SWINE ANIMAL MODELS FOR HUMAN DISEASE AND RESEARCH USES I.INTRODUCTION A.Animal models are analogous diseases or syndromes as observed in animals to human disease. B.Four types of animal models: 1. Spontaneous 2. Experimentally-induced 3. Negative (non-models) 4. Orphan C.Selection criteria for animal models should: 1. Accurately mimic the desired function or disease 2. Species Availbiltiy 3. Data extrapolatable to man 4. Be available to multiple investigators 5. Be handled easily by most investigators 6. Survive long enough to be functional 7. Fit available animal housing facilities 8. Be of sufficient size to provide multiple samples 9. Be polytococous (multiparous) so that multiple offspring are produced for each gestation D.Major Pig Breeds used as models: 1. Domestic pigs 2. Miniature pigs II.REASONS FOR CONSIDERING PIGS AS MODELS A.Better anatomic similarities than dogs B.Better student / facility acceptance C.Cost of pigs versus dog or primates III.CARDIOVASCULAR SYSTEM A.Comparative Anatomy 1. Coronary artery distribution is more similar to humans than are other animals 2. Pigs have a vaso vasorum in the aorta 3. Left azygous vein empties into coronary sinus instead of precava 4. Higher blood pressure (145 - 160/105 BP) 5. Higher heart rate 100 - 150 BPM 6. Very similar cardiac output to humans 7. Higher pulmonary pressure 8. Microscopic anatomy similarities and differences III.CARDIOVASCULAR SYSTEM B.Uses as models 1. Cardiac arrhythmias 2. Myofibrillar Degeneration and Necrosis 3. Myocardial infarct 4. Persistent Ductus Arteriosis (PDA) 5. Cardioplegia 6. Growing heart model 7. Atherosclerosis 8. Hypertrophic cardiomyopathy 9. Congestive cardiomyopathy 10. Infectious endocarditis / pericarditis 11. Heart transplants 12. Bioprothesis heart valve 13. Aortic grafts (flap techniques) and shunt production IV.GASTROINTESTINAL A.Comparative Anatomy 1. Torus pyloricus 2. Branching of mesenteric vessels 3. Spiral colon (Ascending colon) B.Uses as Models 1. Peptic Ulcers 2. Intestinal transplant (mucosal and segmental) 3. Granulomatous Enteritis (Crohn's Disease) 4. Total parenteral nutrition studies 5. Ileal bypass - length and circumference reduction of bypassed segment is similar to humans 6. Pneumatosis intestinalis - respirator induced 7. Bloat / Gastric dilatation 8. Response of intestine to colostrum V.PULMONARY A.Comparative anatomy 1. Submucosal gland of pigs most analogous to humans 2. Striking of glycoprotein composition of submucosal gland of swine and man 3. Lung size is similar to man 4. Lung functional capacity is similar to man V.PULMONARY B.Uses as Models 1. Chronic Bronchitis a. Fascicle Number 96 b. Human Disease: Chronic Bronchitis c. Animal Disease: Enzootic Pneumonia of Swine d. Basic pathology is hypertrophy of bronchial submucosal glands and increased production of mucus (Man and SWine) e. Enz. Pne. of pigs show a direct association of infection to hypertrophy of the glands. Suspected but not proven in man. f. Chemical induction of the same signs by use of isoprenaline in swine has been used. g. Reid Index - Ratio of the thickness of the submucosal gland to the thickness of the entire bronchial wall. Gland - to - wall ratio. VI.RENAL A.Comparative Anatomy 1. Left Kidney is Cranial (as in human) 2. Geretos Fascia in man is surounding fascia to kidney - pig does not have 3. Right adrenal is difficult to work on (location) 4. Analogous physiology a. Urine / plasma osmolal ratio b. Creatinine reabsorbed 5. Uroliths (spontaneous) - surgical and sonification of calculi B.Uses as Models 1. Embryonal Nephroma (Wilm's tumor) 2. Viral Glomerulonephritis a. Fascicle 19 b. Human Disease: Viral associated renal disease c. Animal Disease: Hog Cholera, Swine Fever d. Circulating virus-gamma globulin complexes are deposited in the glomeruli e. Viruses accentuate autoimmune glomerulonephritis f. HC provide a model for acute viral injury to organs other than the kidney (brain, eye, bone, placenta) VI.RENAL B.Uses as Models 3. Hypertension 4. Transplantation / organ preservation VII.IMMUNOLOGIC A.Comparative Anatomy of Lymph Nodes 1. Lymph nodes are inverted (germinal centers are inside not out outside 2. Peyers patches (2 types) 3. Immunologically mature at 6 months 4. Major histocompatibility complex (MHC) is same as man 5. Similar clotting mechanism to humans B.Uses as Models 1. Von Willebrand's Disease a. Fascicle Number 110 b. Human Disease: Von Willebrand's Disease c. Animal Disease: Porcine Von Willebrand's Disease d. Hemophilia - massive, fatal mucosal hemorrhage e. Deficiency in platelet aggregating factor (PAF) and plasma factor VIII f. Autosomal trait g. periarticular bleeding, hematoma, melena, prolonged estrual bleeding h. Poland China breed i. Swine with VWD are apparently resistent to spontaneous atherosclerosis j. Swine with VWD can be treated with hepatic allografts for resolution of the problem 2. Malignant Lymphoma a. Fascicle Number 56 b. Human disease: Malignant Lymphoma c. Swine disease: Malignant Lymphoma d. Certain classifications of lymphoma are seen in swine (and humans) in immature animal predominately e. Strong comparative histologic appearance VII.IMMUNLOGIC B.Uses as Models 3. Porcine Anaphylaxis 4. Pityriasis Rosea 5. Rheumatoid Arthritis a. Fascicle Number 46 b. Human Disease: Rheumatoid Arthritis c. Animal Model: Arthritis due to Mycoplasma sp. or Erysipelothrix sp. d. Synovitis >> arthritis >> ankylosis e. Presence of rheumatoid factor in the serum f. Other organisms also cause similar changes g. Not an ideal model VIII.ENDOCRINE SYSTEM A.Comparative Anatomy 1. Thyroid - unilobular on ventral surface of trachea at thoracic inlet 2. Thymus - Ventral midline of neck 3. Parathyroids - related to thymus rather that thyroid 4. Adrenals - right adrenal embedded in the wall of the post cava 5. Pituitary - may be removed by supraorbital approach IX.METABOLIC A.Comparative anatomy of Pancreas 1. Encompasses the portal vein 2. Fewer islet cells, separate, infiltrated with fat B.Uses as models for metabolic diseases 1. Segmental pancreatic transplants 2. Total pancreatectomy for type I diabetes IX.METABOLIC B.Uses as models 3. Selection of Yucatan pigs for Type II diabetes 4. GM2 Gangliosidosis a. Fascicle Number 104 b. Human Disease: GM2 Gangliosidosis c. Animal Disease: Porcine