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研究生:梁鍾鼎
研究生(外文):Chung-Tiang, Liang
論文名稱:組織內病毒蛋白與核酸偵測之最佳化:鼠肝炎病毒與犬瘟熱病毒
論文名稱(外文):Optimization of the in situ detection of viral protein and nucleic acid in tissue: mouse hepatitis virus and canine distemper virus
指導教授:劉振軒劉振軒引用關係
口試委員:龐飛梁善居李進成
口試日期:2011-05-27
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:獸醫學研究所
學門:獸醫學門
學類:獸醫學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:英文
論文頁數:147
中文關鍵詞:反轉錄聚合酶反轉錄聚合酶反轉錄聚合酶反轉錄聚合酶反轉錄聚合酶反轉錄聚合酶
外文關鍵詞:mouse hepatitis viruscanine distemper virusimmunohistochemistryreverse transcription polymerase chain reactionin situ hybridization
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鼠肝炎病毒(mouse hepatitis virus;MHV)是小鼠族群高度傳染性首要病原。 本研究在缺乏特異性冠狀病毒初級抗體情況下,利用血清酵素免疫吸附法(ELISA)鼠肝炎病毒陽性檢體血清,結合卵白素(avidin)與生物素化 (biotinylated)的二級抗體,在發病免疫缺陷鼠之福馬林固定組織,如肝、胃、脾臟、 盲腸、及結腸等偵測鼠肝炎病毒抗原存在(Chapter II)。犬瘟熱病毒(canine distemper virus, CDV)為一年代久遠的疾病,本病之發生,己遍及全世界。犬瘟熱病毒為一高傳染性疾病,且存在臺灣許多年。然而;犬瘟熱病毒分離,基因型卻不曾有報告。組織病變,免疫化學染色診斷,病理學分析及併發症等均缺乏全面性調查資料。本研究目的為建立快速及正確的犬瘟熱病毒感染診斷方法,分離犬瘟熱病毒株及分析其H基因之遺傳差異,及經免疫化學染色(IHC)或反轉錄聚合酶反應(RT-PCR)確診下之自發病例,分析其中樞神經脫髓鞘發生率及其它病理變化。研究發現經非生物素性聚合山葵過氧化酶 (non-biotin HRP)免疫化學染色方法,對福馬林固定、石蠟包埋組織之犬瘟熱感染病例,其診斷率可達87.5%。犬瘟熱病毒特異性抗原可在下列組織發現:大腦皮層外錐狀細胞及樹狀突細胞質、小腦白質層星狀細胞及細胞質、軟腦膜、神經膠質細胞、神經元、血管內皮細胞、腦室周圍、室管膜細胞、脈胳叢;脊髓灰、白質及中央導水管;腎盂上皮及腎小管上皮細胞;膀胱黏膜上皮細胞;脾臟白髓及淋巴結巨噬細胞及淋巴球;皮膚海綿層細胞及細胞質;肺臟小支氣管黏膜上皮及肺泡巨噬細胞;肝臟巨噬細胞;胃腸黏膜上皮細胞;扁桃腺及食道複層扁平上皮細胞等。組織經高溫高壓滅菌鍋前處理的免疫化學染色方法,其抗原復舊程度遠遠超過傳統微波爐法,大大提高犬瘟熱病毒診斷率(Chapter III,VI)。為了要確認免疫化學染色訊號,本研究建立一個改良的原位雜交染色步驟,應用於上述病例。此方法除了傳統的蛋白水解酶K的雜交前處理外;另外比較了將切片置入於不同(Trilogy, TBS S3006, H3301, S1700)溶液中進行高溫高壓滅菌鍋前處理。同時原位雜交訊號使用平均光密度(IOD)及組織形態完整性進行半定量性效果分析。結果發現進行原位雜交前,切片如果配合蛋白質水解酶K先處理,再以Trilogy溶液高溫高壓處理後進行原位雜交,其訊號及組織完整性均較其它組強,此一方法建立,未來將廣泛應用於犬瘟熱病例或其它病毒性疾病之原位雜交診斷(Chapter IV)。為了解台灣地區犬瘟熱病毒基因型分析,2003-2005年間進行病毒分離,自17隻未經疫苗注射之發病幼犬,應用患犬血液單核球與 B95a 細胞株共同培養之技術,分離出兩株具誘發融合細胞病變之病毒,經免疫螢光染色及抗原測試確認為犬瘟熱病毒。將此兩株病毒之血球凝集素基因(H),與同期間自台灣大學動物醫院臨床送檢病例之另外4株犬瘟熱病毒之H基因進行核酸定序。經比對序列與樹狀圖分析發現,本土病毒株皆有9個N連結配醣位,其中第7個配醣位為日本或中國大陸流行之亞洲1型犬瘟熱病毒所特有。本研究顯示臺灣地區所流行之犬瘟熱病毒,其H基因經分析屬亞洲1型 (Chapter V)。為了解台灣地區是否有犬瘟熱病毒感染之病理變化差異,2000-2009年分析來自收容所或臨床動物醫院之犬瘟熱患犬計52隻(經IHC或RT-PCR確診)。診斷方法包括肉眼檢查、組織病理、脫髓鞘特殊染色(LFB-CEV)、IHC、RT-PCR等。結果發現32隻來自臨床動物醫院,20隻來自收容所。來自臨床動物醫院之犬,75%為6月齡或以下,但來自收容所之犬,85%為大於6月齡。共計11種品種,但67% 為混種犬。在病理學分析,淋巴減少(79%)、間質性肺炎(71%)、中樞神經脫髓鞘(65%)、卡他性腸炎(32%)為主要病變。臨床動物醫院組相對地在淋巴減少(96%)、病毒包涵體(87%)、間質性肺炎(81%)及中樞神經脫髓鞘(81%)發生率很高,且統計差異顯著。腸炎占二組別之30-34%,無統計差異顯著。犬瘟熱病毒病毒包涵体在膀胱、淋巴組織、肺臟及消化系統,二組別有顯著差異。在29種犬瘟熱病毒感染之併發症或協同病變分析中,除了間質性腎炎外,二組間皆無顯著性統計差異。總結而言,淋巴減少、肺炎、中樞神經脫髓鞘是主要病變,然而病毒包涵體出現却以淋巴組織及黏膜上皮如腎臟、膀胱、肺臟及消化系統較高(ChapterIII,VI)。綜合以上結果,本研究證明台灣犬瘟熱病毒至少存在一種以上H基因型(亞洲1型),其彼此間的胺基酸差異小於5%。同時本研究所建立的免疫化學染色及原位雜交染色方法使回溯性犬瘟熱病毒及鼠肝炎病毒之研究及診斷更簡單及正確。犬瘟熱病毒分離之方法可應用於未來臺灣不同地區之病毒分離。犬瘟熱病毒感染之伴隨病變視動物來源、治療病史、年齡及組織分布而定。

