The Minipig in Biomedical Research - Taylor & Francis eBooks

The

MINIPIGin

BIOMEDICAL RESEARCH

CRC Press is an imprint of theTaylor & Francis Group, an informa business

Boca Raton London New York

The

MINIPIGin

BIOMEDICAL RESEARCH

Peter A. McAnulty • Anthony D. DayanNiels-Christian Ganderup • Kenneth L. Hastings

E d i t e d b y

CRC PressTaylor & Francis Group6000 Broken Sound Parkway NW, Suite 300Boca Raton, FL 33487-2742

© 2012 by Taylor & Francis Group, LLCCRC Press is an imprint of Taylor & Francis Group, an Informa business

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v

Contents

Preface ................................................................................................................................................................ xiEditors ..............................................................................................................................................................xiiiContributors ...................................................................................................................................................... xv

Section IOrigin and Management of the Minipig

Chapter 1History and Development of Miniature, Micro- and Minipigs ............................................................................................... 3

Friederike Köhn

Chapter 2Husbandry and Management ..................................................................................................................................................17

Roberta Scipioni Ball

Chapter 3Diseases of Minipigs .............................................................................................................................................................. 37

Nanna Grand

Chapter 4International Transportation of Minipigs .............................................................................................................................. 69

Finn Raaschou-Nielsen

Section IIWelfare and Experimental Usage of the Minipig

Chapter 5Ethical Issues in the Use of Minipigs in Animal Research ................................................................................................... 77

David Morton

Chapter 6Animal Welfare Issues ........................................................................................................................................................... 85

Kathy E. Laber, Alison C. Smith and M. Michael Swindle

Chapter 7Stress in Experiments: Stress Issues in Porcine Research ..................................................................................................... 93

Larry Dale Brown and Laust Peter Gade

Chapter 8Dosing Methods ....................................................................................................................................................................117

Peter Clausing

vi CONTENTS

Chapter 9In-Life Clinical Observations .............................................................................................................................................. 127

David M. Cameron

Section IIIPharmacology and ADME Studies in the Minipig

Chapter 10Minipigs in Absorption, Distribution, Metabolism, and Excretion (ADME) Studies ..........................................................143

Cornelia Preuße and Mette Tingleff Skaanild

Chapter 11The Minipig in Safety Pharmacology ...................................................................................................................................159

Stephane Milano

Section IVSafety Assessment in the Minipig—Principal Body Systems

Chapter 12Dermal Toxicity Studies: Skin Architecture, Metabolism, Penetration and Toxicological and Pharmacological Methods ..............................................................................................................................................185

Andrew Makin, Jens Thing Mortensen and William J. Brock

Chapter 13Gastrointestinal Tract ............................................................................................................................................................211

Chris Van Ginneken

Chapter 14Heart and Cardiotoxicity ..................................................................................................................................................... 237

James R. Turk

Chapter 15Central and Peripheral Nervous Systems ............................................................................................................................ 243

Allan Dahl Rasmussen and Karen Malene Wegener

Chapter 16The Kidney ...........................................................................................................................................................................253

Peter A. McAnulty

Chapter 17Reproductive System Including Studies in Juvenile Minipigs ............................................................................................. 263

Peter A. McAnulty, Paul Barrow and Edward Marsden

viiCONTENTS

Chapter 18The Endocrine System ......................................................................................................................................................... 277

Claudia Stark and Jakob Walter

Chapter 19Skeletal System .................................................................................................................................................................... 283

Hideki Tsutsumi

Chapter 20Ocular Examination and Background Observations ........................................................................................................... 293

Helmut Ehall

Chapter 21Spontaneous/Background Pathology of Göttingen Minipig ................................................................................................ 305

Zuhal Dincer and Mikala Skydsgaard

Section VGenetics and Immunology

Chapter 22A Comparative Assessment of the Pig, Mouse and Human Genomes: Structural and Functional Analysis of Genes Involved in Immunity and In�ammation ............................................................................................................. 323

Harry D. Dawson

Chapter 23The Immune System of Pigs: Structure and Function ......................................................................................................... 343

Patrick Haley

Chapter 24Transplantation in Miniature Swine .....................................................................................................................................357

John S. Hanekamp, Raimon Duran-Struuck and David H. Sachs

Chapter 25Xenotransplantation ..............................................................................................................................................................373

Henk-Jan Schuurman, Melanie L. Graham, Thomas Spizzo, and Clive Patience

Chapter 26Porcine Endogenous Retroviruses in Xenotransplantation: A Review of the Importance of PERVs in Porcine Studies, with Particular Emphasis on the Minipig .............................................................................................................. 387

Linda Scobie and Olga Garkavenko

Chapter 27Immunotoxicology: Studies in the Minipig ......................................................................................................................... 397

André H. Penninks and Geertje J.D. van Mierlo

viii CONTENTS

Section VIDisease Models

Chapter 28Creation and Conservation of Genetically Modi¢ed Pigs: Applications to Genetic Disease Model and Xenotransplantation .......................................................................................................................................................415

Hiroshi Nagashima, Hitomi Matsunari, and Kazuhiro Umeyama

Chapter 29Stem Cell Research and Minipigs .........................................................................................................................................431

Vanessa J. Hall, Stoyan G. Petkov, and Poul Hyttel

Chapter 30Minipig Models of Diabetes Mellitus .................................................................................................................................. 445

Dwight A. Bellinger, Elizabeth P. Merricks, and Timothy C. Nichols

Chapter 31Minipig in Biomedical Research: Diet-Induced Atherosclerosis ........................................................................................ 469

James R. Turk and M. Harold Laughlin

Chapter 32Hemorrhage and Resuscitation Models Using the Miniature Swine ....................................................................................479

John W. Burns and Charles E. Wade

Chapter 33Oral Biology and Dental Models ..........................................................................................................................................491

Susan W. Herring, Yiming Li, Yi Liu, Zi Jun Liu, Tracy E. Popowics, Katherine L. Rafferty, and Songlin Wang

Chapter 34Osteoporosis Model in Minipigs ...........................................................................................................................................517

Hideki Tsutsumi, Satoshi Ikeda, and Toshitaka Nakamura

Chapter 35Wound Healing Models ....................................................................................................................................................... 525

Peter Glerup

Chapter 36The Minipig in Chemical, Biological, and Radiological Research ......................................................................................533

Stanley W. Hulet, Maria Moroni, Mark H. Whitnall, and Robert J. Mioduszewski

Chapter 37The Minipig and Pig in Medical Device Research .............................................................................................................. 549

Shayne C. Gad

ixCONTENTS

Section VIIRegulatory Perspective and Use of the Minipig in Developing Marketed Products

Chapter 38Regulatory Aspects: Pharmaceuticals, Medical Devices, Food Additives: Minipigs and Global Safety Regulations ....... 565

Abigail Jacobs and Jan-Willem van der Laan

Chapter 39Adverse Responses to Drugs in Man: Critical Comparison of Reported Toxicological Findings in Minipigs and Humans .......................................................................................................................................573

Niels-Christian Ganderup

Chapter 40Regulatory Acceptance of the Minipig in Non-Pharmaceutical Industry and Research .................................................... 595

Warren Harvey

Section VIIINew Horizons and perspectives

Chapter 41Future Prospects: Possibilities and Perspectives ..................................................................................................................619

Anthony D. Dayan

xi

Preface

Why the minipig, why now and why this book?There is always the need to review the species used in scienti¢c studies, whether in basic research; in toxicological

investigations, especially if done to support hazard and risk assessment and regulatory evaluation; or in other investigations ranging from applied biology to disease models. Over many years, much fundamental and applied scienti¢c work has been done, or at least has been started, in rodents or, less often, in non-rodent species. Its applicability has been examined in larger animals because of their particular anatomical, pharmacological, physiological, biochemical, or immunological char-acteristics, commonly because they are a better model of humans or other target species.

The domestic pig and, more recently, the minipig have been used less often because of the relative unfamiliarity of the general scienti¢c and regulatory communities with the animals, probably some uncertainty about provenance and concern whether ¢ndings in them would be acceptable to of¢cial agencies whose remit is de¢ned by more or less rigid guidelines. All that is changing as there has been increasing awareness of the paramount need to be certain of the scienti¢c appropriateness of animal studies. The value—especially of the minipig—in many areas of animal biology and applied science has become well appreciated as we have learnt more about the physiology, immunology, and molecular biology of these animals, as pro-cedures have become established, and as reagents have become available. At the same time, animals of known provenance and health status have become available, thanks to carefully de¢ned breeding programs and the application of genomic and other techniques to de¢ne the genetic background of diverse breeding nuclei, colonies, and strains.

The domestic pig carries size and the restriction of experimental experience to certain areas of scienti¢c work as major experimental disadvantages. We consider that the time has come for the particular values, strengths, and weaknesses of the minipig to be more widely appreciated as assured supplies of well-de¢ned strains have been available for several years and they offer many advantages in the basic and applied laboratory. There are still some weaknesses in our experience and understanding of them relative to other non-rodent species but those de¢ciencies are being overcome by vigorous coopera-tive workgroups and extensive research programs whose results are being made publicly available.

This book ranges widely over the biology of the minipig and scienti¢c and practical uses of the minipig in the laboratory, extending from its origins and genomics to welfare, health and husbandry, practical dosing and examination procedures, surgical techniques, physiology and all areas of toxicity testing, pharmacokinetics and xenobiotic metabolism, immunology, and aspects of auto- and xenograft research. The regulatory uses of minipigs are discussed in the evaluation of human and veterinary pharmaceuticals, medical devices, and other classes of xenobiotics. Features of normal health, normal laboratory values, and common diseases are described. Ethical and legal considerations in their supply, housing, and transport are care-fully considered.

The request to every author was to discuss the scienti¢c and practical aspects of their area of special expertise, noting the value and strengths of the minipig but never omitting any dif¢culty or weakness, whether practical or due to lack of information from their own or published experience.

The result is a comprehensive and up-to-date manual about the experimental uses of the minipig describing “How to” and “Why” and “What to expect in the normal,” combining enthusiasm and experience with critical assessment of its values and potential problems.

All editors must be grateful to their authors. We thank our expert contributors for their hard work and critical accounts of their own experiences and those of others.

No book as complex as this can succeed without a great deal of administrative hard work and enthusiasm behind the scenes. We appreciate how much Cristina Kragh Thomsen of Ellegaard Göttingen Minipigs has put into the book and we are very grateful to her for all that she has done.

We are glad to present this monograph as the ¢rst comprehensive and up to date manual about the minipig in the labora-tory. It is intended to encourage consideration of its more extensive use as its strengths become better understood and there is wider of¢cial acceptance of ¢ndings in it by the scienti¢c and regulatory worlds.

Peter A. McAnultyAnthony D. Dayan

Niels-Christian GanderupKenneth L. Hastings

Denmark, Britain, and the USA

xiii

Editors

Peter A. McAnulty, PhD, DABT, ERT, FSB, was trained at the University of London and worked on various biochemical studies at the Institute of Child Health, part of London University. He then moved to Cambridge University and the Strangeways Research Laboratory and began biochemistry and immunology research for the WHO.

Peter A. McAnulty began his CRO career at Life Science Research (LSR), where he became a toxicologist, and special-ized in reproductive studies. When LSR became Pharmaco LSR, Peter McAnulty became the director of pharmaceutical toxicology and, after that, he was the principal toxicologist at HLS. Following this, Peter McAnulty moved to Denmark and became the scienti¢c director of Scantox. Peter A. McAnulty has been a member of the Board of Directors of the American Board of Toxicology and has been their president (2002–2003). Peter A. McAnulty joined Ferring Pharmaceuticals in 2001 as executive director, Nonclinical Development. In 2010 he became an independent nonclinical consultant.

Anthony D. Dayan, LLB, MD, FRCPath, is an emeritus professor of toxicology, University of London. Anthony D. Dayan worked as a pathologist before joining the pharmaceutical industry as a toxicologist and subsequently returning to head a university department of toxicology in London. He has been a member of of¢cial and industrial advisory committees on animal experimentation and the safety of medicines, foods, and pesticides in the United Kingdom and internationally. He has been a consultant to many companies on drug and chemical safety programs.

Niels-Christian Ganderup, M.Sc., is the chief scienti¢c of¢cer, Ellegaard Göttingen Minipigs. Niels-Christian Ganderup trained in experimental biology and has had special experience of toxicology and ecotoxicology. Since 2005, he has been generally concerned with the best use of the minipig in biomedical sciences. His principal role has been active engagement worldwide with academic, pharmaceutical, and other industrial research organizations and CROs in comparing the value of the minipig and other species in research and testing programs in pharmacology and toxicology. His broad interests cover the “Can I …?,” “How can I …?,” and “Who can show me how to …?” questions. This has led him to facilitate cross-company and inter-organization research consortia to extend scienti¢c knowledge about the minipig and its uses in biomedi-cal research. To further increase collaboration and to improve knowledge of techniques, Niels-Christian Ganderup founded the Minipig Research Forum, a non-pro¢t organization which organizes annual scienti¢c conferences in Europe and North America about all aspects of the use of minipigs in biomedical research. He is a regular speaker at conferences and is often consulted by universities, CROs, and industrial groups about many aspects of the use of the minipig, ranging from health and husbandry to training in experimental techniques and the development of new procedures.

Kenneth L. Hastings, DrPH, DABT, Fellow ATS, was trained at the University of North Carolina at Chapel Hill and the Chemical Industry Institute of Toxicology. After being a part of Peace Corps service with the Ministry of Health, Republic of Fiji, he became a research associate in the Department of Anesthesiology, College of Medicine, University of Arizona. He then joined the U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Division of Anti-Viral Drug Products, where he reviewed many of the early drugs for treatment of HIV/AIDS and related diseases. He served as supervisory toxicologist in the Division of Special Pathogen and Immunologic Drug Products, where he was part of review teams for tropical disease and transplant drugs. He concluded his career at FDA as an associate director in the Of¢ce of New Drugs. He represented the agency on many regulatory initiatives, such as the International Conference on Harmonization (ICH). After government service, he joined Sano¢-Aventis as associate vice-president for regulatory policy. He has served as president of the American College of Toxicology, the American Board of Toxicology, and the Immunotoxicology Specialty Section of the Society of Toxicology.

xv

Contributors

Roberta Scipioni BallMarshall BioResourcesNorth Rose, New York

Paul BarrowCiToxLABEvreux, France

Dwight A. BellingerDepartment of Pathology and

Laboratory MedicineUniversity of North Carolina at

Chapel HillChapel Hill, North Carolina

William J. BrockBrock Scienti¢c ConsultingMontgomery, Maryland

Larry Dale BrownSinclair Research CenterColumbia, Missouri

John W. BurnsU.S. Army Institute of Surgical

ResearchHouston, Texas

David M. CameronHuntingdon Life SciencesHuntingdon, United Kingdom

Peter ClausingDeparment of Non-Clinical Drug

SafetyBoehringer IngelheimBiberach, Germany

Harry D. DawsonDepartment of AgricultureDiet, Genomics, and Immunology

LaboratoryBeltsville, Maryland

Anthony D. DayanDepartment of Toxicology University of LondonLondon, United Kingdom

Zuhal DincerP¢zerSandwich, United Kingdom

Raimon Duran-StruuckTransplantation Biology Research

CenterMassachusetts General Hospital and

Harvard Medical SchoolBoston, Massachusetts

Helmut EhallHuntingdon Life SciencesHuntingdon, United Kingdom

Shayne C. GadGad ConsultingCary, North Carolina

Laust Peter GadeNovo NordiskStenloese, Denmark

Niels-Christian GanderupEllegaard GÖttingen MinipigsDalmose, Denmark

Olga GarkavenkoLiving Cell TechnologiesAuckland, New Zealand

Chris Van GinnekenDepartment of Veterinary

SciencesUniversity of AntwerpAntwerp, Belgium

Peter GlerupCiToxLAB ScantoxEjby, Denmark

Melanie L. GrahamDepartment of SurgeryUniversity of MinnesotaMinneapolis, Minnesota

