INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. Hie quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. A Bell & Howell information Company 300 North Zeeb Road. Ann Arbor. Ml 48106-1346 USA 313/761-4700 800/521-0600 CHARACTERIZATION OF THE SPONTANEOUSLY DIABETIC BB WISTAR RAT DISSERTATION Presented in Partial fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By James Roscoe Wright, Jr., B.S., M.A., M.D, ***** The Ohio State University 1995 Dissertation Committee: Approved by C.C. Capen D.A. Senhauser H.M. Sharma riser R.E. Stephens Ddpa^ftment of Pathology A. J . Yates UMI Number: 9526106 UMI Microform 9526106 Copyright 1995, by UMI Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. UMI 300 North Zeeb Road Ann Arbor, MI 48103 To Allan J. Yates, M.D., Ph.D. He chased me around the world until I agreed to finish this 1 ACKNOWLEDGEMENTS My sincere appreciation and thanks are extended to the following people: To Allan J. Yates for his supervision in all aspects of this Ph.D. program. He has been a tremendous role model as both a clinician and a scientist. To Charles C. Capen, Donald A. Senhauser, Hari M. Sharma, Ralph E. Stephens, and Allan J. Yates for their help throughout this Ph.D. program and for their suggestions, criticisms, and editing of this dissertation. To the Ohio State University Department of Neuropathology for wonderful histologic, photographic, and secretarial support; without this help, none of the many papers included in the appendix of this dissertation would have been possible. To Hari M. Sharma and Chull Shim who patiently taught me histopathology. To Ralph E. Stephens and Kenneth C. Ford who taught me tissue culture and autoradiography. To John C. Neff and Ken Smith who taught me immunofluorescence. To David W. Covey for maintaining our BB Wistar rat colony and to Pierre Thibert for providing the rats for these studies. To Rachel L. (Tigner) Wright for support and statistical assistance. To Mary Larlham for typing this dissertation. VITA September 21, 1955 ..... Born - Huntsville, Alabama 1977 . ;.............. ... B.S., Ohio State University, Columbus, OH 1977-1979................. Graduate Research Associate Depts. of Surgery & Pathology, Ohio State University 1984 .................... M.A., Ohio State University 1984 .................... M.D., Ohio State University 1984-1988 .............. Resident, Dept, of Pathology Barnes Hospital, Washington University, St.Louis, MO 1985-87 ................. NIADDKD Trainee (Diabetes) Washington University 1988-1990 ............... Fellow, Pediatric/Perinatal Pathology, IWK Children's Hospital & Grace Maternity Hospital, Dalhousie University, Halifax, Nova Scotia, Canada 1989-1993 ............... Clinical Assistant, IWK Children's Hospital 1989-1994 ............... Assistant Professor of Pathology Dalhousie University 1990-present ............ Assistant Professor of Surgery Dalhousie University 1993 .................... Pathologist, IWK Children’s Hospital & Grace Maternity Hospital 1994-present ............ Associate Professor of Pathology Dalhousie University iv PUBLICATIONS Wright JR Jr and Kearns H: Long-term culture, low temperature culture, and hyperoxic culture do not prolong fish-to-mouse islet xenograft survival. Xenotransplantation - in press. Nguyen T, Wright JR Jr, Nielsen PF, and Conlon JM: Characterization of the pancreatic hormones from the Brockmann body of the tilapia - implications to islet xenograft studies. Comp. Biochem. Physiol. - in press. Wright JR Jr and Kearns H: Fish-to-mouse islet xenograft survival is markedly prolonged by 15- deoxyspergualin (DSG). Transplant. Proc. - in press. Wright JR Jr and Schrezenmeir J: Transplantation of Fish islets. In Methods in Cell Transplantation, edited by C Ricordi, RG Landes Co., Austin - in press. Wright JR Jr: Relationship of surgical oncology and pathology in early 20th century America. In History of Surgery: Proceedings of the 17th International Symposium on the Comparative History of Medicine -- East and West, edited by Y Kawakita, Division of Medical History, The Taniguchi Foundation, Osaka - in press. Wright JR Jr, Thompson DL, McBride JA, and Liston RM: Pulmonary hyperplasia associated with tracheal atresia: pathological and prenatal sonographic findings. Pediatric Pathol. Lab. Med. 15: 81-97, 1995. Wright JR Jr: Procurement of fish islets (Brockmann bodies). In Pancreatic Islet Transplantation Series. Volume 1: Procurement of Pancreatic Islets, edited by RP Lanza and WL Chick, RG Landes Co., Austin, 1994, pp. 123-33. Aiken KD, Yu W, Wright JR Jr, and Roth KA: Adaptation of enteroendocrine cells in response to jejunal-ileal transposition in the rat. Gastroenterol. 