Narrow Therapeutic Window of N-acetylcysteine for Radiocontrast Cytotoxicity

Contrast is widely used in different interventional procedures and image studies but with well-recognized nephrotoxicity. Contrast-induced nephropathy(CIN) accounts for 10% causes of acute renal failure in hospital and incidence even higher as 50% in patients with cardiovascular disease, diabetes mellitus, or preexisting chronic kidney disease. Different methods such as using hydration and sodium bicarbonate had been developed to reduce the incidence of CIN. N-acetylcysteine(NAC) is used for preventing CIN on account of its antioxidant and vasodilating properties but protection effect remains controversial. We demonstrated the different dosage effect of NAC on MDCK and HK-2 cell lines representative of distal and proximal tubular cell. Cell viability of MDCK was reduced by iodixanol (non-ionic iso-osmolar contrast) more than HK-2 in WST assay. HK-2 and MDCK revealed no reduction of cell viability when treated with NAC until 10mM but HK-2 showed less cell viability than MDCK. When cotreated with NAC in the presence of contrast, no protection of NAC was observed in HK-2 but with limited protection in MDCK. Improvement of cell viability was observed in iodixanol 50mgI/mL and 100mgI/mL when cotreated with NAC 10mM and 20mM. NAC showed cytotoxic effect of MDCK in LDH assay in dosage incremental manner. Further analysis with cell cycle showed incremental of subG1 group when treated with NAC in MDCK.ATP depletion was also observed in NAC 20mM and 40mM. We also found mitochondria membrane potential loss of MDCK when treated with iodixanol 100mgI/mL. Mitochondria membrane potential loss was attenuated by NAC when treated with 10mM and 20mM in dose-response manner.The result revealed narrow protection effect of NAC. The negative effect give a hint about cautious dosage adjustment while NAC is applied to CIN prevention.顯影劑在醫學影像檢查的地位相當重要，也廣泛的運用於各種侵入性檢查以及影像檢查。但是顯影劑有廣為所知的腎毒性，據統計在醫院內發生的急性腎衰竭病例中有百分之十是因為顯影劑所引起，而且如果患者有心血管疾病、糖尿病或是慢性腎臟病，其比例會更高，可能達到百分之五十的發生率。過去數十年來，已經發展出各式各樣的方法來預防顯影劑腎病變，例如給水補充或是以碳酸氫鈉預防，但是效果並不一致。N-乙醯半胱胺酸目前也被用來預防顯影劑腎病變，而N-乙醯半胱胺酸具有抗氧化作用以及血管擴張效果，但是臨床效果仍有部分爭議。在本研究中，我們使用不同劑量的N-乙醯半胱胺酸針對MDCK與HK-2細胞株(MDCK代表遠端腎小管細胞，HK-2代表近端腎小管細胞)看是否能降低顯影劑引起的細胞毒性。我們以iodixnaol非離子等滲透壓的顯影劑處理，並用WST分析細胞存活率，發現在不同濃度iodixnaol都是MDCK存活率較HK-2差。而N-乙醯半胱胺酸在NAC 20mM時HK-2的細胞存活率較MDCK低下。在同時給予N-乙醯半胱胺酸與iodixanol時，N-乙醯半胱胺酸對於HK-2完全沒有保護力。而N-乙醯半胱胺酸在10mM與20mM對於MDCK以50mgI/mL與100mgI/mL的iodixanol則有部分的保護效果，N-乙醯半胱胺酸對於MDCK細胞的毒性以LDH assay分析，可以得到劑量-反應圖的確認。我們還觀察到N-乙醯半胱胺酸造成MDCK細胞內ATP含量的下降。另外iodixnaol造成粒線體膜電位的喪失會經由N-乙醯半胱胺酸而減弱。所以N-乙醯半胱胺酸對於顯影劑細胞毒性的保護效果是來自於粒線體膜電位的改善。結果顯示N-乙醯半胱胺酸的保護劑量的範圍很窄。甚至高劑量N-乙醯半胱胺酸會有抑制細胞生長的表現，這個現象暗示了N-乙醯半胱胺酸用來保護顯影劑腎病變時，我們需要謹慎的調整劑量以免反而造成負面的影響。目錄 中文摘要.................................................................................................................................................i 英文摘要...............................................................................................................................................iii 目錄........................................................................................................................................................iv 第一章 緒論.......................................................................................................................................1 第一節 一、 急性腎損傷................................................................................................................................1 二、 顯影劑腎病變...........................................................................................................................1 第二節 目前顯影劑腎病變的治療方法 一、 N-乙醯半胱胺酸(N-acetylcysteine)....................................................................................6 二、 碳酸氫鈉(Sodium bicarbonate)...........................................................................................6 三、 水份補充(Hydration) .............................................................................................................7 第二章 研究目的...............................................................................................................................8 