Mouse hepatitis virus (MHV) is the leading viral pathogen of laboratory mice in Taiwan. This study established a modified alkaline phosphatase-labelled avidin-biotin-complex (ABC-AP) method for detection of MHV in tissues. Mouse hepatitis virus antigen was clearly detected in samples of liver, stomach, caecal and colonic mucosa, and spleen. This method may prove useful in diagnosis when commercial antisera are unavailable or when immunosuppression prevents serological diagnosis. (Chapter II). Canine distemper virus (CDV) causes a highly contagious disease, which has been reported in Taiwan for many years; however the causative and its genes have never been identified and pathogenesis are poorly understood. The objectives of the dissertation were to set up a fast and easy diagnostic method of CDV infection, to isolate the field virus and do phylogenetic analysis of the viral H gene, to characterize the pathology of CD in Taiwan, and to assess the frequency of CNS demyelination and other pathological lesions in cases of CDV infection confirmed by immunohistochemistry (IHC) and/or reverse transcription polymerase chain reaction (RT-PCR). This study describes a modified non-biotin polymerized horseradish peroxidase (HRP) immunohistochemical method for the diagnosis of CDV infection from formalin-fixed, paraffin-embedded tissues. This method confirmed seven out of eight (87.5%) suspected cases. Labeled CDV antigen was observed in cerebrum, cerebellum, meninges, glial cells, neurons, vascular endothelium, periventricular areas and pericytes, and choroid plexus; grey and white matter and central canal of the spinal cord; renal pelvis and tubular epithelium, and urinary bladder epithelium; macrophages and lymphocytes in splenic white pulp and lymph nodes; skin epidermis; bronchiolar epithelium and alveolar macrophages; hepatic Kupffer cells, and gastric and intestinal mucosal epithelium; stratified squamous epithelium of the tongue and oesophagus.With the non-biotin HRP detection system, pretreatment by autoclaving followed by microwave heating gave better labeling results than did microwave pretreatment alone. No obvious difference was noted between the labeling results produced by the non-biotin HRP detection system and the Super Sensitive TM Link-Label IHC detection system (Chapter III, VI). For the purpose of confirming the IHC labeling and improving the detection of CDV nucleoprotein RNA, in situ hybridization (ISH) was applied in paraffin-embedded tissues from selected dogs with spontaneous CDV infections. In addition to proteinase K, autoclaving in various solutions (Trilogy, TBS S3006, H-3301, and S1700) for pre-treatments were compared. The intensity was assessed by using the integrated optical density (IOD) and the integrity of the tissue morphology. The combination of proteinase K digestion and autoclaving in a Trilogy solution resulted in a 5- to 100-fold ISH signal enhancement of CDV RNA. This modified technique can be useful in the retrospective viral studies across a broad range in the future (Chapter IV). For the purpose of CDV genotyping, during the period from 2003 to 2005, two CDV strains were isolated from 17 non-vaccinated puppies with suspected canine distemper by co-culture with peripheral blood mononuclear leucocytes and B95a cells. In addition, four cloned hemagglutinin (H) genes were obtained from 166 dogs infected with CDV. Indirect immunofluorescence assays and antigen tests confirmed that they were CDV. Analysis of the H genes of the six identified strains revealed that the deduced amino acid sequences contained nine potential sites for N-linked glycosylation, as had been found for the H proteins of Japanese isolates. The seventh site is characteristic to the Taiwan strains described in this report and to the recently reported Japanese strains. Furthermore, phylogenetic analysis of the H gene showed that the six isolates belong to the Asia-1 group and are closely related to the recently reported Japanese and Chinese strains (Chapter V). To realize the histopathological lesions of CDV in Taiwan, fifty two (IHC or RT-PCR positive) affected dogs were obtained from either animal clinics or dog shelters from 2000 to 2009, within which 32 were from clinics and 20 were from shelters. Postmortem and laboratory examination included, gross findings, histopathology, Luxol-fast blue cresyl echt violet (LFB-CEV) histochemistry, non-biotin HRP anti-CDV immunohistochemistry, and phosphoprotein gene RT-PCR. Clinic cases had histories of treatment and or vaccination. Twenty four clinic cases (75%) were puppies less than 6 months old. Seventeen shelter cases (85%) were identified as ‘adults’ greater than 6 months old. There were 27 males and 25 females. Eleven dog breeds were represented, but most dogs (35/52, 67%) were crossbred. Totally, 79% (41/52) showed lymphoid depletion, 71% (37/52) had interstitial pneumonia, 65% (34/52) had CNS demyelination, 32% (17/52) had catarrhal enteritis. Younger dogs from clinic group frequently had lymphoid depletion (31/32, 96%), inclusion bodies (28/32, 87%), pneumonia 81% (26/32, 81%), and CNS demyelination (26/32, 81%), which were all statistically significantly different from those from shelter. Enteritis was identified in about one third of the animals in both groups. The distribution of inclusion bodies also showed significant difference in urinary bladder, lymphoid tissues, lung, and alimentary tract between the two groups. Twenty nine co-infections and other associated lesions were identified. However, no significant difference was seen in the frequency of occurrence between two groups with the exception of interstitial nephritis. In conclusion, lymphoid depletion, pneumonia, and CNS demyelination were the most common CDV-infected principal lesions, and the inclusion bodies had a high occurrence in lymph nodes, spleen as well as mucosa epithelium of lung, stomach, urinary bladder and kidney (Chapter III, VI). In the present study, it has been demonstrated that CDV in Taiwan has at least one clade of the phylogenetic tree showing more than 95% amino acid similarity (< 5% amino acid variation) in the H gene. The modified non-biotin polymerlized horseradish peroxidase (HRP) IHC labeling and ISH method are easy, optimal and accurate for retrospective diagnosis of CDV and MHV. The occurrence of CDV-associated pathological lesions depend on the source of the animals, treatment history, age and tissue distribution.