Nanna GrandCiToxLAB ScantoxEjby, Denmark

Patrick HaleyIncyteWilmington, Delaware

Vanessa J. HallDepartment of Basic Animal and

Veterinary SciencesInstitute of Life SciencesCopenhagen UniversityCopenhagen, Denmark

John S. HanekampTransplantation Biology Research



Warren HarveyCharles River LaboratoriesEdinburgh, United Kingdom

Sue HerringDepartment of OrthodonticsUniversity of WashingtonSeattle, Washington

Stanley W. HuletU.S. Army Edgewood Chemical

Biological CenterAberdeen Proving Ground, Maryland

Poul HyttelDepartment of Basic Animal and


Satoshi IkedaDepartment of Orthopaedic SurgeryUniversity of Occupational and

Environmental HealthKitakyushu, Japan

Abigail JacobsCenter for Drug Evaluation and

ResearchOf¢ce of New DrugsSilver Spring, Maryland

xvi CONTRIBUTORS

Friederike KöhnDepartment of Animal Sciences Georg-August-UniversityGÖttingen, Germany

and

Bavarian State Research Center for Agriculture

Institute of Animal BreedingPoing-Grub, Germany

Jan-Willem van der LaanCenter for Biological Medicines and

Medical TechnologyNational Institute for Public Health

and the Environment Bilthoven, The Netherlands

Kathy E. LaberDepartment of Comparative MedicineMedical University of South CarolinaCharleston, South Carolina

M. Harold LaughlinDepartment of Biomedical SciencesUniversity of MissouriColumbia, Missouri

Yiming LiCenter for Dental ResearchLoma Linda University School of

DentistryLoma Linda, California

Yi LiuMolecular Laboratory for Gene

Therapy and Tooth RegenerationCapital Medical University School of

StomatologyBeijing, China

Zi Jun LiuDepartment of OrthodonticsUniversity of WashingtonSeattle, Washington

Andrew MakinCiToxLAB ScantoxEjby, Denmark

Edward MarsdenRicercaLyon, France

Hitomi MatsunariDepartment of Life SciencesMeiji UniversityKawasaki, Japan

Peter A. McAnultyIndependent ConsultantRoskilde, Denmark

Elisabeth P. MerricksDepartment of Pathology and



Geertje J.D. van MierloDepartment of Toxicology and

Applied PharmacologyTNO Triskelion BVZeist, The Netherlands

Stephane MilanoRicercaLyon, France

Robert J. MioduszewskiU.S. Army Edgewood Chemical

Biological CenterAberdeen Proving Ground, Maryland

Maria MoroniArmed Forces Radiobiology Research

InstituteUniformed Services UniversityBethesda, Maryland

Jens Thing MortensenCiToxLAB ScantoxEjby, Denmark

David MortonUniversity of BirminghamBirmingham, United Kingdom

Hiroshi NagashimaDepartment of Life SciencesMeiji UniversityKawasaki, Japan

Toshitaka NakamuraDepartment of Orthopaedic

SurgeryUniversity of Occupational and

Environmental HealthKitakyushu, Japan

Timothy C. NicholsDepartment of Pathology and



Clive PatienceBiogen-IdecCambridge, Massachusetts

André H. PenninksDepartment of Toxicology and

Applied PharmacologyTNO Triskelion BVZeist, The Netherlands

Stoyan G. PetkovDepartment of Basic Animal and


Tracy E. PopowicsDepartment of Oral BiologyUniversity of WashingtonSeattle, Washington

Cornelia PreußeBayer Schering Pharma AGBerlin, Germany

Finn Raaschou-NielsenInternational Transport AdviserHovedstaden, Denmark

Katherine L. RaffertyDepartment of OrthodonticsUniversity of WashingtonSeattle, Washington

Alan Dahl RasmussenH. Lundbeck A/SValby, Denmark

David H. SachsTransplantation Biology Research



xviiCONTRIBUTORS

Henk-Jan SchuurmanSpring Point ProjectMinneapolis, Minnesota

Linda ScobieDepartment of Biological and

Biomedical SciencesGlasgow Caledonian UniversityGlasgow, United Kingdom

Mette Tingleff SkaanildDepartment of Veterinary Disease

BiologyUniversity of CopenhagenCopenhagen, Denmark

Mikala SkydsgaardCiToxLAB ScantoxEjby, Denmark

Alison C. SmithDepartment of Comparative MedicineMedical University of South CarolinaCharleston, South Carolina

Thomas SpizzoSpring Point ProjectMinneapolis, Minnesota

Claudia StarkBayer Schering Pharma AGBerlin, Germany

M. Michael SwindleDepartment of Comparative

MedicineMedical University of South CarolinaCharleston, South Carolina

Hideki TsutsumiCentral Institute for Experimental

AnimalsKanagawa, Japan

James R. TurkAmgenThousand Oaks, California

Kazuhiro UmeyamaDepartment of Life SciencesMeiji UniversityKawasaki, Japan

Charles E. WadeU.S. Army Institute of Surgical

ResearchHouston, Texas

Jakob WalterBayer Schering Pharma AGBerlin, Germany

Songlin WangSalivary Gland Disease Center

and the Molecular Laboratory for Gene Therapy and Tooth Regeneration

Capital Medical University School of Stomatology

Beijing, China

Karen Malene WegenerH. Lundbeck A/SValby, Denmark

Mark H. WhitnallArmed Forces Radiobiology Research

InstituteUniformed Services UniversityBethesda, Maryland

SECTION I

Origin and Management of the Minipig

3

CHAPTER 1

History and Development of Miniature, Micro- and Minipigs

Friederike Köhn

In this chapter, a short introduction to the evolutionary background of pigs, the use of pigs in history, and the develop-ment of minipig breeds are included. For the most important minipig breeds that are used in biomedical research, a short description is given. To facilitate reading, the term minipig is used as synonym for miniature and micropigs, respectively.

1.1 TAXONOMY, EVOLUTION AND PHYLOGENY

Pigs belong to the order of Artiodactyla, the even-toed ungulates (Figure 1.1).

In contrast to the well-established opinion that the sub-order Suina is monophyletic and consists of three families, Suidae (pigs), Tayassuidae (peccaries) and Hippopota-midae (hippopotamuses) (Porter, 1993; Ruvinsky and Rothschild, 1998), there are many evidences from molecular studies that Suidae and Tayassuidae belong to the sub-order Suina but Hippopotamidae build their own sub-order, the Acodonta (Montgelard et al., 1997, 1998). The families

Suidae and Tayassuidae are separated by remarkable genetic differences (Randi et al., 1996).

Within the family Suidae there are ¢ve different genera: Babyrousa (babirusa), Hylochoerus (giant forest hog), Phacochoerus (warthog), Potomochoerus (bush pig) and Sus (pig). Several different species belong to the genus Sus,

CONTENTS

1.1 Taxonomy, Evolution and Phylogeny .............................................................................................................................. 31.2 Domestication of the Pig and Breed Development ......................................................................................................... 41.3 Human Use of Pigs ......................................................................................................................................................... 61.4 Minipigs in Biomedical Research ................................................................................................................................... 61.5 Minipig Breeds ............................................................................................................................................................... 7

1.5.1 Clawn Miniature Swine ...................................................................................................................................... 71.5.2 Göttingen Minipig® ............................................................................................................................................ 81.5.3 Hanford™ Miniature Swine ...............................................................................................................................101.5.4 Munich Miniature Swine (Troll) .......................................................................................................................101.5.5 Panepinto Micropig ...........................................................................................................................................111.5.6 Sinclair™ S-1 Miniature Swine (Minnesota Miniature, Hormel Miniature) .....................................................111.5.7 Westran ............................................................................................................................................................. 121.5.8 Yucatan Miniature Swine ................................................................................................................................. 131.5.9 Micro-Yucatan™ Minature Swine ......................................................................................................................14

References .............................................................................................................................................................................. 15

Mammalia

Artiodactyla

Suina

SuidaeTayassuidae

Babyrousa Hylochoerus Phacochoerus PotomochoerusSus

Figure 1.1 Taxonomy of pigs.

4 THE MINIPIG IN BIOMEDICAL RESEARCH

whereas the species Sus scrofa (Eurasian wild boar) seems to be the wild ancestor of all domestic pig breeds (Figure 1.2). The number of species within the genus Sus varies in the lit-erature dependent on which data were used in the study. Morphological studies using the skull or other bones may result in different number of species compared to studies using molecular data. About 16 sub-species of Sus scrofa are assumed to exist around the world (Chen et al., 2007; Ruvinsky and Rothschild, 1998), usually occurring in spe-ci¢c geographical regions. This re�ects the high adaptability of pigs (e.g., a temperature tolerance of −50°C up to +50°C).

There is still a lot to be learned about the evolution of pigs. Randi et al. (1996) stated that there was an independent evolution of the different ungulate taxa beginning 40–45 million years ago. For the sub-species of Sus scrofa, Randi et al. assumed a common ancestor in the Pleistocene (1.8 mil-lion years up to 11,780 years ago). Giuffra et al. (2000) esti-mated the time since the divergence of ancestors for European and Chinese pigs to be about 500,000 years ago. A probable evolution scenario is proposed by Groves (1981). He sug-gested that the S. barbatus (bearded pig) and the S. verruco-sus (Japanese warty hog) were present in Europe from the beginning of the Pleiocene. Two million years ago, they came to Indonesia and cohabited there with S. celebensis (Sulawesi warty hog). It is assumed that S. celebensis was the ancestor of S. scrofa that came to Europe (origin in Far East) about 700,000 years ago where it displaced the S. verrucosus.

Especially for pigs that are used in biomedical research it is interesting to know the phylogenetic context to other animals used in research and to humans as the species that the studies focus on. Figure 1.3 displays a phylogenetic tree showing an extraction of mammalian animals that are used in biomedical research (Maddison and Schulz, 2007). Only branches and knots that play a role for the relationships of

laboratory animals are shown; others are only indicated. Further, non-mammalian laboratory species such as quails, fruit �ies, or frogs are not included in the graphic to ensure clarity.

1.2 DOMESTICATION OF THE PIG AND BREED DEVELOPMENT

All domesticated pigs have their origin in the Eurasian wild boar. Dependent on the domestication region, the European wild boar (Sus scrofa scrofa), the Asian wild boar (Sus scrofa vittatus), or the Mediterranean wild boar (Sus scrofa meridionalis) formed the basis of the domesticated pig (Pfeiffer, 1978). Mainly the European and the Asian wild boar were involved in the domestication process. These two sub-species have very different phenotypes, whereas there is no indication to split them into two species (Porter, 1993). The main differences occur in size, skull shape (European long, Asian short skull), body shape (European slender, long-legged, Asian round, short-legged) and the colour of the pelage.

Domestication took place in several regions in the world at different times. However, in all domestication cradles a change from nomadic life to that of settled humans was the precondition for using the wild boar as domesticated spe-cies. The Eurasian wild boar was interesting for domestica-tion because it had several advantages. Almost all over the world a huge amount of wild boars existed, they had a long lifespan and offered an acceptable reproduction rate. Further, as wild boars are omnivorous, they were more or less self-feeding in the surrounding of the settlements.

One of the earliest domestication events was documented to take place in the Near East about 9000 years ago (Bökönyi, 1974). From there, the domesticated pig reached ancient

Potamochoerus larvatus

Babyrousa babyrussaPhacochoerus africanus Phacochoerus aethiopicus

Hylochoerus meinertzhageniSus salvanius

Sus scrofaSus bucculentus

Sus barbatus

Sus verrucosus

Sus philippensisSus cebifrons

Sus timoriensis

Sus celebensis

Sus heureniPecari tajacu

Catagonus wagneriTayassu pecari

Commonancestor

Potamochoerus porcus

Figure 1.2 Overview over the genera within Suidae and their species.

5HISTORY AND DEVELOPMENT OF MINIATURE, MICRO- AND MINIPIGS

Syria, Jordan and Palestine and about 7000 years ago wild boars were domesticated in Egypt and Sudan (Porter, 1993). Over the years, domestic pigs were introduced in Greece and southeast Europe and ¢nally reached the rest of Europe during the Neolithic Era through human migration. Pigs of these domestication regions were exceptionally in�uenced by the European wild boar.

Another important cradle of domestic pigs was East Asia. There the domestication of the Asian wild boar took place about 7000 years ago (Jones, 1998; Porter, 1993). As with their wild ancestors, the domestic pigs of Europe and Asia differed; the Asian pigs were smaller with convex pro¢les and shorter lacrimal bones. Further, the Chinese pigs developed a pronounced belly over the years. This pot belly could be the result of arti¢cial selection by humans or an environmental selection due to high-¢bre diets (Jones, 1998).

While the process of domestication took place over many years, certain changes between domestic pigs and their wild ancestors manifested. Domestic pigs are polyoes-tric and much more fertile and precocious; the relation between forehand and hind quarters changed (from 70:30% in the European wild boar to 30:70% in the Bacon pig), the head became smaller with an angle between the muzzle and the forehead, the bristles were reduced, much ¢ner and

sometimes curly, different colours and beside erected ears also lop-eared pigs occurred (Pfeiffer, 1978; Porter, 1993).

During the time after domestication, many factors that affected the pigs resulted in different types of pigs. These were environmental factors such as climate or nutritional resources and anthropogenic factors such as husbandry and conscious or unconscious selection. They were changing the domestic but still wild-looking pigs; but for the development of different breeds, usually human involvement was the basis. They selected pigs of common origin that had certain distinguish-able characteristics that made them different from the rest of the population—the foundation of a new breed (Jones, 1998). While the process of domestication and breed development, natural evolution and selection on the basis of the ‘survival of the ¢ttest’ concept was radically changed with pigs surviving that offered desirable characteristics for humans.

As in the case of domestication, Europe and China were the two main centres for breed development. In Europe, the bases for the most important current breeds were the Celtic and Germanic pigs. They could be divided into lop-eared pigs of North-West Europe and erect-eared pigs from Slavic regions, whereas the lop-eared pigs were bigger with ¢ne legs and good muscles and the erect-eared pigs were smaller and more compact (Pfeiffer, 1978). Main selection criteria in

Eutheria

Carnivora

Primates

Rodentia

Lagomorpha

Leporidae(rabbits)

Muroidea MurinaeCricetinae(hamsters)

Cercopithecidae

Hominidae

Feliformia

Caniformia

Rattini(rats)

Murini(mice)

Macaca(macaque)

Felidae (cats)

Canidae (dogs)

Mustelidae (ferrets)

Suidae

RuminantiaBovidae Bovinae (cattle)

CaprinaeCapra (goats)Ovis (sheep)

Suinae Sus Sus scrofa (wild boar)

Artiodactyla

Perissodactyla Equidae (horses, donkeys)

Homo Homo sapiens(modern humans)

Catarrhini

Platyrrhini(new world monkeys)

Figure 1.3 Phylogenetic tree showing mammals that are used in biomedical research. (Adapted from http://tolweb.org.)


the early time of animal breeding were phenotypic charac-teristics such as colour, size, fertility, or behaviour, whereas lop ears proved to be advantageous in the sense that the ears acted as blinks and the pigs were not so jumpy or even aggressive (Porter, 1993).

In Asia, pig breeds were much more fertile than the European breeds with good fattening characteristics and a high fat production. The most important Asian pig breed is the Meishan breed that was introduced to European breeds about 200 years ago and had an elemental in�uence on pres-ent European pig breeds. Nowadays, Asian alleles with favourable effects like the allele for dominant black colour are ¢xed in many European breeds (Giuffra et al., 2000; Jones, 1998; Pfeiffer, 1978).

The most intensive period for breed development was the nineteenth century where, especially in England, Northern and Middle Europe, and China, breeds such as the Large White and diverse Landrace were developed. From all the different breeds and strains of pigs that occurred worldwide, only one single breed (Large White) accounts today for about one-third of the slaughter pig’s gene pool in the European Union (Laval et al., 2000).

