic receptors expressed in the nucleus tractus solitarii of rats. Exp Physiol 94: 773-784.

Bidlack JM (2000). Detection and function of opioid receptors on cells from the immune system. Clin Diagn Lab Immunol 7: 719-723.

Blanch GT, Freiria-Oliveira AH, Murphy D, Paulin RF, Antunes-Rodrigues J, Colombari E, et al. (2013). Inhibitory mechanism of the nucleus of the solitary tract involved in the control of cardiovascular, dipsogenic, hormonal, and renal responses to hyperosmolality. Am J Physiol Regul Integr Comp Physiol 304: R531-542.

Bohn LM, Gainetdinov RR, Lin FT, Lefkowitz RJ, Caron MG (2000). Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 408: 720-723.

Braam B, Verhaar MC (2007). Understanding eNOS for pharmacological modulation of endothelial function: a translational view. Curr Pharm Des 13: 1727-1740.

Brede M, Wiesmann F, Jahns R, Hadamek K, Arnolt C, Neubauer S, et al. (2002). Feedback inhibition of catecholamine release by two different alpha2-adrenoceptor subtypes prevents progression of heart failure. Circulation 106: 2491-2496.

Breton C, Lukaszewski MA, Risold PY, Enache M, Guillemot J, Riviere G, et al. (2009). Maternal prenatal undernutrition alters the response of POMC neurons to energy status variation in adult male rat offspring. Am J Physiol Endocrinol Metab 296: E462-472.

Bruehl S, Burns JW, Chung OY, Magid E, Chont M, Gilliam W, et al. (2010). Hypoalgesia associated with elevated resting blood pressure: evidence for endogenous opioid involvement. J Behav Med 33: 168-176.

Bucheler MM, Hadamek K, Hein L (2002). Two alpha(2)-adrenergic receptor subtypes, alpha(2A) and alpha(2C), inhibit transmitter release in the brain of gene-targeted mice. Neuroscience 109: 819-826.

Bylund DB, Eikenberg DC, Hieble JP, Langer SZ, Lefkowitz RJ, Minneman KP, et al. (1994). International Union of Pharmacology nomenclature of adrenoceptors. Pharmacol Rev 46: 121-136.

Cai H, Harrison DG (2000). Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 87: 840-844.

Campbell TS, Ditto B, Seguin JR, Sinray S, Tremblay RE (2003). Adolescent pain sensitivity is associated with cardiac autonomic function and blood pressure over 8 years. Hypertension 41: 1228-1233.

Carr JA (1997). Beta-endorphin inhibition of endogenous norepinephrine release from the A2 noradrenergic nucleus in vitro: role of mu opiate receptors and Na+ ion permeability. Brain Res Bull 44: 19-23.

Carrettiero DC, Ferrari MF, Fior-Chadi DR (2012). alpha2-Adrenergic receptor distribution and density within the nucleus tractus solitarii of normotensive and hypertensive rats during development. Auton Neurosci 166: 39-46.

Casado V, Cortes A, Mallol J, Perez-Capote K, Ferre S, Lluis C, et al. (2009). GPCR homomers and heteromers: a better choice as targets for drug development than GPCR monomers? Pharmacol Ther 124: 248-257.

Chavkin C, James IF, Goldstein A (1982). Dynorphin is a specific endogenous ligand of the kappa opioid receptor. Science 215: 413-415.

Chen JF, Eltzschig HK, Fredholm BB (2013). Adenosine receptors as drug targets--what are the challenges? Nat Rev Drug Discov 12: 265-286.

Cheng WH, Lu PJ, Ho WY, Tung CS, Cheng PW, Hsiao M, et al. (2010). Angiotensin II inhibits neuronal nitric oxide synthase activation through the ERK1/2-RSK signaling pathway to modulate central control of blood pressure. Circ Res 106: 788-795.

Cheng WH, Lu PJ, Hsiao M, Hsiao CH, Ho WY, Cheng PW, et al. (2012). Renin activates PI3K-Akt-eNOS signalling through the angiotensin AT(1) and Mas receptors to modulate central blood pressure control in the nucleus tractus solitarii. Br J Pharmacol 166: 2024-2035.

Ciruela F, Casado V, Rodrigues RJ, Lujan R, Burgueno J, Canals M, et al. (2006). Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers. J Neurosci 26: 2080-2087.

Colombari E, Menani JV, Talman WT (1996). Commissural NTS contributes to pressor responses to glutamate injected into the medial NTS of awake rats. Am J Physiol 270: R1220-1225.

Colombari E, Sato MA, Cravo SL, Bergamaschi CT, Campos RR, Jr., Lopes OU (2001). Role of the medulla oblongata in hypertension. Hypertension 38: 549-554.

Cooke JP (2004). The pivotal role of nitric oxide for vascular health. Can J Cardiol 20 Suppl B: 7B-15B.

Dayoub H, Achan V, Adimoolam S, Jacobi J, Stuehlinger MC, Wang BY, et al. (2003). Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Circulation 108: 3042-3047.

De Jong W, Nijkamp FP (1976). Centrally induced hypotension and bradycardia after administration of alpha-methylnoradrenaline into the area of the nucleus tractus solitarii of the rat. Br J Pharmacol 58: 593-598.

de Jong W, Petty MA, Sitsen JM (1983). Role of opioid peptides in brain mechanisms regulating blood pressure. Chest 83: 306-308.

Delbarre B, Casset-Senon D, Delbarre G, Sestillange P, Christin O (1982). Naloxone effects on blood pressure, analgesia and diuresis in spontaneous hypertensive and normotensive rats. Neurosci Lett 30: 167-172.

Denis C, Sauliere A, Galandrin S, Senard JM, Gales C (2012). Probing heterotrimeric G protein activation: applications to biased ligands. Curr Pharm Des 18: 128-144.

Devi LA (2001). Heterodimerization of G-protein-coupled receptors: pharmacology, signaling and trafficking. Trends Pharmacol Sci 22: 532-537.

Dhruva A, Bhatnagar T, Sapru HN (1998). Cardiovascular responses to microinjections of glutamate into the nucleus tractus solitarii of unanesthetized supracollicular decerebrate rats. Brain Res 801: 88-100.

Drasner K, Fields HL (1988). Synergy between the antinociceptive effects of intrathecal clonidine and systemic morphine in the rat. Pain 32: 309-312.

Esler M, Ferrier C, Lambert G, Eisenhofer G, Cox H, Jennings G (1991). Biochemical evidence of sympathetic hyperactivity in human hypertension. Hypertension 17: III29-35.

Evans RG, Ludbrook J (1990). Effects of mu-opioid receptor agonists on circulatory responses to simulated haemorrhage in conscious rabbits. Br J Pharmacol 100: 421-426.

Farsang C, Kapocsi J, Vajda L, Varga K, Malisak Z, Fekete M, et al. (1984). Reversal by naloxone of the antihypertensive action of clonidine: involvement of the sympathetic nervous system. Circulation 69: 461-467.

Ferre S, von Euler G, Johansson B, Fredholm BB, Fuxe K (1991). Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. Proc Natl Acad Sci U S A 88: 7238-7241.

Feuerstein G, Siren AL (1987). The opioid system in cardiac and vascular regulation of normal and hypertensive states. Circulation 75: I125-129.

Filipeanu CM, de Vries R, Danser AH, Kapusta DR (2011). Modulation of alpha(2C) adrenergic receptor temperature-sensitive trafficking by HSP90. Biochim Biophys Acta 1813: 346-357.

Fisher JP, Paton JF (2012). The sympathetic nervous system and blood pressure in humans: implications for hypertension. J Hum Hypertens 26: 463-475.

Fisher JP, Young CN, Fadel PJ (2009). Central sympathetic overactivity: maladies and mechanisms. Auton Neurosci 148: 5-15.

France CR (1999). Decreased pain perception and risk for hypertension: considering a common physiological mechanism. Psychophysiology 36: 683-692.

Franco R (2009). G-protein-coupled receptor heteromers or how neurons can display differently flavoured patterns in response to the same neurotransmitter. Br J Pharmacol 158: 23-31.

Fredriksson S, Gullberg M, Jarvius J, Olsson C, Pietras K, Gustafsdottir SM, et al. (2002). Protein detection using proximity-dependent DNA ligation assays. Nat Biotechnol 20: 473-477.

Fribourg M, Moreno JL, Holloway T, Provasi D, Baki L, Mahajan R, et al. (2011). Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs. Cell 147: 1011-1023.

Galea E, Feinstein DL, Reis DJ (1992). Induction of calcium-independent nitric oxide synthase activity in primary rat glial cultures. Proc Natl Acad Sci U S A 89: 10945-10949.

George SR, O'Dowd BF, Lee SP (2002). G-protein-coupled receptor oligomerization and its potential for drug discovery. Nat Rev Drug Discov 1: 808-820.

George SR, Fan T, Xie Z, Tse R, Tam V, Varghese G, et al. (2000). Oligomerization of mu- and delta-opioid receptors. Generation of novel functional properties. J Biol Chem 275: 26128-26135.

Ghione S (1996). Hypertension-associated hypalgesia. Evidence in experimental animals and humans, pathophysiological mechanisms, and potential clinical consequences. Hypertension 28: 494-504.

Glass MJ, Pickel VM (2002). Alpha(2A)-adrenergic receptors are present in mu-opioid receptor containing neurons in rat medial nucleus tractus solitarius. Synapse 43: 208-218.

Glass MJ, Huang J, Aicher SA, Milner TA, Pickel VM (2001). Subcellular localization of alpha-2A-adrenergic receptors in the rat medial nucleus tractus solitarius: regional targeting and relationship with catecholamine neurons. J Comp Neurol 433: 193-207.

Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. (2013). Heart disease and stroke statistics--2013 update: a report from the American Heart Association. Circulation 127: e6-e245.

Gomes I, Jordan BA, Gupta A, Trapaidze N, Nagy V, Devi LA (2000). Heterodimerization of mu and delta opioid receptors: A role in opiate synergy. J Neurosci 20: RC110.

Gomes I, Gupta A, Filipovska J, Szeto HH, Pintar JE, Devi LA (2004). A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia. Proc Natl Acad Sci U S A 101: 5135-5139.

Gong J, Strong JA, Zhang S, Yue X, DeHaven RN, Daubert JD, et al. (1998). Endomorphins fully activate a cloned human mu opioid receptor. FEBS Lett 439: 152-156.

Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez JF, et al. (2008). Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452: 93-97.

Guasti L, Cattaneo R, Daneri A, Bianchi L, Gaudio G, Regazzi MB, et al. (1996). Endogenous beta-endorphins in hypertension: correlation with 24-hour ambulatory blood pressure. J Am Coll Cardiol 28: 1243-1248.

Gudermann T, Kalkbrenner F, Dippel E, Laugwitz KL, Schultz G (1997). Specificity and complexity of receptor-G-protein interaction. Adv Second Messenger Phosphoprotein Res 31: 253-262.

Guo GB, Abboud FM (1984). Impaired central mediation of the arterial baroreflex in chronic renal hypertension. Am J Physiol 246: H720-727.

Guo ZL, Lai HC, Longhurst JC (2002). Medullary pathways involved in cardiac sympathoexcitatory reflexes in the cat. Brain Res 925: 55-66.

Gutkowska J, Mukaddam-Daher S, Jankowski M, Schiller PW (2004). The cardiovascular and renal effects of the potent and highly selective mu opioid agonist [Dmt1]DALDA. J Cardiovasc Pharmacol 44: 651-658.

Guyenet PG (2006). The sympathetic control of blood pressure. Nat Rev Neurosci 7: 335-346.

Guyenet PG, Koshiya N, Huangfu D, Baraban SC, Stornetta RL, Li YW (1996). Role of medulla oblongata in generation of sympathetic and vagal outflows. Prog Brain Res 107: 127-144.

Guyton AC (1989). Dominant role of the kidneys and accessory role of whole-body autoregulation in the pathogenesis of hypertension. Am J Hypertens 2: 575-585.

Hall WD (1999). Risk reduction associated with lowering systolic blood pressure: review of clinical trial data. Am Heart J 138: 225-230.

Harada S, Tokunaga S, Momohara M, Masaki H, Tagawa T, Imaizumi T, et al. (1993). Inhibition of nitric oxide formation in the nucleus tractus solitarius increases renal sympathetic nerve activity in rabbits. Circ Res 72: 511-516.

Hassen AH, Feuerstein G (1987). mu-Opioid receptors in NTS elicit pressor responses via sympathetic pathways. Am J Physiol 252: H156-162.

Hauser KF, Mangoura D (1998). Diversity of the endogenous opioid system in development. Novel signal transduction translates multiple extracellular signals into neural cell growth and differentiation. Perspect Dev Neurobiol 5: 437-449.