Cerebrospinal Lipodystrophy (GM2 Gangliosidosis) d. Occurs naturally in Yorkshire e. Autosomal Recessive mode of inheritance f. `Goose-stepping' by 3 months of age g. Increasing severity of disease until recumbent at 4 - 6 months of age h. Many features in common with Juvenile (Type 3) Human GM2 Gangliosidosis i. Morphology of the cytoplasmic inclusions and degree of neuronal involvement is similar with Human Type 1 and Type 2 (Sandhoff's Disease) j. Pigs being used in enzyme therapy in lysosomal enzyme deficiencies 5. Bialbuminemia 6. Obesity 7. Malignant Hyperthermia a. Fascicle Number 111 b. Human Disease: Malignant Hyperthermia c. Animal Disease: Malignant Hyperthermia d. Occurs in man 1:15000 anesthetization with 65% mortality e. Clinical signs in man and swine: (1) Rapid rise in body temperature (2) Early on have ventricular arrhythmias: (a) Tachycardia (b) Bigeminy (c) Multifocal PVC (3) Hyperkalemia (4) Hypercalcemia f. More common in males, but occurs in both sexes g. Death from direct myocardial damage although certainly lectrolyte disturbances contribute h. Medicament triggers a defect in tissue membrane control of calcium, resulting in rapid redistribution (internally) IX.METABOLIC B.Uses as models 7. Malignant Hyperthermia i. halothane, isoflurane, succinylcholine, or other anesthetic agents j. Poland China, Yorkshire, Landrace, and Pietrain breeds k. Identify susceptible animals by ATP depletion of biopsied muscle and elevated serum potassium in presence of agent l. Multifactorial autosomal dominant transmission m. In humans use Dantrolene (Dantrim) for muscular relaxation 8. Comparative Anatomy of the Liver a. Blood supply is analogous to humans b. Very similar metabolic function (high tolerance for ischemic injury - same as man) c. Bile duct is separate from the pancreatic duct d. Fibrotic component with septation of organ e. withstands immunologic injury with out immunosuppression 9. Uses as Models (liver) a. Liver transplantation X.REPRODUCTIVE SYSTEM A.Comparative Anatomy 1. Corkscrew fibromuscular penis 2. Accessory sex gland analogous to humans 3. Preputial diverticulum 4. Fallopian tubes in 180 - 200 lb pig same size as human 5. Female histology is second behind primates for similarities 6. Ovaries produce relaxin X.REPRODUCTIVE SYSTEM B.Uses as Models 1. Reversible sterilization techniques 2. Cryptorchidism 3. Sex Reversed XX males 4. Male genital microsurgery 5. Training for laser and microsurgery 6. Fetal surgery XI.NEONATAL MEDICINE AND SURGERY MODELS A.Neonatal Necrotizing Enterocolitis B.Iron Deficiency Anemia C.Congenital Erythropoietic Porphyria XI.NEONATAL MEDICINE AND SURGERY MODELS D.Gross Congenital Abnormalities 1. Fascicle Number 13 2. Human Disease: Congenital malformations due to Vitamin A 3. Animal Disease: Large dose Vitamin A at Known Stages of Pregnancy 4. More than 70 types of malformations attributed to Vitamin A are known a. Ancephaly b. Spina Bifida c. Cleft palate, micrognathia d. microopthalmia e. ventricular septal defect f. situs inversus g. imperforate anus h. etc., etc., etc. E.Transient Hypogammaglobulinemia of Infancy XII.MISCELLANEOUS A.Interventional Radiology 1. Production of vascular embolism / thrombosis 2. Control visceral hemorrhages 3. Decrease blood supply to tumors preoperatively 4. Occlude aterioventricular shunts B.Heterochromia irides XIII.INTEGUMENTARY AND BONE A.Comparative Anatomy 1. Analogous gross, microscopic, and ultrastructural features to human 2. Physiologically similar to humans 3. Similar wound healing properties XIII.INTEGUMENTARY AND BONE B.Uses as Models 1. Melanoma a. Fascicle number 258 b. Human disease: Familial Atypical Multiple Mole Melanoma (FAMM) c. Swine disease: Sinclair Melanoma d. Wide spectrum of benign melanocytic lesions that may transform into malignant tumors e. Sinclair Miniature Swine f. 54% of a selected strain affected g. Metastasis & spontaneous regression occur 90% regression by 18 months h. Hyperdiploidy of normal and affected skin (2N=38 normal 2N=42 - 100 abnormal) i. Differentiate from melanosis 2. Osteoporosis a. Fascicle number 179 b. Human disease: Pregnancy and Lactation Osteoporosis c. Animal model: Porcine Lactation Osteoporosis d. Similar to man in bone structure and mineral metabolism e. Only domestic omnivore that develop fractures spontaneously f. Study of role of diet, exercise, and therapeutic regimens 3. Wound healing 4. Skin flaps 5. Burn healing Animal models are analogous diseases or syndromes as observed in animals to human disease. Four types of animal models: 1. Spontaneous 2. Experimentally-induced 3. Negative (non-models) 4. Orphan Selection criteria for animal models should: 1. Accurately mimic the desired function or disease 2. Species Availbiltiy 3. Data extrapolatable to man 4. Be available to multiple investigators 5. Be handled easily by most investigators Selection criteria for animal models should: 6. Survive long enough to be functional 7. Fit available animal housing facilities 8. Be of sufficient size to provide multiple samples 9. Be polytococous (multiparous) so that multiple offspring are produced for each gestation Major Pig Breeds used as models: 1. Domestic pigs 2. Miniature pigs During the last 15 years there have been over 500 scientific publications on the use of pigs as animal models. Reason for consider pigs as models C. Better anatomic similarities than dogs D. Better student / facility acceptance E. Cost of pigs versus dog or primates Cardiovascular System A. Comparative Anatomy 1. Coronary artery distribution is more similar to humans than are other animals 2. Pigs have a vaso vasorum in the aorta 3. Left azygous vein empties into coronary sinus instead of precava 4. Higher blood pressure (145 - 160/105 BP) 5. Higher heart rate 100 - 150 BPM a. Miniature pigs are lower 6. Very similar cardiac output to humans 7. Higher pulmonary pressure 8. Microscopic anatomy: a. Free running Purkinje fibers b. Blood supply to conduction system similar Cardiovascular System B. Uses as models 1. Cardiac arrhythmias a. Susceptible to stress induce arrhythmias b. Susceptible to anesthetic induced arrhythmias Cardiovascular System B. Uses as models 2. Myofibrillar Degeneration and Necrosis a. Associated with post cardiovascular surgery, myocardial hypoxia, multiple cardiotoxicities