1.3 HUMAN USE OF PIGS

Even before domestication, wild boars were hunted to obtain meat. This source of protein was also one of the most important reasons for domestication (Jones, 1998). Quite early, humans were able to conserve the meat via curing, salt-ing, or drying (Falkenberg and Hammer, 2006). Porcine fat was also used for oil lamps, heating, for greasing machines, or as body oil in ancient Greece (Doll, 2003; Xylouri-Frangiadaki et al., 1997). In addition to meat and fat, more or less all other parts of the carcass were used. Bones were worked to tools for hunting or daily life before metal was used, tusks served for amulets to adore gods or to fend off evil, and leather was used for saddles, clothes, shoes, or even �ails. Bristles were used to produce brushes, and the few breeds with wool ¢bre like the Mangalitza were cut. However, not only the products of pigs were used but also the living pig, which was advantageous for the forest and agriculture by rooting and selective feeding. In ancient Egypt and Greece, farmers used pigs for stepping the seeds into the soil. In England they acted as hunting dogs of poor people looking for small game in the eleventh to ¢fteenth centuries (Benecke, 1994; Falkenberg and Hammer, 2006; Hoffmann and Trede, 1976; Hoffmann et al., 1975; Pfeiffer, 1978).

Pigs were early used as an animal model for human beings. Centuries ago they were used in anatomical studies. Dissecting humans was usually forbidden and only dead-born babies and people dying under death penalty were allowed to be used for dissection.

In ancient Greece animals were used for dissection. One of the most famous anatomists of that time was Galen

(129–201 AD) who dissected monkeys, dogs, and pigs to draw conclusions about the human’s anatomy. For more than 1000 years, his descriptions of the human body were formative for the whole of European medicine (Becker, 2002). In Salerno (1000–1200 AD), anatomical studies �ourished again. Pigs were dissected very accurately due to the assumption that there are essential analogies between the anatomia porcis and the anatomia hominis. It was Vesalius (1514–1564) who dissected pigs (Figure 1.4) as well as humans and who revolutionized anatomical medi-cine in that he discovered many discrepancies between his own ¢ndings and Galen’s description of human anatomy. His work De humani corporis fabrica libri septem built the basis for all later anatomical studies.

1.4 MINIPIGS IN BIOMEDICAL RESEARCH

In the 1940s, scientists started to use pigs more fre-quently in biomedical research. The advantages of small pigs, namely the ease of handling, the decreased require-ments for food and space, and the lower amounts of phar-macological products and anaesthetics needed in the studies, led to ¢rst attempts in breeding miniature pigs in the United States. Since that time, a wide variety of breeds were developed and strains of feral miniature pigs were used for biomedical research. Some of the breeds were often developed directly in the laboratories in which they were used, leading sometimes to an extinction of the breed when the research stopped. A geographical distribution of minipig breeds used in biomedical research is given in Figure 1.5. In this ¢gure, breeds are shown according to the list in Panepinto (1996). It has to be stated, that some of these breeds are no longer used in research and thus, these are not introduced in Section 1.5.

Except for some feral miniature pig breeds that are used in biomedical research like the Yucatan, the Westran, or the Vietnamese Potbellied Pig miniature pig, breeds are usually a product of crossbreeding. Mostly, different miniature pig breeds were crossbred with each other whereas in some breeds an introduction of wild boars or normal-sized dominant white pig breeds was conducted. An overview of

Figure 1.4 Vivisection of a pig. (In Vesalius De humani corporis fabrica, 1543. Reprinted with permission from the National Library of Medicine.)


miniature pig breeds used in biomedical research and their connections to each other is given in Figure 1.6. In this illus-tration the most important breeds are shown (with no claim to completeness). The breeds developed out of feral strains and the Sinclair as a ¢rst crossbred product are displayed at the top. All connections between the breeds are shown and the year of their ¢rst use in research or their year of develop-ment, respectively, is given within parentheses.

1.5 MINIPIG BREEDS

A short description of the minipig breeds that are cur-rently used in biomedical research is included; however, this list does not purport to be complete. The breeds are intro-duced in alphabetical order. A general overview with the main biological characteristics is given in Table 1.1.

1.5.1 Clawn Miniature Swine

The author gratefully acknowledges Junichi Tottori, DVM, PhD of Japan Farm CLAWN Institute, Tokube Isa-shi, Kagoshima, Japan, for providing information about this breed.

The Clawn Miniature Swine (Figure 1.7) was developed in 1978 at Kagoshima University, Japan. This minipig breed is a crossbreed. In the maternal line, F1 sows from crossing Göttingen Miniature with Ohmini minipigs were used and

in the paternal line, F1 boars from crossing Landrace with Large White were used. Today, the breed is managed as an inbred population.

The pigs have an average birth weight of 500 g and an average adult body weight of 40 kg. Sexual maturity occurs at an average age of 6 months and the number of piglets per litter is ¢ve. The pigs are mainly white, but black and spot-ted pigs occur infrequently. They have a very docile temperament.

The main aim of creating the breed was the need of an experimental animal to be used in scienti¢c studies. The main scienti¢c purposes the breed is used for are pharmacological and toxicological research, regenerative medicine, transplanta-tion studies, and the development of medical products and equipment. A special characteristic of the breed is the estab-lishment of two lines (C1 and C2) that differ in the haplotype for the Swine Leukocyte Antigen (SLA). The SLA plays an important role in immunoreactions and the assignment of the haplotype status of transplantation partners is especially impor-tant in xeno- and allo-transplantation (see Section V Genetics and Immunology). With different sequencing methods, the haplotype status of Clawn Miniature Swine can be detected and ¢xed using inbreeding.

At the moment, Clawn Miniature Swine are distributed in Japan, but a worldwide availability will be established in the near future. Reproduction of Clawn Miniature Swine in research institutes needs a licence agreement from the Japan Farm CLAWN Institute.

Micro YucatanNIHHormel-Hanford

MunichGttingen

GttingenClawn

Lee-Sung

Vietnamese

Westran

Pitman-Moore Czech MiniatureBerlin

Mini-LeweMini-Sib

Ohmini

YucatanSinclairHanfordPanepinto

Figure 1.5 Geographical distribution of minipig breeds used in biomedical research. (Adapted from http://digital-vector-maps.com. With permission.)


Contact:Japan Farm CLAWN Institute2267-1 Tokube Isa-shiKagoshima 895-2707, JapanPhone: +81 995 26 5190Fax: +81 995 26 5192Email: [email protected]/gyokai/gloup-010-1.htm

1.5.2 Göttingen Minipig®

As the ¢rst European minipig breed, the Göttingen minipig (Figure 1.8) was developed in the 1960s by Professor Fritz Haring at the Institute of Animal Breeding and Genetics at the University of Göttingen, Germany. The initial breeds were the Minnesota Miniature and the Vietnamese Potbelly

Pitman-Moore(1969)

Hanford(1958)

Ohmini(1945)

Göttingen(1960) Mini-sib

Landrace

Hormel-Hanford

Columbianminiature pig

Munich miniature(1993)

NIH(1970’s)

Minipig of CzechRepublic (1980’s)

Panepinto(1990)

Clawn(1978)

PalouseFeral swamp hog

HampshireDurocLandraceManchurian Chinese pig German Landrace

Swedish LandraceEuopean wild boarAsian wild boar

Yucatan(1972)

Sinclair(1949)

Piney WoodRas-n-LansaCatalinaGuam

Vietnamese(1960’s)

Westran(1976)

Lee-Sung(1974)

Figure 1.6 Schematic overview of minipig breeds used in biomedical research and their connections with year of �rst use in research (within parentheses).

Table 1.1 Overview of Minipig Breeds Used in Biomedical Research and Their Main Biological Characteristics

Breed OriginAverage Birth

Weight (g)Average Adult

Weight (kg)Average No. of

Piglets Colour Foundation Yeara

Clawn Crossbred 500 40 5 White 1978

Göttingen Crossbred 450 45 6.5 White 1961–1962

Hanford Crossbred 730 80–95 6.7 White 1958

Munich Crossbred 600–900 60–100 8.5 White, black, red, brown

1993

Panepinto Crossbred 500–800 25–30 7 Grey, black 1990s

Sinclair Crossbred 590 55–70 7.2 Black, red, white, roan

1949

Westran Native 930 80–93 4.6 Mainly white 1993

Yucatan Native 500–900 70–83 6 Black, slate grey 1960

Micro-Yucatan Native 600–700 55–70 6 Black, slate grey 1985a Year of foundation of the breed or year of �rst use in biomedical research in native breeds.


Pig. Later, German Landrace was introduced to obtain dominant white pigs. Nowadays, the breed proportion in the Göttingen minipig is 59% Vietnamese Potbelly Pig, 33% Minnesota Miniature and 8% German Landrace (Glodek et al., 1977); combining the high fertility of the Vietnamese and of the docile behaviour of the Minnesota Miniature.

After successful years of breeding with a substantial reduction of body weight in the breed, in the year 1992 Ellegaard Göttingen Minipigs A/S in Dalmose, Denmark, acquired from the University of Göttingen the worldwide exclusive right to breed and distribute the Göttingen Minipig. In 2002, Ellegaard Göttingen Minipigs A/S entered a licence agreement with Marshall BioResources, United States, which now supplies the United States and Canada with the Göttingen Minipig; in 2010 a licence agreement with Oriental Yeast Company (OYC) which will supply the Dr. Göttingen Minipig to the Japanese market. The selection of breeders at the full- barrier facility in Denmark and the United States is under supervision of the University of Göttingen. A full pedi-

gree of the animals is kept at the University of Göttingen and selection is based on keeping the colony outbred, with an inbreeding coef¢cient below 10%. Today, there are three breeding facilities worldwide, the University of Göttingen, Germany, Ellegaard Göttingen Minipigs A/S, Denmark and Marshall BioResources, United States; and a breeding facil-ity in Japan is under construction.

The average birth weight of Göttingen Minipigs is 450 g and the average adult body weight is about 35 kg. They reach sexual maturity within 3–5 months and sows have an aver-age litter size of 6.5 piglets.

Göttingen Minipigs are mainly used for regulatory toxic-ity testing; other areas of special use are cardiovascular, dia-betes, orthopaedic, dental, surgical and other studies. They are available worldwide for non-breeding/non-cloning use.

Contact:DenmarkEllegaard Göttingen Minipigs A/SPhone: +45 5818 5818Fax: +45 5818 5880Email: [email protected]

JapanOriental Yeast Company LtdPhone: +81 3 3968 1192Fax: +81 3 3968 4863Email: [email protected]

United StatesMarshall BioResourcesPhone: +1 315 587 2295Fax: +1 315 587 2109Email: [email protected]

Figure 1.7 (See color insert.) Clawn Miniature Swine, non-adult. (Reprinted with permission from the Japan Farm CLAWN Institute, Kagoshima.)

Figure 1.8 (See color insert.) Göttingen Minipig, non-adult. (Reprinted with permission from Marshall BioRe-sources, United States.)


1.5.3 Hanford™ Miniature Swine

The author is grateful to Dr. Guy F. Bouchard, DVM, MS, DACT and Dr. Larry D. Brown, DVM, PhD, DACVPM of Sinclair BioResources, LLC, Auxvasse, MO, United States, for providing information about this breed.

The Hanford Miniature Swine (Figure 1.9) was developed in 1958 at Hanford Laboratories (United States Atomic Energy Commission) in the state of Washington, United States. Individuals involved in the development were Dr. Bustad, Dr. Ensminger, M. E. Kerr, Dr. Horstman and Dr. England. The Hanford National Laboratory was later renamed Battelle Northwest Research Laboratories of Richland, WA (Bustad et al., 1966). The primary aim was the development of a labo-ratory animal for radiation biomedical research.

To establish the new breed, domestic Palouse gilts from the Department of Animal Science, Washington State University, were crossbred with a Pitman-Moore Pharma-ceutical Company (Indianapolis, IN) boar. Feral swamp hogs from Louisiana were later incorporated to reduce body size. In the 1960s, Yucatan miniature pigs were introduced to the new breed. The Hanford miniature was used in develop-ment of other lineages, such as the Munich minipig (Troll), and the FDA Hormel–Hanford.

The main characteristics of this breed are white skin and hair coat, low subcutaneous fat content, and good adaptation to laboratory environment. Pigs of this breed are docile with only infrequent expression of aggression and easy to socialize. Their body size allows serial blood sampling and the size of the heart makes it a well-¢tting model for cardiovascular studies. Further areas of use are dermal studies with a focus on toxicological studies, mus-culoskeletal studies, surgical modelling and research in pharmacology.

Hanford Miniature Swine have an average birth weight of 720 g and an adult body weight of 80–95 kg. They reach

puberty within 4–6 months, reach sexual maturity within 6 months, and have an average litter size of 6.7 piglets.

Today, there is one Hanford breeding population at Sinclair BioResources in Auxvasse, Missouri, United States, that is closed and fully pedigreed. The main breeding goals are high conformity, robustness and docility. The pigs in the breeding facility are free of any common pig disease and are vaccinated. Ear notch skin is banked from all animals in case future genetic analysis is required. From the breeding facil-ity, animals can be shipped worldwide with required permits. Customers must agree to non-breeding/non-cloning uses.

Contact:Sinclair BioResources LLCPO Box 658Columbia, MO 65205, United States562 State Road DD, Auxvasse, MO 65231, United StatesPhone: +1 573 387 4400Fax: +1 573 387 4404Email: [email protected]

1.5.4 Munich Miniature Swine (Troll)

The author thanks Dr. med. vet. Eva Engelhardt, Düsseldorf University Hospital, Düsseldorf, Germany, for providing information about this breed.

The Munich Miniature Swine (Figure 1.10) is a small breed developed in 1993 from the Hanford Miniature Swine and the Columbian Miniature Swine. The breed was

Figure 1.10 (See color insert.) Munich Miniature Swine. (Reprinted with permission from Dr. Engelhardt, Düsseldorf University Hospital, Düsseldorf, Germany.)

Figure 1.9 (See color insert.) Young adult Hanford Miniature Swine. (Reprinted with permission from Dr. Guy F. Bouchard, Sinclair BioResources, LLC, Auxvasse, MO, United States.)


initially developed for melanoma studies. Munich Miniature Swine are white, red, black, dark brown, or spotted. They have an average birth weight of 600–900 g and an average adult body weight of 60–100 kg. They mature within 5–6 months and have an average litter size of 8.5 piglets. Munich Miniature Swine are docile, curious and vigilant, but not aggressive.

Today, there is only one small population at Düsseldorf University Hospital, Düsseldorf, Germany. The main breed-ing goals are body size reduction and an increase of number of teats. The availability of the Munich Miniature Swine is limited. In biomedical research they are mainly used for cardiovascular, orthopaedic and implantation studies as well as shock model.

Contact:TVA Universitätsklinikum DüsseldorfMoorenstrasse 540225 Düsseldorf

1.5.5 Panepinto Micropig

The author acknowledges Linda Panepinto, Managing Director, P&S Farms, Buffalo, Wyoming, United States for providing information about this breed.

The Panepinto breed (Figure 1.11) was initially devel-oped in the 1990s. The background of this breed are Yucatan Micropigs from the Colorado State University breeding stock that have a proportion of 90% in today’s Panepinto micropigs and Vietnamese miniature pigs that have a proportion of 10%. The main aim of the developers of this breed was the use in biomedical research and in chil-dren’s zoos.

Panepinto Micropigs have dark-grey or black skin. They have a calm and docile temperament, a compact appearance, and large ears, and many of them have wattles. The average birth weight is 500–800 g and they have an adult body weight of 25–30 kg. Panepinto Micropigs mature within 5–6 months and have an average litter size of seven piglets.

In biomedical research, they are mainly used for diabe-tes, cardiovascular, and different other studies. For the future, it is planned to establish a special diabetes type II line.

Today, there is one breeding stock in the United States. The population is managed as an outbred population with mating of least-related animals. The main breeding goals are good health, increased fertility including mothering ability, calm temperament and a unique phenotype. Panepinto Micropigs are limited available in North America and are only sold with non-breeding agreements.

Contact:Panepinto & AssociatesEmail: [email protected]

1.5.6 Sinclair™ S-1 Miniature Swine (Minnesota Miniature, Hormel Miniature)

The author acknowledges the help of Dr. Guy F. Bouchard, DVM, MS, DACT and Dr. Larry D. Brown, DVM, PhD, DACVPM of Sinclair BioResources, LLC, Auxvasse, MO, United States, for providing information about this breed.