Hayward LF, Riley AP, Felder RB (2002). alpha(2)-Adrenergic receptors in NTS facilitate baroreflex function in adult spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 282: H2336-2345.

Hebert TE, Moffett S, Morello JP, Loisel TP, Bichet DG, Barret C, et al. (1996). A peptide derived from a beta2-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation. J Biol Chem 271: 16384-16392.

Hein L, Altman JD, Kobilka BK (1999). Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission. Nature 402: 181-184.

Ho WY, Lu PJ, Hsiao M, Hwang HR, Tseng YC, Yen MH, et al. (2008). Adenosine modulates cardiovascular functions through activation of extracellular signal-regulated kinases 1 and 2 and endothelial nitric oxide synthase in the nucleus tractus solitarii of rats. Circulation 117: 773-780.

Hofmann KP, Scheerer P, Hildebrand PW, Choe HW, Park JH, Heck M, et al. (2009). A G protein-coupled receptor at work: the rhodopsin model. Trends Biochem Sci 34: 540-552.

Holden JE, Jeong Y, Forrest JM (2005). The endogenous opioid system and clinical pain management. AACN Clin Issues 16: 291-301.

Huang HN, Lu PJ, Lo WC, Lin CH, Hsiao M, Tseng CJ (2004). In situ Akt phosphorylation in the nucleus tractus solitarii is involved in central control of blood pressure and heart rate. Circulation 110: 2476-2483.

Jennings JR, Heim AF (2012). From Brain to Behavior: Hypertension's Modulation of Cognition and Affect. Int J Hypertens 2012: 701385.

Johnson MW, Mitch WE, Wilcox CS (1985). The cardiovascular actions of morphine and the endogenous opioid peptides. Prog Cardiovasc Dis 27: 435-450.

Jordan BA, Devi LA (1999). G-protein-coupled receptor heterodimerization modulates receptor function. Nature 399: 697-700.

Jordan BA, Gomes I, Rios C, Filipovska J, Devi LA (2003). Functional interactions between mu opioid and alpha 2A-adrenergic receptors. Mol Pharmacol 64: 1317-1324.

Joubert J, Malan SF (2011). Novel nitric oxide synthase inhibitors: a patent review. Expert Opin Ther Pat 21: 537-560.

Kable JW, Murrin LC, Bylund DB (2000). In vivo gene modification elucidates subtype-specific functions of alpha(2)-adrenergic receptors. J Pharmacol Exp Ther 293: 1-7.

Kanagy NL (2005). Alpha(2)-adrenergic receptor signalling in hypertension. Clin Sci (Lond) 109: 431-437.

Kapitzke D, Vetter I, Cabot PJ (2005). Endogenous opioid analgesia in peripheral tissues and the clinical implications for pain control. Ther Clin Risk Manag 1: 279-297.

Kasamatsu K, Chitravanshi VC, Sapru HN (2004). Depressor and bradycardic responses to microinjections of endomorphin-2 into the NTS are mediated via ionotropic glutamate receptors. Am J Physiol Regul Integr Comp Physiol 287: R715-728.

Kaur M, Singh PM (2011). Current role of dexmedetomidine in clinical anesthesia and intensive care. Anesth Essays Res 5: 128-133.

Khoury E, Clement S, Laporte SA (2014). Allosteric and biased g protein-coupled receptor signaling regulation: potentials for new therapeutics. Front Endocrinol (Lausanne) 5: 68.

Kieffer BL (1999). Opioids: first lessons from knockout mice. Trends Pharmacol Sci 20: 19-26.

Knaus AE, Muthig V, Schickinger S, Moura E, Beetz N, Gilsbach R, et al. (2007). Alpha2-adrenoceptor subtypes--unexpected functions for receptors and ligands derived from gene-targeted mouse models. Neurochem Int 51: 277-281.

Krauss RM, Eckel RH, Howard B, Appel LJ, Daniels SR, Deckelbaum RJ, et al. (2000). AHA Dietary Guidelines: revision 2000: A statement for healthcare professionals from the Nutrition Committee of the American Heart Association. Circulation 102: 2284-2299.

Kunos G, Farsang C, Ramirez-Gonzales MD (1981). beta-Endorphin: possible involvement in the antihypertensive effect of central alpha-receptor activation. Science 211: 82-84.

Lang RE, Bruckner UB, Kempf B, Rascher W, Sturm V, Unger T, et al. (1982). Opioid peptides and blood pressure regulation. Clin Exp Hypertens A 4: 249-269.

Larson AA, Kovacs KJ, Cooper JC, Kitto KF (2000). Transient changes in the synthesis of nitric oxide result in long-term as well as short-term changes in acetic acid-induced writhing in mice. Pain 86: 103-111.

Law PY, Wong YH, Loh HH (2000). Molecular mechanisms and regulation of opioid receptor signaling. Annu Rev Pharmacol Toxicol 40: 389-430.

Le Merrer J, Becker JA, Befort K, Kieffer BL (2009). Reward processing by the opioid system in the brain. Physiol Rev 89: 1379-1412.

Leiper J, Nandi M (2011). The therapeutic potential of targeting endogenous inhibitors of nitric oxide synthesis. Nat Rev Drug Discov 10: 277-291.

Leiper J, Nandi M, Torondel B, Murray-Rust J, Malaki M, O'Hara B, et al. (2007). Disruption of methylarginine metabolism impairs vascular homeostasis. Nat Med 13: 198-203.

Leuchowius KJ, Weibrecht I, Landegren U, Gedda L, Soderberg O (2009). Flow cytometric in situ proximity ligation analyses of protein interactions and post-translational modification of the epidermal growth factor receptor family. Cytometry A 75: 833-839.

Lewington S, Clarke R, Qizilbash N, Peto R, Collins R (2002). Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360: 1903-1913.

Lo WC, Jan CR, Chiang HT, Tseng CJ (2000). Modulatory effects of carbon monoxide on baroreflex activation in nucleus tractus solitarii of rats. Hypertension 35: 1253-1257.

Loewy AD (1991). Forebrain nuclei involved in autonomic control. Prog Brain Res 87: 253-268.

Loewy AD, Burton H (1978). Nuclei of the solitary tract: efferent projections to the lower brain stem and spinal cord of the cat. J Comp Neurol 181: 421-449.

Lord JA, Waterfield AA, Hughes J, Kosterlitz HW (1977). Endogenous opioid peptides: multiple agonists and receptors. Nature 267: 495-499.

Lovic D, Manolis AJ, Lovic B, Stojanov V, Lovic M, Pittaras A, et al. (2014). The pathophysiological basis of carotid baroreceptor stimulation for the treatment of resistant hypertension. Curr Vasc Pharmacol 12: 16-22.

Lu WH, Hsieh KS, Lu PJ, Wu YS, Ho WY, Lai CC, et al. (2013). Hexamethonium reverses the lethal cardiopulmonary damages in a rat model of brainstem lesions mimicking fatal enterovirus 71 encephalitis. Crit Care Med 41: 1276-1285.

Lu Z, Xu X, Hu X, Zhu G, Zhang P, van Deel ED, et al. (2008). Extracellular superoxide dismutase deficiency exacerbates pressure overload-induced left ventricular hypertrophy and dysfunction. Hypertension 51: 19-25.

MacMillan LB, Hein L, Smith MS, Piascik MT, Limbird LE (1996). Central hypotensive effects of the alpha2a-adrenergic receptor subtype. Science 273: 801-803.

Makaritsis KP, Johns C, Gavras I, Gavras H (2000). Role of alpha(2)-adrenergic receptor subtypes in the acute hypertensive response to hypertonic saline infusion in anephric mice. Hypertension 35: 609-613.

Makaritsis KP, Johns C, Gavras I, Altman JD, Handy DE, Bresnahan MR, et al. (1999). Sympathoinhibitory function of the alpha(2A)-adrenergic receptor subtype. Hypertension 34: 403-407.

Malpas SC (2010). Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiol Rev 90: 513-557.

Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. (2007). 2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 28: 1462-1536.

Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ (1988). Anatomy of CNS opioid receptors. Trends Neurosci 11: 308-314.

Mao L, Wang JQ (2005). Cardiovascular responses to microinjection of nociceptin and endomorphin-1 into the nucleus tractus solitarii in conscious rats. Neuroscience 132: 1009-1015.

Marinelli PW, Quirion R, Gianoulakis C (2004). An in vivo profile of beta-endorphin release in the arcuate nucleus and nucleus accumbens following exposure to stress or alcohol. Neuroscience 127: 777-784.

Marinissen MJ, Gutkind JS (2001). G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol Sci 22: 368-376.

Martin-Schild S, Gerall AA, Kastin AJ, Zadina JE (1999). Differential distribution of endomorphin 1- and endomorphin 2-like immunoreactivities in the CNS of the rodent. J Comp Neurol 405: 450-471.

McCubbin JA, Surwit RS, Williams RB, Nemeroff CB, McNeilly M (1989). Altered pituitary hormone response to naloxone in hypertension development. Hypertension 14: 636-644.

McCubbin JA, Helfer SG, Switzer FS, 3rd, Galloway C, Griffith WV (2006). Opioid analgesia in persons at risk for hypertension. Psychosom Med 68: 116-120.

McCudden CR, Hains MD, Kimple RJ, Siderovski DP, Willard FS (2005). G-protein signaling: back to the future. Cell Mol Life Sci 62: 551-577.

McGraw DW, Mihlbachler KA, Schwarb MR, Rahman FF, Small KM, Almoosa KF, et al. (2006). Airway smooth muscle prostaglandin-EP1 receptors directly modulate beta2-adrenergic receptors within a unique heterodimeric complex. J Clin Invest 116: 1400-1409.

Minoia P, Sciorsci RL (2001). Metabolic control through L calcium channel, PKC and opioid receptors modulation by an association of naloxone and calcium salts. Curr Drug Targets Immune Endocr Metabol Disord 1: 131-137.

Mizoguchi H, Tseng LF, Suzuki T, Sora I, Narita M (2002). Differential mechanism of G-protein activation induced by endogenous mu-opioid peptides, endomorphin and beta-endorphin. Jpn J Pharmacol 89: 229-234.

Molina PE (2002). Stress-specific opioid modulation of haemodynamic counter-regulation. Clin Exp Pharmacol Physiol 29: 248-253.

Moncada S, Palmer RM, Higgs EA (1991). Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43: 109-142.

Morilak DA, Barrera G, Echevarria DJ, Garcia AS, Hernandez A, Ma S, et al. (2005). Role of brain norepinephrine in the behavioral response to stress. Prog Neuropsychopharmacol Biol Psychiatry 29: 1214-1224.

Mulder AH, Wardeh G, Hogenboom F, Frankhuyzen AL (1989). Selectivity of various opioid peptides towards delta-, kappa; and mu-opioid receptors mediating presynaptic inhibition of neurotransmitter release in the brain. Neuropeptides 14: 99-104.

Murakami A, Ohigashi H (2007). Targeting NOX, INOS and COX-2 in inflammatory cells: chemoprevention using food phytochemicals. Int J Cancer 121: 2357-2363.

Neer EJ (1995). Heterotrimeric G proteins: organizers of transmembrane signals. Cell 80: 249-257.

Negri L, Lattanzi R, Tabacco F, Melchiorri P (1998). Respiratory and cardiovascular effects of the mu-opioid receptor agonist [Lys7]dermorphin in awake rats. Br J Pharmacol 124: 345-355.

Nomura M, Ohtsuji M, Nagata Y (1985). Changes in the alpha-adrenoceptors in the medulla oblongata including nucleus tractus solitarii of spontaneously hypertensive rats. Neurochem Res 10: 1143-1154.

Offermanns S (2003). G-proteins as transducers in transmembrane signalling. Prog Biophys Mol Biol 83: 101-130.

Olson GA, Olson RD, Vaccarino AL, Kastin AJ (1998). Endogenous opiates: 1997. Peptides 19: 1791-1843.

Oparil S, Zaman MA, Calhoun DA (2003). Pathogenesis of hypertension. Ann Intern Med 139: 761-776.

Ordway GA, Jaconetta SM, Halaris AE (1993). Characterization of subtypes of alpha-2 adrenoceptors in the human brain. J Pharmacol Exp Ther 264: 967-976.

Osborn JW, Jacob F, Guzman P (2005). A neural set point for the long-term control of arterial pressure: beyond the arterial baroreceptor reflex. Am J Physiol Regul Integr Comp Physiol 288: R846-855.

Palm F, Onozato ML, Luo Z, Wilcox CS (2007). Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems. Am J Physiol Heart Circ Physiol 293: H3227-3245.

