RABBITS: MODELS AND RESEARCH APPLICATIONS USAMRIID Seminar Series Ron Banks 20 October 1989 ANIMAL MODELS: Analogous diseases or syndromes as observed in animals to the human state of health (normal or diseased) HISTORY OF ANIMAL USAGE A. Hammurabi 1. Animal sacrifice alleviated disease 2. Intentions of the gods revealed in organs of sacrifice B. Greek Physicians 1. Studied anatomy and physiology 2. Used dogs and other animals C. Galen 1. Dissected human remains??? 2. Dissection and experimentation of the Barbary Ape D. Vesalius 1. 16th century test on anatomy closes with a chapter on vivisection HISTORY OF MODELS Development of Models A. Early approaches dependant upon animals at hand B. Bacteriology focused need for defined selections of models C. Koch's Postulate #3 "... inoculation from such cultures must reproduce the disease in susceptible animals..." D. Progression of Model Usage 1. Magical mirrors of disease a. Up till the 19th century b. Rough approximation of human conditions c. Gross agreement of disease states 2. Trial and error subjects a. 19th century to present b. Has resulted in many discoveries 3. Comparison systems at the molecular level a. Malignant hyperthermia b. Diabetes c. Transgenic research d. Embryo transfer TYPES OF MODELS A. Spontaneous: Naturally occurring disease conditions in animals that have comparable disease conditions to man. A. Experimentally-induced: Artificial production of disease in a prepared animal model. B. Negative: An animal model in which a disease cannot be produced. C. Orphan: May be analogous to a disease in man but with an entirely different pathogenesis, or an animal disease looking for a human counterpart. BIASES IN SELECTING MODELS A. Anthropomorphism B. Familiarity MODEL SELECTION CRITERIA A. Approximate the human on basis of: 1. Anatomy 2. Physiology B. Which ever animal provides a disease state of interest C. Species availability D. Data extrapolatable to man E. Available to multiple investigators F. Easily handled G. Functional survival time H. Fit available housing I. Sufficient size for multiple samples J. Multiple offspring NON-ANIMAL MODELS A. Physicochemical techniques B. Computer or Math models C. Microbiological techniques D. Cell or tissue culture HISTORY OF THE RABBIT (IN RESEARCH) A. Discovered in Spain about 100 B.C. B. Domesticated in the 1500's C. Standardization of breeds in 1800's 1. Research Uses a. 1852: Rabbits have DL-hyoscyamine (a) Can survive belladonna (b) Endogenous atropine esterase b. 1884: Pasteur develops rabies vaccine c. 1891: Heape performs embryo transfer (a) Influence on phenotype of the uterine environment d. 1908: Ignatowsky produces atherosclerosis (a) Fed diets of milk, meat, and eggs (b) Produced intimal lesions (c) Believed lesions due to protein e. 1928: Demonstrated intranuclear development of herpes virus f. Graafian follicle was first observed g. Coat colors and Mendelian inheritance h. Immunology studies i. Testing of human use products j. Basic science studies k. Diagnostic requirements l. Eye Research m. Pyrogen testing n. Fetal drug induced teratology o. Parasite research LITERATURE REVIEW OF RABBIT USE A. 1956 to 1800 ... Over 8000 citations B. 1966 to 1987 ... 130,000 citations linking the rabbit to all areas of research C. 1988 to present ... 