The Sinclair Miniature Swine (Figure 1.12) was devel-oped in 1949 under the breed name Minnesota or Hormel Miniature Swine at the Hormel Institute in Austin, Minnesota, United States, under the direction of Dr L. M. Winters. Dr. Hormel from the Hormel Institute and Dr. Essex and Dr. Mayo from the Mayo Clinic developed this breed. In

Figure 1.11 (See color insert.) Panepinto Micropig, non-adult. (Reprinted with permission from L. Panepinto, P&S Farms, Buffalo, WY, United States.)

Figure 1.12 (See color insert.) Young adult Sinclair Miniature Swine. (Reprinted with permission from Dr. Guy F. Bouchard, Sinclair BioResources, LLC, Auxvasse, MO, United States.)


1965, part of the Minnesota Miniature breeding stock was acquired by Dr. Tumbleson of the Sinclair Comparative Medicine Research Farm, University of Missouri, Columbia. Since then, the name Sinclair Miniature Swine has been used for this breed. The breed was developed from four feral pig strains and Ohio Improved Chester Whites. The initial cross was between a Guinea Hog from Alabama and a wild boar from the Catalina Island. Later, Piney-Wood pigs were introduced to the new breed and in 1957, dwarf Ras-n-lansa pig genes from Guam were incorporated to decrease the body size of the Hormel pigs (Dettmers et al., 1965). In the 1960s, the breed was crossbred with Yorkshire to introduce white skin. The proportions of the four basic breeds in the Sinclair Miniature Swine are nowadays 49% Piney-Woods, 22% Ras-n-lansa, 16% Catalina wild boar and 13% Guinea Hog. The Minnesota Miniature breeds 1 and 3 also had a small percentage of Tamworth and Landrace genes, and so this early lineage contained a wide variety of feral and domesticated swine genetics. Minnesota miniature swine were also used as foundation lines for establishment of other breeds of miniature pigs (Nebraska, Göttingen, FDA Hormel–Hanford, NIH Minipig, Minipig of Czech Republic).

The main use of Sinclair Miniature Swine at the University of Missouri Sinclair Research Farm was for alco-holism, cancer and paediatric studies, teratology, environ-mental, osteoporosis and other types of biomedical research. Today, Sinclair S-1 miniatures are further used in cardiovas-cular, musculoskeletal, urogenital, immunology, reproduc-tion toxicology, dermatology, gastroenterology, respiration and nutrition research.

Sinclair Miniature Swine phenotypes include solid black, brown, red (roan), grey or white, or spotted haircoats. One animal can have single coat colour up to being tri-coloured with predominant black or red or white with spots. The average birth weight is 590 g and the average adult body weight is 55–70 kg. The Sinclair Miniature is smaller than the standard Yucatan or Hanford and slightly larger than the Micro-Yucatan. Pigs reach puberty within 4–6 months, reach sexual maturity within 6 months, and sows have on average six piglets per litter. Their temperament is docile and calm with good socialization characteristics; they grow slowly and reach a body size that is adequate for serial blood sampling. One lineage of Sinclair Mini-ature Swine develops a malignant spontaneously regressing melanoma.

Nowadays, there exists one breeding population at Sinclair BioResources, LLC, Auxvasse, Missouri, United States. This population is closed and the mating strategy focuses on mating of least-related animals. The main breed-ing goals are the establishment of unique phenotypes, robust health, docility and calm temperament. Ear notch skin is banked from all animals for the case that genetic material is needed. The pigs are currently shipped to the United States and Canada and shipping to Asia and Europe is also possible. Customers must agree to non-breeding/non-cloning uses.

Contact:Sinclair BioResources LLCPO Box 658Columbia, MO 65205, United States562 State Road DD, Auxvasse, MO 65231, United StatesPhone: +1 573 387 4400Fax: +1 573 387 4404Email: [email protected]

1.5.7 Westran

The author thanks Dr. Wayne J. Hawthorne, Director of National Pancreas and Islet Transplant Laboratories, Westmead Hospital, Weastmead, New South Wales, Australia for providing information about this breed.

The Westran pig (Figure 1.13) was developed out of feral pigs from Kangaroo Island in South Australia. This pig breed is believed to have its origin more than 200 years ago when the French explorer Nicholas Baudin released a breed-ing pair of pigs at Hog Bay on Kangaroo Island in 1803. From this one pair, a highly inbred population of feral pigs has developed. While some of those have mixed with domes-tic pigs bred on the island, others have kept their bloodline pure and their gene pool so small that they have become of major interest for biological and medical research (Moran, 2005). Thus, in 1976 some of the feral pigs from Kangaroo Island were captured by the Australian Commonwealth Scienti¢c and Research Organisation (CSIRO), Division of Human Nutrition in Adelaide, to establish a line for biomed-ical research.

From this line, the Westran pigs developed after one full-sib pair was brought to Sydney in 1993 to Westmead Hospital. The name of the breed is a combination of

Figure 1.13 (See color insert.) Westran Minipigs, non-adult. (Reprinted with permission from Dr. Wayne J. Hawthorne, Westmead Hospital, Weastmead, New South Wales, Australia.)


Westmead Hospital and transplantation, the unit where the line was developed.

The main focus while establishing the breed was the cre-ation of non-human organs and tissue sources for allo- and xeno-transplantation. Due to the fact that the pigs are highly inbred, advantageous characteristics for transplantation research are ¢xed in this breed. Currently, Westran pigs are used as model for pancreatic islet transplantation as a cure for diabetes type I.

Westran pigs are white or white with black spots with both pigmented hairs and skin. The average birth weight is around 930 g and the average adult body weight is around 80 kg in females and 93 kg in males. Pigs mature within 6–7 months and have an average litter size of 4.6 piglets. Even though the Westran line is a young breed, pigs are well domesticated and relatively docile and easy to handle.

There is one breeding population in Sydney, Australia, which is based on full-sib mating. Thus, a high degree of inbreeding can be achieved and the major histocompatibil-ity complex (MHC) reaches a high similarity between the animals in the population allowing transplantation between animals without rejection. Currently, only one out of 53 alleles chosen for testing the homozygosity in the MHC is segregating. Further, all animals of the breed have blood group type O. A negative side effect of the high inbreeding coef¢cients in the population is the infrequent occurrence of congenital abnormalities of the heart causing sudden death of piglets. Recently, the breeding population was divided in a core population in which full-sib mating is con-ducted and a non-core population where the breeding strat-egy is based on mating animals that are most related within one generation. The main breeding goals are reduced body weight and small size, increased number of piglets born alive, and increased number of weaned piglets. However, due to the fact that full-sib mating is obligatory and the breeding stock is still small, the genetic progress in these traits is slow.

For the Westran pigs, a huge amount of genetic material is banked. Sera samples were kept from all core animals from the very ¢rst pair. Sperm and ova are also kept since the ¢rst generation. Thus, for almost all animals from the start of the breed, DNA material exists.

Due to the geographical isolation of Australia and the limited number of animals available for research until now, no international shipping is conducted. Customers are asked to agree with non-breeding restrictions.

Contact:Dr. Wayne HawthorneSenior Research FellowCentre for Transplant and Renal ResearchC/- Departement of SurgeryWestmead HospitalWestmead NSW 2145, AustraliaPhone: +61 2 9845 6962Fax: +61 2 9633 9351

Email: [email protected]

1.5.8 Yucatan Miniature Swine

The author is grateful to Linda Panepinto, Managing Director, P&S Farms, Buffalo, Wyoming, United States, Dr. Guy F. Bouchard, DVM, MS, DACT and Dr. Larry D. Brown, DVM, PhD, DACVPM of Sinclair BioResources, LLC, Auxvasse, MO, United States for providing informa-tion about this breed.

Like the Westran pig, the Yucatan Miniature Swine (Figure 1.14) is a purebred miniature pig breed derived from one primary natural gene pool and adapted for use in bio-medical research. They originate from Mexico, Central and South America where they are also known as Maya, Pelon, Cuino, Tabasqueno, Birish, or Hairless. In 1960, 25 Yucatan pigs were imported to the United States from Frontera area, Mexican Yucatan Peninsula, by the veterinarian Dr. Harry Quick to develop a research strain of Yucatan pigs. This new research strain was called Labco and was only minimally used. The breeding stock was ¢rstly housed at Thompson Research Farm in Monee, Illinois, United States and was acquired by the Colorado State University in the early 1970s. It was also in the 1970s that the Yucatan Miniature Swine was ¢rstly characterized as an animal model for biomedical research in a scienti¢c paper (Panepinto et al., 1978). Besides the increasing demand for biomedical studies, the pigs were also sold to children’s zoos. Nowadays, the breed is used in biomedical research in the ¢elds of cardiovascular, diabetes, dermal/wound healing, dental, orthopaedic, renal, surgical,

Figure 1.14 (See color insert.) Yucatan Miniature Swine. (Reprinted with permission from Dr. Guy F. Bouchard, Sinclair BioResources, LLC, Auxvasse, MO, United States.)


mineral metabolism, hyperlipidaemia, exercise physiology, ophthalmic, haemodynamic and other studies.

The purebred Yucatan Miniature Swine has a black to slate grey skin. Typical for this breed is the minimal haircoat; some animals are even hairless. Cervical wattles (skin appendages) are present in certain lines. The birth weight varies from 500 to 900 g and the adult body weight varies from 70 to 80 kg. Pigs reach puberty within 4–6 months and become sexually mature within 5–6 months. The average lit-ter size is six piglets. An important characteristic of Yucatan Miniature Swine is their docile and calm temperament. Additionally, they have a high sensitivity to cold tempera-tures that can be expressed in respiratory problems. However, the Yucatan Miniature Swine can tolerate cooler tempera-tures if housed in social groups and with adequate bedding.

Currently, there are ¢ve breeding and multiplier sites in the United States. The LoneStar Laboratory Swine (Exemplar Genetics), Sioux Center, IA, Sinclair BioResources, Auxvasse, Missouri, S&S Farms in California and Michigan and Cerdo Micro in California. With regard to breeding, a strategy of mating less-related animals is conducted. High levels of inbreeding lead to a susceptibility to atrial septal and ventricular septal defects (VSDs) and to a decrease in reproductive performance due to inbreeding depression. Thus, the main breeding goals are a minimization of inbreed-ing, an increase in reproductive performance combined with good mothering abilities, docile behaviour and robustness.

Yucatan pigs can be shipped to North America and Europe. A non-breeding agreement is required unless the research involves reproductive studies. In reproductive stud-ies, only limited breeding is allowed and the offspring has to be castrated at the end of the study. Other customers must agree to non-breeding/non-cloning uses.

Contact:Cerdo MicroEmail: LPanepinto@netscape.comwww.panepinto.comwww.CerdoMicro.comSinclair BioResources LLCPO Box 658Columbia, MO 65205, United States562 State Road DD, Auxvasse, MO 65231, USAPhone: +1 573 387 4400Fax: +1 573 387 4404Email: [email protected]

1.5.9 Micro-Yucatan™ Minature Swine

Dr. Guy F. Bouchard, DVM, MS, DACT and Dr. Larry D. Brown, DVM, PhD, DACVPM of Sinclair BioResources, LLC, Auxvasse, MO, United States kindly provided infor-mation about this breed.

The Micro-Yucatan Miniature Swine (Figure 1.15) was established in 1985 by selecting and breeding small purebred

Yucatan Miniature Swine by the Charles River Laboratories, CRL), Inc. This effort continued earlier model developmen-tal work conducted at the Colorado State University during the 1970s (Panepinto and Kroc, 1995). The Yucatan micropig is a strain of Yucatan that differs primarily in size only. In 2002, Sinclair BioResources, LLC acquired the CRL breeding population. Today, they are mainly used for cardiovascular, dermal, diabetes and preclinical safety studies.

Like Yucatan Miniature Swine, Micro-Yucatan Miniature Swine have grey to dark skin with little or no hair. They are very docile and easy to handle and have an average birth weight of 600–700 g and an adult body weight in the range of 55–70 kg. Puberty is achieved within 4–6 months (14–20 kg), sexual maturity is reached within 6 months (18–20 kg), and the average litter size is 6 piglets.

The breeding population is located at Sinclair BioResources, LLC, in Windham, Maine, United States. It is an outbred and closed population in which the most important breeding goals are small size, unique phenotypes, and further improvement of good temperament and behav-ioural characteristics. Genetic material of all animals in the population is banked in the form of ear notch skin. Currently, animals of this breed are shipped to North America includ-ing Canada and shipping to Asia and Europe is possible. Pigs expressing the VSD are available. Customers must agree to non-breeding/non-cloning uses.

Contact:Sinclair BioResources LLCPO Box 658Columbia, MO 65205, USA562 State Road DD, Auxvasse, MO 65231, United StatesPhone: +1 573 387 4400Fax: +1 573 387 4404Email: [email protected]

Figure 1.15 (See color insert.) Young adult Micro-Yucatan Miniature Swine. (Reprinted with permission from Dr. Guy F. Bouchard, Sinclair BioResources, LLC, Auxvasse, MO, United States.)


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1 Chapter 1: History and Development ofMiniature, Micro- and Minipigs

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van der Beek, E.M., Wiegant, V.M., Schouten, W.G., vanEerdenburg, F.J., Loijens, L.W., Plas, C., Benning, M.A.,Vries, H de, de Kloet, E.R., Lucassen, P.J. 2004. Neuronalnumber, volume, and apoptosis of the left dentate gyrus ofchronically stressed pigs correlate negatively with basalsaliva cortisol levels. Hippocampus 14:688–700.

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8 Chapter 8: Dosing Methods

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9 Chapter 9: In-Life Clinical Observations

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Bollen, P.J.A., Lemmens, A.G., Beynen, A.C., Meyer, O., andRitskes-Hoitinga, J. 2006. Bone composition in male andfemale Göttingen minipigs fed variously restrictedly andnear ad libitum. Scand J Lab Anim Sci 33(3):149–158.

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Bollen, P.J.A. 2001. Nutrition of Göttingen minipigs: Astudy of the in�uence of ad libitum and restricted feedingon the physiology of the Göttingen minipig. PhD thesis,University of Southern Denmark.

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Direct gene transfer in the Göttingen minipig CNS usingstereotaxic lentiviral microinjections. Acta NeurobiolExp (Wars). 70(3):308-315. Golovkin, M., Spitsin, S.,Andrianov, V. et al. 2007. Small subunit vaccine producedin prsxs protection in mice. PNAS 104:6864–6869. Haynes,N.B. 1971. Changes in pig cervical mucus in relation tothe oestrous cycle. J Reprod Fert 27:211–218.

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Jackson, P.G.G. and Cockroft, P.D. 2002. ClinicalExamination of Farm Animals. Blackwell Science.

Jankord, R., Ganjam, V.K., Turk, J.R., Hamilton, M.T., andLaughlin, M.H. 2008. Exercise training alters effect ofhighfat feeding on the ACTH stress response in pigs. ApplPhysiol Nutr Metab 33(3):461–469.

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JØrgenssen, K.D., Kledal, T.S.A., Svendsen, O., andSkakkebæk, N.E. 1998. The GÖttingen minipig as a model forstudying effects on male fertility. Scand J Lab Anim Sci25(1):161–169.

Kornum, B.R. 2009. A pig model for studies of serotonergicmechanisms in memory disorders. PhD Thesis, University ofCopenhagen.

Krohn, T.C., Ellegaard, L., and Hansen, A.K. 2000. Apreliminary study of the impact of stocking density on thebehaviour of group housed Göttingen minipigs. Scand J LabAnim Sci 4(27):203–210.

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Lehmann, H. 1998. The minipig in general toxicology. ScandJ Lab Anim Sci Suppl. 1, 25:59–62.

Lind, N.M., Arnfred, S.M., Hemmingsen, R.P., Hansen, A.K.,and Jensen, K.H. 2005. Open ¢eld behaviour and reaction tonovelty in Göttingen minipigs: Effects of amphetamine andhaloperidol. Scand J Lab Anim Sci 32(2):103–112.

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Rayner, V. and Wenham, G. 1986. Small intestinal motilityand transit by electromyography and radiology in thefasted and fed pig. J Physiol 379:245–256.