Pan YZ, Li DP, Chen SR, Pan HL (2004). Activation of mu-opioid receptors excites a population of locus coeruleus-spinal neurons through presynaptic disinhibition. Brain Res 997: 67-78.

Pert CB, Snyder SH (1973). Opiate receptor: demonstration in nervous tissue. Science 179: 1011-1014.

Pfeiffer A, Feuerstein G, Kopin IJ, Faden AI (1983). Cardiovascular and respiratory effects of mu-, delta- and kappa-opiate agonists microinjected into the anterior hypothalamic brain area of awake rats. J Pharmacol Exp Ther 225: 735-741.

Philipp M, Brede M, Hein L (2002). Physiological significance of alpha(2)-adrenergic receptor subtype diversity: one receptor is not enough. Am J Physiol Regul Integr Comp Physiol 283: R287-295.

Pierce KL, Premont RT, Lefkowitz RJ (2002). Seven-transmembrane receptors. Nat Rev Mol Cell Biol 3: 639-650.

Pugsley MK (2002). The diverse molecular mechanisms responsible for the actions of opioids on the cardiovascular system. Pharmacol Ther 93: 51-75.

Quaglia W, Del Bello F, Giannella M, Piergentili A, Pigini M (2011). alpha2C-adrenoceptor modulators: a patent review. Expert Opin Ther Pat 21: 455-481.

Quitterer U, AbdAlla S (2014). Vasopressor meets vasodepressor: The AT1-B2 receptor heterodimer. Biochem Pharmacol 88: 284-290.

Quock RM, Kouchich FJ, Vaughn LK, Fries DS (1985). Narcotic antagonist-induced hypotension in the spontaneously hypertensive rat. Life Sci 37: 819-826.

Raehal KM, Walker JK, Bohn LM (2005). Morphine side effects in beta-arrestin 2 knockout mice. J Pharmacol Exp Ther 314: 1195-1201.

Rafikov R, Fonseca FV, Kumar S, Pardo D, Darragh C, Elms S, et al. (2011). eNOS activation and NO function: structural motifs responsible for the posttranslational control of endothelial nitric oxide synthase activity. J Endocrinol 210: 271-284.

Rees DD, Palmer RM, Schulz R, Hodson HF, Moncada S (1990). Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br J Pharmacol 101: 746-752.

Reis DJ, Ruggiero DA, Morrison SF (1989). The C1 area of the rostral ventrolateral medulla oblongata. A critical brainstem region for control of resting and reflex integration of arterial pressure. Am J Hypertens 2: 363S-374S.

Ring C, France CR, al'Absi M, Edwards L, McIntyre D, Carroll D, et al. (2008). Effects of naltrexone on electrocutaneous pain in patients with hypertension compared to normotensive individuals. Biol Psychol 77: 191-196.

Rompler H, Staubert C, Thor D, Schulz A, Hofreiter M, Schoneberg T (2007). G protein-coupled time travel: evolutionary aspects of GPCR research. Mol Interv 7: 17-25.

Ross CA, Ruggiero DA, Reis DJ (1985). Projections from the nucleus tractus solitarii to the rostral ventrolateral medulla. J Comp Neurol 242: 511-534.

Rozenfeld R, Devi LA (2011). Exploring a role for heteromerization in GPCR signalling specificity. Biochem J 433: 11-18.

Ruffolo RR, Jr., Nichols AJ, Stadel JM, Hieble JP (1991). Structure and function of alpha-adrenoceptors. Pharmacol Rev 43: 475-505.

Saha RN, Pahan K (2006). Regulation of inducible nitric oxide synthase gene in glial cells. Antioxid Redox Signal 8: 929-947.

Sakai K, Hirooka Y, Matsuo I, Eshima K, Shigematsu H, Shimokawa H, et al. (2000). Overexpression of eNOS in NTS causes hypotension and bradycardia in vivo. Hypertension 36: 1023-1028.

Salon JA, Lodowski DT, Palczewski K (2011). The significance of G protein-coupled receptor crystallography for drug discovery. Pharmacol Rev 63: 901-937.

Santiago FE, Fior-Chadi DR, Carrettiero DC (2015). Alpha2-adrenoceptor and adenosine A1 receptor within the nucleus tractus solitarii in hypertension development. Auton Neurosci 187: 36-44.

Sato MA, Colombari E, Morrison SF (2002). Inhibition of neurons in commissural nucleus of solitary tract reduces sympathetic nerve activity in SHR. Am J Physiol Heart Circ Physiol 282: H1679-1684.

Sato MA, Menani JV, Lopes OU, Colombari E (1999). Commissural NTS lesions and cardiovascular responses in aortic baroreceptor-denervated rats. Hypertension 34: 739-743.

Schulz R, Kelm M, Heusch G (2004). Nitric oxide in myocardial ischemia/reperfusion injury. Cardiovasc Res 61: 402-413.

Sim LJ, Liu Q, Childers SR, Selley DE (1998). Endomorphin-stimulated [35S]GTPgammaS binding in rat brain: evidence for partial agonist activity at mu-opioid receptors. J Neurochem 70: 1567-1576.

Simon MI, Strathmann MP, Gautam N (1991). Diversity of G proteins in signal transduction. Science 252: 802-808.

Sondek J, Bohm A, Lambright DG, Hamm HE, Sigler PB (1996). Crystal structure of a G-protein beta gamma dimer at 2.1A resolution. Nature 379: 369-374.

Stone LS, MacMillan LB, Kitto KF, Limbird LE, Wilcox GL (1997). The alpha2a adrenergic receptor subtype mediates spinal analgesia evoked by alpha2 agonists and is necessary for spinal adrenergic-opioid synergy. J Neurosci 17: 7157-7165.

Summy-Long JY, Keil LC, Deen K, Rosella L, Severs WB (1981). Endogenous opioid peptide inhibition of the central actions of angiotensin. J Pharmacol Exp Ther 217: 619-629.

Tai MH, Hsiao M, Chan JY, Lo WC, Wang FS, Liu GS, et al. (2004). Gene delivery of endothelial nitric oxide synthase into nucleus tractus solitarii induces biphasic response in cardiovascular functions of hypertensive rats. Am J Hypertens 17: 63-70.

Takaki A, Morikawa K, Tsutsui M, Murayama Y, Tekes E, Yamagishi H, et al. (2008). Crucial role of nitric oxide synthases system in endothelium-dependent hyperpolarization in mice. J Exp Med 205: 2053-2063.

Tan CM, Wilson MH, MacMillan LB, Kobilka BK, Limbird LE (2002). Heterozygous alpha 2A-adrenergic receptor mice unveil unique therapeutic benefits of partial agonists. Proc Natl Acad Sci U S A 99: 12471-12476.

Tan M, Walwyn WM, Evans CJ, Xie CW (2009). p38 MAPK and beta-arrestin 2 mediate functional interactions between endogenous micro-opioid and alpha2A-adrenergic receptors in neurons. J Biol Chem 284: 6270-6281.

Taussig R, Iniguez-Lluhi JA, Gilman AG (1993). Inhibition of adenylyl cyclase by Gi alpha. Science 261: 218-221.

Tavares A, Handy DE, Bogdanova NN, Rosene DL, Gavras H (1996). Localization of alpha 2A- and alpha 2B-adrenergic receptor subtypes in brain. Hypertension 27: 449-455.

Taylor BK, Roderick RE, St Lezin E, Basbaum AI (2001). Hypoalgesia and hyperalgesia with inherited hypertension in the rat. Am J Physiol Regul Integr Comp Physiol 280: R345-354.

Teitler M, Klein MT (2012). A new approach for studying GPCR dimers: drug-induced inactivation and reactivation to reveal GPCR dimer function in vitro, in primary culture, and in vivo. Pharmacol Ther 133: 205-217.

Trendelenburg AU, Klebroff W, Hein L, Starke K (2001). A study of presynaptic alpha2-autoreceptors in alpha2A/D-, alpha2B- and alpha2C-adrenoceptor-deficient mice. Naunyn Schmiedebergs Arch Pharmacol 364: 117-130.

Tseng CJ, Biaggioni I, Appalsamy M, Robertson D (1988). Purinergic receptors in the brainstem mediate hypotension and bradycardia. Hypertension 11: 191-197.

Tseng CJ, Mosqueda-Garcia R, Appalsamy M, Robertson D (1989). Cardiovascular effects of neuropeptide Y in rat brainstem nuclei. Circ Res 64: 55-61.

Tseng CJ, Appalsamy M, Robertson D, Mosqueda-Garcia R (1993). Effects of nicotine on brain stem mechanisms of cardiovascular control. J Pharmacol Exp Ther 265: 1511-1518.

Tseng CJ, Chou LL, Ger LP, Tung CS (1994). Cardiovascular effects of angiotensin III in brainstem nuclei of normotensive and hypertensive rats. J Pharmacol Exp Ther 268: 558-564.

Tseng CJ, Liu HY, Lin HC, Ger LP, Tung CS, Yen MH (1996). Cardiovascular effects of nitric oxide in the brain stem nuclei of rats. Hypertension 27: 36-42.

Tsikas D, Boger RH, Sandmann J, Bode-Boger SM, Frolich JC (2000). Endogenous nitric oxide synthase inhibitors are responsible for the L-arginine paradox. FEBS Lett 478: 1-3.

Tsuda K, Tsuda S, Nishio I, Masuyama Y (2000). Effects of beta-endorphin on norepinephrine release in hypertension. J Cardiovasc Pharmacol 36 Suppl 2: S65-67.

Uhlen S, Wikberg JE (1991). Delineation of rat kidney alpha 2A- and alpha 2B-adrenoceptors with [3H]RX821002 radioligand binding: computer modelling reveals that guanfacine is an alpha 2A-selective compound. Eur J Pharmacol 202: 235-243.

Unnerstall JR, Kopajtic TA, Kuhar MJ (1984). Distribution of alpha 2 agonist binding sites in the rat and human central nervous system: analysis of some functional, anatomic correlates of the pharmacologic effects of clonidine and related adrenergic agents. Brain Res 319: 69-101.

Vanhoutte PM (1989). Endothelium and control of vascular function. State of the Art lecture. Hypertension 13: 658-667.

Vieira-Coelho MA, Serrao MP, Afonso J, Pinto CE, Moura E (2009). Catecholamine synthesis and metabolism in the central nervous system of mice lacking alpha-adrenoceptor subtypes. Br J Pharmacol 158: 726-737.

Vieira AA, De Luca LA, Jr., Colombari E, Colombari DS, Menani JV (2012). Commissural NTS lesions enhance the pressor response to central cholinergic and adrenergic activation. Neurosci Lett 521: 31-36.

Vilardaga JP, Nikolaev VO, Lorenz K, Ferrandon S, Zhuang Z, Lohse MJ (2008). Conformational cross-talk between alpha2A-adrenergic and mu-opioid receptors controls cell signaling. Nat Chem Biol 4: 126-131.

Vincent SR, Kimura H (1992). Histochemical mapping of nitric oxide synthase in the rat brain. Neuroscience 46: 755-784.

Vogt I, Prinz J, Campillos M (2014). Molecularly and clinically related drugs and diseases are enriched in phenotypically similar drug-disease pairs. Genome Med 6: 52.

Von Wowern F, Bengtsson K, Lindblad U, Rastam L, Melander O (2004). Functional variant in the (alpha)2B adrenoceptor gene, a positional candidate on chromosome 2, associates with hypertension. Hypertension 43: 592-597.

Waki H, Murphy D, Yao ST, Kasparov S, Paton JF (2006). Endothelial NO synthase activity in nucleus tractus solitarii contributes to hypertension in spontaneously hypertensive rats. Hypertension 48: 644-650.

Wnorowski A, Jozwiak K (2014). Homo- and hetero-oligomerization of beta2-adrenergic receptor in receptor trafficking, signaling pathways and receptor pharmacology. Cell Signal 26: 2259-2265.

Wood PL (1988). The significance of multiple CNS opioid receptor types: a review of critical considerations relating to technical details and anatomy in the study of central opioid actions. Peptides 9 Suppl 1: 49-55.

Yamada K, Nabeshima T (1995). Stress-induced behavioral responses and multiple opioid systems in the brain. Behav Brain Res 67: 133-145.

Yamada S, Ashizawa N, Nakayama K, Tomita T, Hayashi E (1989). Decreased density of alpha 2-adrenoceptors in medulla oblongata of spontaneously hypertensive rats. J Cardiovasc Pharmacol 13: 440-446.

Zadina JE, Hackler L, Ge LJ, Kastin AJ (1997). A potent and selective endogenous agonist for the mu-opiate receptor. Nature 386: 499-502.

Zagon IS, Wu Y, McLaughlin PJ (1999). Opioid growth factor and organ development in rat and human embryos. Brain Res 839: 313-322.