b. Myofibrillar degeneration or necrosis with contraction bands is the principle pathologic alteration. c. Hepatosis dietetica d. Vitamin E / selenium deficiency disease offers similar signs in the hearts of affected animals e. Prominent myocardial congestion and hemorrhage of the heart has resulted in the name "mulberry heart disease" Cardiovascular System B. Uses as models 2. Myofibrillar Degeneration and Necrosis f. No evidence to suggest that selenium - vitamin E deficiency is the cause of the disease in humans g. Wide variety of diseases are known to present these types of signs h. So, probable that this lesion is an example of common pathological reaction of cardiac tissue to injury initiated by a wide variety of etiologies Cardiovascular System B. Uses as models 3. Myocardial infarct a. Collateralization of blood supply following ischemia (unlike dog and calf) b. Exercise study as it relates to postinfarction recovery Cardiovascular System B. Uses as models 4. Persistent Ductus Arteriosis (PDA) a. Anatomically but not functionally open for 6 weeks b. Functionally open for 7 days Cardiovascular System B. Uses as models 5. Cardioplegia a. Development of chemical cardioplegics b. Development of cryocardioplegics c. Reprofusion injury following use of cardioplegics Cardiovascular System 6. Growing heart model a. Heart and Great vessels 6 week to 6 month analogous to humans Cardiovascular System 7. Atherosclerosis a. Spontaneous incidence ranges from 15 to 35% in pigs b. Induced models also exist approaching 100% (1) Use a susceptible breed (2) Balloon catheter damage to endothelial cells (3) 2% cholesterol diet c. Similar lipoproteins to humans d. Morphology and biochemistry of plaque is similar to humans Cardiovascular System 8. Hypertrophic cardiomyopathy 9. Congestive cardiomyopathy 10. Infectious endocarditis / pericarditis 11. Heart transplants 12. Bioprothesis heart valve 13. Aortic grafts (flap techniques) and shunt production Gastrointestinal A. Comparative Anatomy 1. Torus pyloricus a. Accentuates the pylorus b. Muscle and adipose tissue c. Function is uncertain 2. Branching of mesenteric vessels 3. Spiral colon (Ascending colon) Gastrointestinal B. Using as Models 1. Peptic Ulcers a. Definition: a circumcised break, penetrating below the muscularis mucosa b. Location is different for pigs and humans (1) Pig - Gastric pars oesophaga (85%) squamous epithelium (2) Human - Fundic stomach or proximal duodenum c. Frequency: (1) Pigs - 0 to 60% at slaughter (2) Humans - 7 - 11% unexpectedly found at necropsy d. Young pigs - 40-60 kg e. Spontaneous: Stress and diet f. Induced: Depohistamine Gastrointestinal 2. Intestinal transplant (mucosal and segmental) a. Short Bowel Syndrome (1) chronic diarrhea and malabsorption resulting from loss of large amounts of the GI tract ADJ Small bowel allograft and gross intestinal tract transplant Gastrointestinal 3. Granulomatous Enteritis (Crohn's Disease) a. In man lesion predominate in the ileum but may range from the esophagus to the anus b. Disease is usually segmental (sick - unaffected - sick) c. Signs in man include cobblestone appearence with elongated ulcers d. Histology is charicterized by plasma cells e. Etiology is unclear g. Terminal ileitis caused by Campylobacter sputorum subspecies mucosalis is the proposed model Gastrointestinal 4. Total parenteral nutrition studies a. Possible replacement for monkey in many studies b. Normal nutritional requirements c. Nutritional requirements for cancer patients Gastrointestinal 5. Ileal bypass - length and circumference reduction of bypassed segment is similar to humans 6. Pneumatosis intestinalis - respirator induced 7. Bloat / Gastric dilatation 8. Response of intestine to colostrum Pulmonary A. Comparative anatomy 1. Submucosal gland of pigs most analogous to humans 2. Striking of glycoprotein composition of submucosal gland of swine and man 3. Lung size is similar to man 4. Lung functional capacity is similar to man Pulmonary B. Uses as Models 1. Chronic Bronchitis a. Fascicle Number 96 b. Human Disease: Chronic Bronchitis c. Animal Disease: Enzootic Pneumonia of Swine d. Basic pathology is hypertrophy of bronchial submucosal glands and increased production of mucus (Man and SWine) e. Chemical induction of the same signs by use of isoprenaline in swine has been used. f. Reid Index - Ratio of the thickness of the submucosal gland to the thickness of the entire bronchial wall. Gland -to - wall ratio. Renal A. Comparative Anatomy 1. Left Kidney is Cranial (as in human) 2. Geretos Fascia in man is surounding fascia to kidney - pig does not have 3. Right adrenal is difficult to work on (location) 4. Analogous physiology 5. Uroliths (spontaneous) Renal B. Uses as Models 1. Embryonal Nephroma (Wilm's tumor) a. Malignant mixed cell tumor b. Common tumor in pigs (females) c. Childern less than 5 years of age Renal 2. Viral Glomerulonephritis a. Fascicle 19 b. Human Disease: Viral associated renal disease c. Animal Disease: Hog Cholera, Swine Fever d. Circulating virus-gamma globulin complexes are deposited in the glomeruli e. Viruses accentuate autoimmune glomerulonephritis f. HC provide a model for acute viral injury to organs other than the kidney (brain, eye, bone, placenta) Renal 3. Hypertension a. Addisons Disease b. 2 kidney DOCA (Desoxycorticosterone acetate) Renal 4. Transplantation / organ preservation (kidney & ureter) a. Transplantation techniques b. Rejection syndromes of kidneys c. Ureteral bioprothesis grafts Immunologic A. Comparative Anatomy of Lymph Nodes 1. Lymph nodes are inverted (germinal centers are inside not out outside 2. Peyers patches (2 types) 3. Immunologically mature at 6 months 4. Major histocompatibility complex (MHC) is same as man 5. Similar clotting mechanism to humans Immunologic B. Uses as Models 1. Von Willebrand's Disease a. Fascicle Number 110 b. Human Disease: Von Willebrand's Disease c. Animal Disease: Porcine Von Willebrand's Disease d. Hemophilia - massive, fatal mucosal hemorrhage e. Deficiency in platelet aggregating factor (PAF) and plasma factor VIII Immunologic 1. Von Willebrand's Disease f. Autosomal trait g. periarticular bleeding, hematoma, melena, prolonged estrual bleeding h. Poland China breed i. Swine with VWD are apparently resistent to spontaneous