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10 Chapter 10: Minipigs in Absorption,Distribution, Metabolism, and Excretion(ADME) Studies

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11 Chapter 11: The Minipig in SafetyPharmacology

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14 Chapter 14: Heart and Cardiotoxicity

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Herman, E. H., Ferrans, V. J., Young, R. S., and Balazs,T., 1989. A comparative study of minoxidil-inducedmyocardial lesions in beagle dogs and miniature swine.Toxicol Pathol, 17(1 Pt 2):182–92.

Hill, G. M., Ku, P. K., Miller, E. R., Ullrey, D. E.,Losty, T. A., and O’Dell, B. L., 1983. A copper de¢ciencyin neonatal pigs induced by a high zinc maternal diet. JNutr, 113(4):867–72.

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Seifert, C. F., Nesser, M. E., and Thompson, D. F., 1994.Dexrazoxane in the prevention of doxorubicin-inducedcardiotoxicity. Ann Pharmacother, 28(9):1063–72. Smith, G.W., Constable, P. D., Bacon, C. W., Meredith, F. I., andHaschek, W. M., 1996. Cardiovascular effects of fumonisinsin swine. Fundam Appl Toxicol, 31(2):169–72. Torrado, M.,López, E., Centeno, A., Medrano, C., Castro-Beiras, A.,and Mikhailov, A. T., 2003. Myocardin mRNA is augmented inthe failing myocardium: Expression pro¢ling in the porcinemodel and human dilated cardiomyopathy. J Mol Med,81(9):566–77. Turk, J. R., 2000. Reference Point.Physiologic and patho physiologic effects of natriureticpeptides: Implications in cardiopulmonary disease. J Am VetMed Assoc, 216(12):1970–6. Vadlamudi, R. K., McCormick, R.J., Medeiros, D. M., Vossoughi, J., and Failla, M. L.,1993. Copper de¢ciency alters collagen types and covalentcross-linking in swine myocardium and cardiac valves. Am J

Physiol, 264(6 Pt 2):H2154–61. Van Gelder, G. A., Buck, W.B., Osweiler, G. D., and Stahr, H. M., 1972. Researchactivities of a veterinary toxicology laboratory. ClinToxicol, 5(2):271–81. Van Vleet, J. F., Boon, G. D., andFerrans, V. J., 1981. Induction of lesions ofselenium-vitamin E de¢ciency in weanling swine fed silver,cobalt, tellurium, zinc, cadmium, and vanadium. Am J VetRes, 42(5):789–99. Van Vleet, J. F., Herman, E. H., andFerrans, V. J., 1984. Cardiac morphologic alterations inacute minoxidil cardiotoxicity in miniature swine. Exp MolPathol, 41(1):10–25. Van Vleet, J. F., and Ferrans, V. J.,1986. Myocardial diseases of animals. Am J Pathol,124(1):98–178. Van Vleet, J. F., Runnels, L. J., Cook, J.R. Jr, and Scheidt, A. B., 1987. Monensin toxicosis inswine: Potentiation by tiamulin administration andameliorative effect of treatment with selenium and/orvitamin E. Am J Vet Res, 48(10):1520–4. Vick, J., Joseph,X., Whitehurst, V., Herman, E., and Balazs, T., 1989.Cardiotoxic effects of the combined use of caffeine andisoproterenol in the minipig. J Toxicol Environ Health,26(4):425–35. Vikenes, K., Westby, J., Matre, K., Kuiper,K. K., Farstad, M., and Nordrehaug, J. E., 2002. Releaseof cardiac troponin I after temporally graded acutecoronary ischaemia with electro cardiographic STdepression. Int J Cardiol, 85(2–3):243–51. Vadlamudi, R.K., McCormick, R. J., Medeiros, D. M., Vossoughi, J., andFailla, M. L., 1993. Copper de¢ciency alters collagentypes and covalent cross-linking in swine myocardium andcardiac valves. Am J Physiol, 264(6 Pt 2):H2154–61. Wang,G. K., Zhu, J. K., Zhang, J. T. Li, Q., Li, Y., He, J.,et al., 2010. Circulating microRNA: A novel potentialbiomarker for early diagnosis of acute myocardialinfarction in humans. Eur Heart J, 31(6):659–66. Wildman,R. E., Medeiros, D. M., Hamlin, R. L., Stills, H., Jones,D. A., and Bonagura, J. D., 1996. Aspects of cardiomyopathy in copper-de¢cient pigs. Electrocardiography,echocardiography, and ultrastructural ¢ndings. Biol TraceElem Res, 55(1–2):55–70. Wisialowski, T., Crimin, K.,Engtrakul, J., O’Donnell, J., Fermini, B., and Fossa, A.A., 2006. Differentiation of arrhythmia risk of theantibacterials moxi�oxacin, erythromycin, andtelithromycin based on analysis of monophasic actionpotential duration alternans and cardiac instability. JPharmacol Exp Ther, 318(1):352–9.

15 Chapter 15: Central and PeripheralNervous Systems

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Bjarkam, C.R., Nielsen, M.S., Glud, A.N., and Rosendal, F.2008. Neuromodulation in minipig MPTP model of Parkisondisease. British Journal of Neurosurgery. 22(suppl.1):S9–S12.

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Bolon, B., Anthony, D.C., Butt, M., Dorman, D., Green,M.V., Little, P.B., Valentine, W.M., Weinstock, D., Yan,J., and Sills, R.C. 2008. “Current pathology techniques”Symposium review: Advances and issues in neuropathology.Toxicologic Pathology 36:871–89.

Borsook, D., Becerra, L., and Hargreaves, R. 2006. A rolefor fMRI in optimising CNS drug development. NatureReviews Drug Discovery. Advance Online Publication.

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Lind N.M., Moustgaard, A., Jelsing, J., Vajta, G., Cumming,P., and Hansen, A.K. 2007. The use of pigs inneuroscience: Modeling brain disorders. Neuroscience &Behavioural Reviews 31(5):728–51.

Mikkelsen, M., Møller, A., Jensen, L.H., Pedersen, A., BergHarajehi, J., and Pakkenberg, H. 1999. MPTP-inducedParkinsonism in minipigs: A behavioural, biomedical andhistological study. Neurotoxicology and Teratology 21(2):169–75.

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Nielsen, M.S., Sørensen J.C., and Bjarkam C.R. 2009. Thesubstantia nigra pars compacta of the Göttingen minipig: an

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Rosendal, F., Pedersen, M., Sangill, R.,Stødkilde-Jørgensen, H., Nielsen, M.S., Bjarkam, C.R., andSørensen, J.C. 2009a. MRI protocol for in vivovisualization of the Göttingen minipig brain improvestargeting in experimental functional neurosurgery. BrainResearch Bulletin 79:41–5. Rosendal, F., Frandsen, J.,Chakravarty, M.M., Bjarkam, C.R., Pedersen, M., Sangill,R., and Sørensen, J.C. 2009b. New surgical techniquesreduces the susceptibility artefact at airtissue interfaceson in vivo cerebral MRI in the Göttingen minipig. BrainResearch Bulletin 80:403–7. Saxena, A., Sun, W., Dabisch,P.A., Hulet, S.W., Hastings, N.B., Jakubowski, E.M.,Mioduszewski, R.J., and Doctor, B.P. 2008. Ef¢cacy ofhuman serum butyrylcholinesterase against sarin vapor.Chemico-Biological Interactions 175:267–72. Skytte, C. andSøeborg, H. 2009. Convulsions in minipigs. Newsletter 32,Autumn 2009, Ellegaard Göttingen Minipigs A/S. Denmark.Data presented at the Opening of Barrier 3, EllegaardGöttingen Minipigs A/S, June 12, 2009. Switzer, R.C.I.2000. Application of silver degeneration stains toneurotoxicity testing. Toxicologic Pathology 28:70–83.Syvänen, S., Lindhe, Ö., Palner, M., Kornum, B.R., Rahman,O., Långström, B., Knudsen, G.M., and Hammarlund-Udenaes,M. 2009. Species differences in blood-brain barriertransport of three position emission tomographyradioligands with emphasis on p-glycoprotein transport. TheAmerican Society for Pharmacology and ExperimentalTherapeutics 37:635–43. Vezina, M., Patel, A., and Wise, S.2009. Short-term EEG recording in conscious Göttingenminipigs as an alternative to nonhuman primates and dogs.Journal of Pharmacological and Toxicological Methods

60(2):232. Watanabe, H., Andersen, F., Simonsen, C.Z.,Evans, S.M., Gjedde, A., and Cumming, P. 2001. MR-basedstatistical atlas of the Göttingen minipig brain.NeuroImage 14:1089–96. Wood, S.L., Beyer, B.K., and Cappon,G.D. 2003. Species comparison of postnatal CNS development:Functional measures. Birth Defects Research Part B68:391–407. Yoshikawa, T., Yoshida, N., and Oka, M. 2001.The broad-spectrum anti-emetic activity of AS-8112, anovel domamine D 2 , D 3 and 5-HT 3 receptor antagonist.British Journal of Pharmacology 133:253–60.

16 Chapter 16: The Kidney

Coulthard, M.G., Flecknell, P., Orr, H. et al., 2002. Renalscarring caused by vesicoureteric re�ux and urinaryinfection: A study in pigs. Pediatr Nephrol 17: 481–4.

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Dekel, B., Buracova, T., Arditti, F.D. et al., 2002. Humanand porcine early kidney precursors as a new source fortransplantation. Nat Med 9: 53–60.

Elashry, O.M., Wolf, J.S., Rayala, H.J. et al., 1997.Recent advances in laparoscopic partial nephrectomy:Comparative study of electrosurgical snare electrode andultrasound dissection. J Endourol 11: 15–22.

EMEA 2005. Pramipexole. Product Names: Mirapexin & Sifrol.

EMEA/H/C/169/X/38 and EMEA/H/C/255/X/39. 2007. RivastigmineScienti�c Discussions. Product Names: Exelon (London,September 17, 2007) & Prometax (London, September 25,2007).

EMEA/465248/2008. CHMP Assessment Report for Protopic(INN: Tacrolimus). London, February 26, 2009.

EMEA/533232/2009. CHMP Assessment Report for A¢nitor (INN:Everolimus). London, May 29, 2009.

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Herrera, B., Eisenberg, G., Desco, M.M. et al., 2000.Perfusate lactate dehydrogenase level and intrarenalresistence could not be adequate markers of perfusionquality during isolated kidney perfusion. Artif Organs 24:899–918.

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response and improves kidney function after risk-situationabdominal aortic surgery. J Vasc Surg 42: 129–39. Marini,C.P., Russo, G.C., Nathan, I.M. et al., 2000. Effect ofhematocrit on regional oxygen delivery and extraction in anadult respiratory distress syndrome animal model. Am J Surg180: 108–14. Marquardt, R.R. and Frohlich, A.A. 1992. Areview of recent advances in understanding ochratoxicosis.J Anim Sci 70: 3968–88. Marr, B., Wright, K.C., Carrasco,C.H. et al., 1997. Experimental evaluation of a new devicefor percutaneous transrenal ureteral occlusion. J VascInterv Radiol 8: 775–80. McDougall, E.M., Elashry, O.M.,Clayman, R.V. et al., 1997. Laparoscopic pyeloplasty inthe animal model. J Soc Laparoendosc Surg 1: 113–18.Nakada, S.Y., Soble, J.J., Gardner, S.M. et al., 1996.Comparison of Acucise endopyelotomy and endoballoonrupture for management of secondary proximal ureteralstricture in the porcine model. J Endourol 10: 312–18.Nielsen, T.W., Maaske, C.A., Booth, N.H. 1969. Somecomparative aspects of porcine renal function. In L.K.Bustad and R.O. McClellan (eds.), Swine in BiomedicalResearch, pp. 529– 36. Seattle, WA: Paci¢c NorthwestLaboratory. Olsen, L.H., Dalmose, A.L., Swindle, M.M.et al., 2001. Male fetal pig lower urinary tract functionin mid second and early third trimester of gestation. JUrol 165: 2331–4. Olweny, E.O., Portis, A.J., Sundaram,C.P. et al., 2000. Evaluation of a chronic indwellingprototype mesh ureteral stent in a porcine model. Urology56: 857–62. Ozono, R., Wang, Z.Q., Moore, A.F. et al.,1997. Expression of the subtype 2 angiotensin (AT2)receptor protein in rat kidney. Hypertension 30: 1238–46.Paltiel, H.J., Mulkern, R.V., Perez-Atayde, A. et al.,2000. Effect of chronic low pressure, sterilevesicoureteral re�ux on renal growth and function in aporcine model: A radiologic and pathologic study.Radiology 217: 507–15. Paterson, R.F., Barret, E.,Siqueira, T.M. et al., 2003. Laparoscopic partial kidneyablation with high intensity focused ultrasound. J Urol169: 347–51. Ransley, P.G. and Risdon, R.A. 1978. Re�ux andrenal scarring. Br J Radiol (Suppl)14:1–35. Ransley, P.G.,Risdon, R.A., and Godley, 1984. High pressuresterile vesicoureteral re�ux and renal scarring: Anexperimental study in the pig and minipig. Contrib Nephrol39: 320–43. Rossi, R.M., Kist, T., Wurster, U. et al.,1994. Estimation of ifosfadmide/cisplatinum-induced renaltoxicity by urinary protein analysis. Pediatr Nephrol 8:151–6.

Sansing, G.A., Lillihoj, E.B. and Detroy, R.W. 1976.Synergistic toxic effect of citrinin, ochratoxin A andpenicillic acid in mice. Toxicon 14: 213–20.

Schieber, A. and Ghisla, S. 1992. Prostaglandin9-ketoreductase from pig and human kidney: Puri¢cation,properties and identity with human carbonyl reductase.Eicosanoids 5: 37–8.

Shah, G., Azizian, M., Bruch, D. et al., 2004.Cross-species comparison of gene expression between humanand porcine tissue, using single microarrayplatform—Preliminary results. Clin Transplan 18: 76–80.

Siskin, G.P., Dowling, K., Virmani, R. et al., 2003.Pathologic evaluation of a spherical polyvinyl alcoholembolic agent in a porcine renal model. J Vasc IntervRadiol 14: 89–98.

Soucek, P., Zuber, R., Anzenbacherova, E. et al., 2001.Minipig cytochrome P450 3A, 2A and 2C enzymes have similarproperties to human analogs. BMC Pharmacol 1: 11–15.

Stamp�, S., Stamp�, U., Rehnitz, C. et al., 2007.Experimental evaluation of early and long-term effects ofmicroparticle embolization in two different mini-pigmodels. Part 1: Kidney. Cardiovasc Interv Radiol 30:257–67.

Stamp�, S., Stamp�, U., Bellemann, N. et al., 2008a.Biocompatability and recanalisation characterisitics ofhydrogel microspheres with Polyzene-F as polymer coating.Cardiovasc Interv Radiol 31: 799–806.

Stamp�, S., Bellemann, N., Stamp�, U. et al., 2008b.In�ammation and recanalization of four different sphericalembolization agents in the porcine kidney model. J VascInterv Radiol 19: 577–86.

