臺灣博碩士論文加值系統

犬瘟熱 (canine distemper, CD) 是一種嚴重感染犬科動物，並具高度傳染性之病毒性疾病。病原為一負向單股且具有封套之RNA病毒−犬瘟熱病毒 (canine distemper virus, CDV)，以侵害犬中樞神經、呼吸及消化系統為主。根據過去非正式報告，本病被認為是台灣地區最重要的犬病毒性疾病。自1995年起，陸續出現成犬疑似犬瘟熱引起脫髓鞘性腦炎 (demyelinating encephalitis) 之病例。但是對於病原的確認仍以病理學觀察為主，因此，本研究係嘗試結合並比較形態病理學及反轉錄聚合鏈反應 (RT-PCR) 診斷方法，以確認台灣地區之犬瘟熱病毒感染及其型式，同時測定CDV感染後腦脊髓液與腦組織中2´, 3´-cyclic nucleotide 3´-phosphohydrolase (CNP) 活性之變化以評估做為脫髓鞘疾病診斷之可能性。自民國88年3月至90年3月間，由全省各地區動物醫院及棄犬收容中心，於臨床上發現疑似犬瘟熱症狀之自然死亡或經畜主同意安樂死之患犬，共33例，進行病理學檢查、免疫組織化學染色、組織化學染色及穿透式電子顯微鏡觀察形態病理學變化。同時，採取新鮮中樞神經系統、淋巴結、肺臟、腦脊髓液及全血，使用RT-PCR以偵測CD病毒磷酸蛋白基因 (phosphoprotein gene)。結果發現16例 (16/33) 具有特徵性病理變化及出現典型包涵體而診斷為CD；使用RT-PCR診斷，則陽性病例增為27例 (27/33)。此外，本研究亦發現2例脫髓鞘性腦炎，經RT-PCR產物之核酸定序分析結果，證實為CDV感染所致。本實驗結合病理學及RT-PCR核酸偵測技術，確認台灣地區有全身性及脫髓鞘性犬瘟熱病例，RT-PCR技術之應用，不僅提升診斷之特異性及敏感性，而且可以提供為臨床診斷的實用工具。此外，利用分光光度法偵測CDV感染後腦白質部組織及腦脊髓液之CNP活性，結果發現CDV感染同時伴隨脫髓鞘病變的犬隻，腦脊髓液中之CNP活性呈現明顯上升 (p<0.05)；而CDV感染的犬隻，無論有無出現脫髓鞘病變，腦組織中之CNP活性皆明顯下降 (p<0.05)。由此推論，此項CNP活性測定技術的建立，未來有潛力應用於評估中樞神經系統髓鞘的流失情形，而當做脫髓鞘性疾病的輔助診斷工具。

Canine distemper (CD) is a highly contagious viral disease, which has been reported in dogs for many years in Taiwan. Ever since 1995, apart from systemic CD, there has been continuous emergence of CD-like demyelinating encephalitis in adult dogs. The goal of this study is to identify CD in Taiwan using pathology and RT-PCR as diagnostic tools and to assay 2´, 3´-cyclic nucleotide 3´-phosphohydrolase (CNP) activity of cerebrospinal fluid and brain tissue with canine distemper virus infection. This report collected 33 cases from animal hospitals throughout the country as well as from the dog pounds. The affected dogs died either natural cause or by euthanasia. All cases were conducted to perform pathological investigation, ABC immunohistochemistry, luxol-fast blue cresyl echt violet (LFB-CEV) histochemistry as well as transmissible electron microscopy. Phosphoprotein gene of canine distemper virus (CDV) was used as the target gene for RT-PCR. Under histopathological examination, 16 cases (48.48%) were diagnosed as CD. With the aid of RT-PCR, 27 cases (81.82%) were diagnosed as CDV positive. This study also found that 2 cases of demyelinating encephalitis were diagnosed as CDV infection with histopathology, LEB-CEV stain and RT-PCR. On conclusion, systemic and demyelinating CD were identified in Taiwan using RT-PCR along with histopathology. Combination of the two techniques not only raises CD diagnostic rate, but also provides a more rapid, specific, and sensitive method to confirm CDV infection. Additionally, spectrophotography was employed in the CNP assay of the brain tissues and cerebrospinal fluid. The results showed that CNP activity in CD infected dogs with demyelinating lesion had a significant elevation in the CSF (p<0.05). On the other hand, CD infected dogs with or without demyelinating lesion demonstrated a significant decline in CNP activity (p<0.05). Based on the results, CNP assay will be potentially to reflect status of myelin loss and diagnose demyelinating diseases.