Abstract II
中文摘要 V
Chapter I General Introduction 1

Chapter II Immunohistochemical diagnosis of mouse hepatitis
virus and Mycoplasma pulmonis infection with murine antiserum 28

Chapter III A non-biotin polymerized horseradish - peroxidase method for the immunohistochemical diagnosis of canine distemper 36

Chapter IV Improving detection of canine distemper virus in formalin-fixed, paraffin-embedded, tissues: using in situ hybridization with integrated optical density to give a semi-quantitative assessment 45

Chapter V Phylogenetic analysis and isolation of canine distemper viruses in Taiwan 73

Chapter VI Canine Distemper in Taiwan from 2000 – 2009: co-infections, and use of RT-PCR and immunohistochemistry to detect tissue involvement in two groups of dogs 87

Chapter VII General Discussion 125
Appendix 136
Curriculum Vitae 143


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46.Liang, S.C., Lian, W.C., Leu, F. J., Lee, P.J., Chao, A. J., Hong, C. C. , Chen, W. F.,1995. Epizootic of low virulence hepatotropic murine hepatitis virus in a nude mice breeding colony in Taiwan. Lab Anim Sci 45, 519–522.
47.Masuoka, J., Guthrie, L.N. and Hazen, K.C., 2002. Complications in cell-surface labeling by biotinylation of Canada albicans due to avidin conjugate binding to cell-wall proteins. Microbiology 148, 1073-1079.
48.Mcquaid, S., Isserte, S., Allan, G.A., Taylor, M.J., Allen, I.V., Cosby, S.L., 1990. Use of immunocytochemistry and biotinylated in situ hybridization for detecting measles virus in central nervous system tissue. J Clinical Pathol 43, 329-333.
49.Metzler, A.E., Higgins, R.J., Krakowka, S., Koestner, A., 1981. Characterization of bovine cells, supporting in vitro growth of virulent and attenuated canine distemper virus. Am J Vet Res 42, 1257-1262.
50.Metzler, A.E., Krakowka, S., Axthelm, M.K., Gorham, J.R., 1984. In vitro propagation of canine distemper virus: Establishment of persistent infection in Vero cells. Amer J Vet Res 45, 2211-2215.
51.Mitchell, W.J., Summers, B.A. and Appel, M.J.G., 1991. Viral expression in experimental canine distemper demyelinating encephalitis. J Comp Pathol 104, 77-88.
52.Mori, T., Shin, Y.S., Okita, M., Hiray, N., Miyashita, N., Gemma, T., Kai, C., Mikami, T., 1994, The biological characrization of field isolates of canine distemper virus from Japan. J Gen Virol 75, 2403-2408.
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54.Muller, C. F., Fatzer, R. S., Beck, K., Vandevelde, M., Zurbriggen, A., 1995.
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55.National Research Council, 1991. Infectious Disease of Mice and Rats, a Report of the Institute of Laboratory Animal Resources, Committee on Infectious Diseases of Mice and Rats, National Academy Press, Washington DC, pp. 33–163.
56.Okita, M., Yanai,T., Ochikubo, F., Gemma, T., Mori, T., Maseki, T., Yamanouchi, K., Mikami, T., Kai, C.,1997. Histopathological features of canine distemper recently observed in Japan. J Comp Pathol 116, 403- 408.
57.Palmer, D.G., Huxtable, C.R. and Thomas, J.B., 1990. Immunohistochemical demonstration of canine distemper virus antigen as an aid in the diagnosis of canine distemper encephalomyelitis. Res Vet Sci 49, 177-181.
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61.Shin, Y., Mori, T., Okita, M., Gemma, T., Kai, C., Mikami, T., 1995. Detection of canine distemper virus nucleocapsid protein gene in canine peripheral blood mononuclear cells by RT-PCR. J Vet Med Sci 57, 439-445.
62.Sidhu, M.S., Husar, W., Cook, S.D., Dowling, P.C., Udem, S.A., 1993. Canine distemper terminal and intergenic non-protein coding nucleotide sequences: completion of the entire CDV genome sequences. Virology 93, 66-72.
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64.Srinivasan, M., Sedmak, D., Jewell, S., 2002. Effect of fixatives and tissue processing on the content and integrity of nucleic acids. Amer J Pathol 161, 1961-1970.
65.Stanton, J.B., Poet, S., Frasca, S., Bienzle, D. and Brown, C.C., 2002. Development of a semi-nested reverse transcription polymerase chain reaction assay for the retrospective diagnosis of canine distemper virus infection. J Vet Diag Invest 14, 47-52.
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68.Summers, B.A., Greisen, H.A., Appel, M.J.G. ,1984. Canine distemper encephalomyelitis variation with virus strain. J Comp Pathol 94, 65-75.
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74.Wu, S.C., Chueh, L.L., Pang, V.F., Jeng, C.R., Lee, C.C., Liu, C.H., 2000. Pathology and RT-PCR employed in the identification of canine distemper virus infection in Taiwan. J Chin Soc Vet Sci 26, 328-338.
75.Yamawaki, M., Zurbriggen, A., Richard, A., Vandevelde, M., 1993. Saponin treatment for in situ hybridization maintains good morphological preservation. Journal of Histochemistry and Cytochemistry 41, 105-109.
76.Yan, F., Wu, X., Crawford, M., Duan, W., Wilding, E. E., Gao, L., Nana-Sinkam, S. P., Villalona-Calero, M. A., Baiocchi, R. A., Otterson, G. A., 2010. The search for an optimal DNA, RNA, and protein detection by in situ hybridization, immunohistochemistry, and solution-based methods. Methods 52, 281-286.
77.Yu, C.L., Chueh, L.L., Chen, H.C., Liu, C.H., 2001. The detection of dural infection of canine distemper virus and canine adenovirus by histopathology and polymerase chain reaction. J Chin Soc Vet Sci 27, 288-294.