821 citations under the search criteria: Rabbit: Model: Human Disease D. Numbers of Rabbits Used (APHIS; ILAR records 1989) 1967 504,500 1978 439,986 1982 547,312 1983 466,810 1984 529,101 1985 544,621 1986 521,773 1987 534,385 ADVANTAGES OF USING RABBITS A. Provides repeatability of animal model studies B. Large enough for single samples C. Many stocks/strains as animal models D. Easily managed E. Quality of immunologic products F. Ease of reproductive control DISADVANTAGES OF USING RABBITS A. Most colonies are a storehouse of diseases B. Extremely variable to responses to general anesthetics RESEARCH APPLICATIONS RITARD = Removable Intestinal Tie - Adult Rabbit Diarrhea 1. Ligate at the ileocecal junction 2. Campylobacter fetus ssp. jejuni 3. Restore patency 4 hours post infection 4. Develop mucus diarrhea lasting 10 days 5. Organisms present in feces THIRY-VELLA 1. Isolated loop of intestine 2. Fistulated to skin 3. Obtain pure intestinal juice 4. Used in mucosal immunity APPENDICULAR CATHETERIZATION 1. Catheter in tip of appendix 2. Port buried subcutaneously in neck 3. Delivery of antigens to GALT 4. Bypassing upper GI tract PLACENTATION A. Hemochorial type as seen in humans and rodents B. Fetal tissues bathe in "lake" of maternal blood C. Useful for study of agents crossing maternal - fetal tissues Epitheliochorial Endotheliochorial Hemochorial Horse Dog Rodents Pig Cat Lagomorphs Cow Primates Man D. Tissue present in each placenta type FETUS FETUS FETUS Endothelium Endothelium Endothelium Mesenchyme Mesenchyme Mesenchyme Chorion Chorion Chorion Epi. of Endom. Connect. Tissue Endothelium Endothelium MOM MOM MOM DRAIZE A. Developed in 1944 by J.H. Draize B. Provides a pseudo-objective scoring system of the eye irritancy potential C. Four primary groups which require assessment: 1. Pharmaceutics (Eye therapeutics) 2. Cosmetics and toiletries (Shampoo, soap) 3. Consumer products (Detergents) 4. Industrial chemicals (Hazardous agents) D. Performing the Draize test 1. Liquid = 0.1 ml 2. Solid = 0.1 gram 3. Conjunctival sac 4. 4-6 rabbits A. Advantages of test 1. Whole animal/organ evaluation 2. Complete products/specific chemicals can be tested in concentrated or dilute form 3. Observe healing and recovery phase 4. Several Acts require eye-irritation testing 5. Yields quantitative and qualitative information through the scoring system 6. Test is easily modifiable 7. Rabbits are easy to handle 8. Ocular surface is large and easy to interpret degree of response 9. Give a conservative estimate that err's in mans favor B. Criticisms 1. Lack of reproducibility between labs 2. Subjectiveness of scoring 3. Lack of fine discrimination 4. Basic physiologic eye differences 5. Ethical unacceptibility of the test C. Alternatives 1. Cell toxicity: a. Adherence b. Membrane integrity c. Metabolic changes 2. Organ culture 3. Water Flea Assay 4. Sperm Motility 5. Chorioallantoic Membrane (Hen Egg) Assay 6. Tetrahymena thermophila POLYCLONAL ANTIBODIES A. Mouse is the primary animal, but... B. Rabbits are used for significant quantities of polyclonals due to: 1. High Quality 2. High Quantity SERA PRODUCTION A. Rabbit anti-goat, rabbit anti-sheep B. Other antibodies ACQUIRED IMMUNODEFICIENCY SYN. (AFIP Fascicle Number 320) A. Human 1. Characterized by: a. Profound immune dysfunction b. Opportunistic infection c. Spread of malignant tumors 2. T cells are the major target cell 3. Transmitted by `direct' contact B. Rabbit 1. Poxvirus related to: Shope Fibroma Virus Rabbit Myxoma Virus C. Profound T and B cell suppression D. Cultures produce lymphokines that inhibit antibody production responses of normal cells E. Transmitted by direct contact ACUTE ACALCULOUS CHOLECYSTITIS (AFIP Model Number 336) A. Human 1. Seen post surgery of trauma a. Child birth b. Multiple transfusions c. Bacterial sepsis d. SLE 2. Signs include: a. Inflammation of gall bladder b. Vascular dilatation c. Edema d. Erosion of epithelium B. Rabbit a. Induced by Lysophosphatidylcholine b. Perfusion of the gall bladder c. Lesions include: (1) Mucosal damage (2) Vascular dilatation (3) Edema (4) Erosion of epithelium ACUTE RESPIR. DISTRESS SYN. (AFIP Fascicle Number 275) A. Human 1. Characterized by: a. Interstitial inflammation b. Hemorrhage c. Edema d. Infiltration of plasma cells and macrophages 2. Acute and chronic injury B. Rabbit 1. Single injection of Phorbol Myristate Acetate 2. Characterized by: a. Chronic neutropenia b. Thrombocytopenia c. Acute Respiratory Distress d. Hemorrhagic pneumonitis 3. Pathogenic mechanisms not understood ANENCEPHALY (ACLAM Text) A. Human 1. Partial or total absence of forebrain 2. Most common congenital malformation of the brain 3. Exencephaly proceeds to anencephaly 4. Causes unclear but may include; a. Poor maternal nutrition b. Consanguinity of parents c. Ancestors with anencephalic posterity d. Previous birth of anencephalic B. Rabbit 1. Exencephaly is more frequent due to short gestation time relative to man 2. Affected female outnumber males 7:1 3. Twinning does not affect rate 4. Genetic basis supported by 3 percent offspring 5. Periodic fluctuation point to environment ATHEROSCLEROSIS (ACLAM Text) A. Human 1. Deposits of yellowish plaque (atheromas) 2. Inner media of: a. Large arteries b. Medium sized arteries 3. Deposits contain: a. Cholesterol b. Lipoid material c. Lipophages B. Rabbit 1. Significant dissimilarities exist: a. Medial mineralization b. Affects aortic arch and thoracic aorta c. Affects proximal carotid arteries d. Plaques in pulmonary arteries and vein 2. To produce similar "human" lesions: a. Inject with foreign serum proteins b. Feed high cholesterol diet 3. Useful to study interrelationships of: a. Hypercholesterolemia... b. Immune complex damage... c. Endothelial damage... and ... d. Pathogenesis of atherosclerosis e. WHHL (Watanabe) (1) Watanabe Heritable HyperLipidemic CAMPYLOBACTER ENTERITIS (AFIP Model Number 329) A. Human 1. Campylobacter fetus ssp. jejuni 2. Major cause of bacterial diarrhea (Worldwide) 3. Dysentery-like syndrome with: a. Profuse watery diarrhea b. Mucus c. Leukocytes d. Blood B. Rabbit 1. RITARD technique used to study 2. 2-7 day incubation period 3. Biopsies show: a. Edema of lamina propria b. Inflammatory infiltrates c. Crypt abscesses d. Mucin depletion e. Increased mitotic index CARDIOMYOPATHY (ACLAM Text) A. Human 1. Non-specific term applying to lesion located in the myocardium 2. Less common than ischemic myocardial disease with atherosclerosis 3. An important cause of myocardial failure B. Rabbit 1. Due to stress of over crowding 2. Useful for structural and functional studies of the damaged myocardium CHAGAS'S DISEASE (AFIP Fascicle Number 334) C. Human 1. Trypanosoma cruzi, flagellate protozoan 2. Macrophages and muscle cells are penetrated (But can parasitize any cell) 3. 2/3 of acute infections are silent 4. Characterized by: Fever Splenomegaly Lymphadenopathy Myositis Ganglioneuritis Cardiomegaly Cardiac dilatation D. Rabbit 1. Inbred III/J rabbits 2. Characterized by: Fever Splenomegaly Lymphadenopathy Myositis Ganglioneuritis Cardiomegaly Cardiac dilatation CHOLERA OR CYSTIC FIBROSIS (ACLAM Text) A. Human 1. Cholera: Hypersecretion of electrolytes water and mucus from a healthy epithelium 2. CF: Derangement of transport of electrolytes and production of mucus B. Rabbit 1. Enterotoxin induced secretory disease 2. Hypersecrete electrolytes water and mucus from a normal epithelium 3. Link in pathogenesis at cellular level CLEFT PALATE / CLEFT LIP PALATOSCHISIS / CHEILOSCHISIS (ACLAM Text) A. Human 1. Cleft of hard palate, soft palate or both 2. Cleft in upper lip; maybe into nose 3. Severely affected not survive past 1 year 4. Etiology is unknown a. Genetic b. Environmental c. Both 5. Single gene or polygenic B. Rabbit 1. 