Zamir N, Simantov R, Segal M (1980). Pain sensitivity and opioid activity in genetically and experimentally hypertensive rats. Brain Res 184: 299-310.

Zandberg P, de Jong W (1979). Hypotensive response in spontaneously hypertensive rats following microinjection of alpha-methylnoradrenaline in the caudal brain-stem. Neurosci Lett 14: 119-122.

Zaugg M, Schaub MC (2005). Genetic modulation of adrenergic activity in the heart and vasculature: implications for perioperative medicine. Anesthesiology 102: 429-446.

Zhang T, Reid K, Acuff CG, Jin CB, Rockhold RW (1994). Cardiovascular and analgesic effects of a highly palatable diet in spontaneously hypertensive and Wistar-Kyoto rats. Pharmacol Biochem Behav 48: 57-61.

Zhang Z, Zhuang J, Zhang C, Xu F (2011). Activation of opioid mu-receptors in the commissural subdivision of the nucleus tractus solitarius abolishes the ventilatory response to hypoxia in anesthetized rats. Anesthesiology 115: 353-363.

Zhu WZ, Chakir K, Zhang S, Yang D, Lavoie C, Bouvier M, et al. (2005). Heterodimerization of beta1- and beta2-adrenergic receptor subtypes optimizes beta-adrenergic modulation of cardiac contractility. Circ Res 97: 244-251.

Zimlichman R, Gefel D, Eliahou H, Matas Z, Rosen B, Gass S, et al. (1996). Expression of opioid receptors during heart ontogeny in normotensive and hypertensive rats. Circulation 93: 1020-1025.

------------------------------------------------------------------------ 第 16 筆 ---------------------------------------------------------------------
系統識別號 U0026-0707201510213800
論文名稱(中文) 應用模組化商業模型發展企業多管理層級決策支援系統
論文名稱(英文) Using Component Business Model to Develop Multi-level Decision Support System of the Firm
校院名稱 成功大學
系所名稱(中) 資訊管理研究所
系所名稱(英) Institute of Information Management
學年度 103
學期 2
出版年 104
研究生(中文) 盧心慧
學號 R76021087
學位類別 碩士
語文別 英文
口試日期 2015-05-31
論文頁數 78頁
口試委員 指導教授-林清河
口試委員-李昇暾
口試委員-耿伯文
口試委員-葉榮懋
關鍵字(中) 決策支援系統
模組化商業模型
案例式推理
關鍵字(英) Decision Support System
Component Business Model
Case-Based Reasoning
學科別分類
中文摘要 全球化的競爭以及外部環境的快速變遷讓企業經營的過程中充滿挑戰和不確定 性,許多企業透過決策支援系統以協助其管理者制定策略、提升企業對環境的反應能 力與競爭力。然而過去對於決策支援系統之研究均侷限於單一管理層級與單一情境, 忽略其他管理層級之使用需求或只偏重某一功能部門之需求。由於外部環境是變動的, 企業營運時會面臨各種不同的情境,進行策略規劃時應該將所有可能面臨之情境均納 入考量。此外,不同管理層級管理者所面對的決策範圍與類型均不相同,亦應將此納 入考量。因此,本研究將以此為方向,提出一整合多管理層級與多情境之決策支援系 統架構供企業後續建置其決策支援系統,本研究將結合模組化商業模型以及案例式推 理,首先使用模組化商業模型分析各功能部門與各管理層級之需求,並根據模組內容 發展案例格式,再透過案例式推理之流程找出適合之策略,供企業作為後續系統實際 建置之參考。
本研究透過前述提出之方法進行個案實作,在實作前先進行個案公司之訪談,並 針對實作時遇到之阻礙根據個案公司之意見進行部分調整,最後將實作之結果進行專 家訪談確定方法之可行性,並於最後彙整歸納專家之建議。最後獲得以下結論:(1) 透 過模組化商業模型能夠分析出企業內各部門之高階管理者、中階管理者與基層管理者 之所有重要業務,並協助其辨識出更完整之決策支援系統資訊需求;(2) 案例式推理 能夠適用於企業內部依賴經驗累積之業務;反之,(3) 技術實作導向之業務不適合成 為案例。
英文摘要 In recent years, business management has become more challenging than ever due to fierce global competition and environmental volatility. Since the widespread adoption of information communication technologies and enterprise software packages, enterprises have acquired many channel capabilities. Information technology has its surge of mainstream popularity, motivating researchers to apply it to assist enterprise operation. However, the majority of research in the decision support system only focus on single decision issues, and only support managers of the same level. Few empirical studies have been done on multi-level users and assist multi decision issues. There has, thus, been relatively few researches into these areas. Hence, this research propose an integrated framework for developing a decision support system for managers of all levels that assist decision-making in multiple issues. In addition, a case study and an interview with experts is implemented to evaluate the proposed method. Finally, conclusions are drawn as follows: (1) Component business model can analyze the framework of enterprises or organizations, define the important services in each department and level, and help them recognize their information needs; (2) Case-based reasoning is fit for experience-oriented operations in the enterprise; (3) Case-based reasoning are not suitable for technique-oriented operations.
論文目次 Chapter 1 Introduction 1
1.1 Research Background and Motivation 1
1.2 Research Purposes 2
1.3 Research Procedure 3
Chapter 2 Literature Review 5
2.1 Management Levels and Decision-Making 5
2.1.1 Management Levels 5
2.1.2 Decision-Making 7
2.1.3 Component Business Model (CBM) 8
2.2 Decision Support System (DSS) 11
2.2.1 Definition of Decision Support System 11
2.2.2 Researches Related to Decision Support System 12
2.2.3 Knowledge-Based Problem Solving Method 14
2.3 Decision Support System Development Methodology 17
Chapter 3 Research Methodology 19
3.1 Research framework 19
3.2 Construct the CBM for Firms 21
3.3 Define the Case Format 24
3.4 System Modeling 26
3.5 In-Depth Interview 31
3.5.1 Types of Interviews 32
3.5.2 Interviewee 32
3.5.3 Interview Guide 33
Chapter 4 Case Implementation 34
4.1 Case Implementation 34
4.1.1 Case interview—Machine industry 34
4.1.2 Case Implementation—Machine industry 36
4.1.3 System Prototype 38
4.2 Analysis of Interview Data 46
4.2.1 Integrity of Component Business Model Analysis 46
4.2.2 Users of Decision Support System 50
4.2.3 Adaptability of Case-Based Reasoning 51
4.2.4 Other Suggestions 53
Chapter 5 Conclusion and Future Research 55
5.1 Conclusion 55
5.2 Recommendations for Future Research Work 56
Reference 57
Appendix A 60
Appendix B 62
Appendix C 76
參考文獻 Aamodt, A., & Plaza, E. (1994). Case-based reasoning: Foundational issues, methodological variations, and system approaches. AI communications, 7(1), 39-59.
Alptekin, G. I., & Büyüközkan, G. (2011). An integrated case-based reasoning and MCDM system for Web based tourism destination planning. Expert Systems with Applications, 38(3), 2125-2132.
Alter, S. (1977). A taxonomy of decision support systems. Sloan Management Review, 19(1), 39-56.
Alter, S. (2004). A work system view of DSS in its fourth decade. Decision Support Systems, 38(3), 319-327.
Álvarez-Socarrás, A. M., Berrones, A., Moreno, G. J., Rodríguez-Sarasty, J. A., & Cabrera-Ríos, M. (2013). Practice summary: Enhancing forecasting and capacity planning capabilities in a telecommunications company. Interfaces, 43(4), 385-387.
Amailef, K., & Lu, J. (2013). Ontology-supported case-based reasoning approach for intelligent m-Government emergency response services. Decision Support Systems, 55(1), 79-97.
Berka, P. (2011). Nest: A compositional approach to rule-based and case-based reasoning. Advances in Artificial Intelligence, 2011, 4.
Bhargava, H. K., Power, D. J., & Sun, D. (2007). Progress in Web-based decision support technologies. Decision Support Systems, 43(4), 1083-1095.
Bouhana, A., Fekih, A., Abed, M., & Chabchoub, H. (2013). An integrated case-based reasoning approach for personalized itinerary search in multimodal transportation systems. Transportation Research Part C: Emerging Technologies, 31, 30-50.
Brandas, C. (2011). Decision support systems development: A methodological approach. Journal of Applied Business Information Systems, 2(4), 151-158.
Chan, S. W., & Franklin, J. (2011). A text-based decision support system for financial sequence prediction. Decision Support Systems, 52(1), 189-198.
Chang, P.-C., & Lai, C.-Y. (2005). A hybrid system combining self-organizing maps with case-based reasoning in wholesaler's new-release book forecasting. Expert Systems with Applications, 29(1), 183-192.
Demirkan, H., & Spohrer, J. (2014). Developing a framework to improve virtual shopping in digital malls with intelligent self-service systems. Journal of Retailing and Consumer Services, 21(5), 860-868.
Drnevich, P. L., & Croson, D. C. (2013). Information technology and business-level strategy: Toward an integrated theoretical perspective. Mis Quarterly, 37(2), 483-509.
Elimam, A. A., & Girgis, M. A. (2012). Optimization of water resources planning for Jordan's aqaba special economic zone. Interfaces, 42(6), 528-543.
Fan, Z.-P., Li, Y.-H., Wang, X., & Liu, Y. (2014). Hybrid similarity measure for case retrieval in CBR and its application to emergency response towards gas explosion. Expert Systems with Applications, 41(5), 2526-2534.
Frye, D., Zelazo, P. D., & Palfai, T. (1995). Theory of mind and rule-based reasoning. Cognitive Development, 10(4), 483-527.
Gorry, G. A., & Morton, M. S. (1989). A framework for management information systems. Sloan Management Review, 30(3), 49-61.
Hill, C. W. L., & Jones, G. R. (2013). Strategic Management: Theory & Cases: An Integrated Approach: Cengage Learning.
Hormby, S., Morrison, J., Dave, P., Meyers, M., & Tenca, T. (2010). Marriott international increases revenue by implementing a group pricing optimizer. Interfaces, 40(1), 47-57.
Hubert Ofner, M., Straub, K., Otto, B., & Österle, H. (2013). Management of the master data lifecycle: A framework for analysis. Journal of Enterprise Information Management, 26(4), 472-491.
Keen, P. G. W., & Scott Morton, M. S. (1978). Decision Support Systems: An Organizational Perspective: Addison-Wesley.
Li, H., Adeli, H., Sun, J., & Han, J.-G. (2011). Hybridizing principles of TOPSIS with case-based reasoning for business failure prediction. Computers & Operations Research, 38(2), 409-419.
Lin, C., & Hsieh, P.-J. (2004). A fuzzy decision support system for strategic portfolio management. Decision Support Systems, 38(3), 383-398.
Lin, C., Lin, C.-M., Yen, D. C., & Wu, W.-h. (2012). The Integrated Information Architecture: A Pilot Study Approach to Leveraging Logistics Management with Regard to Influenza Preparedness. Journal of medical systems, 36(1), 187-200.
Lin, C., Liu, A. C., Hsu, M.-L., & Wu, J.-C. (2008). Pursuing excellence in firm core knowledge through intelligent group decision support system. Industrial Management & Data Systems, 108(3), 277-296.
López, B., Pous, C., Gay, P., Pla, A., Sanz, J., & Brunet, J. (2011). eXiT* CBR: A framework for case-based medical diagnosis development and experimentation. Artificial intelligence in medicine, 51(2), 81-91.
Mahar, S., Winston, W., & Wright, P. D. (2013). Eli Lilly and company uses integer programming to form volunteer teams in impoverished countries. Interfaces, 43(3), 268-284.
Martens, B. J., Scheibe, K. P., & Bergey, P. K. (2012). Supply chains in Sub‐Saharan Africa: A decision support system for small‐scale seed entrepreneurs. Decision Sciences, 43(5), 737-759.
McLeod, R., & Schell, G. (2001). Management Information Systems 8/e: Prentice-Hall, Inc.
Patton, M. Q. (2002). Qualitative Research and Evaluation Methods Sage Publications, Inc.
Pla, A., López, B., Gay, P., & Pous, C. (2013). eXiT* CBR. v2: Distributed case-based reasoning tool for medical prognosis. Decision Support Systems, 54(3), 1499-1510.
Pohle, G., Korsten, P., & Ramamurthy, S. (2005). Component business models: Making specialization real. IBM Institute for Business Value. August, 19.
Robbins, S. P., & Coulter, M. (2013). Management, 12/e: Pearson Educational.
Shivade, C., Mukri, F., Ramnath, R., & Ramanathan, J. (2011). Method for continuous generation of component business model heat map using execution data for a complex service enterprise. Paper presented at the Service Oriented System Engineering (SOSE), 2011 IEEE 6th International Symposium on.
Simon, H. A. (1997). Administrative behavior: A study of decision-making processes in administrative organization: The Free Press.
Tian, Q., Ma, J., Liang, J., Kwok, R. C., & Liu, O. (2005). An organizational decision support system for effective R&D project selection. Decision Support Systems, 39(3), 403-413.
Turban, E., Aronson, J., & Liang, T.-P. (2005). Decision Support Systems and Intelligent Systems: Pearson Prentice Hall.
Xie, X., Lin, L., & Zhong, S. (2013). Handling missing values and unmatched features in a CBR system for hydro-generator design. Computer-Aided Design, 45(6), 963-976.
Zhang, J., Tang, O., Zhao, J., Huo, J., & Xia, Y. (2013). CPEL redesigns its land express network. Interfaces, 43(3), 221-231.