Chapter 2. Immunohistochemical diagnosis of mouse hepatitis virus

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17.Liang, C.T., Wang, H.C. and Liu, C.H. (2000). A modified immunohistochemical staining method employed in formalin or alcohol-fixed, paraffin-embedded porcine tissue sections. Journal of the Chinese Society of Veterinary Science, 26, 213-222.
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26.Weir, E.C., Bhatt, P.N., Barthold, S.W., Cameron, G.A. and Simack, P.A. (1987). Elimination of mouse hepatitis virus from a breeding colony by temporary cessation of breeding. Laboratory Animal Science, 37, 455-458.

Chapter 3. Immunohistochemical diagnosis of canine distemper

1.Baumgartner, W., Orvell, C. and Reinacher, M. (1989).Naturally occurring canine distemper virus encephalitis: distribution and expression of viral polypeptides in nervous tissues. Acta Neuropathologica, 78, 504-512.
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3.Frisk, A.L., Konig, M., Motitz, A. and Baumgartner, W. (1999). Detection of canine distemper virus nucleoprotein RNA by reverse transcription-PCR using serum, whole blood, and cerebrospinal fluid from dogs with distemper. Journal of Clinical Microbiology, 37, 3634-3643.
4.Haines, D.M. and Chelack, B.J. (1991). Technical considerations for developing enzyme immunohistochemical staining procedures on formalin-fixed paraffin-embedded tissues for diagnostic pathology. Journal of Veterinary Diagnostic Investigation, 11, 396-399.
5.Haines, D.M., Martin, K.M., Chelack, B.J., Sargent, R.A., Outerbridge, C.A. and Clark, E.G. (1999). Immunohistochemical detection of canine distemper virus in haired skin, nasal mucosa, and footpad epithelium: a method for antemortem diagnosis of infection. Journal of Veterinary Diagnostic Investigation, 11, 396-399.
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8.Kim, Y. H., Cho K.W., Youn, H.Y., Yoo, H.S. and Han, H.R. (2001). Detection of canine distemper virus (CDV) through one step RT-PCR combined with nested PCR. Journal of Veterinary Sciences, 2, 59-63.
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10.Liang, C.T., Wang, H.C. and Liu, C.H. (2000). A modified immunohistochemical staining method employed in formalin or alcohol-fixed, paraffin-embedded porcine tissue sections. Journal of the Chinese Society of Veterinary Science, 26, 213-222.
11.Liang, C.T., Wu, S.C., Huang, Y. T., Lin, Y.C., Chang, W.J., Chou, J.Y., Liang, S.C. and Liu, C.H. (2004). Immunohistochemical diagnosis of mouse hepatitis virus and Mycoplasma pulmonis infection with murine antiserum. Journal of Comparative Pathology, 131, 214-220.
12.Masuoka, J., Guthrie, L.N. and Hazen, K.C. (2002). Complications in cell-surface labeling by biotinylation of Canada albicans due to avidin conjugate binding to cell-wall proteins. Microbiology, 148, 1073-1079.
13.Mitchell, W.J., Summers, B.A. and Appel, M.J.G. (1991). Viral expression in experimental canine distemper demyelinating encephalitis. Journal of Comparative Pathology, 104, 77-88.
14.Okita, M., Yanai, T., Ochikubo, F., Gemma, T., Mori, T., Maseki, T.,Yamanouchi, K., Mikami, T. and Kai, C. (1997). Histopathological features of canine distemper recently observed in Japan. Journal of Comparative Pathology, 116, 403- 408.
15.Palmer, D.G., Huxtable, C.R. and Thomas, J.B. (1990). Immunohistochemical demonstration of canine distemper virus antigen as an aid in the diagnosis of canine distemper encephalomyelitis. Research in Veterinary Science, 49, 177-181.
16.Ramos-Vara, J.A. (2005). Technical aspects of immunohistochemistry. Veterinary Pathology, 42, 405-426.
17.Ramos-Vara, J.A. and Beissenherz, M.E. (2000). Optimization of immunohistochemical methods using two different antigen retrieval methods on formalin - fixed, paraffin-embedded tissues: experience with 63 markers. Journal of Veterinary Diagnostic Investigation, 12, 307-311.
18.Shi, S.R., Cote, R.J. and Taylor, C.R. (2001). Antigen retrieval techniques: current perspectives. Journal of Histochemistry and Cytochemistry, 49, 931-937.
19.Stanton, J.B., Poet, S., Frasca, S., Bienzle, D. and Brown, C.C. (2002). Development of a semi-nested reverse transcription polymerase chain reaction assay for the retrospective diagnosis of canine distemper virus infection. Journal of Veterinary Diagnostic Investigation, 14, 47-52.
20.Summers, B.A. and Appel, M.J.G. (1985).Syncytia formation: an aid in the diagnosis of canine distemper encephalomyelitis. Journal of Comparative Pathology, 95, 425-435.
21.Summers, B.A. and Appel, M.J.G. (1994). Aspects of canine distemper virus and measles virus encephalomyelitis. Neuropathology and Applied Neurobiology, 20, 525-534.
22.Summers, B.A., Greisen, H.A. and Appel, M.J.G. (1984).Canine distemper
encephalomyelitis variation with virus strain. Journal of Comparative Pathology, 94,
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23.True, L.D. (1990). Principles of immunohistochemistry. In: Atlas of Diagnostic Immunohistopathology, 1st Edit., L.D.True and J. Rosai, Eds, J.B.Lippincott, New York, NY, pp. 1-34.
24.Wu, S.C., Chueh, L.L., Pang, V.F., Jeng, C.R., Lee, C.C. and Liu, C.H. (2000). Pathology and RT-PCR employed in the identification of canine distemper virus infection in Taiwan. Journal of the Chinese Society of Veterinary Science, 26, 328-338.
25.Yu, C.L., Chueh, L.L., Chen, H.C. and Liu, C.H. (2001).The detection of dural infection of canine distemper virus and canine adenovirus by histopathology and polymerase chain reaction. Journal of the Chinese Society of Veterinary Science, 27, 288-294.