13 percent in one colony born over a 2 year period had palatoschisis and hydrocephalus 2. Interaction between genes and environment 3. Often associated with: a. Spina bifida b. Dwarfism CRYPTOCOCCAL MENINGITIS (AFIP Model Number 318) A. Human 1. Cryptococcus neoformans 2. Low grade pathogen that causes subacute or chronic meningitis 3. Lesions seen include: a. Gray glistening exudate b. Packing of the subarachnoid space with organisms and mononuclear cells B. Rabbit 1. Cryptococcus neoformans 2. Innately resistant to infection 3. Require immunosuppressive event for chronic infection to occur 4. Lesions seen include: a. Gray glistening exudate b. Packing of the subarachnoid space with organisms and mononuclear cells CYSTIC DISORDERS OF THE KIDNEY (ACLAM Text) A. Human 1. May be unilateral or bilateral 2. May involve medulla or cortex 3. May occur in children or adults 4. Adult - Autosomal dominant 5. Children - Autosomal recessive B. Rabbit 1. Autosomal recessive 2. Both sexes affected 3. Cyst of tubular origin 4. Found in cortex 5. Occur after 1 month of age 6. Strain IIIvo DEFICIENCY OF C6 (ACLAM Text) A. Human 1. Inherited as autosomal recessive 2. Increased susceptibility to: a. Gonococcal infection b. Meningococcal infection B. Rabbit 1. Autosomal recessive trait 2. Prolonged clotting time 3. Retarded prothrombin consumption 4. Can be corrected by adding purified C6 DIABETES MELLITUS (AFIP Fascicle Number 266) A. Human 1. Insulin dependent (Children) 2. Insulin independent (Adult) a. Often obesity associated B. Rabbit 1. Spontaneous in the NZW rabbit 2. Lesions limited to beta cells 3. No increase in atherosclerosis or peripheral capillary basement membrane alterations have been noted ENDOCARDITIS (ACLAM Text) A. Human 1. Inflammation of the endocardium 2. Associated with febrile disease 3. Acute or chronic 4. Bacterial or non-bacterial B. Rabbit 1. Catheter placement of 100 organisms 2. Good model to study aspects a. Bacterial b. Pathological c. Immunologic 3. Reproduces complications of chronic indwelling catheters in humans ENDOMETRIAL ADENOCARCINOMA (AFIP Model Number 21 in Fascicles) A. Human 1. Cessation of menstruation is related to incidence of endometrial adenocarcinoma 2. Generally is associated with; a. Glandular hyperplasia b. Diabetes c. Obesity d. Hypertension B. Rabbit 1. Incidence high in rabbits 2. 4 to 7 year old rabbits 3. Multicentric, both uterine horns 4. Loss of estrogen ... increasing tumor incidence GLAUCOMA (ACLAM Text) A. Human 1. One of 3 major causes of blindness 2. Increase in intraocular pressure 3. Pathogenesis dependent on type of glaucoma B. Rabbit 1. Inherited glaucoma of NZW 2. Semi-lethal trait a. Small litters b. Poor viability c. Lower fertility C. Pressure reducing drugs have no effect HERPES SIMPLEX ENCEPHALITIS (AFIP Model Number 352) A. Human 1. Herpes Simplex Type 1 2. Ubiquitous among humans 3. 70% fatality in untreated 4. Brain access is not clear B. Rabbit 1. NZW injected in olfactory bulb 2. 30% develop clinical seizures 3. Inclusion bodies, perivascular cuffing 4. Only real difference is with: a. Documentable dysphagia b. Confusion HYPERCALCEMIC NEPHROPATHY (ACLAM Text) HYPERCALCEMIA OF MALIGNANCY (AFIP Model Number 168) A. Human 1. Insidious and progressive 2. Secondary to neoplastic involvement 3. Impair ability to concentrate urine B. Rabbit 1. Transplantable 2. Profound hypercalcemia and calcium nephropathy 3-4 weeks after transplant 3. VX-2 produces prostaglandin 2 (potent bone resorption stimulating agent 4. Reverse hypercalcemia with: a. Tumor excision b. Indomethacin administration HYDROCEPHALUS (AFIP Fascicle Number 38) A. Human 1. Increased quantity of CSF 2. Classified as: a. Communicating (1) Secretion/absorption imbalance (2) Absorptive dysfunction b. Non-communicating (1) Developmental abnormalities (2) Inflammatory lesions (3) Neoplasms B. Rabbit 1. Essentially identical to the human condition (Communicating type) 2. Direct relationship between the maternal blood levels of Vitamin A and presence o hydrocephalus. 