------------------------------------------------------------------------ 第 17 筆 ---------------------------------------------------------------------
系統識別號 U0026-0707201510485800
論文名稱(中文) 在異質細胞網路中依據基地台流量避免乒乓效應之卸載分流機制
論文名稱(英文) A Load-Based Offloading Scheme for Mitigating Ping-Pong Effect in Heterogeneous Cellular Networks
校院名稱 成功大學
系所名稱(中) 電腦與通信工程研究所
系所名稱(英) Institute of Computer & Communication
學年度 103
學期 2
出版年 104
研究生(中文) 葛庭瑞
學號 Q36024507
學位類別 碩士
語文別 英文
口試日期 2015-07-02
論文頁數 32頁
口試委員 指導教授-劉光浩
口試委員-蘇賜麟
口試委員-張志文
關鍵字(中) 細胞選擇機制
異質性網路
小細胞
卸載分流
關鍵字(英) Cell association
Heterogeneous cellular networks
Small cell
Offload
學科別分類
中文摘要 在日趨增加的頻寬需求下,傳統的細胞網路架構已經逐漸不敷使用。為了解決此問題,增設小基地台被認為一種可能的解決方案,增設小基地台雖可分擔大基地台的流量,但若採用傳統以接收訊號強度為判斷基準的基地台選擇機制,除了分擔流量的效果相當有限,大多數的大基地台仍會出現過載的情況。因此,目前廣受學界討論的做法是將原判定和大基地台連線卻因為大基地台的過載而連線失敗的使用者,卸載給小基地台。但若不考慮卸載目標基地台的負載情況,卸載的目標基地台仍可能為過載,進而造成因為過多無意義的卸載而導致的連線失敗。為解決此問題,我們提出了一種考量基地台負載情況的卸載機制,該機制可以根據各基地台的負載情況將使用者卸載,並成功地避免掉過多無意義的卸載而導致的連線失敗。根據模擬的結果,所提出的卸載機制能達到更高卸載成功的機率。
英文摘要 The development of small cells which shifts the traditional macro-based homogeneous network to the heterogeneous networks (HetNets) is regarded as one of the major breakthroughs to improve the network capacity. With the traditional Max-SINR association scheme, a user will choose the base station (BS) which offers the strongest received signal strength as its serving BS. Consequently, severe congestions may happen at the high-power macro base stations (MBSs) because most users tend to associate with the more powerful MBS rather than the low-power pico base stations (PBSs). To release the congestion problem, users can be shifted from the overloaded BSs to other BSs, known as user offloading. However, without taking the BS load into consideration, users may be offloaded to a neighboring BS that is overloaded, leading to failure cell association that is undesirable from both users' and operators' perspectives. In this work, we propose a load-based offloading scheme to address the aforementioned issue. We first formulate the optimal load-based offloading problem and shows that it is NP-hard. To facilitate practical implementation, a heuristic algorithm is proposed that is featured by the use of an offset parameter to mitigate offloading users to over-loaded BSs. From simulation results, the proposed heuristic algorithm is shown to increase the association rate and the average user rate, as compared to the traditional offloading scheme without considering the BS load.
論文目次 1 Introduction 1
1.1 Challenges and Problem Statement . . . . . . . . . .1
1.2 Thesis Structure . . . . . . . . . . . . . . . . . .2
2 Background and Literature Review . . . . . . . . . . .3
2.1 Background . . . . . . . . . . . . . . . . . . . . .3
2.1.1 Small Cells . . . . . . . . . . . . . . . . . . . 3
2.1.2 Cell Association . . . . . . . . . . . . . . . . 5
2.2 Literature Review . . . . . . . . . . . . . . . . . 6
3 System Model and Proposed Scheme . . . . . . . . . . .8
3.1 System Model . . . . . . . . . . . . . . . . . . . .8
3.2 Proposed Scheme . . . . . . . . . . . . . . . . . . 9
3.2.1 The Back Effect . . . . . . . . . . . . . . . . .10
3.2.2 Problem Formulation and Solution . . . . . . . . 10
4 Results and Discussions . . . . . . . . . . . . . . .15
4.1 Maximized Throughput Algorithm (MTA) . . . . . . ..18
4.2 The Benefit of Heuristic Approach . . . . . . . . .22
4.3 The Impact of Overloading Offsets . . . . . . . . 23
4.4 The Impact of Cell Range Expansion . . . . . . . . 24
5 Conclusions . . . . . . . . . . . . . . . . . . . . .27
5.1 Summary of Thesis . . . . . . . . . . . . . . . . 27
5.2 Future Work . . . . . . . . . . . . . . . . . . . 28
Appendix . . . . . . .. . . . . . . . . . . . . . . . .29
Reference. . . . . .. . . . . . . . . . . . . . . . . .31
參考文獻 [1] 3GPP TR 36.839 V11.1.0 Technical Specification Group Radio Access Network
and Evolved Universal Terrestrial Radio Access (E-UTRA); Mobility
Enhancements in Heterogeneous Networks (Release 11).
[2] J. G. Andrews, “Seven Ways that HetNets Are a Cellular Paradigm Shift,”
IEEE Commun. Mag., vol. 51, no. 3, pp. 136-144, Mar. 2013.
[3] M. Shirakabe, A. Morimoto, and N. Miki, “Performance Evaluation of Intercell
Interference Coordination and Cell Range Expansion in Heterogeneous
Networks for LTE-Advanced Downlink,” in Proc. IEEE ISWCS, Nov. 2011.
[4] D. Bai, C. Park, and J. Lee, “LTE-Advanced Modem Design: Challenges and
Perspectives,” IEEE Commun. Mag., vol. 50, no. 2, pp. 178-186, Feb. 2012.
[5] J. G. Andrews, S. Singh, Q. Ye, X. Lin, and H. S. Dhillon, “An Overview of
Load Balancing in HetNets: Old Myths and Open Problems,”IEEE Commun.
Mag., vol. 21, no. 2, pp. 18–25, Apr. 2014.
[6] A. Ghosh, N. Mangalvedhe, R. Ratasuk, B. Mondal, M. Cudak, E. Visotsky,
and T. A. Thomas, “Heterogeneous Cellular Networks: From Theory to
Practice,” IEEE Commun. Mag., vol. 50, no. 6, pp. 54–64, Jun. 2012.
[7] S. Singh, H. S. Dhillon, and J. G. Andrews, “Offloading in Heterogeneous
Networks: Modeling, Analysis, and Design Insights,”IEEE Trans. Wireless
Commun., vol. 12, no. 5, pp. 2484–2497, May 2013.
[8] H. Tang, J. Peng, P. Hong, and K. Xue, “Offloading Performance of Range
Expansion in Picocell Networks: A Stochastic Geometry Analysis,”IEEE
Wireless Commun. Lett., vol. 2, no. 5, pp. 511-514, Jul. 2013.
[9] T. Zhou, Y. Huang, and L. Yang, “QoS-Aware User Association for Load
Balancing in Heterogeneous Cellular Networks,”in Proc. IEEE VTC, Sep.
2014.
[10] T. Jansen, I. M. Balan, I. Moerman, and T. Kurner, “Handover Parameter
Optimization in LTE Self-Organizing Networks,”in Proc. IEEE VTC, Sep.
2010.
[11] Q. Ye, B. Rong, Y. Chen, M. A. Shalash, C. Caramanis, and J. G. Andrews,
“User Association for Load Balancing in Heterogeneous Cellular Networks,”
IEEE Trans. Wireless Commun., vol. 12, no. 6, pp. 2706–2716, Jun. 2013.
[12] A. S. Sznitman, “Topics in Random Walks in Random Environment,” http://
www.math.ethz.ch/.sznitman/topics-paper.pdf.
[13] R. Pemantle. “A Survey of Random Processes with Reinforcement,” Probability
Surveys, vol. 4, pp. 1–79, Feb. 2007.
[14] J. Csirik, “Heuristics for the 01 Knapsack Problem,” http:// www.inf.uszeged.
hu/actacybernetica/edb/vol10n1.pdf.
[15] S. Martello and P. Toth, “Knapsack Problems: Algorithms and Computer
Implementations,” Wiley, Chichester, UK, 1990.
[16] G. J. Woeginger, “Exact Algorithms for NP-hard Problems: A Survey,” Combinatorial
Optimization: Eureka, You Shrink., Springer-Verlage, LNCS, vol.
2570, pp. 185–207, Mar. 2003.

------------------------------------------------------------------------ 第 18 筆 ---------------------------------------------------------------------
系統識別號 U0026-0707201517480700
論文名稱(中文) 探討印尼血液透析病患疲憊感之相關因素
論文名稱(英文) Fatigue among clients undergoing hemodialysis in Indonesia
校院名稱 成功大學
系所名稱(中) 護理學系
系所名稱(英) Department of Nursing
學年度 103
學期 2
出版年 104
研究生(中文) 哈桑
學號 T26027158
學位類別 碩士
語文別 英文
口試日期 2015-06-04
論文頁數 61頁
口試委員 指導教授-顏妙芬
召集委員-丘周萍
口試委員-宋俊銘
關鍵字(中) none
關鍵字(英) fatigue
patients with routine hemodialysis.
學科別分類
中文摘要 none
英文摘要 Background: Fatigue is the most common among the many troublesome symptoms experienced by patients undergoing hemodialysis, and this can significantly decrease the patient’s quality of life.
Purpose: The purpose of this study was to identify the severity of fatigue and it’s associated in physiological, psychological and situational factors among patients undergoing HD in Indonesia.
Method: To achieve these goals a cross-sectional study was conducted. This study examined 140 patients with End Stage Renal Disease (ESRD) undergoing routine hemodialysis. Three questionnaires and one scoring system were used in this study. Fatigue was assessed using the 4th version of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). The Depression, Anxiety and Stress Scale-Short Form (DASS-SF) was used to measure psychological factors. The Charlson Comorbidity Index (CCI) was used to measure comorbidity among clients undergoing hemodialysis. Bivariate and multivariate analyses were used to assess the associations between independent variables and fatigue, and to find the predictors of fatigue among the various physical, psychological, and situational factors.
Result: The results showed that among the situational factors, namely the demographic factors, length of hemodialysis and frequency of hemodialysis, age was significantly associated (r = .204, p = .015) and becomes a predictor of fatigue (β = .13, p = < .05). The psychological factors such as depression, anxiety and stress were highly correlated with fatigue but only anxiety (β = .886, p = < .001) becomes a predictor of fatigue. Finally, the physiological factors namely urea, creatinin, hemoglobin, and comorbidity, both comorbidity (β = .1.56, p = < .001) and hemoglobin level (β = -.593, p = < .001) were predictors of fatigue.
Conclusions: Age, hemoglobin, comorbidity, and anxiety have significant associations with fatigue and also predictors of fatigue. Improving these may thus reduce fatigue and increase the quality of life in patients undergoing routine hemodialysis.