Chapter 4. In situ hybridization detection of canine distemper

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7.Frisk, A.L., Konig, M., Moritz, A., Baumgartner, W.,1999. Detection of canine
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8.Gaedke, K., Zurbriggen, A., Baumgartner, W., 1997. In vivo and in vitro detectionof canine distemper virus nucleoprotein gene with digoxigenin-labelled RNA, double-stranded DNA probes and oligonucleotides by in situ hybridization. J Vet Med 44, 329-340.
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12.Liang, C.T., Chueh, L.L., Pang, V.F., Zhuo, Y.X., Liang, S.C., Yu, C.K., Chiang, H., Lee, C.C., Liu, C.H., 2007. A non-biotin polymerized horseradish-peroxidase
method for the immunohistochemical diagnosis of canine distemper. J Comp Pathol 136, 57-64.
13.Liang, C.T., Chueh, L.L., Lee, K.H., Huang, H.S., Uema, M., Watanabe, A., Miura, R., Kai, C., Liang, S.C., Yu, C.K., Liu, C.H., 2008. Phylogenetic analysis and isolation of canine distemper viruses in Taiwan. Taiwan Vet J 34, 198-210.
14.Mcquaid, S., Isserte, S., Allan, G.A., Taylor, M.J., Allen, I.V., Cosby, S.L., 1990. Use of immunocytochemistry and biotinylated in situ hybridization for detecting measles virus in central nervous system tissue. J Clin Pathol 43, 329-333.
15.Mitchell, W.J., Summers, B.A., Appel, M.J.G., 1991.Viral expression in experimental canine distemper demyelinating encephalitis. J Comp Pathol 104, 77-87.
16.Mcnicol, A.M., Farquharson, M.A., 1997. In situ hybridization and its diagnostic application in pathology. J Pathol 182, 250-261.
17.Muller, C.F., Fatzer, R.S., Beck, K., Vandevelde, M., Zurbriggen, A., 1995. Studies on Canine distemper virus persistence in the central nervous system. Acta Neuropathol 89, 438-445.
18.Nuovo, G. J., 1995. In situ PCR: protocols and applications. Genome Res 4, S151-S167.
19.Relf, B. L., Machaalani, R., Waters, K. A., 2002. Retrieval of mRNA from paraffin-embedded human infant brain tissue for non-radioactive in situ hybridization using oligonucleotides. J Neurosci Methods 115, 129-136.
20.Shi, S.R., Cote, R.J., Taylor, C.R., 2001. Antigen retrieval techniques: current perspectives. J Histo Cytochem 49, 931-937.
21.Srinivasan, M., Sedmak, D., Jewell, S., 2002. Effect of fixatives and tissue processing on the content and integrity of nucleic acids. Amer J Pathol 161, 1961-1970.
21, Vandevelde, M., Zurbriggen, A., 2005. Demyelination in canine distemper virus infection: a review. Acta Neuropathol 109, 56-68.
22.Ward, J. M.,Wobus, C.E., Thackray, L.B., Erexson, C.R.,Faucette, L.J., Belliot,
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23.Weise, A., Liehr, T., Claussen, U., Halbhuber, K.J., 2005. Increased efficiency of fluorescence in situ hybridization (FISH) using the microwave. J Histo Cytochem 53, 1301-1303.
24.Xu Q., Zhang Z., Zhang P., Chen W., 2008. Antisense oligonucleotides and
all-trans retinoic acid have a synergistic anti-tumor effect on oral squamous cell
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25.Yamashita, S., 2007. Heat-induced antigen retrieval: mechanisms and application to histochemistry. Prog Histo Cytochem 41, 141-200.
26.Yamawaki, M., Zurbriggen, A., Richard, A., Vandevelde, M.,1993. Saponin treatment for in situ hybridization maintains good morphological preservation. J Histo Cytochem 41, 105-109.
27.Zurbriggen, A., Schmid, I., Graber, H.U., Vandevelde, M. , 1998. Oligodendroglial pathology in canine distemper. Acta Neuropathol 95, 71-77.