3. Vitamin A deficient diet 4. Numerous strains can be used 5. Also genetic form (autosomal recessive) a. (hy) gene frequently associated with dwarfism b. May be genetically controlled vitamin A metabolism INFLAMMATORY BOWEL DISEASE (AFIP Fascicle Number 205) A. Human 1. Ulcerative colitis 2. Crohn's Disease 3. Exogenous antigens initiate immune response in colon B. Rabbit 1. Dinitrochlorobenzene (DNCB) 2. Sensitize on skin with DNCB 3. Challenge by intrarectal drop of DNCB 4. Anamnestic response is rapid with: a. Mononuclear cells b. Edema c. Tissue necrosis KYPHOSIS (ACLAM Text) A. Human 1. Often associated with other defects: a. Metatrophic dwarfism b. Enzyme defects c. Metabolic defects d. Scoliosis B. Rabbit 1. Seems associated with spina bifida 2. Minimal SB... free of kyphosis 3. Significant SB... kyphosis MANDIBULAR PROGNATHISM (ACLAM Text) A. Human 1. Lower jaw larger than normal -or- 2. Is normal and positioned forward 3. May be hormonal (acromegaly) 4. May be strictly genetic B. Rabbit 1. Walrus teeth, Buck teeth, Malocclusion 2. Due to facial (maxillary) shortening... not mandible lengthening 3. Believed to be genetic (autosomal recessive) NEPHROBLASTOMA (AFIP Fascicle Number 193) A. Human 1. Rare tumor appearing before age 10 (Ave. age is 3) 2. Close association of epithelial and mesenchymal elements 3. Many names for the condition Wilms Tumor Embryonal Nephroma Embryoma Adenomyosarcoma Mixed Teratoid Tumor B. Rabbit 1. Experimentally induced (transplacental ethylnitrosourea) 2. Tumors do metastasize 3. Develop renal insufficiency 4. May be a good model for chemotherapy, radiotherapy, or surgery. OSTEOPETROSIS (ACLAM Text) A. Human 1. Marble Bone Disease, Albers-Schonberg Disease 2. Rare inherited disorder 3. Severe generalized osteosclerosis 4. Bone marrow transplantation corrects abnormalities of infantile osteopetrosis B. Rabbit 1. Hereditary condition transmitted by autosomal recessive (os) gene 2. Dutch-belted breed; OS/J strain 3. Incisor eruption delayed 4. Growth rate declines 5. Condition un-correctable OTITIS MEDIA (ACLAM Text) A. Human 1. Inflammation of the ear Pain Deafness Fever Tinnitus Vertigo 2. Importance during speech development B. Rabbit 1. Wry Neck, Torticollis 2. Pasteurella multocida 3. Common rabbit pathogen 4. Susceptibility under genetic control PELGER-HUET ANOMALY (AFIP Fascicle Number 278) A. Human 1. Nonsex-linked dominant trait affecting 1 in 6000 people 2. Characterized by: Reduced nuclear segments (Neutrophils) Coarseness of nuclear chromatin 3. Neutrophil function is not affected 4. May be a feature or pre-leukemia B. Rabbit 1. Inherited nonsex-lined dominant trait 2. If homozygous - lethal (Super-Pelger) a. Most die intrauterine (18% live birth) b. If survive - skeletal malformations c. It may be pre-leukemic SCOLIOSIS (ACLAM Text) A. Human 1. Usually acquired post - natally 2. Congenital form associated with: a. Arthrogryposis b. Dwarfism c. Club hand d. Hemivertebra 3. Autosomal recessive trait B. Rabbit 1. Characterized by: a. Reduced, missing, or hemisegments b. Differs from man in absence of associated defects 2. Two unrelated inbred strains exhibit the syndrome at rate of 1:15 normal SPINA BIFIDA (ACLAM Text) A. Human 1. Spectrum of patterns 2. Determinants are unknown 3. Considerable speculation on mechanisms of neural tube defects B. Rabbit 1. AC strain of Dutch Belted 2. Lethal autosomal recessive (sb) 3. Frequency is relatively high and unpredictable 4. Associated conditions: a. Cleft lip and palate Kyphosis b. Ventral deviation of tail c. Etc...etc..etc STAPHYLOCOCCAL BLEPHARITIS (AFIP Model Number 361) A. Human 1. Inflammatory disorder of the eyelids 2. Etiology not clear: a. Staphylococcus aureus b. Exotoxin c. Hypersensitivity B. Rabbit 1. NZW immunized for 90 days 2. Rabbit studies suggest hypersensitivity 3. Meibomian glands are spared SYSTEMIC HYPERTENSION (ACLAM Text) A. Human 1. Multifactorial in cause a. Genetics Environmental 2. Increase in blood pressure above levels expected in the general population 3. 