Keywords: Fatigue, Patients with routine hemodialysis.
論文目次 ABSTRACT I
TABLE OF CONTENTS III
LIST OF TABLES VI
LIST OF FIGURES VII
CHAPTER ONE INTRODUCTION 1
1.1 Research Background 1
1.2 Research Purpose 3
CHAPTER TWO LITERATURE REVIEW 5
2.1 General Theory of Fatigue 5
2.2 Fatigue in Chronic Disease 6
2.3 Fatigue in Patient with HD 7
2.4 Factors Affecting Fatigue 8
2.5 Comorbidity 10
2.6 Patient with HD in Indonesia 11
2.7 Research Framework 12
CHAPTER THREE RESEARCH DESIGN AND METHODOLOGY 13
3.1 Subject and Methods 13
3.2 Procedure 14
3.3 Instruments 15
3.3.1 Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Instrument 15
3.3.2 Depression, Anxiety and Stress Short Form (DASS-SF) 16
3.3.3 Assessment of the Comorbidity 17
3.4 Section 4 - Data Analysis 17
CHAPTER FOUR RESEARCH RESULTS 19
4.1 Characteristics of Participants 19
4.2 Correlation among Covariates and Fatigue 21
4.3 The Predictors of Fatigue 23
CHAPTER FIVE DISCUSSION AND SUGGESTIONS 26
5.1 Discussion 26
5.1.1 Factors Associated with Fatigue 26
5.1.2 Factors not associated with fatigue 29
5.2 Limitations 31
5.3 Conclusions and suggestions 31
REFERENCES 33
APPENDICES 43
Appendix 1: Institutional Review Board (IRB) Approval 43
Appendix 2: Consent to Participants in Research 44
Appendix 3: Research Permit from Hospital 46
Appendix 4: Instrument to Measure Demographic data. 47
Appendix 5: Score of Physiological factors. 48
Appendix 6: Functional Assessment Chronic Illness Therapy - Fatigue (FACIT-F) Instrument (English Version). 49
Appendix 7: Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Instrument (Indonesian Version). 50
Appendix 8: Functional Assessment of Chronic Ilness Therapy - Fatigue (FACIT-F) Certified Translation. 51
Appendix 9: Email Communication with the Author of FACIT-F Instrument. 52
Appendix 10: Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) License. 54
Appendix 11: Depression, Anxiety Stress Scale Short Form (DAAS-SF) instrument (English Version) 56
Appendix 12: Depression, Anxiety and Stress Scale Short Form (DASS-SF) Permission. 58
Appendix 13: Depression, Anxiety Stress Scale Short Form (DASS-SF) Instrument (Indonesian Version). 59
Appendix 14: Charlson Comorbidity Index (CCI) 61
參考文獻 Baldree, I., & Murphy, S. A Powers, M. (1982). Stress identification and coping patterns in patients on hemodialysis. Nursing Research, 31,107-112.

Bates, D. W., Schmitt, W., Buchwald, D., Ware, N. C., Lee, J., Thoyer, E., . . . Komaroff, A. L. (1993). Prevalence of fatigue and chronic fatigue syndrome in a primary care practice. Archives of Internal Medicine, 153(24), 2759.

Bonner, A., Wellard, S., & Caltabiano, M. (2010). The impact of fatigue on daily activity in people with chronic kidney disease. Journal of Clinical Nursing, 19(21-22), 3006-3015. doi: 10.1111/j.1365-2702.2010.03381.x

Bossola, M., Luciani, G., & Tazza, L. (2009). Fatigue and its correlates in chronic hemodialysis patients. Blood Purification, 28(3), 245-252. doi: 10.1159/000231985

Breitbart, W., Chochinov, H., & Passik, S. (1998). Psychiatric aspects of palliative care (933-954). Oxford, UK: Oxford Textbook of Palliative Medicine.
Brown, L. F., & Kroenke, K. (2009). Cancer-related fatigue and its associations with depression and anxiety: a systematic review. Psychosomatics, 50(5), 440-447.
Brunier, G., & Graydon, J. (1993). The influence of physical activity on fatigue in patients with ESRD on hemodialysis. The American Journal of Nephrology, 20(4), 457-461; discussion 462, 521.
Brunier, G., & Graydon, J. (1996). A comparison of two methods of measuring fatigue in patients on chronic haemodialysis: visual analogue vs Likert scale. International Journal of Nursing Studies, 33(3), 338-348.
Cardenas, D., & Kutner, N. (1982). The problem of fatigue in dialysis patients. KARGER Medical and Scientific, 30(4), 336-340.
Cauch-Dudek, K., Heathcote, E., Huterer, N., Driver, H., & Shapiro, C. (1998). Fatigue in primary billiary cirrhosis. British Medical Journal of Gastroenterology, 43(5), 705-710.
Cella, D. (1997). The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: a new tool for the assessment of outcomes in cancer anemia and fatigue. Seminars in Hematology, 34(3 Suppl 2), 13-19.
Cella, D., Lai, J.-S., & Stone, A. (2011). Self-reported fatigue: one dimension or more? Lessons from the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire. Supportive Care in Cancer, 19(9), 1441-1450. doi: 10.1007/s00520-010-0971-1
Chang, W. K., Hung, K. Y., Huang, J. W., Wu, K. D., & Tsai, T. J. (2001). Chronic Fatigue in Long-Term Peritoneal Dialysis Patients. American Journal of Nephrology, 21(6), 479-485.
Charlson, M. E., Pompei, P., Ales, K. L., & MacKenzie, C. R. (1987). A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. Journal of Chronic Diseases, 40(5), 373-383. doi: http://dx.doi.org/10.1016/0021-9681(87)90171-8
Chen, C.-K., Tsai, Y.-C., Hsu, H.-J., Wu, I. W., Sun, C.-Y., Chou, C.-C., . . . Wang, L.-J. (2010). Depression and Suicide Risk in Hemodialysis Patients With Chronic Renal Failure. Psychosomatics, 51(6), 528-528.e526. doi: http://dx.doi.org/10.1016/S0033-3182(10)70747-7
Chen, M. K. (1986). The epidemiology of self-perceived fatigue among adults. Preventive Medicine, 15(1), 74-81.
Chertow, G. M., Levin, N. W., Beck, G. J., Depner, T. A., Eggers, P. W., Gassman, J. J., . . . Kliger, A. S. (2010). In-center hemodialysis six times per week versus three times per week. The New England Journal of Medicine, 363(24), 2287-2300. doi: 10.1056/NEJMoa1001593
Cleary, J., & Drennan, J. (2005). Quality of life of patients on haemodialysis for end‐stage renal disease. Journal of Advanced Nursing, 51(6), 577-586.
Couser, W. G., Remuzzi, G., Mendis, S., & Tonelli, M. (2011). The contribution of chronic kidney disease to the global burden of major noncommunicable diseases. Kidney International, 80(12), 1258-1270.
Crawford, J. R., & Henry, J. D. (2003). The Depression Anxiety Stress Scales (DASS): Normative data and latent structure in a large non-clinical sample. British Journal of Clinical Psychology, 42(2), 111-131. doi: 10.1348/014466503321903544
Cukor, D., Coplan, J., Brown, C., Friedman, S., Cromwell-Smith, A., Peterson, R. A., & Kimmel, P. L. (2007). Depression and Anxiety in Urban Hemodialysis Patients. Clinical Journal of the American Society of Nephrology, 2(3), 484-490. doi: 10.2215/cjn.00040107
Cukor, D., Coplan, J., Brown, C., Friedman, S., Newville, H., Safier, M., . . . Kimmel, P. L. (2008). Anxiety Disorders in Adults Treated by Hemodialysis: A Single-Center Study. American Journal of Kidney Diseases, 52(1), 128-136. doi: http://dx.doi.org/10.1053/j.ajkd.2008.02.300
Damanik, E. D. (2011). The Measurement of Reliability, Validity, Items Analysis and Normative Data of Depression Anxiety Stress Scale (DASS). Thesis di Fakultas Psikologi, Universitas Indonesia, Indonesia. 60.
Denburg, S., Carbotte, R., & Denburg, J. (1997). Psychological aspects of systemic lupus erythematosus: cognitive function, mood, and self-report. The Journal of Rheumatology, 24(5), 998-1003.
Eggers, P. W. (2011). Has the incidence of end-stage renal disease in the USA and other countries stabilized? Current Opinion in Nephrology and Hypertension, 20(3), 241-245 210.1097/MNH.1090b1013e3283454319.
Elder, S. J., Pisoni, R. L., Akizawa, T., Fissell, R., Andreucci, V. E., Fukuhara, S., . . . Saran, R. (2008). Sleep quality predicts quality of life and mortality risk in haemodialysis patients: Results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrology Dialysis Transplantation, 23(3), 998-1004. doi: 10.1093/ndt/gfm630
Eschbach, J. W., Kelly, M. R., Haley, N. R., Abels, R. I., & Adamson, J. W. (1989). Treatment of the anemia of progressive renal failure with recombinant human erythropoietin. New England Journal of Medicine, 321(3), 158-163.
Freal, J., Kraft, G., & Coryell, J. (1984). Symptomatic fatigue in multiple sclerosis. Archives of Physical Medicine and Rehabilitation, 65(3), 135-138.
Glaus, A. (1993). Assessment of fatigue in cancer and non-cancer patients and in healthy individuals. Supportive Care in Cancer, 1(6), 305-315.
Gurklis, J. A., & Menke, E. M. (1988). Identification of stressors and use of coping methods in chronic hemodialysis patients. Nursing Research, 37(4), 236-239.
Harman, D. (1981). The aging process. Proceedings of the National Academy of Sciences, 78(11), 7124-7128.
Hensyl, W. (1990). Stedman’s medical dictionary. Baltimore, USA: Lippincott Williams & Wilkins.
Horigan, A. E. (2012). Fatigue in Hemodialysis Patients: A Review of Current Knowledge. Journal of Pain and Symptom Management, 44(5), 715-724. doi: http://dx.doi.org/10.1016/j.jpainsymman.2011.10.015
Huyser, B. A., Parker, J. C., Thoreson, R., Smarr, K. L., Johnson, J. C., & Hoffman, R. (1998). Predictors of subjective fatigue among individuals with rheumatoid arthritis. Journal of the American College of Rheumatology, 41(12), 2230-2237.
Indonesian Renal Registry. (2013). 5th annual report of Indonesian renal registry. Retrieved May 21, 2014, from http://www.pernefri-inasn.org/gallery.html
Jablonski, A. (2007). The multidimensional characteristics of symptoms reported by patients on hemodialysis. Nephrology Nursing Journal, 34(1).
Jhamb, M., Argyropoulos, C., Steel, J. L., Plantinga, L., Wu, A. W., Fink, N. E., . . . Unruh, M. L. (2009). Correlates and outcomes of fatigue among incident dialysis patients. Clinical Journal of The American Society of Nephrology, 4(11), 1779-1786. doi: 10.2215/cjn.00190109
Jhamb, M., Pike, F., Ramer, S., Argyropoulos, C., Steel, J., Dew, M. A., . . . Unruh, M. (2011). Impact of Fatigue on Outcomes in the Hemodialysis (HEMO) Study. American Journal of Nephrology, 33(6), 515-523.
Jhamb, M., Weisbord, S. D., Steel, J. L., & Unruh, M. (2008). Fatigue in Patients Receiving Maintenance Dialysis: A Review of Definitions, Measures, and Contributing Factors. American Journal of Kidney Diseases, 52(2), 353-365. doi: http://dx.doi.org/10.1053/j.ajkd.2008.05.005
Jones, E. A. (1995). Fatigue associated with chronic liver disease: a riddle wrapped in a mystery inside an enigma. Hepatology, 22(5), 1606-1608.
Kim, H. R., & Son, G. R. (2005). Fatigue and its related factors in Korean patients on hemodialysis. Taehan Kanho Hakhoe chi, 35(4), 701-708.
Kim, S.-D., & Kim, H.-S. (2005). Effects of a relaxation breathing exercise on fatigue in haemopoietic stem cell transplantation patients. Journal of Clinical Nursing, 14(1), 51-55. doi: 10.1111/j.1365-2702.2004.00938.x
Kimmel, P., Levy, N., Daugirdas, J., Blake, P., & Ing, T. (2001). Psychology and rehabilitation, Handbook of Dialysis (Volume 3), (413-419). New York, NY: Lippincott Williams & Wilkins.
Kimmel, P. L., & Peterson, R. A. (2006). Depression in patients with end-stage renal disease treated with dialysis: has the time to treat arrived? Clinical Journal of The American Society of Nephrology, 1(3), 349-352.
Koyama, H., Fukuda, S., Shoji, T., Inaba, M., Tsujimoto, Y., Tabata, T., . . . Nishizawa, Y. (2010). Fatigue is a predictor for cardiovascular outcomes in patients undergoing hemodialysis. Clinical Journal of The American Society of Nephrology, 5(4), 659-666. doi: 10.2215/cjn.08151109
Krupp, L., LaRocca, N., Muir, J., & Steinberg, A. (1990). A study of fatigue in systemic lupus erythematosus. The Journal of Rheumatology, 17(11), 1450-1452.
Krupp, L. B., Alvarez, L. A., LaRocca, N. G., & Scheinberg, L. C. (1988). Fatigue in multiple sclerosis. Archives of Neurology, 45(4), 435.
Kutner, N. G., Brogan, D., Hall, W. D., Haber, M., & Daniels, D. S. (2000). Functional impairment, depression, and life satisfaction among older hemodialysis patients and age-matched controls: A prospective study. Archives of Physical Medicine and Rehabilitation, 81(4), 453-459. doi: http://dx.doi.org/10.1053/mr.2000.3878
Laupacis, A., Muirhead, N., Keown, P., & Wong, C. (1992). A Disease-Specific Questionnaire for Assessing Quality of Life in Patients on Hemodialysis. KARGER Medical and Scientific, 60(3), 302-306.
Lee, K. A., Hicks, G., & Nino-Murcia, G. (1991). Validity and reliability of a scale to assess fatigue. Psychiatry Research, 36(3), 291-298. doi: http://dx.doi.org/10.1016/0165-1781(91)90027-M
Leinau, L., Murphy, T. E., Bradley, E., & Fried, T. (2009). Relationship between Conditions Addressed by Hemodialysis Guidelines and Non-ESRD-Specific Conditions Affecting Quality of Life. Clinical Journal of the American Society of Nephrology, 4(3), 572-578. doi: 10.2215/cjn.03370708
Lenz, E. R., Suppe, F., Gift, A. G., Pugh, L. C., & Miligan, R. A. (1995). Collaborative development of middle-range nursing theories: Toward a theory of unpleasant symptoms. Advances in Nursing Science, 17(3), 1-13.
Letchmi, S., Das, S., Halim, H., Zakariah, F. A., Hassan, H., Mat, S., & Packiavathy, R. (2011). Fatigue experienced by patients receiving maintenance dialysis in hemodialysis units. Nursing & Health Sciences, 13(1), 60-64. doi: 10.1111/j.1442-2018.2011.00579.x
Lewis, S. F., & Haller, R. G. (1991). Physiologic measurement of exercise and fatigue with special reference to chronic fatigue syndrome. Review of Infectious Diseases, 13(Supplement 1), S98-S108.
Liu, H. E. (2006). Fatigue and associated factors in hemodialysis patients in Taiwan. Research in Nursing & Health, 29(1), 40-50. doi: 10.1002/nur.20109
Lovibond, P. F., & Lovibond, S. H. (1995). The structure of negative emotional states: Comparison of the Depression Anxiety Stress Scales (DASS) with the Beck Depression and Anxiety Inventories. Behaviour Research and Therapy, 33(3), 335-343. doi: http://dx.doi.org/10.1016/0005-7967(94)00075-U
McCann, K., & Boore, J. R. P. (2000). Fatigue in persons with renal failure who require maintenance haemodialysis. Journal of Advanced Nursing, 32(5), 1132-1142. doi: 10.1046/j.1365-2648.2000.01584.x
McDonald, E., David, A. S., Pelosi, A. J., & Mann, A. H. (1993). Chronic fatigue in primary care attenders. Psychological Medicine, 23(04), 987-998.
Morsch, C. M., Gonçalves, L. F., & Barros, E. (2006). Health‐related quality of life among haemodialysis patients–relationship with clinical indicators, morbidity and mortality. Journal of Clinical Nursing, 15(4), 498-504.
O'Sullivan, D., & McCarthy, G. (2007). An exploration of the relationship between fatigue and physical functioning in patients with end stage renal disease receiving haemodialysis. Journal of Clinical Nursing, 16(11c), 276-284.
O'Sullivan, D., & McCarthy, G. (2009). Exploring the symptom of fatigue in patients with end stage renal disease. Nephrology Nursing Journal, 36(1).
Parfrey, P. S., Vavasour, H. M., Henry, S., Bullock, M., & Gault, M. H. (1988). Clinical Features and Severity of Nonspecific Symptoms in Dialysis Patients. KARGER Medical and Scientific, 50(2), 121-128.
Pawlikowska, T., Chalder, T., Hirsch, S. R., Wallace, P., Wright, D. J. M., & Wessely, S. C. (1994). Population based study of fatigue and psychological distress. British Medical Journal, 308(6931), 763-766. doi: 10.1136/bmj.308.6931.763.
Piper, B., Lindsey, A., & Dodd, M. (1987). Fatigue mechanisms in cancer patients: developing nursing theory. The Oncology Nursing Forum, 14(6), 17-23.
Piper, B., Lindsey, A., Dodd, M., Ferketich, S., Paul, S., & Weller, S. (1989). The development of an instrument to measure the subjective dimension of fatigue: Key Aspects of Comfort. Management of Pain, Fatigue and Nausea. New York: Springer.
Polaschek, N. (2003). Living on dialysis: concerns of clients in a renal setting. Journal of Advanced Nursing, 41(1), 44-52.
Prodjosudjadi, W., & Suhardjono, A. (2009). End-stage renal disease in Indonesia: Treatment development. Ethnicity & Disease, 19(1), 33.
Sidani, S., Doran, D. M., & Mitchell, P. H. (2004). A Theory-Driven Approach to Evaluating Quality of Nursing Care. Journal of Nursing Scholarship, 36(1), 60-65. doi: 10.1111/j.1547-5069.2004.04014.x
Sklar, A. H., Riesenberg, L. A., Silber, A. K., Ahmed, W., & Ali, A. (1996). Postdialysis fatigue. American Journal of Kidney Diseases, 28(5), 732-736.
Srivastava, R. (1986). Fatigue in the renal patient. The Journal of American Nephrology Nurses Association, 13(5), 246-249.
Srivastava, R. H. (1989). Fatigue in end-stage renal disease patients. Key Aspects of Comfort. Management of Pain, Fatigue and Nausea (pp.217-224). New York: Springer.
Stone, P., Richards, M., & Hardy, J. (1998). Fatigue in patients with cancer. European Journal of Cancer, 34(11), 1670-1676. doi: http://dx.doi.org/10.1016/S0959-8049(98)00167-1
Swain, M. G. (2000). Fatigue in chronic disease. Clinical Science, 99(1), 1-8.
Ting, G. O., Kjellstrand, C., Freitas, T., Carrie, B. J., & Zarghamee, S. (2003). Long-term study of high-comorbidity ESRD patients converted from conventional to short daily hemodialysis. American Journal of Kidney Diseases, 42(5), 1020-1035. doi: http://dx.doi.org/10.1016/j.ajkd.2003.07.020
Ward, W., Hahn, E., Mo, F., Hernandez, L., Tulsky, D., & Cella, D. (1999). Reliability and validity of the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) quality of life instrument. Quality of Life Research, 8(3), 181-195. doi: 10.1023/A:1008821826499
Weisbord, S. D., Fried, L. F., Mor, M. K., Resnick, A. L., Unruh, M. L., Palevsky, P. M., . . . Arnold, R. M. (2007). Renal Provider Recognition of Symptoms in Patients on Maintenance Hemodialysis. Clinical Journal of the American Society of Nephrology, 2(5), 960-967. doi: 10.2215/cjn.00990207
Windsor, P. M., Nicol, K. F., & Potter, J. (2004). A randomized, controlled trial of aerobic exercise for treatment-related fatigue in men receiving radical external beam radiotherapy for localized prostate carcinoma. The Journal of American Cancer Society, 101(3), 550-557. doi: 10.1002/cncr.20378
Wolfe, F., Hawley, D. J., & Wilson, K. (1996). The prevalence and meaning of fatigue in rheumatic disease. The Journal of Rheumatology, 23(8), 1407-1417.
Yellen, S. B., Cella, D. F., Webster, K., Blendowski, C., & Kaplan, E. (1997). Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. Journal of Pain and Symptom Management, 13(2), 63-74.