Chapter 5. Phylogenetic analysis and isolation of canine distemper viruses
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10.Hashimoto M, Une Y, Mochizuki M. Hemagglutinin genotype profiles of canine distemper virus from domestic dogs in Japan. Arch Virol 146: 149-155, 2001.
11.Hirama K, Goto Y, Uema M, Endo Y, Miura R, Kai C. Phylogenetic analysis of the hemagglutinin (H) gene of canine distemper viruses isolated from wild masked palm cives(Paguma larvata). J Vet Med Sci 66: 1575-1578, 2004.
12.Imagawa DT, Howard EB, van Pelt LF, Ryan CP, Bui HD, Shapshak P. Isolation of canine distemper virus from dogs with chronic neurological diseases. Proc Soc Exp Bio Med 164: 355-362, 1980.
13.Iwatsuki K, Miyashita N, Yoshida E, Gemma T, Shin YS, Mori T, Hirayama N, Kai C, Mikami T. Molecular and phylogenetic analyses of the haemagglutinin (H) proteins of field isolates of canine distemper virus from naturally infected dogs. J General Virol 78: 373-380, 1997.
14.Iwatsuki K, Tokiyoshi S, Hirayama N, Nakamura K, Ohashi K, Wakasa C, Mikami T, Kai C. Antigenic differences in the H proteins of canine distemper viruses. Vet Microbiol 71: 281-286, 2000.
15.Kai C, Ochikubo F, Okita M, Iinuma T, Mikami T, Kobune F, Yamanouchi K. Use of B95a cells for isolation of canine distemper virus from clinical cases. J Vet Med Sci 55: 1067-1070, 1993.
16.Kimoto T. In vitro and in vivo properties of the virus causing natural canine distemper encephalitis. J General Virol 67: 487-503, 1986.
17.Kovamees J, Blixenkrone-Moller M, Norrby E. The nucleotide and predicted amino acid sequence of the attachment protein of canine distemper virus. Virus Res 19: 223-233, 1991.
18.Lan NT, Yamaguchi R, Kawabata A, Uchida K, Sugano S, Tateyama S. Comparison of molecular and growth properties for two different canine distemper virus clusters, Asia 1 and 2, in Japan. J Vet Med Sci 69: 739-744, 2007.
19.Lan NT, Yamaguchi R, Inomata A, Furuya Y, Uchida K, Sugano S, Tateyama S. Comparative analyses of canine distemper viral isolates from clinical cases of canine distemper in vaccinated dogs. Vet Microbiol 115: 32-42, 2006.
20.Lednicky JA, Dubach J, Kinsel MJ, Meehan TP, Bocchetta M, Hungerford LL, Sarich NA, Witecki KE, Braid MD, Pedrak C, Houde CM. Genetically distant American Canine distemper virus lineages have recently caused epizootics with somewhat different characteristics in raccoons living around a large suburban zoo in the USA. Virol J 1: 1-14, 2004.
21.Lednicky JA, Meehan TP, Kinsel MJ, Dubach J, Hungerford LL, Sarich NA, Witecki KE, Braid MD, Pedrak C, Houde, CM.. Effective primary isolation of wild-type canine distemper virus in MDCK, MV1 Lu and Vero cells without nucleotide sequence changes within the entire haemagglutin protein gene and in subgenomic sections of the fusion and phosphor protein genes. J Virol Method 118: 147-157, 2004.
22. Liang CT, Chueh LL, Pang VF, Zhuo YX, Liang SC, Yu CK, Chiang H, Lee CC, Liu CH. A non-biotin polymerized horseradish peroxidase method for the immunohistochemical diagnose of canine distemper virus infection. J Comp Pathol 136: 57-64, 2007.
23. Martella V, Cirone F, Elia G, Lorusso E, Decaro N, Campolo M, Desario C, Lucente MS, Bellacicco AL, Blixenkrone-Moller M, Carmichael LE, Buonavoglia C. Heterogeneity within the hemagglutinin genes of canine distemper virus (CDV) strains detected in Italy. Vet Microbiol 116: 301-309, 2006.
24. Martella V, Pratelli A, Cirone F, Zizzo N, Decaro N, Tinelli A, Foti M, Buonavoglia C. Detection and genetic characterization of canine distemper virus (CDV) from free-ranging red foxes in Italy. Mol Cellular Probes 16: 77-83, 2002.
25. Metzler AE, Krakowka S, Axthelm MK, Gorham JR. In vitro propagation of canine distemper virus: Establishment of persistent infection in Vero cells. Am J Vet Res 45: 2211-2215, 1984.
26. Mochizuki M, Hashimoto M, Hagiwara S, Yoshida Y, Ishiguro S. Genotypes of canine distemper virus determined by analysis of the hemagglutinin genes of recent isolates from dogs in Japan. J Clin Microbiol 37: 2936-2942, 1999.
27. Mori T, Shin YS, Okita M, Hiray N, Miyashita N, Gemma T, Kai C, Mikami T. The biological characrization of field isolates of canine distemper virus from Japan. J Gen Virol 75: 2403-2408,1994.
28.Sidhu MS, Husar W, Cook SD, Dowling PC, Udem SA. Canine distemper terminal and intergenic non-protein coding nucleotide sequences: completion of the entire CDV genome sequences. Virology 93: 66-72,1993.
29.Tamura K, Dudley J, Nei M, Kumar S. MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol 24: 1596-1599, 2007.
30. Uema M, Ohashi K, Wakasa C, Kai C. Phylogenetic and restriction fragment length polymorphism analyses of hemagglutinin (H) protein of canine distemper virus isolates from domestic dogs in Japan. Virus Res 109: 59-63, 2005.
31. von Messling V, Zimmer G, Herrler G, Haas L, Cattaneo R. The hemagglutinin of canine distemper virus determines tropism and cytopathogenicity. J Virol 75: 6418-6427, 2001.