85-90 percent is essential (No etiology) B. Rabbit 1. Certain strains have increased systolic pressure (30-40 mm Hg) 2. Incidence can be increased by successive breeding (20% heritability) 3. SHR rat is by far more important VESICOURETERAL REFLUX (ACLAM Text) A. Human 1. Defective ureter valve allows reflux 2. High incidence in kids with urinary tract infections 3. Relationships ??????? a. Urinary Tract Infection b. Vesicoureteral reflux c. Pyelonephritis B. Rabbit 1. Occurs in 40 - 80 percent of all rabbits 2. Specific strain, sex differences are not known 3. Little has been done to date on relationships of the syndrome VON WILLEBRAND'S DISEASE (ACLAM Text) A. Human 1. Complex multifaceted disorder of hemostasis 2. Autosomal inheritance 3. Decreased platelet activity B. Rabbit 1. Flemish Giant - Chinchilla rabbits 2. Autosomal with variable penetrance 3. Mild to moderate bleeding tendency 4. Trait has been maintained in a line OTHER SUGGESTED MODELS (ACLAM Text) ALBINISM A. Graded series of alleles at the C locus B. Provides a stepped system to study B-ADRENERGIC RESPONSE A. Decreased B-Adrenergic response B. May be same as decrease in aqueous humor formation of humans CONTACT DERMATITIS A. Two clinical entities: Allergic and Irritant EMPHYSEMA A. Fairly common in older rabbits B. Irregular distribution C. Asymptomatic until advanced V ENDOMETRIOSIS A. NHP'S are the only spontaneous model B. Has been induced in rabbits C. Surgically implanted endometrium D. Induced by Estradiol Cypionate ENTROPION A. Congenital Entropion is relatively common B. Believed to be genetically controlled HYPOGONADIA A. Partial of complete sterility B. Affects both sexes C. ACEP strain from Jax Labs IMMUNE DAMAGE A. Hypersensitivity pneumonitis B. Induced with Ovalbumin in Complete Freund's Adjuvant C. Thickening of alveolar septa D. Increased numbers of: Monocytes Eosinophils Lymphocytes Macrophages LYSOZYME DEFICIENCY A. Autosomal recessive B. Not a model of human disease but... C. Useful in understanding role of lysozyme in mammalian tissue D. Affected rabbits have less than 1 percent of lysozyme in all body tissues except thymus ... which is normal. OSTEOARTHRITIS A. Induced model in the rabbit: 1. Long Bone; IV Staph. aureus 2. Joints; Papain B. Useful for studies of; 1. Pathogenesis 2. Radiologic lesions 3. Treatment regimens XANTHOMAS A. Papule, nodule, or plaque of yellow skin color on skin B. Due to deposits of lipids C. Light cells with foamy cytoplasm D. Ham been induced in the rabbit... by feeding high cholesterol diet E. Chicken; Model (naturally occurring) REFERENCES 1. Health Benefits of Animal Research. Edited by William I.. Gay, DVM. Foundation for Biomedical Research. Chapter entitled: The Rabbit as a Research Subject. by Richard R. Fox. 2. Spontaneous Animal Models of Human Disease, Volumes I. Edited by Edwin J. Andrews, Billy C. Ward, and Norman H. Altman. 1979. The American College of Laboratory Animal Medicine Series. Academic Press. 3. Spontaneous Animal Models of Human Disease, Volumes II. Edited by Edwin J. Andrews, Billy C. Ward, and Norman H. Altman. 1979. The American College of Laboratory Animal Medicine Series. Academic Press. 4. Handbook: Animal Models of Human Disease. (The AFIP Fascicles 1 through 16). Registry of Comparative Pathology, AFIP, Wash. D.C. 5. Laboratory Animal Medicine. Edited by James G. Fox, Bennett J. Cohen, Franklin M. Loew. 1984. The American College of Laboratory Animal Medicine Series. Academic Press. 