------------------------------------------------------------------------ 第 19 筆 ---------------------------------------------------------------------
系統識別號 U0026-0708201516292300
論文名稱(中文) 非線性混合效用模型下之重複量測加速衰變測試規劃
論文名稱(英文) Planning Repeated Measures Accelerated Degradation Tests under Non-linear Mixed Effect Models
校院名稱 成功大學
系所名稱(中) 統計學系
系所名稱(英) Department of Statistics
學年度 103
學期 2
出版年 104
研究生(中文) 葉耿傑
學號 R26021100
學位類別 碩士
語文別 英文
口試日期 2015-07-16
論文頁數 56頁
口試委員 指導教授-鄭順林
口試委員-張升懋
口試委員-王婉倫
關鍵字(中) 重複量測的加速衰變測試
非線性混合效用模型
擬蒙地卡羅積分
關鍵字(英) Repeated Measures Accelerated Degradation Test
Non-linear Mixed Effect Model
Quasi Monte Carlo Integration
學科別分類
中文摘要 在一般的壽命測試和衰變測試中,若在實驗期間無法看到足夠的產品失效,則無法對於產品壽命提供足夠的資訊,此時便會進而考慮重複量測的加速衰變測試。在非線性的退化模型假設下,本文處理此種測試規劃的最佳化問題,同時,測試單元間變異亦以非線性之隨機項存在於模型中。

由於模型的非線性型態,概似函數與費雪訊息矩陣,以及退化模型所衍生出的壽命分佈之推算有其難處。因此,本文以蒙地卡羅積分方法計算測試規劃最佳化之準則,即參數估計量的漸進變異數,並以格子點搜索的方式找到最佳的測試規劃。為了減輕計算上的負擔,本文將最佳化問題考慮在一些限制條件下進行處理,同時並使用擬蒙地卡羅法及一些R套件來進行有效率的統計計算。本文亦將所提出之方法應用在一集成電路裝置之實例上。
英文摘要 Repeated measures accelerated degradation tests (RMADTs) can provide more information about the product reliability
when one would expect few or even no failures during a study. In this paper, we deal with the optimal test planning problem under the non-linear Arrhenius acceleration model. Further, unit-to-unit variability is described by the random effects, which is also non-linear in time.