Stamp�, S., Stamp�, U., Bellemann, N. et al., 2009.Immunohistochemical characterization of speci¢c in�ammatorytissue reactions following embolization with four differentspherical agents in the minipig kidney model. J Vasc IntervRadiol 20: 936–45. Suarez, C.A., Guerrero, A.A., Musil, G.et al., 1968. Renal function and nephron structure in theminiature pig. Am J Vet Res 29: 995–1007. Sun, X., Zhang,L., Cheng, J. et al., 2004. Study of renal functionmatching between Banna minipig inbred line and human.Transplant Proc 36: 2488–9. Swindle, M.M. and Smith. A.C.1998. Comparative anatomy and physiology of the pig. ScandJ Lab Anim Sci 25 (Suppl 1): 11–21. Swindle, M.M. andSmith, A.C. 2000. Animal models in biomedical research:Swine. AWIC Resource Series No 11. US Department of

Agriculture, Beltsville, MD: Animal Welfare InformationCenter. Terris, J.M. 1986. Swine as a model in renalphysiology and nephrology: An overview. In M.E. Tumbleson(ed.), Swine in Biomedical Research, (3rd edn), 1673–89.New York, NY: Plenum Press. Villanueva, J., Chandler,C.J., Shimasaki, N. et al., 1994. Effects of ethanolfeeding on liver, kidney and jejunal membranes ofmicropigs. Hepatology 19: 1229–40. Villanueva, J.A.,Devlin, A.M., and Halsted, C.H. 2001. Reduced folatecarrier: Tissue distribution and effects of chronicethanol intake in the micropig. Alcohol Clin Exp Res 25:415–20. Wiederschain, G.Y. and Beyer, E.M. 1977.α-d-Fucosidase activity of human and pig kidney: Aproperty of α-d-galactosidase. Arch Biochem Biophys 182:335–42. Willis, L.R., Evan, A.P., Connors, B.A. et al.,1996. Effects of extracorporeal shock wave lithotripsy toone kidney on bilateral glomerular ¢ltration rate and PAHclearance in minipigs. J Urol 156: 1502–6. Willis, L.R.,Evan, A.P., Connors, B.A. et al., 1997. Effects of SWL onglomerular ¢ltration rate and renal plasma �ow inuninephrectomized minipigs. J Endourol 11: 27–32.

17 Chapter 17: Reproductive SystemIncluding Studies in Juvenile Minipigs

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European Commission. 2006. Regulation (EC) No 1901/2006 ofthe European Parliament and of the Council of 12 December2006 on medicinal products for paediatric use and amendingRegulation (EEC) No 1768/92, Directive 2001/20/EC,Directive 2001/83/EC and Regulation (EC) No 726/2004.

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18 Chapter 18: The Endocrine System

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19 Chapter 19: Skeletal System

1. Glorieux, F. H., Travers, R., Taylor, A., Bowen, J. R.,Rauch, F., Norman, M., and Par¢tt, A. M. 2000. Normativedata for iliac bone histomorphometry in growing children.Bone 26: 103–109. 2. Johnson-Delaney, C. A. 1994.Primate. Vet. Clin. North. Am. Small Anim. Pract. 24:121–156. 3. Lees, C. J. and Ramsay, H. 1999.Histomorphometry and bone biomarkers in cynomolgusfemales: A study in young, mature, and old monkeys. Bone24: 25–28. 4. Masaro, E. J. 1995. Aging: current concepts.In: Masaro, E. J. (ed.), Handbook of Physiology, SectionII: Aging, pp. 4–5. New York: Oxford University Press. 5.Mosekilde, L. 1995. Assessing bone quality—Animal modelsin preclinical osteoporosis research. Bone 17: 343S–352S.6. Mosekilde, L. 1998. Age-related changes in spinal bonemass, structure and strength. Jpn. Soc. Bone Morphom. 8:9–18. 7. Nakamura, T. 1999. The front line of bonehistomorphometry. Clin. Calcium 9: 478–483 (in Japanese).8. Nishizawa, Y. 2001. Meaning of bone biomarkers inclinical ¢elds. In: Nishizawa, Y. (ed.), Bone Biomarkers,pp. 16–27. Tokyo: Iyaku Journal Co. Ltd. (in Japanese).9. Nishizawa, Y., Nakamura, T., Ohata, H., Kushida, K.,Gorai, I., Shiraki, M., Fukunaga, M. et al., 2001.Guidelines on the use of biochemical markers of boneturnover in osteoporosis. J. Bone Miner. Metabol. 19:338–344. 10. Panepinto, L. M. 1996. Miniature swine breedsused worldwide in research. In: Tumblesson, M. E. andSchook L. B. (eds), Advances in Swine in BiomedicalResearch, pp. 681– 691. New York: Plenum Press. 11.Par¢tt, A. M., Drezner, M. K., Glorieux, F. H., Kanis, J.A., Malluche, H., Meunier, P. J., Ott, S. M., and Recker,R. R. 1987. Bone histomorphometry: Standardization ofnomenclature, symbols, and units. Report of the ASBMRHistomorphometry Nomenclature Committee. J. Bone Miner.Res. 2: 595–610. 12. Recker, R. R., Kimmel, D. B., Par¢tt,A. M., Davies, K. M., Keshawarz, N., and Hinders, S. 1988.Static and tetracycline-based bone histomorphometric datafrom 34 normal postmenopausal females. J. Bone Miner. Res.3: 133–144. 13. Schönau, E. and Rauch, F. 1997. Markers ofbone and collagen metabolism—Problems and perspectives inpaediatrics. Hormone Res. 48 (Suppl. 5): 50–59. 14.Swaminathan, R. 2001. Biochemical markers of bone turnover.Clin. Chem. Acta 313: 95–105. 15. Swindle, M. M. 1998.Biology, husbandry, handling and anatomy. In: Swindle, M.M. (ed.), Surgery, Anesthesia and Experimental Techniquesin Swine, pp. 3–32. Iowa: Iowa State University Press.16. Szulc, P., Seeman, E., and Delmas, P. D. 2000.Biochemical measurements of bone turnover in children andadolescents. Osteoporos. Int. 11: 281–294.

20 Chapter 20: Ocular Examination andBackground Observations

1. Moore, C.P. and Whitley, R.D.: Ophthalmic diseases ofsmall domestic ruminants. Vet. Clin. North Am. Large Anim.Pract. 6, 641–665, 1984.

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3. Kirschner, S.E.: Modi¢ed brow sling technique for uppereyelid entropion. Proc. Am. Coll. Vet. Ophthalmol. 25, 68,1994.

4. Elder, M.J.: Mersilene mesh and fascia lata in browsuspension: A comparative study. Ophthalmic Surg. 24,105–108, 1993.

5. Brightman, A.H., Everitt, J., and Bevier, G.: Epibulbarsolid dermoid choristoma in a pig. Vet. Pathol. 22,292–294, 1984.

6. Barkyomb, S.D. and Leipold, H.W.: Nature and cause ofbilateral ocular dermoids in Hereford cattle. Vet. Pathol.21, 316–324, 1984.

7. Magli, A., DeMarco, R., and Capasso, L.: Presence ofbilateral limbal dermids and choroidal osteomas in a familywith inherited limbal dermoids. Ophthalmic Genetics. 20,101– 106, 1999.

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21 Chapter 21: Spontaneous/BackgroundPathology of Göttingen Minipig

Figure 21.33 (See color insert.) Mouse skin (abdominalarea): partial epidermal regeneration (reepithelization)with minimal in¥ammation in the dermis at 48 h aftertreatment (HE-stain ×20). (From Dincer, Z., Jones, S., andHaworth, R. 2006. Exp Tox Path 57:351– 357. Withpermission.)

Figure 21.34 (See color insert.) Cerebellum, meninges:Mineralized foci in the meninges. (HE-stain ×20).

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22 Chapter 22: A Comparative Assessmentof the Pig, Mouse and Human Genomes :Structural and Functional Analysis ofGenes Involved in Immunity andInflammation

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24 Chapter 24: Transplantation inMiniature Swine

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25 Chapter 25: Xenotransplantation

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39. Huang, C.A. Y. Fuchimoto, Z.L. Gleit et al. 2001.Posttransplantation lymphoproliferative disease inminiature swine after allogeneic hematopoietic celltransplantation: similarity to human PTLD and association

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40. Mueller, N.J., K. Kuwaki, F.J. Dor et al. 2004.Reduction of consumptive coagulopathy using porcinecytomegalovirusfree cardiac porcine grafts inpig-to-primate xenotransplantation. Transplantation78:1449–1453.

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26 Chapter 26: Porcine EndogenousRetroviruses in Xenotransplantation : AReview of the Importance of PERVs inPorcine Studies, with Particular Emphasison the Minipig

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28 Chapter 28: Creation and Conservationof Genetically Modified Pigs :Applications to Genetic Disease Model andXenotransplantation

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Table 28.6 Production Efficiency of Cloned Piglets fromCryopreserved or Noncryopreserved Embryos

Cryopreservation NT Embryos Produced Normally Cleaved(%) Developed to the Morula Stage (%) Vitri¡ed (%)Recovered and Cultured (%) Developed to the BlastocystStage (%) Transferred to Recipients (%) Cloned PigletsDelivered (%) Live Offspring (%)

+ 532 382 (71.8) 257 (48.3) 236 (44.4) 232 (43.6) 130(24.4) 103 (19.4) a 6 (1.1) 5 (0.9)

– 635 154/325 c (47.4) — — — — 400 (63.0) b 17 (2.7) 10(1.6)

Source: Adapted from. Nakano, K. et al., 2011. J ReprodDev 55: submitted.

a Cloned embryos were transferred to the uterine horns ofthe recipients.

b Cloned embryos were transferred to the oviducts of therecipients.

c Embryos cultured for 2 days before transfer wereevaluated for normal cleavage.

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29 Chapter 29: Stem Cell Research andMinipigs

Alberio, R., Croxall, N., and Allegrucci, C. 2010. Pigepiblast stem cells depend on activin/nodal signaling forpluripotency and self renewal. Stem Cells Dev19(10):1627–1636.

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30 Chapter 30: Minipig Models of DiabetesMellitus

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32 Chapter 32: Hemorrhage andResuscitation Models Usingthe Miniature Swine

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34 Chapter 34: Osteoporosis Model inMinipigs

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36 Chapter 36: The Minipig in Chemical,Biological, and Radiological Research

Table 36.5 Occurrence of Hemorrhages (%) in SelectedOrgans of Irradiated Göttingen Minipigs ( 60 Co, 0.6Gy/min) Lethal Irradiation (n = 9) Sublethal Irradiation)(n = 6) Hematopoietic Organs

Lymph nodes 100% 67%

Bone marrow 100% 67%

Spleen 100% 67%

Tonsil 100% 50%

Adrenal gland 33% 0% Nonhematopoietic Organs

Brain/cerebellum 100% 0%

Heart 100% 0%

Lungs 90% 17%

Urinary bladder 90% 0%

Kidney 90% 17%

Stomach 90% 17%

GALT 90% 30%

Testis 87% 50%

Intestine, large 75% 0%

Intestine, small 55% 0%

Pancreas 62% 0%

Liver 33% 17% Cholinesterase Levels in Rats. US GovernmentTechnical Report ECBC-TR-428; US Army Edgewood ChemicalBiological Center: Aberdeen Proving Ground, MD.

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37 Chapter 37: The Minipig and Pig inMedical Device Research

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Meinert, L. 2005. Pointing us in the right direction,Applied Clinical Trials.

Device Guidelines

FDA (GUIDANCES)

FDA, Design Control Guidance for Medical DeviceManufactures (1997),http://www.fda.gov/cdrh/comp/designgd.html

FDA, Device Advice, Clinical Trials and IDE GuidanceDocuments,http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfIDE/da_ide_topic.cfm

FDA, Guidance for the Medical Device Industry on PMA ShellDevelopment and Modular Review (1998), http://www.fda.gov/ohrms/dockets/98fr/980896gd.pdf

FDA, Medical Device Reporting Guidance Documents, http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfTopic/topicindex/guidance.cfm?topi c=224

FDA, Device Advice, http://www.fda.gov/cdrh/devadvice/

ISO

AAMI TIR19:1998 & TIR 19/A1:1999, Guidance for ANSI/AAMI/ISO 10993-7:1995, Biological evaluation of medicaldevices—Part 7: Ethylene oxide sterilization residuals.

ANSI/AAMI/ISO 10993-1:1997, Biological evaluation ofmedical devices—Part 1: Evaluation and testing.

ANSI/AAMI/ISO 10993-2:1993/(R)2001, Biological evaluationof medical devices—Part 2: Animal protection requirements.

ANSI/AAMI/ISO 10993-3:1993, Biological evaluation ofmedical devices—Part 3: Tests for genotoxicity,carcinogenicity, and reproductive toxicity.

ANSI/AAMI/ISO 10993-4:2002, Biological evaluation ofmedical devices—Part 4: Selection of tests for interactionwith blood.

ANSI/AAMI/ISO 10993-5:1999, Biological evaluation ofmedical devices—Part 5: Tests for cytotoxicity, in vitromethods.

ANSI/AAMI/ISO 10993-6:1995/(R)2001, Biological evaluationof medical devices—Part 6: Tests for local effects afterimplantation.

ANSI/AAMI/ISO 10993-7:1995/(R)2001, Biological evaluationof medical devices—Part 7: Ethylene oxide sterilizationresiduals.

ANSI/AAMI/ISO 10993-8:2000, Biological evaluation ofmedical devices—Part 8: Selection and quali¢cation ofreference materials for biological tests.

ANSI/AAMI/ISO 10993-9:1999, Biological evaluation ofmedical devices—Part 9: Framework for identi¢cation andquanti¢cation of potential degradation products.

ANSI/AAMI BE78:2002, Biological evaluation of medicaldevices—Part 10: Tests for irritation and delayed typehypersensitivity.

ANSI/AAMI/ISO 10993-11:1993, Biological evaluation ofmedical devices—Part 11: Tests for systemic toxicity.

ANSI/AAMI/ISO 10993-12:2002, Biological evaluation ofmedical devices—Part 12: Sample preparation and reference

materials.

ANSI/AAMI/ISO 10993-13:1999, Biological evaluation ofmedical devices—Part 13: Identi¢cation and quanti¢cation ofdegradation products from polymeric devices. ANSI/AAMI/ISO10993-14:2001, Biological evaluation of medicaldevices—Part 14: Identi¢cation and quanti¢cation ofdegradation products from ceramics. ANSI/AAMI/ISO10993-15:2000, Biological evaluation of medicaldevices—Part 15: Identi¢cation and quanti¢cation ofdegradation products from metals and alloys. ANSI/AAMI/ISO10993-16:1997/(R)2003, Biological evaluation of medicaldevices—Part 16: Toxicokinetic study design fordegradation products and leachables from medical devices.ANSI/AAMI/ISO 10993-16:1997, Biological evaluation ofmedical devices—Part 16: Toxicokinetic study design fordegradation products and leachables from medical devices.ANSI/AAMI/ISO 10993-17:2002, Biological evaluation ofmedical devices—Part 17: Methods for the establishment ofallowable limits for leachable substances. ANSI/AAMI/ISO14155-1:2003, Clinical investigation of medical devicesfor human subjects—Part 1: General requirements.ANSI/AAMI/ISO 14155-2:2003, Clinical investigation ofmedical devices for human subjects—Part 2: Clinicalinvestigation plans. Japan Guidelines for Basic BiologicalTests of Medical Materials and Devices Ohno, Yasuo, ICHGuidelines-Implementation of the 3Rs (Re¢nement,Reduction, and Replacement): Incorporating Best Scienti¢cPractices into the Regulatory Process, ILAR Journal,43(Suppl), 2002,

Ohno, Yasuo, ICH Guidelines-Implementation of the 3Rs(Re¢nement, Reduction, and Replacement): IncorporatingBest Scienti¢c Practices into the Regulatory Process, ILARJournal, 43, (Suppl.), 2002, http://dels.nas.edu/ilar_n/ilarjournal/43_supp/v43supOhno.pdf

PowerPoint Slides: GCP and Post Marketing SurveillanceRequirements, Janet Vessotskie

Forms

FDA, Device Evaluation Information-Forms,http://www.fda.gov/ cdrh/ode/ode-forms.html

FDA, Medical Device Reporting-Forms and Instructions,http:// www.fda.gov/cdrh/mdr/mdr-forms.html

Acronyms

FDA, Abbreviations and Acronyms,http://www.fda.gov/cdrh/ost/reports/fy95/abbreviations_acronyms.html

FDA, FDA/CVM-Related Acronyms and Abbreviations, http://www.fda.gov/cvm/acronym.htm

FDA, Glossary of Acronyms, http://www.fda.gov/oc/oms/ofm/budget/2004/Tables/glossary.htm, 2004. Websites

Code of Federal Regulations,http://www.access.gpo.gov/nara/cfr/ cfr-table-search.html

FDA Consumer, http://www.fda.gov/fdac/fdacindex.html

FDA Databases (see medical device list) http://www.fda.gov/search/databases.html

FDA, Device Advice, Clinical Trials and IDE GuidanceDocuments,http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfIDE/da_ide_topic.cfm FDA, Device Advice,http://www.fda.gov/cdrh/devadvice/ FDA, Device EvaluationInformation-Forms, http://www.fda.gov/cdrh/ode/ode-forms.html FDA Medical Bulletin (1996-1999),http://www.fda.gov/medbull/ mblistin.htmlhttp://www.drugdigest.org/DD/Home Health Insite(Australian, contains many links), http://www.healthinsite.gov.au Medical Device Reporting-Forms andInstructions, http://www.fda. gov/cdrh/mdr/mdr-forms.htmlRegulatory Affairs Professionals Society, www.raps.org TheFood and Drug Law Institute, http://www.fdli.org/Books/Publications Alder, S. and Zbinden, National andInternational Drug Safety Guidelines, M.T.C. VerlagZollikon, 1988. Food and Drug Law Journal, 60(1), 2005.Other Australia and NZ Set Schedule for Joint RegulatoryAgency, Ref: 24213, Script Daily News Alert, 10/04/2006.Ohno, Yasuo, ICH Guidelines-Implementation of the 3Rs(Re¢nement, Reduction, and Replacement): IncorporatingBest Scienti¢c Practices into the Regulatory Process, ILARJournal, 43, (Suppl), 2002. SECTION VII RegulatoryPerspective and Use of the Minipig in Developing MarketedProducts

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39 Chapter 39: Adverse Responses to Drugsin Man : Critical Comparison of ReportedToxicological Findingsin Minipigs and Humans

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Fluocinolone Acetonide; Hydroquinone; Tretinoin, Anonymous,2000. FDA CDER Medical review for NDA 21-112. Date stamped13JAN2000. [21-112_TRI-Luma_medr_P1].