Chapter 6. Pathological analysis of canine distemper in Taiwan
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2.Baumgartner W, Boyce RW, Alldinger S, Axthelm MK, Weisbrode SE, Krakowka S, Gaedke K: Metaphyseal bone lesions in young dogs with systemic canine distemper virus infection. Vet Microbiol 1995; 44: 201-209.
3.Beineke A, Puff C, Seehusen F, Baumgartner W: Pathogenesis and immunopathology of systemic and nervous canine distemper. Vet Immunol Immunopathol 2009;127: 1-18.
4.Blixenkrone-Moller M: Biological properties of phocine distemper virus and canine distemper virus. APMIS Suppl 1993;36: 1-51.
5.Chvala S, Benetka V, Mostl K, Zeugswetter F, Spergser J, Weissenbock H,:Simultaneous canine distemper virus, canine adenovirus type 2, and Mycoplasma cynos infection in a dog with pneumonia. Vet Pathol 2007; 44: 508-512.
6.Damian M, Morales E, Salas G, Trigo FJ,: Immunohistochemical detection of antigens of distemper, adenovirus and parainfluenza viruses in domestic dogs with pneumonia. J Comp Pathol 2005;133; 289-293.
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8.Haines DM, Martin KM, Chelack BJ, Sargent RA, Outerbridge CA, Clark EG: Immunohistochemical detection of canine distemper virus in haired skin, nasal mucosa, and footpad epithelium: a method for antemortem diagnosis of infection. J Vet Diagn Invest 1999; 11: 396-399.
9.Headley SA, Shirota K, Baba T, Ikeda T, Sukura A: Diagnostic exercise: Tyzzer''s disease, distemper, and coccidiosis in a pup. Vet Pathol 2009;46:151-154.
10.Higgins RJ, Krakowka S, Metzler AE, Koestner A: Canine distemper virus-associated cardiac necrosis in the dog. Vet Pathol 1981;18: 472-486.
11.Kabay MJ, Robinson WF, Huxtable CR, McAleer R: The pathology of disseminated Aspergillus terreus infection in dogs. Vet Pathol 1985;22: 540-547.
12.Koutinas AF, Baumgartner W, Tontis D, Polizopoulou Z, Saridomichelakis MN, Lekkas S: Histopathology and immunohistochemistry of canine distemper virus-induced footpad hyperkeratosis (hard Pad disease) in dogs with natural canine distemper. Vet Pathol 2004;41: 2-9.
13.Liang CT, Chueh, L.L., Lee, K.H., Huang, H.S., Takehara, K., Miura, R., Kai, C., Liang, S.C., Yu, C.K., Liu, C.H.2008, Isolation and the phylogenetic analysis of canine distemper viruses in Taiwan. Taiwan Vet J 2008; 34: 198-210.
14.Liang CT, Chueh LL, Pang VF, Zhuo YX, Liang SC, Yu CK, Chiang H, Lee CC, Liu CH: A non-biotin polymerized horseradish-peroxidase method for the immunohistochemical diagnosis of canine distemper. J Comp Pathol 2007;136:57-64.
15.Lisiak JA, Vandevelde M: Polioencephalomalacia associated with canine distemper virus infection. Vet Pathol 1979;16: 650-660.
16.Messick JB: New perspectives about Hemotrophic mycoplasma (formerly, Haemobartonella and Eperythrozoon species) infections in dogs and cats. Vet Clin North Am Small Anim Pract 2003; 33: 1453-1465.
17.Moretti L, Da Silva AV, Ribeiro MG, Paes AC, Langoni H: Toxoplasma gondii genotyping in a dog co-infected with distemper virus and ehrlichiosis rickettsia. Rev Inst Med Trop Sao Paulo 2006; 48: 359-363.
18.Okita M, Yanai T, Ochikubo, F, Gemma T, Mori T, Maseki T, Yamanouchi K, Mikami T, Kai C: Histopathological features of canine distemper recently observed in Japan. J Comp Pathol 1997;116: 403-408.
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20.Pandher K, Podell B, Gould DH, Johnson BJ, Thompson S: Interstitial pneumonia in neonatal canine pups with evidence of canine distemper virus infection. J Vet Diagn Invest 2006;18: 201-204.
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22.Saey V, Vanhaesebrouck A, Maes S, Van Simaey L, Van Ham L, Deschaght P, Ducatelle R: Granulomatous Meningoencephalitis Associated With Sporobolomyces roseus in a Dog. Vet Pathol 2010;
23.Stanton JB, Poet S, Frasca S, Jr Bienzle D, Brown CC: Development of a semi-nested reverse transcription polymerase chain reaction assay for the retrospective diagnosis of canine distemper virus infection. J Vet Diagn Invest 2002;14: 47-52.
24.Summers BA, Appel MJ: Syncytia formation: an aid in the diagnosis of canine distemper encephalomyelitis. J Comp Pathol 1985;95: 425-435.
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26.Vandevelde M, Kristensen B, Braund KG, Greene CE, Swango LJ, Hoerlein BF: Chronic canine distemper virus encephalitis in mature dogs. Vet Pathol 1980;17:17-28.
27.Vandevelde M, Zurbriggen A: Demyelination in canine distemper virus infection: a review. Acta Neuropathol 2005;109: 56-68.
28.Wada Y, Kondo H, Nakaoka Y, Kubo M: Gastric attaching and effacing Escherichia coli lesions in a puppy with naturally occurring enteric colibacillosis and concurrent canine distemper virus infection. Vet Pathol 1996; 33: 717-720.
29.Wu SC, Chueh LL, Pang VF, Jeng CR, Lee CC, Liu CH: Pathology and RT-PCR employed in the identification of canine distemper virus infection in Taiwan. J Chin Soc Vet Sci 2000;26: 328-338.