第三章 材料與方法...........................................................................................................................9 一、 細胞株培養................................................................................................................................9 二、 藥物處理.....................................................................................................................................9 三、 細胞存活率測試.......................................................................................................................9 四、 乳糖去氫酶活性測量...........................................................................................................10 五、 流式細胞儀之分析................................................................................................................10 六、 細胞內腺嘌呤核甘三磷酸(ATP)測量............................................................................11 七、 粒腺體膜電位測量................................................................................................................11 八、 分析與統計方法....................................................................................................................11 第四章 結果.......................................................................................................................................13 一、 顯影劑對於近端腎小管細胞(HK-2)與遠端腎小管細胞(MDCK)存活的差異,有劑量的不同反應....................................................................................................................13 二、 N-乙醯半胱胺酸對於近端腎小管細胞(HK-2)與遠端腎小管細胞(MDCK)存活的差異,有劑量上不同的反應...........................................................................................13 三、 N-乙醯半胱胺酸對於顯影劑造成的近端腎小管細胞(HK-2)與遠端腎小管細胞(MDCK)的保護力有差異................................................................................................13 四、 以乳糖去氫酶活性顯示N-乙醯半胱胺酸劑量增加時MDCK的細胞壞死情形..............................................................................................................................................13 五、 N-乙醯半胱胺酸濃度上升時增加遠端腎小管細胞(MDCK)的細胞凋亡….....14 六、 高濃度N-乙醯半胱胺酸造成遠端腎小管細胞(MDCK)的胞內嘌呤核甘三磷酸(ATP)濃度下降.......................................................................................................................14 七、 N-乙醯半胱胺可以改善因為顯影劑所造成的粒線體膜電位的喪失................14 第五章 結論.......................................................................................................................................15 第六章 討論.......................................................................................................................................16 第七章 參考文獻.............................................................................................................................18 第八章 實驗結果圖........................................................................................................................25 圖一、顯影劑對於近端腎小管細胞(HK-2)與遠端腎小管細胞(MDCK)存活的差異,有劑量的不同反應...........................................................................................................................25 圖二、N-乙醯半胱胺酸對於近端腎小管細胞(HK-2)與遠端腎小管細胞(MDCK)存活的差異,有劑量上不同的反應......................................................................................................26 圖三、N-乙醯半胱胺酸對於顯影劑造成的近端腎小管細胞(HK-2)產生的細胞毒性沒有保護力.........................................................................................................................................27 圖四、N-乙醯半胱胺酸對於顯影劑造成遠端腎小管細胞(MDCK)的細胞毒性只有部分保護..............................................................................................................................................28 圖五、以乳糖去氫酶活性顯示N-乙醯半胱胺酸劑量增加時MDCK的細胞壞死情形............................................................................................................................................................29 圖六、N-乙醯半胱胺酸濃度上升時增加遠端腎小管細胞(MDCK)的細胞凋亡...30 圖七、高濃度N-乙醯半胱胺酸造成遠端腎小管細胞(MDCK)的胞內嘌呤核甘三磷酸(ATP)濃度下降.............................................................................................................................31 圖八、N-乙醯半胱胺酸可以改善因為顯影劑所造成的粒線體膜電位的喪失………………………………………………………….............................................................................3