6. Reproduction of Laboratory Animals. Kevin Ohair, USAMRIID Seminar Series. 1986. 7. Rabbit: Animal Models of Human Disease. Jim McMillian, USAMRIID Seminar Series. 1986. 8. Species Reference Briefs: Alternatives to the use of Animals in Research and Education. National Agricultural Library. NAL SRB 88-11. September 1988. 9. Species Reference Briefs: Alternatives to the use of Animals in Research and Education. National Agricultural Library. NAL SRB 89-02. November 1988. 10. Tetrahymena thermophila as an Indicator of Ocular Irritancy in Rabbits. Jerald Silverman, Stephan Pennisi. Alternative Methods in Toxicology. Volume 3. 1985. 11. The Rabbit Eye Irritancy Test - Are there In Vitro Alternatives?. Michael Scaife. ATLA Volume 12. 1985. DEFINITION AND INTRODUCTION ANIMAL MODELS Evaluation and understanding of a human disease conditions is the first step in eliminating that disease condition from the earth. This has been exemplified by the removal of smallpox as a major disease problem for many nations. Often however, study of the human condition presents significant problems; ethical ... studies of humans as they died from a disease, therapeutic ... deciding who receives a trial medication that may do as much damage as good, statistical ... having enough people on both sides of the therapeutic screen (some live and some die), and many other considerations. It therefore makes ethical, biomedical sense to me that similar disease conditions of animals be evaluated; thereby preserving and improving the human state of health. Thus we are in search for a surrogate state of the human condition, or a model of human disease. By definition, animal models are analogous diseases or syndromes as observed in animals to the human state of health (normal or diseased). History of animal model study: In the time of Hammurabi animals were often used as surrogates for humans. If you had contracted a disease, then you would have offered an animal sacrifice to the appropriate god. When a god accepted your animal sacrifice, it included the disease for which you suffered and for which the animal gave its life. Your future would have also been revealed in the organs of the sacrificed animal ... especially the liver. During the era of ancient Egypt, Greek physicians of Alexandria studied anatomy and physiology of dogs and other animals, attempting to understand the human body and methods of extending a more healthful state of life. Many stories have been passed around concerning Claudius Galenus' (130 - 200 A.D.) antics of dissecting human bodies washed out of graves by floods. Certainly however, this celebrated Greek physician and personal surgeon to the Roman Emperor Marcus Aurelius, would have never stooped to such gutter medicine. His most significant contributions however, were involving dissection and experimentation on animals ... especially the Barbary Ape (Macaca sylvanus). If for nothing else, we should remember the immortal remarks of the astute physician " ... nature does nothing in vain ...". So profound were his activities, and the strength of the church, that for almost 1000 years (until the Renaissance) nothing changed. In the sixteenth century, Vesalius penned an anatomic text in which he discussed at length vivisection of animals. Development of animals as models for human disease: Early approaches to selection of animal models was primarily dependent upon the animal at hand (with the exception of Galen's anthropomorphic interest in primates). Waiting for a precipitating event to establish a direction for biomedical research, finally arrived with the development of the science of bacteriology (19th