atherosclerosis j. Swine with VWD can be treated with hepatic allografts for resolution of the problem Immunologic 2. Malignant Lymphoma a. Fascicle Number 56 b. Human disease: Malignant Lymphoma c. Swine disease: Malignant Lymphoma d. Certain classifications of lymphoma are seen in swine (and humans) in immature animal predominately e. Strong comparative histologic appearance Immunologic 3. Porcine Anaphylaxis a. Anaphylactic reactions result from pharmacologically active substances released by the reaction of antigen with cells passively sensitized by antibody b. the type of lesion depends on: k. Dose of antigen (1) Route of Contact (2) Frequency of contact (3) Tendency for a given organ system to react (4) Degree of sensitivity of a given individual Immunologic 4. Pityriasis Rosea a. Acute inflammatory dermatosis b. Usually 10 to 35 year of age individuals c. Clinical diagnosis = ring- shaped lesions d. Pigs are the only other animal to exhibit the disease e. Hereditary predisposition has been identified in swine f. Horizontal transmission may also be a factor g. Recovery in 2 - 8 weeks Immunologic 5. Rheumatoid Arthritis a. Fascicle Number 46 b. Human Disease: Rheumatoid Arthritis c. Animal Model: Arthritis due to Mycoplasma sp. or Erysipelothrix sp. d. Synovitis >> arthritis >> ankylosis e. Presence of rheumatoid factor in the serum f. Other organisms also cause similar changes g. Not an ideal model Endocrine System A. Comparative Anatomy 1. Thyroid - unilobular on ventral surface of trachea at thoracic inlet 2. Thymus - Ventral midline of neck 3. Parathyroids - related to thymus rather that thyroid 4. Adrenals - right adrenal embedded in the wall of the post cava 5. Pituitary - may be removed by supraorbital approach Metabolic A. Comparative anatomy of Pancreas 1. Encompasses the portal vein 2. Fewer islet cells, separate, infiltrated with fat Metabolic B. Uses as models for pancreatic diseases 1. Segmental pancreatic transplants 2. Total pancreatectomy for type I diabetes (insulin dependent diabetes or juvenile diabetes) a. Not yet feasible in man b. Pig has low immunoreaction c. Similarity of gross anatomy 3. Selection of Yucatan pigs for Type II diabetes a. Not insulin dependent b. Model for gestational diabetes Metabolic C. GM2 Gangliosidosis 1. Fascicle Number 104 2. Human Disease: GM2 Gangliosidosis 3. Animal Disease: Porcine Cerebrospinal Lipodystrophy (GM2 Gangliosidosis) 4. Occurs naturally in Yorkshire 5. Autosomal Recessive mode of inheritance 6. `Goose-stepping' by 3 months of age 7. Increasing severity of disease until recumbent at 4 - 6 months of age 8. Many features in common with Juvenile (Type 3) Human GM2 Gangliosidosis 9. Morphology of the cytoplasmic inclusions and degree of neuronal involvement is similar with Human Type 1 and Type 2 (Sandhoff's Disease) 10. Pigs being used in enzyme therapy in lysosomal enzyme deficiencies Metabolic D. Bialbuminemia 1. Albumin polymorphism of two distinct bands on electrophoretogram 2. Not of clinical significance except in slightly less thyroxine-binding ability of the blood constituents. 3. Certain genotypes of pigs have consistent bialbuminemia 4. Primarily of interest to scientist studying DNA structure Metabolic E. Obesity 1. Affect all people in times of plenty 2. Maybe some genetics, but requires favorable environment for manifestation of the condition 3. The Ossabaw obese pig is a feral strain a. Has developed increased capability to store calories as fat compared to yorkshire pigs b. Grows more slowly c. Less muscle mass d. Lipogenic enzymes in adipose tissue are 7 times more active than other pigs 4. increase incidence of: a. hypertension b. diabetes mellitus c. renal disorders d. arthritis Metabolic F. Malignant Hyperthermia 1. Fascicle Number 111 2. Human Disease: Malignant Hyperthermia 3. Animal Disease: Malignant Hyperthermia 4. Occurs in man 1:15000 anesthetization with 65% mortality 5. Clinical signs in man and swine: a. Rapid rise in body temperature b. Early on have ventricular arrhythmias: 1) Tachycardia 2) Bigeminy 3) Multifocal PVC c. Hyperkalemia d. Hypercalcemia Metabolic F. Malignant Hyperthermia 6. More common in males, but occurs in both sexes 7. Death from direct myocardial damage although certainly electrolyte disturbances contribute 8. halothane, isoflurane, succinylcholine, or other anesthetic agents 9. Poland China, Yorkshire, Landrace, and Pietrain breeds 10. Identify susceptible animals by ATP depletion of biopsied muscle and elevated serum potassium in presence of agent 11. Multifactorial autosomal dominant 12. In humans use Dantrolene (Dantrim) Metabolic A. Comparative Anatomy of the Liver 1. Blood supply is analogous to humans 2. Very similar metabolic function (high tolerance for ischemic injury - same as man) 3. Bile duct is separate from the pancreatic duct 4. Fibrotic component with septation of organ 5. withstands immunologic injury with out immunosuppression Metabolic B. Uses as Models 1. Liver transplantation Reproductive System A. Comparative Anatomy 1. Corkscrew fibromuscular penis 2. Accessory sex gland analogous to humans 3. Preputial diverticulum 4. Fallopian tubes in 180 - 200 lb pig same size as human 5. Female histology is second behind primates for similarities 6. Ovaries produce relaxin Reproductive System B. Uses as Models 1. Reversible sterilization techniques a. Prosthetic vas deferens b. Laser reconstruction of the oviduct Reproductive System 2. Cryptorchidism a. Incidence is 0.8% in human males b. High relationship of testicular tumor incidence c. High relationship of inguinal hernia incidence d. In swine is autosomal recessive associated Reproductive System 3. Sex Reversed XX males a. Testicular gonadal differentiation without ovarian tissue b. incidence is 1:9000 male births c. Resemble Klinefelter's Syndrome without mental retardation d. Testicles in genetic female pigs is a fairly common inherited condition (incidence not established) Reproductive System 4. Male genital microsurgery 5. Training for laser and microsurgery 6. Fetal surgery a. diffuse, epitheliochorial placentation b. fetal tissue transplantation Neonatal Medicine and Surgery Models A. Neonatal Necrotizing Enterocolitis 1. The best model for this syndrome 2. Fairly common and is a severe disease of premature infants Neonatal