臺灣博碩士論文加值系統

三聚氰胺是一種三嗪類含氮雜環之有機化合物，是重要的化工原料，由於其含氮量高，因此被不肖商人利用，非法添加到牛奶和其他食品中，而引發食品安全的問題。根據近年研究結果得知，三聚氰胺相關性腎病變主要會造成腎臟結石，但其症狀、臨床表徵、致病機轉與相關危險因子仍缺乏詳盡的研究與瞭解。國立陽明大學附設醫院在2008年9月份開辦特別門診，提供民眾進行篩檢；本論文研究即以此為樣本來源，經國立陽明大學附設醫院人體試驗委員會核准通過執行，嘗試針對宜蘭地區服食三聚氰胺污染奶粉的兒童進行尿液與腎臟超音波篩檢，統計其比例、尿檢結果，與食用奶粉污染濃度的差異性進行分析，並追蹤其預後。在所收集的436個病患中，0-18歲兒童共388人 (女162人、男226人)，檢出三聚氰胺相關結石者共45人，罹患率11.6％，男性多於女性，結石主要分佈於雙側腎臟 (77.3%)。尿液檢查結果顯示，除了潛血反應有顯著差異之外，蛋白尿、比重、血尿、尿酸鹼值，在高三聚氰胺暴露組 (＞2.5 ppm) 和低三聚氰胺暴露組 (0.05~2.5 ppm) 兒童並無顯著差異。超音波檢查結果顯示：patch/stone/nodule (>4mm) 組，主要與高濃度三聚氰胺暴露史相關；而foci (<4mm) 組則與低濃度三聚氰胺暴露史相關。根據3年的追蹤發現，給予保守療法後，三聚氰胺相關腎結石仍然存在且未得到改善；比較2008年及2011年，病患之超音波結石與尿液檢查結果皆無改善情形，反而在蛋白尿方面有顯著惡化之現象。我們將2011年追蹤回診的23個病童依其結石大小，分類為大於7mm、4-7mm及小於4mm三組，收集其新鮮尿液樣本，利用蛋白質體學技術分析尿液中是否有造成腎病變或腎結石相關的關鍵蛋白質，並觀察可能造成腎臟損傷的相關因子。主要以二維電泳、膠片影像擷取分析搭配串聯式質譜儀鑑定及生物資訊學分析；結果顯示，在所選取的9個表現量具顯著差異的蛋白質點中，經由液相層析電噴灑離子化四極棒飛行時間串聯式質譜儀分析共鑑定出五種蛋白質身分，包括：凝集素相關絲氨酸蛋白酶第2型 (Mannan-binding lectin serine protease 2；MASP2)、β2-微球蛋白 (Beta-2-Microglobulin；β2-m)、免疫球蛋白kappa 輕鏈恆定區 (Ig kappa light chain C-region)、基底膜特異之硫酸乙醯肝素蛋白聚醣 (Basement membrane-specific heparin sulfate proteoglycan core protein) 及囊泡整合膜蛋白VIP36 (Vesicular integral membrane protein VIP36)。因此推論，三聚氰胺相關腎結石造成之腎損傷可能與腎小管或腎小球基底膜損傷有關。

Melamine, a nitrogen-containing heterocyclic triazine compound, is an important material in chemical engineering. Because of its high nitrogen content, it has been illegally added into milk and other protein products, thus resulting in food safety issues. A recent epidemic study of melamine contamination of baby formula milk powder in China has been associated with the development of urinary tract stones, though the clinical manifestations, disease mechanism, and predisposing factors are incompletely understood. The approval of this study was annually reviewed by the institutional review board (IRB) of National Yang-Ming University Hospital. We have screened 436 people (200 females and 236 males) from September to October in 2008. Total 388 people under 18 years old (162 girls and 226 boys) were enrolled in our investigation and under thorough history taking including feeding history, symptoms and signs of nephrolithiasis, urinalysis and ultrasonography of kidney. Though all were asymptomatic, some were screened by abnormal findings of ultrasonography. A total of 45 children with melamine exposure history were suspected with nephrolithiasis with prevalence of 11.6%. Boys are obviously dominant than girls. The patients were classified into one control group with negative findings and three groups with different ultrasonographic hyperechogenic findings and its size included: patch or stone (>7mm), nodule (4-7mm), and foci (<4mm). The abnormal ultrasonographic findings were essentially found on both kidneys (77.3%). Urinalysis results show that there was a significant difference in occult blood. Patch/stone/nodule (>4mm) group is correlated with high melamine exposure, while Foci (<4mm) group is correlated with low melamine exposure. 23 of the patients were called back for follow-up in 2011 and found that stones and urinalysis results from these patients are not improved. Furthermore, we used proteomic technologies to analyze urinary samples from 3 groups: patch or stone (>7mm), nodule (4-7mm), and foci (<4mm). Samples were analyzed by two-dimensional gel electrophoresis and image analysis by Prodigy SameSpots software. Nine protein spots significantly altered (at least 2-fold change) were subjected to LC-ESI Q-TOF MS/MS analysis and were identified by Mascot program as mannan-binding lectin serine protease 2, beta-2-microglobulin, Ig kappa light chain C-region, basement membrane-specific heparin sulfate proteoglycan core protein and vesicular integral membrane protein VIP36. We thereby concluded that the melamine-induced renal stones and nephropathy may be attributed to damages in the basement membrane of renal tubules and glomeruli.

中文摘要 1
英文摘要 3
目錄 5
表目錄 7
圖目錄 8
第一章、 前言 9
第一節、 三聚氰胺簡介 9
第二節、 三聚氰胺對動物之影響 11
第三節、 三聚氰胺對人體之影響 16
第四節、 三聚氰胺對實驗動物腎臟以外組織和器官之毒性 19
第五節、 蛋白質體學在腎結石及腎損傷之研究 20
第二章、 實驗目的 23
第三章、 實驗儀器與藥品試劑 24
第一節、 實驗儀器 24
第二節、 藥品試劑 25
第四章、實驗方法 27
第一節、實驗流程 27
第二節、尿液樣品收集與前處理 28
第三節、蛋白質定量 29
第四節、二維凝膠電泳 29
第五節、膠體內水解 31
第六節、液相層析電噴灑離子化四極棒飛行時間串聯式質譜儀 31
第五章、結果 33
第一節、尿液生化學檢驗及腎臟超音波檢查 33
第二節、二維電泳分析圖譜 36
第三節、蛋白質身分鑑定 36
第六章、討論 37
第一節、腎臟超音波檢查及尿液生化學檢驗結果探討 37
第二節、尿液蛋白質體分析結果探討 38
第三節、各蛋白質與腎臟結石及腎病變之間的探討 43
第七章、結論與未來展望 44
第八章、參考文獻 45
表 58
圖 71

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