Due to the assumption of non-linear mixed effect model (NLMEM), the analytical calculation of the likelihood and some related functions such as Fisher information matrix are difficult. Therefore, we perform the Monte Carlo integration to calculate the asymptotic variance of estimators as the optimality criterion. Grid search procedures are conducted to find the optimum test plan under some constraints. Quasi-random low-discrepancy sequences and some R packages for efficient computation are used to relief the computational burden. The method is illustrated with an application of an integrated circuit device example.
論文目次 1 Introduction 1
1.1 Background and Motivation . . . . . . . . . . . . . . . . . . 1
1.2 Literature Review . . . . . . . . . . . . . . . . . . . . . . . . 2
1.2.1 Planning the RMADTs . . . . . . . . . . . . . . . . . 2
1.2.2 Evaluation of Fisher Information Matrix under NLMEMs 3
1.3 Motivating Example and Previous Work . . . . . . . . . . . . 3
1.4 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2 Degradation Models and Lifetime Distribution 6
2.1 Accelerated Degradation Model . . . . . . . . . . . . . . . . 6
2.1.1 General Degradation Path Model . . . . . . . . . . . . 6
2.1.2 Arrhenius Acceleration Factor . . . . . . . . . . . . . 6
2.1.3 Re-parameterization . . . . . . . . . . . . . . . . . . 7
2.2 Likelihood, MLE and Fisher Information . . . . . . . . . . . 9
2.3 Lifetime Distribution for Degradation Models . . . . . . . . . 10
2.3.1 Relationship between Degradation and Failures . . . . 10
2.3.2 p Quantile of Lifetime Distribution . . . . . . . . . . 12
3 Planning RMADTs 13
3.1 Planning Information and Constraints . . . . . . . . . . . . . 13
3.2 Specification of RMADT Plans . . . . . . . . . . . . . . . . . 13
3.2.1 Stress Level and Test Units Allocation . . . . . . . . . 13
3.2.2 Inspection Schedule . . . . . . . . . . . . . . . . . . 14
3.3 Criterion for Choosing a Plan . . . . . . . . . . . . . . . . . . 15
3.3.1 Variance Covariance Matrix of Parameters Estimators 15
3.3.2 Asymptotic Variance of Estimator of p Quantile . . . . 16
4 Methodology in Computation 18
4.1 Monte Carlo Integration . . . . . . . . . . . . . . . . . . . . 18
4.2 Quasi Monte Carlo Integration . . . . . . . . . . . . . . . . . 18
5 Application 22
5.1 Computational Performance and Efficiency . . . . . . . . . . 22
5.1.1 Evaluation of Likelihood and Information . . . . . . . 24
5.1.2 Evaluation of Lifetime Distribution and Derivatives
of F . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
5.2 Grid Search for Optimal RMADT Plans . . . . . . . . . . . . 33
5.2.1 Re-allocation of Device-B Example . . . . . . . . . . 33
5.2.2 Optimal Choice of Number of Stress Levels . . . . . . 34
5.3 Validation of Optimality with Finite Sample . . . . . . . . . . 39
5.3.1 Variability of Estimators . . . . . . . . . . . . . . . . 39
5.3.2 Convergence of Variance with Increasing Sample Size 39
6 Conclusions and Future Work 42
Bibliography 44
Appendix 47
Appendix A Derivation of Fisher Information 47
Appendix B Derivation of AVar of tp 50
Appendix C Figures and Tables 52
參考文獻 Comets, E., Lavenu, A., and Lavielle, M. (2011), “SAEMIX, an R version of
the SAEM algorithm”, 20th meeting of the Population Approach Group in
Europe, Athens, Greece.
Das, S., Spall, J. C., and Ghanem, R. (2010), “Efficient monte carlo computation
of fisher information matrix using prior information”, Computational
Statistics & Data Analysis, 54(2), 272–289.
Guan, Q. and Tang, Y. (2013), “Optimal design of accelerated degradation
test based on gamma process models”, Chinese Journal of Applied Probability
and Statistics, 29(2).
Kim, S. J. and Bae, S. J. (2013), “Cost-effective degradation test plan for a
nonlinear random-coefficients model”, Reliability Engineering and System
Safety, 110, 68–79.
Krykova, I. (2003), “Evaluating of path-dependent securities with low discrepancy
methods”, Master’s thesis, Worcester Polytechnic Institute.
Kuhn, E. and Lavielle, M. (2005), “Maximum likelihood estimation in nonlinear
mixed effects models”, Computational Statistics & Data Analysis,
49, 1020–1038.
Lim, H. and Yum, B. J. (2011), “Optimal design of accelerated degradation
tests based on wiener process models”, Journal of Applied Statistics, 38(2),
309–325.
Meeker, W. Q. and Escobar, L. A. (1998), Statistical methods for reliability
data, volume 78, Wiley New York.
Nguyen, T. T. and Mentré, F. (2014), “Evaluation of the fisher information
matrix in nonlinear mixed effect models using adaptive gaussian quadrature”,
Computational Statistics & Data Analysis, 80, 57–69.
Niederreiter, H. (1992), Random Number Generation and Quasi Monte Carlo
Methods, SIAM, Philadelphia.
Pillai, G. C., Mentre, F., and Steimer, J. L. (2005), “Non-linear mixed effects
modeling - from methodology and software development to driving implementation
in drug development science”, Journal of Pharmacokinetics and
Pharmacodynamics, 32(2), 161–83.
Plan, E. L., Maloney, A., Mentre, F., Karlsson, M. O., and Bertrand, J.
(2012), “Performance comparison of various maximum likelihood nonlinear
mixed-effects estimation methods for dose-response models”, The
AAPS Journal, 14(3), 420–32.
Robert, C. P. and Casella, G. (1999), Monte Carlo Statistical Method,
Springer.
Spall, J. C. (2005), “Monte carlo computation of the fisher information matrix
in nonstandard settings”, Journal of Computational and Graphical Statistics,
14(4), 889–909.
(2008), “Improved methods for monte carlo estimation of the fisher
information matrix”, in American Control Conference, 2008, 2395–2400.
Tang, S., Guo, X., Yu, C., Xue, H., and Zhou, Z. (2014), “Accelerated degradation
tests modeling based on the nonlinear wiener process with random
effects”, Mathematical Problems in Engineering, 2014, 1–11.
Tsai, C. C., Tseng, S. T., and Balakrishnan, N. (2012), “Optimal design for
degradation tests based on gamma processes with random effects”, IEEE
Transactions on Reliability, 61(2), 604–613.
Weaver, B. P. and Meeker, W. Q. (2014), “Methods for planning repeated
measures accelerated degradation tests”, Applied Stochastic Models in
Business and Industry, 30(6), 658–671.
Weaver, B. P., Meeker, W. Q., Escobar, L. A., and Wendelberger, Joanne
(2013), “Methods for planning repeated measures degradation studies”,
Technometrics, 55(2), 122–134.
Weisstein, E. W. (1999), “Leibniz integral rule. From MathWorld – A Wolfram
Web Resource”, URL http://mathworld.wolfram.com/
LeibnizIntegralRule.html.
Ye, Z. S., Chen, L. P., Tang, L. C., and Xie, M. (2014), “Accelerated degradation
test planning using the inverse gaussian process”, IEEE Transactions
on Reliability, 63(3), 750–763.
Yuan, X. X. and Pandey, M. D. (2009), “A nonlinear mixed-effects model
for degradation data obtained from in-service inspections”, Reliability Engineering
& System Safety, 94(2), 509–519.

------------------------------------------------------------------------ 第 20 筆 ---------------------------------------------------------------------
系統識別號 U0026-3012201415383700
論文名稱(中文) FMEA應用於降低廠務系統運轉風險之探討-以太陽能廠PCW系統為例
論文名稱(英文) The FMEA Research for Safety and Benefit of the Facility System on PCW System
校院名稱 成功大學
系所名稱(中) 航空太空工程學系碩士在職專班
系所名稱(英) Department of Aeronautics & Astronautics (on the job class)
學年度 103
學期 1
出版年 104
研究生(中文) 杜松嶸
學號 P47001163
學位類別 碩士
語文別 中文
口試日期 2015-01-08
論文頁數 73頁
口試委員 指導教授-林清一
口試委員-陳杏圓
口試委員-郭仕堯
關鍵字(中) 太陽能廠務
失效模式與效應分析(FMEA)
製程冷卻水(PCW)
關鍵字(英) Solar Panel Factory Service
Failure Mode and Effects Analysis (FMEA)
process cooling water (PCW)
學科別分類
中文摘要 失效模式與效應分析(Failure Mode and Effects Analysis,FMEA)是用來分析系統內潛在之失效模式並對此系統可能造成之不良後果提出適當之改善作業以防止故障的發生。廠務工程師透過嚴密的分析作業列出並評估系統內可能失效之模式及可能造成之影響,使廠務系統運轉得以被改善,並配合不斷地預估、驗證及改進,使得廠務系統逐漸趨向最佳設計之目標。由相關文獻得知FMEA被廣泛地應用於國防、航空、工業製品及民生用品等有形產品之設計。本研究擬對此有所突破,係利用FMEA來探討太陽能廠之製程冷卻水 (Process Cooling Water,PCW )系統,提昇系統之運轉可靠度。
  在本研究中,以M公司太陽能廠來說明整個FMEA於PCW系統的分析流程。並藉由分析之過程,讓該廠之廠務工程師重新檢視系統。並讓廠務工程師了解到該系統究竟存在有哪些失效風險;一旦發生失效後,其影響的層面、範圍有多廣,衝擊有多大。其因應、預防策略為何。而分析之結果,則提供該廠廠務部門,於未來在擬定建廠設計、系統檢修、維護、保養計畫、廠務設備、元件更新(採購)計畫時之重要參考依據。並據此不斷地修改系統,以提昇系統之可靠度,達到系統穩定運轉之目標。
英文摘要 Failure Modes and Effects Analysis (Failure Mode and Effects Analysis, FMEA) is used for the analysis of potential system failure modes. This system may result in adverse consequences of proposed improvements proper job to prevent failure. Facility Engineer jobs list through rigorous analysis and assessment of possible failure modes. System performance may cause possible impact of factory service system operation. It should be improved with constant estimates, verification and improvement. The efforts make the plant gradually moving traffic system toward the best design target. FMEA is designed widely used in national defense, aerospace, industrial products and consumer goods and other tangible products known by the relevant literature. In this study, this breakthrough solar system to explore the use of FMEA process the plant cooling water (Process Cooling Water, PCW) system to enhance the reliability of system operation.
In this study, an illustration of the entire solar M company in PCW system FMEA analysis process is presented. By the process of analysis, the factory staff re-examine the system works. It will allow system engineers to know exactly what is the failures of the system risks. Once failure occurs, the level of its impact, how wide the scope, impact how much can be identified shortly by its response and prevention strategies. The results of analysis provide the plant factory service department with references in future of plant design, system maintenance, facility equipment, component update (Procurement) program. Accordingly, the result continuously modifies the operating system to enhance the reliability of the system to achieve stable operation of the target system.
論文目次 摘要 I
Extended Abstract II
誌謝 VII
目錄 VIII
表目錄 XI
圖目錄 XII
第1章 緒論 1
1.1 前言 1
1.2 研究動機 2
1.3 研究方法 3
第2章 文獻探討 4
2.1 太陽能電池介紹 4
2.1.1 太陽能電池的原理 4
2.1.2 太陽能cell 日照與溫度特性 7
2.1.3 太陽能電池的種類與特性 9
2.1.4 太陽電池之優點與缺點 10
2.2 PCW系統功能及架構說明 12
2.2.1 PCW系統功能 12
2.2.2 PCW系統架構 12
2.3 FMEA分析方法之簡介 19
2.3.1 FMEA之意義 19
2.3.2 FMEA之目的功能 19
2.3.3 FMEA之相關名詞定義 20
2.3.4 FMEA之實施程序 21
2.3.5 備用防護設計說明 23
第3章 研究內容 24
3.1 研究對象 24
3.2 PCW在太陽能電池製程重要性說明 25
3.2.1 PCW之SPC 要求條件 (溫度及壓差) 25
3.2.2 長晶製程 29
3.2.3 切晶製程 30
3.2.4 太陽能電池製程 31
3.3 研究實施FMEA之流程設計 34
3.3.1 定義所要分析之系統功能、任務輪廓與環境輪廓、以及操作環境 35
3.3.2 建立系統可靠性關聯圖 35
3.3.3 編訂識別號碼(Identification number) 35
3.3.4 推測所有可能潛在之失效現象 35
3.3.5 列出失效現象的潛在效應及評定其嚴重度(Severity)等級 36
3.3.6 列出失效現象的發生原因及評定其發生度(Occurrence)等級36
3.3.7 列出失效現象的現行措施及評定其難檢度(Detection)等級37
3.3.8 為每個失效現象計算風險優先指數(Risk Priority Number,RPN) 37
3.3.9 研究失效偵檢方法及失效之預防與改進措施 38
3.3.10 作成分析報告,並進行改善行動 38
3.3.11 去除或減少失效現象後,重新評估RPN風險優先指數 38
第4章 研究結果 42
4.1 個案公司簡介 42
4.2 現行PCW系統失效之處理方式與潛在問題分析 43
4.3 個案FMEA分析模式之建立 43
4.3.1 FMEA執行專案程序 43
4.4 FMEA措施改善說明 59
4.4.1 FMEA改善總表 59
4.4.2 改善項目說明 60
4.5 改善效益之評估 69
第5章 結論與建議 70
5.1 結論 70
5.2 未來研究建議 71
參考文獻 72
參考文獻 [1]李天安,太陽能電池導電線路雙層網印良率提升,成功大學航空太空工程學系碩士論文,民國103年。
[2]Energy Trend,2014夏普太陽能日本業務轉虧為盈 季獲利預估將破十億美元。民國103年,取自: http://pv.energytrend.com.tw/news/20140206-7771.html
[3]黃女瑛,2014進軍日本太陽能市場 報酬率高、然稅負沉重。DIGITIMES電子時報,民國103年,取自:
http://www.digitimes.com.tw/TW/DT/N/SHWNWS.ASP?ID=0000371478_ZYU5VV0U6HA81N9TQJ72F
[4]陳谷豪,光電廠NOx (黃煙)減量淨化處理之研究,屏東科技大學環境工程與科學系碩士學位論文,民國101年。
[5]馮垛生,太陽能發電原理與應用,太陽能發電概述,第1章,民國98年。
[6]張豐瑞,太陽能光伏發電系統建置及維護,綠科國際股份有限公司,民國103年。
[7]施華,社區發展太陽能發電系統之成本效益評估,交通大學工學院碩士在職專班產業安全與防災組碩士論文,民國98年。
[8]楊正吉,彰化、花蓮及台南地區太陽能發電系統成效探討,屏東科技大學環境工程與科學系碩士學位論文,民國103年。
[9]鄭智純,我國再生能源發展條例過程與法案內容之研究,台灣大學政治學研究所碩士論文,民國100年。
[10]莊嘉琛,太陽能工程太陽能電池篇,全華科技圖書股份有限公司,第4章,民國95年。
[11]何健忠,2005 經濟部節約能源績優廠商觀摩會之主要設備馬達採用變頻器控制,聯華電子股份有限公司,民國94年。
[12]小野寺勝重 原著,實踐FMEA手法 - 提升產品或系統的可靠性、維護性和安全性,張書文 譯著,財團法人中衛發展中心,台北,民國90年。
[13]黃清賢,危害分析與風險評估,三民書局,民國85年。
[14]華強,應用FMEA於氣動工具產品設計之研究-以衝擊扳手為例,朝陽科技大學工業設計學系碩士論文,民國99年。

 


如您有疑問,請聯絡圖書館
聯絡電話:(06)2757575#65773
聯絡E-mail:etds@email.ncku.edu.tw