Medicine and Surgery Models B. Erythroblastosis Fetalis 1. RBC's bearing antigenic determinant not found in the mother cross the placental barrier 2. Stimulate production of maternal antibody to fetal RBC's 3. If the antibody is IgG --- cross placenta (only in the pig and human) and kill baby 4. Other species the immunoglobulin crosses via colostrum to destroy neonatal RBC's 5. May sensitize adult swine and cause isoerythrolysis by vaccinating with hog cholera contaminated with homologous RBC's Neonatal Medicine and Surgery Models C. Iron Deficiency Anemia 1. Most common human anemia in the world 2. Premature and bottle fed infants and women of reproductive age 3. Hookworm infestation is an important cause in children in endemic areas 4. Suckling pigs are used (after developing the syndrome) to evaluate therapeutics and the course of the disease Neonatal Medicine and Surgery Models D. Congenital Erythropoietic Porphyria 1. Group of diseases involving defects in the heme synthesis pathway 2. Seen shortly after birth or during first 2 years of life 3. Inherited as autosomal recessive 4. Signs in humans include: a. Photosensitivity b. Discolored teeth c. Anemia 5. Signs in swine include: a. Accumulation of porphyrins in skeletal bones b. Do not exhibit photosensitivity Neonatal Medicine and Surgery Models E. Gross Congenital Abnormalities 1. Fascicle Number 13 2. Human Disease: Congenital malformations due to Vitamin A 3. Animal Disease: Large dose Vitamin A at Known Stages of Pregnancy 4. More than 70 types of malformations attributed to Vitamin A are known Neonatal Medicine and Surgery Models F. Transient Hypogammaglobulinemia of Infancy 1. Transient delay of active synthesis of immunoglobulins 2. Only affect production of IgG 3. Newborn pigs are agammaglobulinemic (need colostrum) 4. Deny colostrum means hypogammaglobulinemic for a few week to a few months Miscellaneous A. Interventional Radiology 1. Production of vascular embolism / thrombosis 2. Control visceral hemorrhages 3. Decrease blood supply to tumors preoperatively 4. Occlude aterioventricular shunts Miscellaneous B. Heterochromia irides 1. a difference in color of the the part of the same iris 2. is a component of Waardenburg syndrome a. segmented heterochromia of both irises and choroid b. complete lack of uveal pigmentation c. hearing defects 3. inherited as autosomal recessive in white miniature pig Integumentary and Bone A. Comparative Anatomy 1. Analogous gross, microscopic, and ultrastructural features to human 2. Physiologically similar to humans 3. Similar wound healing properties Integumentary and Bone B. Uses as Models 1. Melanoma a. Fascicle number 258 b. Human disease: Familial Atypical Multiple Mole Melanoma (FAMM) c. Swine disease: Sinclair Melanoma d. Wide spectrum of benign melanocytic lesions that may transform into malignant tumors e. Sinclair Miniature Swine f. 54% of a selected strain affected g. Metastasis & spontaneous regression occur 90% regression by 18 months h. Hyperdiploidy of normal and affected skin (2N=38 normal 2N=42 - 100 abnormal) i. Differentiate from melanosis Integumentary and Bone 1. Osteoporosis a. Fascicle number 179 b. Human disease: Pregnancy and Lactation Osteoporosis c. Animal model: Porcine Lactation Osteoporosis d. Similar to man in bone structure and mineral metabolism e. Only domestic omnivore that develop fractures spontaneously f. Study of role of diet, exercise, and therapeutic regimens Integumentary and Bone 2. Wound healing a. Hairless skin, thick epidermis like man 3. Skin flaps (arterial, myocutaneous, fasciocutaneous) 4. Burn healing a. Evaluate therapeutic agents on healing process b. Porcine xenografts used to "bandage" burned wound XIV. Introduction A. Animal models are analogous diseases or syndromes as observed in animals to human disease. 1\ Four types of animal models: 1. Spontaneous a. Usually more closely resemble the natural course of the disease of humans than induced models b. Naturally occuring disease condition in aniamals and man 2. Experimentally-induced a. Artificial production of disease 3. Negative (non-models) a. Animal model in which a disease process cannot be produced. b. Why are certain animals resistant to a disease 4. Orphan a. Animal diseases in search of a human disease entity b. Analogous to a disease in man but with an entirely different pathogenesis C. Selection criteria for animal models should: 1. Accurately mimic the desired function or disease 2. Species Availbiltiy 3. Data extrapolatable to man 4. Be available to multiple investigators 5. Be handled easily by most investigators 6. Survive long enough to be functional 7. Fit available animal housing facilities 8. Be of sufficient size to provide multiple samples 9. Be polytococous (multiparous) so that multiple offspring are produced for each gestation D. Major Pig Breeds used as models: 1. Domestic pigs a. Yorkshire b. Landrace c. Poland China 2. Miniature pigs a. HORMEL - Also called Sinclair or Minnesota Minature - Developed in the 1950's at U. of Minn. - 4 Feral strains used to create the Hormel: - Piney Woods - Ras-n-Lansa - Catalina - Guam - In the 60's, Yorkshire blood was added b. HANFORD - Developed by Hanford Labs (later became Batelle Labs of Richland, Washington) - Palouse gilts were mated to a Pitman-Moore boar - Later, light swamp hogs and Yucatan minatures were added to the bloodline - Dr. ME Tumbleson (U. of Ill.) is closely associated with the past and current development of the breed - Adult weight at about 100 kg c. YUCATAN - Also called Mexican Hairless or Labco - Developed by CSU during the 1970's` - Slate gray to black animal (occasional white) - Minauture weigh = 70 kg - Micro pigs weigh = 45 kg d. PITMAN-MOORE - Developed by PM from swamp hogs of Florida - Adult weight = 70 kg e. GOETTINGEN - Developed during the 60's at the U. of Goettingen, W. Germamy - Heritage: - small vietanmese pigs - German Landrace - Hormel minature - Adult weight = 40 kg - Very common pig in Europe for biomedical research f. OHMINI - Developed in 1945 in Japan - Crosses of Manchurian pigs with Hampshire, Duroc, and Hormel (later) - Black coarse haircoat, exceptionally long ears, wrinkled skin - Weight = 35 kg g. LEE SUNG - Developed in 1975 - Univ of Taiwan - Adult weight = 30 kg E. During the last 15 years there have been over 500 scientific publications on the use of pigs as animal models. QUESTION?: Why use pigs as animal models? XV. Reasons for consider pigs as models A. Better anatomic similarities than dogs B. Better student / facility acceptance C. Cost of pigs ($300) versus dog (350) or primates (1500) XVI. Cardiovascular System A. Comparative Anatomy 1. Coronary artery distribution is more similar to humans than are other animals 2. Pigs have a vaso vasorum in the aorta NOTE: Vaso vasorum are small arteries in the walls of vessels. They arise from the branches of the artery they supply or from adjecent arteries. 