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40 Chapter 40: Regulatory Acceptance ofthe Minipig in Non-PharmaceuticalIndustry and Research

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41 Chapter 41: Future Prospects :Possibilities and Perspectives

Figure 1.7 Clawn Miniature Swine, non-adult. (Reprintedwith permission from the Japan Farm CLAWN Institute,Kagoshima.)

Figure 1.8 Göttingen Minipig, non-adult. (Reprinted withpermission from Marshall BioRe sources, United States.)

Figure 1.9 Young adult Hanford Miniature Swine. (Reprintedwith permission from Dr. Guy F. Bouchard, SinclairBioResources, LLC, Auxvasse, MO, United States.)

Figure 1.10 Munich Miniature Swine. (Reprinted withpermission from Dr. Engelhardt, Düsseldorf UniversityHospital, Düsseldorf, Germany.)

Figure 1.11 Panepinto Micropig, non-adult. (Reprinted withpermission from L. Panepinto, P&S Farms, Buffalo, UnitedStates.)

Figure 1.12 Young adult Sinclair Miniature Swine.(Reprinted with permission from Dr. Guy F. Bouchard,Sinclair BioResources, LLC, Auxvasse, MO, United States.)

Figure 1.13 Westran Minipigs, non-adult. (Reprinted withpermission from Dr. Wayne J. Hawthorne, Westmead Hospital,Weastmead, New South Wales, Australia.)

Figure 1.14 Yucatan Miniature Swine. (Reprinted withpermission from Dr. Guy F. Bouchard, Sinclair BioResources,LLC, Auxvasse, MO, United States.)

Figure 1.15 Young adult Micro-Yucatan Miniature Swine.(Reprinted with permission from Dr. Guy F. Bouchard,Sinclair BioResources, LLC, Auxvasse, MO, United States.)

Figure 2.4 Litter of weaned Sinclair S-1 miniswine (noteheterogeneous coat color) housed on a plastic-coatedparallel grid ¥oor surface (Tenderfoot ® ). The round Kane® creep feeder hooks to the ¥ooring to prevent spillage.The radial design and partitions discourage aggression bymaximizing space per pig and segregating feed allotments.(Photo courtesy of Sinclair BioResources.) StressorBiochemical physiological psychological changes ResponseMaladaptive behavior Adaptive behavior Comfort DiscomfortAcute stress Chronic stress Distress Age, gender, strain,previous experiences, current psychological and physicalstate

Figure 7.1 Continuum of comfort to distress and potentialresponses to stressors.

Figure 7.2 Lowest ranking minipig in group with possiblechronic distress (Cowering Response).(Courtesy of EllegaardGottingen Minipigs, Dalmose, Denmark.)

Figure 7.3 Healthy unstressed young adult Yucatan female.(Courtesy of Dr. Guy F. Bouchard, Sinclair BioResources,LLC, Auxvasse, MO, USA.)

Figure 10.3 Histological sections (top) and distributionof radioactivity (bottom) in minipig brain at 3 and 6 hafter oral administration of 14C-labeled drug.

Figure 11.4 Göttingen minipig equipped with an externaljacketed-telemetry system (JET™-Blood Pressure; DataScience International, St. Paul, MN, USA). Thisnoninvasive jacketed telemetry allows to continuouslymonitor a six-leads ECG (right upper panel) and bloodpressure (right lower panel). The JET™ Blood Pressureadd-on module consists of a remote antenna receiver andelectronics module that are interfaced directly to the JET™device. Together, these components receive a signal from apressure implant placed in the femoral artery to enable adirect blood pressure measurement via a simple, fast, andminimally invasive surgical procedure. 0.25 0.30 0.20 0.150.10 0.05 R e c t i fi e d E M G ( a . u . ) 0 0 1 2 3Diaphragm Ext. intercostal Before nebulization 4 5 6 87 910 0.25 0.30 0.20 0.15 0.10 0.05 0 0 1 2 3 Diaphragm Ext.intercostal Neb. saline 0.9%; 2 min 4 5 6 87 9 10 0.25 0.300.20 0.15 0.10 0.05 R e c t i fi e d E M G ( a . u . ) 0 01 2 3 Diaphragm Ext. intercostal Neb. metacholine (0.3mg/mL; 2 min) 4 5 Time (s) Time (s) 6 87 9 10 0.25 0.300.20 0.15 0.10 0.05 0 0 1 2 3 Neb. metacholine (1 mg/mL; 2min) 4 5 6 87 9 10

Figure 11.7 Electromyographic (EMG) activity of thediaphragm and the external intercostal muscles recorded bytelemetry in the conscious cynomolgus monkey. EMG signalsare �ltered (50 Hz) and recti�ed. Bronchoconstriction wasinduced by nebulization (via a face mask) ofescalating-dose of methacholine. Note the increase inbreathing rate and EMG amplitude induced by thebronchoconstrictive agent (lower panels). Applyingnebulized sodium chloride 0.9% has no effect (right upperpanel). SF = 0.25 SF = 0.5 P o w e r dB P o w e r dB 0 0 24 6 Frequency (C.P.M.) 8 10 12 14 0 2 4 6 Frequency(C.P.M.) 8 10 12 14 4 6 8 10 12 14 0 2 4 8 10 12 14 09:58

09:56 09:54 09:52 09:50 09:48 09:46 09:44 09:42 09:40 09:3809:36 09:34 09:28 09:26 09:24 09:22 09:20 09:18 09:16 09:1409:12 09:10 09:08 09:06 09:04

Figure 11.9 Left panel: Electrogastrography inexperimental pigs. General arrangement of the electrodesplacement for EGG recording. Right top panel: Protocol ofEGG recording with prevailing rhythm of three cycles perminute as baseline activity (60% running spectrum percentactivity). Right bottom panel: Protocol of EGG recordingwith prevailing bradygastria (96% running spectrum percentactivity). Hair shaft Pore Stratum corneum Stratum lucidiumStratum granulosum Stratum corneum Stratum lucidium Stratumgranulosum Germinatiucum (spinosum and basale layers)Stratum spinosum Stratum basale Stratum corneum Stratumlucidium Stratum granulosum Stratum spinosum Stratum basaleFree nerve endings Nerve endings Artery Vein Capillary bedAdipose tissue Hair follice Blood capillaries Erectormuscle (for making hair stand “on end”) Sweat glandSebaceous gland (secrets oil -sebum) Deep sensory receptorEpidermis Dermis (also includes connective tissues)Subcutaneous (hypodermis)

Figure 12.1 Anatomy of the skin.

Figure 13.2 Schematic drawing of the porcine stomach. Nearthe cardiac inlet (1), a diverticulum (2) surmounts thecorpus of the stomach (3). Chyme leaves the stomach viathe antrum pyloricum (4). The inner surface of the stomachis lined by a nonglandular (yellow) and glandular mucosa.The latter can be divided into the cardiac (pink-grey),fundic (brown-red), and pyloric (yellowpink) gland region.

Figure 14.1 Sections of left verticle fromselenium-de�cient pig. (a) Hematoxylin and eosin, (b) samesection under polarized light. Loss of cross striationsand formation of contraction bands, black arrows. (c)Basophilic cytoplasmic mineralization in hematoxylinand eosin, gray arrows, and (d) brown-black cytoplasmicmineralization in von Kossa stained section, grey arrows.Bar = 100 microns.

Figure 14.2 Sections of left ventricle with myocardial�brosis stained with picrosirius red. (a) Red (dark)collagens type I and III hematoxylin and eosin within thesubendoardium and interstitium, and (b) same sectionpolarized to show collagen birefringence (white).

Figure 15.1 Preparation of coronal slices starting fromthe ventral aspect of the minipig brain. The majority of

the slices are prepared from the ventral aspect of thebrain because of the distinct anatomical landmarks. Thecerebellum is sliced starting from the dorsal aspect, dueto its prominent contours.

Figure 15.2 Trimming of the minipig brain. Eleven brainslices are prepared from standardised locations, in orderto obtain representative sections of key neuroanatomicregions. After the method recommended by Garman (2003) formicroscopic evaluation of large-sized brains.

Figure 17.1 Alizarin stained minipig skeleton on day 110of gestation.

Figure 17.3 Restraining position for oral administration.2.5 2.0 1.5 1.0 4.5 4.0 5.0 3.5 3.0 n g / m L 0.5 0 40mg/kgControl Prevalue Day 56 Prevalue Day 56 Prevalue Day56 250 mg/kg FSH LH

Figure 18.2 In¥uence of testosterone enanthateadministration on the levels of FSH and LH in maleminipigs. (Unpublished data of the Bayer Pharma AG.) 5 4 32 9 8 7 6 n g / m L 1 0 40 mg/kgControl Prevalue Day 60Prevalue Day 60 Prevalue Day 60 250 mg/kg FSH LH

Figure 18.3 In¥uence of cyproterone acetate administrationon the levels of FSH and LH in male minipigs. (Unpublisheddata of the Bayer Pharma AG.) 25 20 15 10 40 35 30 n m o l/ m L 1500 1000 500 0 3000 2500 Testosterone Estradiole2000 p m o l / m L 5 0 10 mg/kg Control Prevalue Day 60Day24 Prevalue Day 60Day 24 32 mg/kg Prevalue Day 60Day 24 100mg/kg Prevalue Day 60Day 24

Figure 18.4 In¥uence of cyproterone acetate administrationon the levels of testosterone and estradiol in maleminipigs. (Unpublished data of the Bayer Pharma AG.)

Figure 18.5 Testis, minipig. Reduced number ofproliferating tubular epithelium (T) and atrophic Leydigcells (L). Left: control; right: cyproterone acetate 100mg/kg; Ki-67 staining (black dots)

Figure 20.1 Reddish brown mucoid and crusty discharge.

Figure 20.2 Entropion of the lower eyelid.

Figure 20.3 Lower eyelid of same pig as in Figure 20.1. 1week after a modi�ed Hotz–Celsus procedure was performed.

Figure 20.4 Conjunctiva visible in the lateral half of the

lower eyelid.

Figure 20.5 Dermoid on the temporo-ventral aspect of thecornea.

Figure 20.6 Super�cial keratectomy of a dermoid. Theaberrant skin, held up by the forceps and still attached tothe conjunctiva at the lateral limbus is carefully peeledoff the cornea.

Figure 20.7 Cornea of the same pig as in Figures 20.5 and20.6 approximately 2 weeks post surgery showingneovascularisation over the surgical area.

Figure 20.8 Heterochromia irides.

Figure 20.9 Heterochromia iridum.

Figure 20.10 Iris coloboma at a typical position at 6O’clock.

Figure 20.11 Microphakia.

Figure 20.12 Microphakia.

Figure 20.13 Anterior subcapsular opacity with peripheralextension.

Figure 20.14 Posterior polar subcapsular cataract.

Figure 20.15 Total cataract.

Figure 20.16 Hyaloid remnant.

Figure 20.17 Hyperplastic hyaloid remnant.

Figure 20.18 Persistent hyaloid artery.

Figure 20.19 Normal variations in pigmentations of theretina.




Figure 20.23 Optic disc showing the deep cup oftenobserved in the minipig.

Figure 20.24 Optic disc showing the deep cup oftenobserved in the minipig.

Figure 20.25 Cross-section disc showing the deep cup ofthe optic disc (magni�cation ×40).

Figure 20.26 Optic disc coloboma.

Figure 20.27 Retinal coloboma involving the optic disc ata typical 6 O’Clock position.

Figure 21.1 Macroscopic appearance of skin in HaemorrhagicSyndrome. (From Madsen, W.L., Jensen, A.L., and Larsen, S.1998. Scand J Lab Anim Sci 25(3):159–166. Withpermission.)

Figure 21.2 Macroscopic appearance of urinary bladder inHaemorrhagic Syndrome. (From Madsen, W.L., Jensen, A.L.,and Larsen, S. 1998. Scand J Lab Anim Sci 25(3):159–166.With permission.)

Figure 21.3 Macroscopic appearance of kidneys inHaemorrhagic Syndrome. (From Madsen, W.L., Jensen, A.L.,and Larsen, S. 1998. Scand J Lab Anim Sci 25(3):159–166.With permission.)

Figure 21.4 Vagina, serosal layer—interstitialhaemorrhages—haemorrhagic syndrome (HE-stain ×20).

Figure 21.5 Femur—normal adipocytes in bone marrow(HE-stain ×5).

Figure 21.6 Sternum—moderate serous atrophy of adipocytesin bone marrow (HE-stain ×5).

Figure 21.7 Femur—marked serous atrophy of adipocytes inbone marrow (HE-stain ×5).

Figure 21.8 Gall bladder—chronic necrotizingcholecystitits (HE-stain ×20).

Figure 21.9 Gall bladder—chronic necrotizingcholecystitits including �brosis and macrophages withpigmented cytoplasm (HE-stain ×40).

Figure 21.10 Microscopic appearance of hypoplastic gallbladder (HE-stain ×10).

Figure 21.11 Skeletal muscle—chronic myositis includingnecrotic myo�bers and regeneration (HE-stain ×20).

Figure 21.12 Skeletal muscle—chronic myositis includingmineralization (HE-stain ×20).

Figure 21.13 Artery, urinary bladder—�brinoid necrotizingarteritis (HE-stain ×20).

Figure 21.14 Artery, urinary bladder—Fibrinoid necrotizingarteritis w. periarteritis (HE-stain ×20).

Figure 21.15 Lung—granuloma with foreign particles(HE-stain ×40).

Figure 21.16 Stomach, glandular part, cardiacregion—erosions/ulceration (HE-stain ×5).

Figure 21.17 Stomach, glandular part, cardiacregion—erosions/ulceration (HE-stain ×20).

Figure 21.18 Normal liver—(HE-stain ×21/2).

Figure 21.19 Normal pancreas—(HE-stain ×10).

Figure 21.21 Normal microscopic structure of mesentericlymph node (HE-stain ×5).

Figure 21.20 Kidney, cortex—focal tubular basophilia(HE-stain ×40).

Figure 21.22 Pituitary—vacuolated pituicytes ofadenohypophysis (HE-stain ×40).

Figure 21.23 Thyroid—haemorrhage and in¥ammation as theresult of blood sampling (HE-stain ×10).

Figure 21.24 Thyroid—ultimobranchial cysts lined bysquamous epithelium with lumenal cellular debris (HE-stain×5).

Figure 21.25 Testes—marked tubular hypoplasia (HE-stain×10).