106: 1576-83, 1994 . Wright JR Jr, Stinson D, Wade A, Haldane D, and Heifetz SA: Necrotizing funisitis associated with Actinomyces meyeri infection: A case report. Pediatric Pathol. 14: 927-34, 1994. v Yang H, Yu W, Wan X, Al-Abdullah I, and Wright JR Jr: Recyclable Islet isografts: A biological insulin pump to facilitate surgery in diabetic rats. Cell Transplant. 3: 107-11, 1994. Yang H, Issekutz TB, and Wright JR Jr: Treatment with anti-VLA-4 and LFA-1 monoclonal antibodies prolongs intraportal rat islet allograft survival. Transplant. Proc. 26: 3325-6, 1994. Wright JR Jr and Kearns H: Immunomodulation and fish- to-mouse islet xenograft survival. Transplant. Proc. 26: 4089, 1994, Wright JR Jr, Kearns H, and MacDonald AS: Leflunomide and cyclosporin-A prolong fish-to-mouse islet xenograft survival in Balb/c mice. Transplant. Proc. 26: 1310, 1994. Theil M, McAlister VC, He G, Wright J, MacDonald AS, Bitter-Suermann H, Lee TDG: Effect of auxilliary liver transplantation on the simultaneously transplanted small bowel allograft. Transplant. Proc. 26: 1620, 1994. He G, McAlister VC, Lee TDG, Bitter-Suermann H, Theil M, Wright J, and MacDonald AS: Oral leflunomide prevents small bowel allograft rejection in the rat. Transplant. Proc. 26: 1613, 1994. Wan X, Yu W, Yang H, Al-Abdullah I, Coddington D, Bitter-Suermann H, and Wright JR Jr: Long-term survival of Wistar-Furth islet allografts in Lewis rats is associated with spontaneously tolerated orthotopic liver allografts. Transplant. Proc. 26: 723-4, 1994. Wright JR Jr, Kearns H, Polvi S, MacLean H, and Yang H: Experimental xenotransplantation using principal islets of teleost fish (Brockmann bodies): Graft survival in selected strains of inbred mice. Transplant. Proc. 26: 770, 1994. Yu W, Wan X, Wright JR Jr, Coddington D, and Bitter- Suermann H: Heterotopic liver transplantation in rats: the effect of intrahepatic islet isografts and split portal blood flow on liver integrity following auxiliary liver isotransplantation. Surgery 115: 108- 117, 1994. Lawen JG, Yu W, Cook HW, and Wright JR Jr: Failure of donor essential fatty acid deficiency to prevent renal allograft rejection in rats. Transplantation 56: 1269- 70, 1993. vi Wright JR Jr and Gillis DA: Mediastinal foregut cyst containing an intramural adrenal cortical rest: A case report and review of supradiphragmatic adrenal cortical rests. Pediatric Pathol. 13: 401-407, 1993. Wright JR Jr: review of A.M. Silverstein's A History of Immunology (San Diego: Academic Press, 1989). Bull. Hist. Med. 67: 199-200, 1993. Wright JR Jr: Experimental transplantation using principal islets of teleost fish (Brockmann bodies). In Pancreatic Islet Cell Transplantation: 1892-1992 ^ One Century of Transplantation for Diabetes, edited by C Ricordi, RG Landes Co., Austin, 1992, pp. 336-51. Wright JR Jr, Polvi S, and MacLean H: Experimental transplantation using principal islet of teleost fish (Brockmann bodies): Long-term function of tilapia islet tissue in diabetic nude mice. Diabetes 41: 1528-1532, 1992. Yu W, Wan X, Wright JR Jr, Coddington D, and Bitter- Suermann H: The effect of intrahepatic islet isografts on hepatocyte integrity following auxiliary heterotopic liver isotransplantation in rats. Transplant. Proc. 24: 2920-2921, 1992. Wright JR Jr, Polvi SL, Schrezenmeir J, and Al-Abdullah I: Longterm function of teleost fish principal islets (Brockmann bodies) after transplantation under the renal capsule in diabetic nude mice. Transplant. Proc. 24: 3029-3030, 1992. Lawen