3. Left azygous vein empties into coronary sinus instead of precava 4. Higher blood pressure (145 - 160/105 BP) 5. Higher heart rate 100 - 150 BPM 6. Very similar cardiac output to humans 7. Higher pulmonary pressure 8. Microscopic anatomy: a. Blood supply and conduction system similar with the exception of: b. Free running Purkinje fibers NOTE: Fibers extend 1/4 to 1/2 of the way through the myocardium in DOGS, CATS, PRIMATES, and RODENTS. Fibers penetrate the full myocardium in RUMINANTS, HORSES, SWINE, and BIRDS. B. Uses as models 1. Swine have been used to study cardiac arrhythmias: a. Stress induced arrhythmias 1) vagal stimulation 2) suctioning of the bronchi b. Anesthetic induced arrhythmias 1) PVC 2) Atrial fibrillation c. Ventriculo-atrial conduction pathways (pacemakers) 2. Myofibrillar Degeneration and Necrosis AD In Humans, it is associated with post cardiovascular surgery, myocardial hypoxia, multiple cardiotoxicities b. Myofibrillar degeneration or necrosis of contraction bands is the principle pathologic alteration in both man and swine. c. In swine, ... hepatosis dietetica, unclearly associated with P.S.S., Fatty liver disease, and dietary liver necrosis, .. related to... d. Vitamin E / selenium deficiency disease offers similar signs in the hearts of affected animals. e. Prominent myocardial congestion and hemorrhage of the heart has resulted in the term "mulberry heart disease" f. However, there is no evidence to suggest that selenium - vitamin E deficiency is the cause of the disease in humans g. Wide variety of diseases are known to present these types of signs So, probable that this lesion is an example of common pathological reaction of cardiac tissue to injury initiated by a wide variety of etiologies 3. Myocardial infarct a. The pig exhibits Collateralization of blood supply following ischemia similarily as it occurs in humans (unlike dog and calf) b. Exercise study as it relates to postinfarction recovery 4. Persistent Ductus Arteriosis (PDA) a. Anatomically but not functionally open for 6 weeks b. Functionally open for 7 days c. Creation of functional PDA's using baloon catheters 5. Cardioplegics NOTES: Interruption of myocardial contraction a. Development of chemical cardioplegics b. Development of cryocardioplegics c. Reprofusion injury following use of cardioplegics 6. Growing heart model a. Heart and Great vessels 6 week to 6 month analogous to humans b. Used to study the rapid growth on vascular grafts and repair techniques 7. Atherosclerosis a. Spontaneous incidence ranges from 15 to 35% in pigs b. Induced models also exist approaching 100% NOTE: How do you make ath pigs? c. Use a susceptible breed \AD Balloon catheter damage to endothelial cells (or laser therapy) (2) 2% cholesterol diet d. Similar lipoproteins to humans e. Morphology and biochemistry of plaque is similar to humans 8. Hypertrophic cardiomyopathy 9. Congestive cardiomyopathy 10. Infectious endocarditis / pericarditis 11. Heart transplants - Europeans have long used pigs insted of dogs - Midsternal approach insted of lateral thoracotomy 12. Bioprothesis heart valve 13. Aortic grafts (flap techniques) and shunt production XVII. Gastrointestinal A. Comparative Anatomy 1. Torus pyloricus a. Accentuates the pylorus b. Muscle and adipose tissue c. Function is uncertain 2. Branching of mesenteric vessels differ from human 3. Spiral colon (Ascending colon) B. Using as Models 1. Peptic Ulcers a. Definition: a circumcised break, penetrating below the muscularis mucosa b. Location is different for pigs and humans (1) Pig - Gastric pars oesophaga (85%) squamous epithelium (2) Human - Fundic stomach or proximal duodenum c. Frequency: (1) Pigs - 0 to 60% at slaughter (2) Humans - 7 - 11% unexpectedly found at necropsy d. Young pigs - 40-60 kg e. Spontaneous: Stress and diet f. Induced: Depohistamine 2. Intestinal transplant (mucosal and segmental) a. Short Bowel Syndrome (1) Signs include chronic diarrhea and malabsorption resulting from loss of large amounts of the GI tract (2) Research studies in the area of small bowel allograft and gross intestinal tract transplant 3. Granulomatous Enteritis (Crohn's Disease) a. In man, lesions predominate in the ileum but may range from the esophagus to the anus b. Disease is usually segmental (sick - unaffected - sick) c. Signs in man: (1) Normal to nodular to cobblestoned in appearance (2) Elongated to linear ulcers extending to submucosa (3) Loops of bowel may be adhered to each other (4) Fistula formation is common (5) Mesentery is thickened and edematous d. Histology: (1) All layers of bowel have plasma cells and lymphocytes (2) Granulomas with multinucleated giant cells e. Etiology is unclear (1) May be complex immunodeficiency (2) May be an infectious agent f. In the pig, terminal ileitis has been as the suggested model (1) Characterized by mucosal hyperplasia and muscular hypertrophy (2) This disease in pigs may be caused by Campylobacter sputorum subspecies mucosalis Trivia : What was the name of the kicker for the San Diego Chargers that had Chron's Disease? His father is a well known veterinary pathologist. Rolf Benirschky (Father - Kurt Benirschky) 4. Total parenteral nutrition studies a. Possible replacement for monkey in many studies b. Normal nutritional requirements c. Nutritional requirements for cancer patients 5. Ileal bypass - length and circumference reduction of bypassed segment is similar to humans 6. Pneumatosis intestinalis - respirator induced - Gas filled cyst im the mucosa / submucosa 7. Bloat / Gastric dilatation 8. Response of intestine to colostrum XVIII. Pulmonary A. Comparative anatomy 1. Submucosal gland (tracheal gland - produces mucus to