Figure 21.27 Prostate—subacute in¥ammation in alveoli andinterstitium (HE-stain ×20).

Figure 21.26 Testes—marked tubular hypoplasia (HE-stain×40).

Figure 21.30 Minipig skin (abdominal area): super�cialepidermal necrosis with minimal dermal in¥ammation at 4 hafter treatment (arrow indicates small, round, blackparticles representing gold observed in the epidermis anddermis as a result of PMED application) (HE-stain ×20).(From Dincer, Z., Jones, S., and Haworth, R. 2006. Exp ToxPath 57:351–357. With permission.)

Figure 21.29 Normal minipig skin (abdominal area)(HE-stain ×10).

Figure 21.28 Normal human skin (abdominal area) (HE-stain×10).

Figure 21.31 Minipig skin (abdominal area): completeepidermal regeneration (reepithelization) with resolutionof in¥ammation at 48 h after treatment (HE-stain ×20).(From Dincer, Z., Jones, S., and Haworth, R. 2006. Exp ToxPath 57:351–357. With permission.)

Figure 21.32 Mouse skin (abdominal area): full-thicknessepidermal necrosis (affecting all the layers with nuclearloss of keratinocytes) and minimal dermal in¥ammation at 4h after treatment (HE-stain ×20). (From Dincer, Z., Jones,S., and Haworth, R. 2006. Exp Tox Path 57:351–357. Withpermission.)

Figure 21.34 Cerebellum, meninges: Mineralized foci in themeninges. (HE-stain ×20).

Figure 21.33 Mouse skin (abdominal area): partialepidermal regeneration (reepithelization) with minimalin¥ammation in the dermis at 48 h after treatment(HE-stain ×20). (From Dincer, Z., Jones, S., and Haworth,R. 2006. Exp Tox Path 57:351–357. With permission.) HumanHuman Pig Cow Horse Dog Mouse Rat Pig Cow Horse Dog MouseRat MM M K S F P M M V V P P Q L L L L I F L P L G G L P PP D F F F F F N S S F T K K K K M M M M M G L S L A S A V LL A S L L S L H L G TA T R G G I G S DV A F F F S P P N F FY Y Y V VY S M M L A A A A P K F Y K I T V I I I L P P P PP P L L L H H H S S G D Q S S S K K K Y Y Y F F F K K K V VV I M D D D S S S S E S G G G S D I S K T C C F Q Y S HK PL P W W R Q N H I R Y Y L K K K S H W V Y S T T S S S SW WV V Q R K Q Q E T R H I I I I I V R R R F R EE E E A D R QQ Q Q Q Q Q Q V V V V V W W W W W S L L L L LL L L L L S SS S Y Y Y Y Y V V R V W W W W W W W W W TWV R S Y CC C C CCC C CC C C C A K K K K G G A A A V V P P P P P P C C C C CC C C SSS S S S Q Q R A A A A A Q QSS S S S S S C C C C C SS L F F I I M I F F L F F I V FL L L S V V R R Q D Q V V V

V H L L G G G G G G H H S S S S S L L L L L L L L L L L LLL A A A A A V V V V I F TT K K K V V V V V R G G G G G G GV I F F F F Y F F F I I I I I V V V V V V V I I A A L L T AA V T V V T R R R C C E P A A A A A T T T T T TH P Q Q Q QF T T T T T T T T T T T K K KK K K K K K H R Q Q Q H RK K KK T T K K K K K K K K Y Y Y Y Y K R K A Q Q Q Q Q Q Q K K LLL K T P K QLI K Q L L Q N H L HW S H R Q R K A A E T AR R N N V A F N N N S S S K T R R R K K Q R D D I L Q K Q QG G EDI T T P T T T T F F E F F TE E E E N 1 10 20 CCR3Binding CCR1, 2 and 5 Binding CCR1, 2 and 5 Binding 30 4050 51 60 70 80 90 94 –

Figure 22.2 Comparison of mammalian CCL26 functionaldomains.

Figure 24.3 Miniature swine thymokidney transplantation:(a) composite thymokidney on the day of transplantation,showing engrafted thymic tissue under kidney capsule; (b)histology of thymic tissue in biopsy of thymokidney (H&E).

Figure 28.2 Nuclear donor cells (fetal �broblast cells)for pig cloning. Cells with small size are suitable asnuclear donors. Is virus present in source herd Yes Canorganism be eradicated from source animal populationUnknown Unknown Evaluate further Weigh risk/benefit oftreatment if needed and potential disease to patient andcontact Evaluate further No No Okay to use No No Is viruspresent in donors age group Is virus present in islet cellsor accompanying cells Can organism infect human cells YesYes Yes Yes No

Figure 26.2 Using the ‘selection algorithm’ in axenotransplantation programme allows a multi-level herdmonitoring that should include regular screening of thewhole herd on the individual basis, sows’ screening,donors’ screening and product screening. Where PERV �tsinto the algorithm is highlighted in red. (Kindly providedby O. Garkavenko, LCT.) (a) (c) (d) (e) (b) HNF-1 α(Normal gene construct) Active form (Normal homodimer)Inactive form (Heterodimer) Inactive form (mutanthomodimer) HNF-1α P291fsinsC (Mutant gene construct)Dimeriz atio n domai n (1 – 32 ) Dimerization domai n(1 – 32 ) DN – binding domai n (15 0 – 280) Transactivation domai n (381 – 315) DNA – bindin g domain (15 0 – 280) T ransactivation domai n (3 81 – 631)

Figure 28.5 Dominant-negative mechanism through which amutant human hepatocyte nuclear factor 1α gene disrupt theactivity of an endogenous wild-type gene. Normal HF-1α :P291fsinsC-HNF-1α : gg G G ccc P ccc P ccc P ccc P

ccc P cca P ggg G cca P ggc G ccg P gga G cct Pgcg A ctg L ccc P gct A cac H agc S tcc S cctp ggc G ctg L cct P cca P cct P gcc A ctc Ltcc S ccc P agt S aag K gtc V cac H agc S agc Sagg R gcc A agg R ccc P ggg G acc T tgc C gctA gcc A cgc R tca S cag Q ctc L ccc P tgg Wcct P gcc A tcc S acc T tgc C cct P ctc L cccP cag Q taa ggt cca STOP 290 300 310 310 300 290 Theinsertion site of C added in the poly C tract Chickenβ−globin insulator (1.2 kbp) CMV enhancer (0.4 kbp) Piginsulin promoter (0.7 kbp) Human HNF-1α P291 fsinsC (2.3kbp) SV40 poly -A (0.1 kbp) Chicken β−globin insulator(1.2 kbp) c ggc

Figure 28.4 Expression vector of mutant human hepatocytenuclear factor 1α gene (HNF-1α P291fsinsC). 700 600 500 400300 200 100 0 Control (n = 3) DI09 DI12 DI17 DI21 Daysafter birth B l o o d g l u c o s e ( m g / d L ) 14 28 4256 70 84 98 112 120 140 1540

Figure 28.8 Nonfasting blood glucose concentration of thediabetes-model transgenic-cloned pigs carrying mutant humanhepatocyte nuclear factor Iα gene (DI09, 12, 17, 21) andcontrol wild-type pigs. (From Umeyama, K. et al., 2009.Trans Res 18: 697–706. With permission.) Control Tg pig-1(Max glucose : 285 mg/dL) Tg pig-2 (Max glucose : 646mg/dL) (a) (b) (c) (c′) (b′) (a′)

Figure 28.7 Histochemical analysis of the pancreas of thediabetes-model transgenic-cloned pig carrying mutant humanhepatocyte nuclear factor 1α gene. 900 800 700 600 500 400300 200 100 0 Time after administration (min) B l o o d g lu c o s e ( m g / d L ) Control (n=3) DI12 180 240 300Glucose 3 g/kgBW p . o. 0 60 120

Figure 28.9 Oral glucose tolerance test of thediabetes-model transgenic-cloned pig (DI12) and controlpigs. (From Umeyama, K. et al., 2009. Trans Res 18:697–706. With permission.) N o v o l i n R 0 . 1 U / K g BW s . c I n s u l i n ( – ) I n s u l i n ( + ) M i l k0 6 0 1 2 0 T i m e a f t e r a d m i n i s t r a t i o n (m i n . ) B l o o d g l u c o s e ( m g / d L ) 1 8 0 2 4 04 5 0 4 0 0 3 5 0 3 0 0 2 5 0 2 0 0 1 5 0 1 0 0 5 0 0

Figure 28.10 Response of the diabetes-modeltransgenic-cloned pig to insulin administration.

Figure 28.12 Removal of cytoplasmic lipid droplets(delipation) of porcine morula stage embryos. (a)Delipation of an in vitro-derived morula using

micromanipulation. (b) Noninvasive delipation of an invitro-produced morula. The embryo was centrifuged withoutbeing pretreated for swelling of the zona pellucida. (c)Noninvasive delipation of an in vitro-produced morula. Theembryo was centrifuged after trypsin treatment to induceswelling of the zona pellucida. (d) Piglets born fromsomatic cellcloned embryos vitri�ed at the morula stageusing noninvasive delipation and MVC vitri�cation. Day 5Embryonic Stem cells (ESC) I I Bona fide procine ESC andEpiSC have not been established Characterization of stemcells Use of stem cells Embryonic stem cells •Differentiation into cell types from all three embryonicgerm lineages and the germline • Ability to form teratomas• Ability to form somatic and germline chimeras Somaticstem cells • Differentiation into one or more cell typesfrom at least one embryonic germ lineage Studying theprocess of cell differentiation • Investigating biologicalmechanisms that control cell fate Studying diseasemechanisms • Produce invitro cell models from animalmodels of disease Potential cell therapy • Celltransplantation of differentiated cells to replacedamaged, diseased tissue invivo Epiblast stem cells (EpiSC)I Embryonic germ cells (EGC) Fibroblasts Inducedpluripotent stem cells (iPSC) Somatic stem cells •Mesenchymal stem cells • Neural stem cells • Skin stemcells Day 10 Day 21 Post natus

Figure 29.1 Overall presentation of the different types ofporcine stem cells addressed in this presentation. Theupper panel illustrates the development of the porcineembryo with arrows pointing to the inner cell mass (day 5),the epiblast (day 10), and the mesonephros with thedeveloping genital ridge (day 21). The origins of differenttypes of stem cells are indicated in the lower panel.

Figure 31.2 Immunohistochemistry of macrophage foam cellsin coronary artery of minipig with diet-inducedatherosclerosis. (a) Co-localization of CRP and SRA, (b)Co-localization of SRA and oxLDL, (c) Co-localization ofoxLDL and MCP1, (d) Co-localization of oxLDL and CRP.Scale bar = 50 microns.

Figure 31.1 (a) Abdominal aorta and iliac bifurcation of apig fed a high fat and cholesterol diet stained with SudanIV showing fatty streaks (red) and raised plaques. (b)Common carotid artery of a pig fed a high fat andcholesterol diet stained with Sudan IV showing fattystreaks (red), (c) Cross section of the left anteriordescending branch of the coronary artery showing fattystreaks (red).

Figure 31.3 Immunohistochemistry for VCAM-1. (a) Noimmunoreactivity in endothelium from minipig on controldiet. (b) Immunoreactivity in endothelium from minipigwith diet-induced hypercholesterolemia overtain by foamcells. (a) Ch Ch HP HP NP NP SP SP Ep Ep OP OP Es Es HB HBMan Man TB TB (b)

Figure 33.5 Cone-beam computer-aided tomographic imagesshowing sagittal slices through the oral cavity of aYucatan minipig (a) and a human (b) HP–hard palate;SP–soft palate; TB–tongue base; HB–hyoid bone;Ep–epiglottis; Es–esophagus; Ch–choana; Man–mandible;NP–nasopharyngeal airway; OP–oropharyngeal airway(highlighted to show area). The cross hairs in b indicatethe orientation of the image slices.

Figure 33.4 Sagittal sections through thetemporomandibular joint of growing minipigs. The condylarcartilage is the major growth site of the mandible.Anterior is to the left. (a) Fetal Yucatan minipig. Thecondylar cartilage is thick and comprises most of thecondyle. (b) 16 week-old Hanford minipig (composite photo).Active growth continues posteriorly, while anteriorly thecondylar cartilage is undergoing endochondral ossi�cation.a and b differ in magni�cation; both scale bars are 1 mm.Temp – articular eminence of the temporal bone.Hematoxylin and eosin. (a) (c) (b) (d) dp 4 M 1 M 1 M 2 M 2M 1 dp 4 dp 3 dp 2 M 1 dp 4 dp 3 dp 2 p 1 M 1 dp 4 dp 3 dp2 C dp 4 dp 3 dp 2 p 1 i 3 i 3 i 2 i 1 i 2 i 1 C M 1 dp 4dp 4 dp 3 dp 2 c dp 3 dp 2 i 3 c dp 3 dp 3 dp 4 i 3 i 3 i 1i 1 c c

Figure 33.2 Lateral views of the dentition of Hanfordminipigs showing the �rst year of tooth eruption:approximately 1 mo of age (a), 3 mo (b), 6 mo (c), and ayear (d).

Figure 33.6 Tongue of a Yucatan minipig in lateral view.LN–lingual nerve; HN–hypoglossal nerve; MB and LB–medialand lateral branches of hypoglossal nerve;CP–circumvallate papillae; FP–fungiform papillae;LF–lingual frenum.

Figure 33.7 Tongue reduction surgery in Yucatan minipigs.(a) Diagram of surgical procedure in dorsal view (upperdrawing) and coronal section (lower drawing). The �lled-inareas indicate lines of incision and the part removed. Thedorsal view shows the circumvallate papillae and thecoronal section indicates the position of the neurovascular

bundles. b and c. Examples of tongues 4 weekspostreduction (b) and post-sham surgery (c) seen from thefront (upper frames) and in dorsal view (lower frames).

Figure 33.9 Dentition of a 5 year-old Yucatan sow withoutovert periodontal in¥ammation. (a) Entire cheek tooth rowin right lateral view. Both upper and lower �rst molars(M1) are worn down to the roots and are on the point ofbeing shed. The lower third and fourth premolars(asterisks) show extensive calculus accumulation associatedwith alveolar bone loss. There is also marked loss ofmaxillary alveolar bone, and the upper third premolar waslost premortem. (b) Enlarged view of the premolar region.Planimentry in a 20 mm di ameter full thickness wound modelin adult female Göttingens minipigs 3.5 3 2.5 2 1.5 10.5 0 S u r f a c e ( c m 2 ) 1 3 5 8 11 Days 14 17 20Epithelialization Granulation Unspecified would area

Figure 35.1 Representative full skin thickness woundhealing kinetic

Figure 36.1 Collage of infrared eye images captured duringthe progression of pupil constriction from baseline tocomplete miosis during a 60 min whole-body vapor exposureto 0.47 mg/m 3 GB. (From Hulet, S. W., et al., 2006a.Inhal Toxicol 18(2):143–153. With permission.) –6 0.1 1 ×1 0 3 c e l l s / μ L 10 100 1000 4 1.6 Gy 1.7 Gy 1.8 Gy 2Gy 1.6 Gy 1.8 Gy 1.7 Gy 1.8 Gy 2 Gy 2 Gy 1.6 Gy 1.8 Gy 1.7Gy 1.8 Gy 2 Gy 2 Gy 1.9 GY 2 Gy 1.6 Gy 1.8 Gy 14 Time(days) Platelets 24 –6 0 2 4 6 12 10 8 4 14 Time (days)Time (days) Time (days) RBCs 24 –6 0 1 × 1 0 3 c e l l s /μ L × 1 0 3 c e l l s / μ L × 1 0 3 c e l l s / μ L 2 5 4 37 6 8 4 14 Lymphocytes 24 –6 0 2 4 6 12 14 10 8 4 14Neutrophils 24

Figure 36.3 Hematological changes in Gottingen minipigsirradiated with lethal and high-sublethal single acutedoses of 60 Co (TBI), at a dose rate of 0.6 Gy/min.

Figure 36.4 Gross pathology of lethally irradiatedGöttingen at necropsy. (a) Intestine, (b) heart, (c) brain,and (d) lungs.

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