Studies on the Climate Effect on Growth Character in Potato (Solanum tuberosur L.)

本試驗利用大葉種(kenebec)及卡迪娜（cardinal)兩個馬鈴薯品種參試，於不同栽培地區及相同栽培環境之不同栽植期的氣候下，探討其對塊莖產量及薯形大小與乾物率等收稻品質之影響，1990年冬季裡作在后里、斗南及溪口三地栽植之結果顯示，大葉種在溪口地區栽値產量最高，卡迪娜則在后里地區產量最高。1991年冬季裡作在后里地區之栽植期試驗結果顯示，第一次植植（9月24日）之塊莖產量最高，隨栽植期之延後，塊莖產量都隨之降低：另就塊莖收穫品質而言，亦呈現與產量相似之情形，隨栽植期之延後而降低。1992年冬季裡作在溪口地區之結果則顯示，大葉種在早、晚兩_値期問，其產量均無大差異；但卡迪娜則以晚植期產量較高，惟早植者因塊莖肥大期受寒流及乾旱氣候影響，晚植者於塊莖形成期亦遭遇寒流及生長後期之雨量過多，故生產之塊莖多呈現不具經濟價値之形態，塊莖乾物率因生長後期突遇甚高雨量(189 mm)而下降。藉相關分析探討氣象因子與馬鈴薯生育間之相關關係，結果發現塊莖與全株乾重分配比例及生長後期之日夜溫差呈顯著正相關，塊莖乾物率與生育期氣溫及生育前期之日夜溫差呈顯著負相關，但與生育後期之日夜溫差及生育前期之日射量呈極顯著正相關。 Potato varieties, Kenebec and Cardinal, were used to study the effects of growth region and planting date on tuber yield and quality. Results indicated that tuber yield of kenebec of winter crop (1990) at Hsikou was the highest among the growth regions, but cardinal at Houli had the highest tuber yield. Among the four planting dates at Houli, it showed that both varieties obtained the highest yield and quality when planted on 24 September of 1991. In the winter crop of 1992，the tuber yield was similar for Kenebec planted at either earlier or later season at Hsikou. However, the yield of Cardinal was higher when planted earlier than that of planted later. The distribution ratio of tuber and whole plant dry weight were postively correlated with difference between day and night temperature of later growth stage. Percentage of tuber dry matter was negatively correlated with mean air temperature of whole growth period and difference between day and night temperature of early growth stage, but was postively correlated with difference between day and night temperature of later growth stage and solar radiation of early growth stage

Don''t-Care Computation via Adjustable Interpolation

　近年來在邏輯合成與驗證的領域中，內插法的應用與日俱增，相關範疇包括函數相依、二元分解、亞氏分解等。本研究係利用內插法針對多層次電路之節點計算邏輯無關項。傳統上，內插可藉由可滿足性問題求解器產生之反證求得，並可利用改寫反證之結構對內插大小進行調整。但我們在研究過程發現，大部分狀況中，調整可滿足性問題求解器產生反證後所求得之內插並無太大的改變，內插法的效能因而受限。本論文中，我們提出利用可滿足性問題求解之演算法來計算邏輯無關項，並發展出一套針對可滿足性問題求解器改變內插大小的技巧，包括調整初始變數優先序及改變布林初始值，同時利用電路結構簡化問題模型以加快求解速度。實驗結果顯示，該改變內插大小的方法讓求解邏輯無關項之演算法在可接受的時間內，較未使用該方法時求出更多的邏輯無關項。In recent years, there have been a variety of applications of interpolation in logic synthesis and verification, such as functional dependency, bi-decomposition, and Ashenhurst decomposition. The goal of this research is to compute don’t-cares for a given node in a multi-level network by using interpolation. Traditionally, an interpolant can be derived from a refutation proof given by a SAT solver, and its onset can be adjusted via rewriting the structure of the refutation proof. However, in most cases, the interpolant derived by the refutation proof generated by a SAT solver can not be adjusted too much. As a result, the application of interpolation is limited. In this thesis, we propose SAT-based don’t-care computation algorithms via interpolation. In addition, a set of techniques has been developed for a SAT solver to adjust the solution space of the interpolant. The methods include setting the initial variable activities and altering the Boolean initial values. The circuit structure has also been utilized to simplify the problem to accelerate SAT solving. Experiments show that the algorithms can get more don’t-cares while applying the interpolation sizing method to the algorithms.Acknowledgements i要 iibstract iiiontents ivist of Figures viist of Tables viiihapter 1 Introduction 1.1 The Origin of Don’t-Cares 1.2 Previous Work 3.3 Our Contributions 5.4 Organization of the Thesis 6hapter 2 Preliminaries 7.1 Boolean Network and Function 7.2 Satisfiability Problem and Solver 8.3 Resolution and Refutation Proof 9.4 Craig Interpolation Theorem 10.4.1 Interpolant Strengthen 12.5 Circuit to CNF Conversion 14hapter 3 Don’t-Care Computation Algorithms 15.1 CDC Computation Method 1 (CDCC1) 16.2 CDC Computation Method 2 (CDCC2) 18.3 CNF Simplification 20.4 Adjustable Interpolation 21.4.1 Swap Rules 21.4.2 Initial Variable Activities 26.4.3 Boolean Initial Values 28.5 Verification 28.5.1 Combinational Equivalence Checking 28.5.2 Absorbing Checking 29hapter 4 Experimental Results 30.1 Variable Decision Order 30.2 Adjustable Interpolation on CDCC1 33.3 Adjustable Interpolation on CDCC2 40hapter 5 Conclusions and Future Work 46ibliography 4