trap particulate matter) of pigs most analogous to humans 2. Striking similarity of glycoprotein composition of submucosal gland of swine and man 3. Lung size is similar to man 4. Lung functional capacity is similar to man B. Uses as Models 1. Chronic Bronchitis a. Fascicle Number 96 b. Human Disease: Chronic Bronchitis c. Animal Disease: Enzootic Pneumonia of Swine d. Basic pathology is hypertrophy of bronchial submucosal glands and increased production of mucus (Man and Swine) e. Enz. Pne. of pigs show a direct association between infection and hypertrophy of the glands. An infectious agent is suspected but not proven in man. f. Chemical induction of the same signs by use of isoprenaline in swine has been used. g. Reid Index - Ratio of the thickness of the submucosal gland to the thickness of the entire bronchial wall. Gland - to - wall ratio. XIX. Renal A. Comparative Anatomy 1. Left Kidney is Cranial (as in human) 2. Geretos Fascia in man is surounding fascia to kidney - pig does not have 3. Right adrenal is difficult to work on (location) 4. Analogous physiology a. Urine / plasma osmolal ratio b. Creatinine reabsorbed 5. Uroliths (spontaneous) - surgical and sonification of calculi B. Uses as Models 1. Embryonal Nephroma (Wilm's tumor) a. Malignant mixed cell tumor b. Most common tumor in pigs (females) c. Childern less than 5 years of age d. Fatal tumor of people, not so in swine e. Histologically identical in both 2. Viral Glomerulonephritis a. Fascicle 19 b. Human Disease: Viral associated renal disease c. Animal Disease: Hog Cholera, Swine Fever d. Lesions develop due to circulating virus-gamma globulin complexes deposition in the glomeruli e. It has been documented that viruses accentuate autoimmune glomerulonephritis f. Besides Viral Glom., HC provide a model for acute viral injury to organs other than the kidney (brain, eye, bone, placenta) 3. Hypertension a. Addisons Disease b. 2 kidney DOCA (Desoxycorticosterone acetate) 4. Transplantation / organ preservation (kidney & ureter) a. Transplantation techniques b. Rejection syndromes of kidneys c. Ureteral bioprothesis grafts XX. Immunologic A. Comparative Anatomy of Lymph Nodes 1. Lymph nodes are inverted in swine and elephants (germinal centers are inside not out outside 2. Peyers patches (2 types) 3. Immunologically mature at 6 months 4. Major histocompatibility complex (MHC) is same as man 5. Similar clotting mechanism to humans B. Uses as Models 1. Von Willebrand's Disease a. Fascicle Number 110 b. Human Disease: Von Willebrand's Disease c. Animal Disease: Porcine Von Willebrand's Disease d. Poland China breed e. Deficiency in platelet aggregating factor (PAF) and plasma factor VIII f. Autosomal trait g. Hemophilia - massive, fatal mucosal hemorrhage with ... h. periarticular bleeding, hematoma, melena, prolonged estrual bleeding i. Swine with VWD are apparently resistent to spontaneous atherosclerosis j. Swine with VWD can be treated with hepatic allografts for resolution of the problem 2. Malignant Lymphoma a. Fascicle Number 56 b. Human disease: Malignant Lymphoma c. Swine disease: Malignant Lymphoma d. Certain classifications of lymphoma in immature animals are seen in swine (and humans) e. Strong comparative histologic appearance 3. Porcine Anaphylaxis a. Anaphylactic reactions result from pharmacologically active substances released by the reaction of antigen with cells passively sensitized by antibody b. the type of lesion depends on: (1) Dose of antigen (2) Route of Contact (3) Frequency of contact (4) Tendency for an organ system to react (5) Degree of sensitivity of a given individual 4. Pityriasis Rosea a. Acute inflammatory dermatosis b. Usually 10 to 35 year of age individuals c. Clinical diagnosis = ring-shaped lesions d. Pigs are the only other animal to exhibit the disease e. Hereditary predisposition has been identified in swine f. Horizontal transmission may also be a factor g. Recovery in 2 - 8 weeks 5. Rheumatoid Arthritis a. Fascicle Number 46 b. Human Disease: Rheumatoid Arthritis c. Animal Model: Arthritis due to Mycoplasma sp. or Erysipelothrix sp. d. Synovitis >> arthritis >> ankylosis e. Presence of rheumatoid factor in the serum f. Other organisms also cause similar changes g. Not an ideal model XXI. Endocrine System A. Comparative Anatomy 1. Thyroid - unilobular on ventral surface of trachea at thoracic inlet 2. Thymus - Ventral midline of neck 3. Parathyroids - related to thymus rather than thyroid 4. Adrenals - right adrenal embedded in the wall of the post cava 5. Pituitary - may be removed by supraorbital approach XXII. Metabolic A. Comparative anatomy of Pancreas 1. Encompasses the portal vein 2. Fewer islet cells, separate, infiltrated with fat B. Uses as models for pancreatic diseases 1. Segmental pancreatic transplants 2. Total pancreatectomy and transplant for type I diabetes (insulin dependent diabetes or juvenile diabetes) a. Not yet feasible in man b. Pig has low immunoreaction (accepts transplants) c. The pig is used because of similarity of gross anatomy d. Not always 100% successful since pig may produce some insulin in gastric mucosa (confuses study) 3. Selection of Yucatan pigs for Type II diabetes a. Not insulin dependent (Adult onset) b. Model for gestational diabetes C. GM2 Gangliosidosis 1. Fascicle Number 104 2. Human Disease: GM2 Gangliosidosis 3. Animal Disease: Porcine Cerebrospinal Lipodystrophy (GM2 Gangliosidosis) 4. Occurs naturally in Yorkshire 5. Autosomal Recessive mode of inheritance 6. `Goose-stepping' by 3 months of age 7. Increasing severity of disease until recumbent at 4 - 6 months of age 8. Many features in common with Juvenile (Type 3) Human GM2 Gangliosidosis 9. Morphology of the cytoplasmic inclusions and degree of neuronal involvement is similar with Human Type 1 and Type 2 (Sandhoff's Disease) 10. Pigs being used in enzyme therapy in lysosomal enzyme deficiencies D. Bialbuminemia 1. Albumin polymorphism of two distinct bands on electrophoretogram 2. Not of clinical significance except in slightly less thyroxine-binding ability of the blood constituents. 