Chapter 7. General Discussion

1.Blixenkrone-Moller, M., Svansson, V., Appel, M.J.G., Krogsrud, J., Have, P., Orvell, C., 1992. Antigenic relationships between field isolates of morbillivirus from different canivores. Arch Virol 123, 279-294.
2.Calderon, M.G., Remorini, P., Periolo, O., Iglesias, M., Mattion, N., Torre, J.L., 2007. Detection by RT-PCR and genetic characterization of canine distemper virus from vaccinated and non-vaccinated dogs in Argentina. Vet Microbiol 125, 341-349.
3.Demeter, Z., Lakatos,B., Palade ,E.A., Kozma , T., Forgach, P., Rusvai,M., 2007. Genetic diversity of Hungarian canine distemper virus strains. Vet Microbiol 122, 258-269.
4.Haas, L., Liermann, H., Harder, T.C., Barrett, T., Lochelt, M., von Messling, V., Baumgartner, W., Greiser-Wilke, I., 1999. Analysis of the H gene, the central untranslated region and the proximal coding part of the F gene of wild-type and vaccine canine distemper viruses. Vet Microbiol 69, 15-18.
5.Haas, L., Martens, W., Greiser-Wilke, I., Mamaev, L., Butina, T., Maack, D., Barrett, T., 1997. Analysis of the haemagglutinin gene of current wild-type canine distemper virus isolates from Germany. Virus Res 48, 165-171.
6.Hashimoto, M., Une, Y., Mochizuki, M., 2001. Hemagglutinin genotype profiles of canine distemper virus from domestic dogs in Japan. Arch Virol 146, 149-155.
7.Hirama, K., Goto, Y., Uema, M., Endo, Y., Miura, R., Kai, C., 2004. Phylogenetic analysis of the hemagglutinin (H) gene of canine distemper viruses isolated from wild masked palm cives(Paguma larvata). J Vet Med Sci 66, 1575-1578.
8.Iwatsuki, K., Miyashita, N., Yoshida, E., Gemma, T., Shin, Y.S., Mori, T., Hirayama, N., Kai, C., Mikami, T., 1997. Molecular and phylogenetic analyses of the haemagglutinin (H) proteins of field isolates of canine distemper virus from naturally infected dogs. J Gen Virol 78, 373-380.
9.Iwatsuki K, Tokiyoshi S, Hirayama N, Nakamura K, Ohashi K, Wakasa C, Mikami T, Kai C., 2000. Antigenic differences in the H proteins of canine distemper viruses. Vet Microbiol 71, 281-286.
10.Kai, C., Ochikubo, F., Okita, M., Iinuma, T., Mikami, T., Kobune, F., Yamanouchi, K., 1993. Use of B95a cells for isolation of canine distemper virus from clinical cases. J Vet Med Sci 55, 1067-1070.
11.Kim, J., Chae, C., 2003. Optimal enhancement of in situ hybridization for the
detection of porcine circovirus 2 in formalin-fixed, paraffin-wax-embedded tissues using a combined pretreatment of thermocycler and proteinase K. Res Vet Sci 74, 235-240.
12.Lan, N.T., Yamaguchi, R., Inomata, A., Furuya, Y., Uchida, K., Sugano, S., Tateyama, S., 2006. Comparative analyses of canine distemper viral isolates from clinical cases of canine distemper in vaccinated dogs. Vet Microbiol 115, 32-42.
13.Lan, N.T., Yamaguchi, R., Kawabata, A., Uchida, K., Sugano, S., Tateyama, S., 2007. Comparison of molecular and growth properties for two different canine distemper virus clusters, Asia 1 and 2, in Japan. J Vet Med Sci 69, 739-744.
14.Lednicky, J.A., Dubach, J., Kinsel, M.J., Meehan, T.P., Bocchetta, M., Hungerford, L.L., Sarich, N.A., Witecki, K.E., Braid, M.D., Pedrak, C., Houde, C.M., 2004. Genetically distant American Canine distemper virus lineages have recently caused epizootics with somewhat different characteristics in raccoons living around a large suburban zoo in the USA. Virol J 1, 1-14.
15.Liang, C.T., Wang, H.C., Liu, C.H., 2000. A modified immunohistochemical staining method employed in formalin or alcohol-fixed, paraffin-embedded porcine tissue sections. J Chin Soc Vet Sci 26, 213-222. (in Chinese).
16.Liang, C.T., Wu, S.C., Huang, Y. T., Lin, Y.C., Chang, W.J., Chou, J.Y., Liang, S.C. Liu, C.H., 2004. Immunohistochemical diagnosis of mouse hepatitis virus and Mycoplasma pulmonis infection with murine antiserum. J Comp Pathol 131, 214-220.
17.Martella, V., Cirone, F., Elia, G., Lorusso, E., Decaro, N., Campolo, M., Desario, C., Lucente, M.S., Bellacicco, A.L., Blixenkrone-Moller, M., Carmichael, L.E., Buonavoglia, C., 2006. Heterogeneity within the hemagglutinin genes of canine distemper virus (CDV) strains detected in Italy. Vet Microbiol 116, 301-309.
18.Martella, V., Pratelli, A., Cirone, F., Zizzo, N., Decaro, N., Tinelli, A., Foti, M., Buonavoglia, C., 2002.Detection and genetic characterization of canine distemper virus (CDV) from free-ranging red foxes in Italy. Mol Cell Probes 16, 77-83.
19.Mcquaid, S., Isserte, S., Allan, G.A., Taylor, M.J., Allen, I.V., Cosby, S.L.,1990. Use of immunocytochemistry and biotinylated in situ hybridization for detecting measles virus in central nervous system tissue. J Clinical Pathol 43, 329-333.
20.Mochizuki, M., Hashimoto, M., Hagiwara, S., Yoshida, Y., Ishiguro, S., 1999. Genotypes of canine distemper virus determined by analysis of the hemagglutinin genes of recent isolates from dogs in Japan. J Clin Microbiol 37, 2936-2942.
21.Mori, T., Shin, Y.S., Okita, M., Hiray, N., Miyashita, N., Gemma, T., Kai, C., Mikami, T., 1994. The biological characrization of field isolates of canine distemper virus from Japan. J Gen Virol 75, 2403-2408.
22.Okita, M., Yanai, T., Ochikubo, F., Gemma, T., Mori, T., Maseki, T., Yamanouchi, K., Mikami, T., Kai, C:,1997. Histopathological features of canine distemper recently observed in Japan. J Comp Pathol 116, 403-408.
23.Ramos-Vara, J.A., Beissenherz, M.E., 2000. Optimization of immunohistochemical methods using two different antigen retrieval methods on formalin - fixed, paraffin-embedded tissues: experience with 63 markers. J Vet Diag Invest 12, 307-311.



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