Playful Memory. Fantastic Land─Statement of Chinese Ink Painting Creation by Chen Yi-Hsin

[[abstract]]　　This research thesis mainly focuses on the derivation of mind images in self-awareness as the starting point, and discusses the energetic significance of contemporary art. By the way of self-dialogue, this achieves the spiritual aspects for the symbol transmission. From the self-awareness, this thesis inspects indirectly of the intrinsic psychological mood, responses each behavior for the fantastic images, and analyzes each concealed language. In addition, this research thesis attempts to allow this argument and the characteristic to have the connection with the creational images. 　　Besides, taking advantage of famous psychologist, Carl Gustav Jung (1875-1961), I use the idea of “collective unconscious” as the axel of this thesis. Through elaboration of viewpoints such as archetype and shadow at the same time, this connects with my own creation and make an analysis which links the creation of unconsciousness psychic writing and the consciously self-mood together again. 　　Cuts thorough into direction of unconscious, the discussion focuses on memory, fantasy and so on the behavior of thoughts. Seeking variety of ways, this presents each picture with psychological idea. Again, by the way of the drawing style, constitution and form, transfers the way of play into the inspection of reading. Also, images are decomposed by the semantics of visual art. As a result, concepts of abstract distortion and flat -like space elaborate purely writings of intrinsic spirituality. Continues this idea with the drawing in the form of analysis, and uses the layout arrangement of pictures, the process of visual focal point builds up visualization of pictures. The situation is represented through special types of material medium. This is also mixed with the computer cartography which attempts many different styles of picture design. Both integrate with the ideas, create more possibilities, and also make the idealistic discussion of symbolic language for the traditional Chinese ink painting. Therefore, this causes to model individual special characteristic and to create new vocabulary for the Chinese ink painting.

(43(2):135-142)Studies on the Panicle Density of Rice Ⅱ. Relationships between the Constructed Characters of Panicle and Grains Yield Per Hill

以25個穗著粒密度相異的稉稻品種（系）為材料探討11個稻穗構成性狀間的關係，結果發現一期作高單株產量之材料，具有穗重較重、一次枝梗平均粒數、二次枝梗數、二次枝梗總粒數、每穗粒數等較多、稔實率高與穗長較長等特徵，顯示穗型較大、粒數較多之材料，較能發揮高產之潛能：二期作高單株產量之材料群則為穗重、二次枝梗數、二次枝梗總粒數、每穗粒數與穗長中等者有較高產量表現。此外，一期作穗著粒密度雖與單株產量呈高正相關關係，然由主成份因子分布圖中顯示，高穗著粒密度者其單株產量並不一定高。Twenty five rice entries with different types of panicle density were used as materials to study the relationships between the 11 constructed characters of the panicle and grain yield per hill under Chaiyi environment conditions. In the first rice crop season, result revealed that entries with high yielding capacity pontenial were charactered by heavier panicle weight, a lot of average grain number per primary branch, secondary branch number per panicle, total grain number of secondary branches, total grain number per panicle, higher seed set and larger factor of panicle length. This might infer that the entries with high yielding pontenial in first crop season are largely due to heavier panicle weight and lots of grain number. On the other hand, in second crop season, entries with high yielding pontenial were along with reasonable panicle weight, secondary branch number per panicle, total grain number of secondary branches total grain number per panicle, and factors of panicle length. This might conc-lude that the entries with high yielding pontenial are mainly associateed with medial constructed characters of the panicles. A significant Positive correlat-ion between panicle density and grain yield per hill was found from the present studies However, as shown in the scattrer diagram of principal factor analysis, thar entries with higher panicle density were not always along with higher grain yield per hill was also observed. These suggest that the relationships between the constructed characters of the panicle and grain yield per hill is unjustifiable from the present data