3. Certain genotypes of pigs have consistent bialbuminemia 4. Primarily of interest to scientist studying DNA structure E. Obesity 1. Affect all people in times of plenty 2. Maybe some genetics, but requires favorable environment for manifestation of the condition 3. The Ossabaw obese pig is a feral strain a. Has developed increased capability to store calories as fat compared to yorkshire pigs b. Grows more slowly c. Less muscle mass d. Lipogenic enzymes in adipose tissue are 7 times more active than other pigs 4. increase incidence of: a. hypertension b. diabetes mellitus c. renal disorders d. arthritis F. Malignant Hyperthermia 1. Fascicle Number 111 2. Human Disease: Malignant Hyperthermia 3. Animal Disease: Malignant Hyperthermia 4. Occurs in man 1:15000 anesthetization with 65% mortality 5. Clinical signs in man and swine: a. Rapid rise in body temperature b. Early on have ventricular arrhythmias: (1) Tachycardia (: Bigeminy (3) Multifocal PVC c. Hyperkalemia d. Hypercalcemia 6. More common in males, but occurs in both sexes 7. Death from direct myocardial damage although certainly lectrolyte disturbances contribute 8. Medicament triggers a defect in tissue membrane control of calcium, resulting in rapid redistribution (internally) 9. halothane, isoflurane, succinylcholine, or other anesthetic agents 10. Poland China, Yorkshire, Landrace, and Pietrain breeds 11. Identify susceptible animals by ATP depletion of biopsied muscle and elevated serum potassium in presence of agent 12. Multifactorial autosomal dominant transmission 13. In humans use Dantrolene (Dantrim) for muscular relaxation G. Liver 1. Comparative Anatomy a. Blood supply is analogous to humans b. Very similar metabolic function (high tolerance for ischemic injury - same as man) c. Bile duct is separate from the pancreatic duct d. Fibrotic component with septation of organ e. withstands immunologic injury with out immunosuppression 2. Uses as Models a. Liver transplantation XXIII. Reproductive System A. Comparative Anatomy 1. Corkscrew fibromuscular penis 2. Accessory sex gland analogous to humans 3. Preputial diverticulum 4. Fallopian tubes in 180 - 200 lb pig same size as human 5. Female histology is second behind primates for similarities 6. Ovaries produce relaxin B. Uses as Models 1. Reversible sterilization techniques a. Prosthetic vas deferens b. Laser reconstruction of the oviduct 2. Cryptorchidism a. Incidence is 0.8% in human males b. High relationship of testicular tumor incidence c. High relationship of inguinal hernia incidence d. In swine is autosomal recessive associated 3. Sex Reversed XX males a. Testicular gonadal differentiation without ovarian tissue b. incidence is 1:9000 male births c. Resemble Klinefelter's Syndrome without mental retardation d. Testicles in genetic female pigs is a fairly common inherited condition (incidence not established) 4. Male genital microsurgery 5. Training for laser and microsurgery 6. Fetal surgery a. diffuse, epitheliochorial placentation b. fetal tissue transplantation XXIV. Neonatal Medicine and Surgery Models A. Neonatal Necrotizing Enterocolitis 1. A model for this syndrome? The only other animal to get this disease. 2. Fairly common and is a severe disease of premature infants B. Iron Deficiency Anemia 1. Most common human anemia in the world 2. Premature and bottle fed infants and women of reproductive age 3. Hookworm infestation is an important cause in children in endemic areas 4. Suckling pigs are used (after developing the syndrome) to evaluate therapeutics and the course of the disease C. Congenital Erythropoietic Porphyria 1. Group of diseases involving defects in the heme synthesis pathway 2. Seen shortly after birth or during first 2 years of life 3. Inherited as autosomal recessive 4. Signs in humans include: a. Photosensitivity b. Discolored teeth 51 Anemia 5. Signs in swine include: a. Accumulation of porphyrins in skeletal bones b. Do not exhibit photosensitivity D. Gross Congenital Abnormalities 1. Fascicle Number 13 2. Human Disease: Congenital malformations due to Vitamin A 3. Animal Disease: Large dose Vitamin A at Known Stages of Pregnancy 4. More than 70 types of malformations attributed to Vitamin A are known a. Ancephaly b. Spina Bifida c. Cleft palate, micrognathia d. microopthalmia e. ventricular septal defect f. situs inversus g. imperforate anus h. etc., etc., etc. E. Transient Hypogammaglobulinemia of Infancy 1. Transient delay of active synthesis of immunoglobulins 2. Only affect production of IgG 3. Newborn pigs are agammaglobulinemic (need colostrum) 4. Deny colostrum means hypogammaglobulinemic for a few week to a few months XXV. Miscellaneous A. Interventional Radiology 1. Production of vascular embolism / thrombosis 2. Control visceral hemorrhages 3. Decrease blood supply to tumors preoperatively 4. Occlude aterioventricular shunts B. Heterochromia irides 1. a difference in color of the the part of the same iris 2. is a component of Waardenburg syndrome a. segmented heterochromia of both iris and choroid b. complete lack of uveal pigmentation c. hearing defects 3. inherited as autosomal recessive in white miniature pig XXVI. Integumentary and Bone A. Comparative Anatomy 1. Analogous gross, microscopic, and ultrastructural features to human 2. Physiologically similar to humans 3. Similar wound healing properties B. Uses as Models 1. Melanoma a. Fascicle number 258 b. Human disease: Familial Atypical Multiple Mole Melanoma (FAMM) c. Swine disease: Sinclair Melanoma d. In swine and man there is a wide spectrum of benign melanocytic lesions that may transform into malignant tumors e. Sinclair Miniature Swine f. As high as 54% of a selected strain affected g. Metastasis & spontaneous regression occur 90% regression by 18 months h. Hyperdiploidy of normal and affected skin (2N=38 normal 2N=42 - 100 abnormal) i. Differentiate from melanosis 2. Osteoporosis a. Fascicle number 179 b. Human disease: Pregnancy and Lactation Osteoporosis c. Animal model: Porcine Lactation Osteoporosis d. Swine bone is similar to human bone in structure and mineral metabolism e. Only domestic omnivore that develop fractures spontaneously f. Swine have been used to study of role of diet, exercise, and therapeutic regimens 3. Wound healing a. Hairless skin, thick epidermis like man b. Have been used to study how wound healing occurs 4. Skin flaps (arterial, myocutaneous, fasciocutaneous) 5. Burn healing a. Evaluate therapeutic agents on healing process b. Porcine xenografts used to "bandage" burned wound