第一章 文獻探討與實驗目的----------------------------------1
第一節 犬瘟熱病毒之歷史背景、宿主及流行----------------1
第二節 犬瘟熱病毒之病毒特性----------------------------3
第三節 犬瘟熱病毒感染之臨床症狀------------------------5
第四節 犬瘟熱病毒感染之形態病理學變化------------------8
第五節 犬瘟熱病毒之致病機轉----------------------------13
第六節 犬瘟熱病毒之診斷--------------------------------15
第七節 犬瘟熱於比較醫學之應用--------------------------17
第八節 髓鞘特異性酵素----------------------------------19
第九節 實驗目的----------------------------------------20
第二章 材料與方法------------------------------------------21
第一節 實驗設計及流程圖--------------------------------21
第二節 材料來源----------------------------------------22
第三節 形態病理學檢查----------------------------------22
2.3.1 肉眼病理學檢查------------------------------22
2.3.2 組織病理學檢查------------------------------23
2.3.3 組織化學染色--------------------------------25
2.3.4 免疫組織化學染色----------------------------27
2.3.5 穿透式電子顯微鏡檢查------------------------29
第四節 利用反轉錄聚合鏈反應檢測犬瘟熱病毒之感染------32
2.4.1 引子之選定----------------------------------32
2.4.2 病毒核酸之萃取------------------------------32
2.4.3 反轉錄反應----------------------------------34
2.4.4 聚合鏈反應--------------------------------35
2.4.5 聚合鏈反應之電泳分析----------------------36
2.4.6 聚合鏈反應產物之定序----------------------37
2.4.7 聚合鏈反應產物之序列分析------------------37
第五節 髓鞘特異性酵素-CNP活性之測定--------------------37
2.5.1 蛋白質定量----------------------------------38
2.5.2 利用分光光度法測定CNP活性-------------------39
2.5.3 CNP活性之計算方法---------------------------41
2.5.4 統計----------------------------------------41
第三章 結果------------------------------------------------42
第一節 形態病理學檢查----------------------------------42
3.1.1 肉眼病理學檢查------------------------------42
3.1.2 組織病理學檢查------------------------------43
3.1.3 組織化學染色--------------------------------45
3.1.4 免疫組織化學染色----------------------------45
3.1.5 穿透式電子顯微鏡檢查------------------------45
第二節 反轉錄聚合鏈反應檢測及核酸定序分析------------46
3.2.1 反轉錄聚合鏈反應檢測----------------------46
3.2.2 核酸定序分析--------------------------------46
第三節 髓鞘特異性酵素-CNP活性之測定--------------------47
第四章 討論------------------------------------------------49
第五章 參考文獻--------------------------------------------58
圖次
圖1.犬瘟熱病毒模式圖---------------------------------------74
圖2.犬瘟熱病毒之基因模式圖---------------------------------74
圖3.犬瘟熱病毒之複製模式圖---------------------------------75
圖4.Morbillivirus之親緣樹狀圖------------------------------75
圖5.犬瘟熱病毒之致病機轉-----------------------------------76
圖6.髓鞘生成模式圖及其超顯微結構---------------------------77
圖7.臨床症狀-----------------------------------------------78
圖8.肉眼病理學變化-----------------------------------------78
圖9.組織病理學變化------中樞神經系統-----------------------79
圖10.組織病理學變化-----淋巴組織---------------------------81
圖11.組織病理學變化-----呼吸系統---------------------------82
圖12.組織病理學變化-----消化系統---------------------------83
圖13.組織病理學變化-----泌尿系統---------------------------84
圖14.組織病理學變化-----皮膚-------------------------------84
圖15.其他合併感染------------------------------------------85
圖16.組織化學染色-Luxol fast blue-cresyl echt violet-------86
圖17.穿透式電子顯微鏡觀察脫髓鞘性病變----------------------86
圖18.免疫組織化學染色偵測犬瘟熱病毒核蛋白抗原及星狀膠質細胞增--------------------------------------------------------------88
圖19.RT-PCR檢測犬瘟熱病毒磷酸蛋白基因----------------------89
圖20.犬瘟熱病毒磷酸蛋白基因核酸片斷之序列比對--------------91
圖21.犬瘟熱病毒磷酸蛋白基因核酸片斷之相似百分比、差異性與親緣樹狀圖-------------------------------------------------------93
圖22.BSA之標準曲線-----------------------------------------94
圖23.腦脊髓液、大腦、小腦及腦幹於犬瘟熱病毒感染後CNP活性之比---------------------------------------------------------------95
表次
表1.Morbillivirus自然與實驗感染之宿主----------------------96
表2.髓鞘之主要組成-----------------------------------------97
表3.人與動物髓鞘生成障礙 (dysmyelination) 及脫髓鞘性疾病病因分類---------------------------------------------------------98
表4.33隻疑似犬瘟熱患犬之主要組織病理學變化與合併感染症-----99
表5.犬瘟熱病毒包涵體於33隻疑似犬瘟熱患犬體內組織之分佈-----100
表6.RT-PCR檢測33隻疑似犬瘟熱患犬之犬瘟熱病毒磷酸蛋白基因之結果-------------------------------------------------------------101

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