century). The needs of bacteriologists for reproducible events led to the modern antecedents of animal models. Through studying organisms and attempting to understand the infection process, observed differences in specie susceptibility to microbes were identified. This focused attention to the physical world led to the development of Koch's postulates ... specifically number 3 which states: "... inoculations from such cultures must reproduce the disease in susceptible animals ..." Eras of animal model usage: Looking at biomedical research using animals as models for the human condition, we can find 3 eras of animal model usage. First, the period where animals were used as magical mirrors of disease, lasted thousands of years ... till around the 19th century. It was characterized by rough approximations of human anatomy and disease and the beginnings of understanding a need for a replacement to the human condition. During the 19th century, a period of scientific trial and error research used animals for infectious disease research. Intense activity of disease research has continued, much in the vein of trial and error (rabies, plague, polio, malaria). And now we are moving into a new era, one in which we see a comparison of animal disease with human disease at the molecular level. An example of this is the disease diabetes, for it was only after fairly recent research that subtle yet important differences were found between the animal condition and man. Animals do not have capillary basement membrane thickening as occurs in human diabetes. Other aspects of this disease may still be useful to study in animals. There are four types of animal models: 1) Spontaneous; 2) Experimentally-induced; 3) Negative (non-models); and 4) Orphan. Spontaneous models more closely resemble the natural course of a disease in humans. These are naturally occurring disease conditions in animals that have comparable disease conditions in man. An example would be melanomas of man and animals. Experimentally-induced models result through the artificial production of disease, giving an animal a disease or condition it would not normally have. An example would be cholera infection of prepared rabbits. Negative or non-models are animal models in which a disease process cannot be produced. Why are certain animals resistant to a disease? An example might be why don't birds get rabies? And then lastly, there are orphan models. Animal diseases in search of a human disease entity. Orphan models may be analogous to a disease in man but with an entirely different pathogenesis. An example might be canine distemper. Biases often seen when selecting animals as models: The proper selection of an animal to use as a model for the condition of interest is paramount. The proper model may reap rewards, while the wrong model will certainly garner frustration and failure. As support personnel, veterinarians need to be on guard for these biases to effect a fruitful study. Often a concern of investigators is the desire to work with primates to the exclusion of other animals due to the belief of unparalleled similarities. Some investigators believe that only primates, of all the animals in the animal kingdom, have sufficient human similarities to justify research. This is termed anthropomorphism. An additional bias that must be discouraged is familiarity, which I will define as the desire to maintain working with the animals with which we have held as pets or have worked with in our earlier days. The probability of finding an animal model truly identical to a specific human pathology is low. However, similar models do exist, and often the use of animal models in more than one species provides greater insight into determining the etiology of the disease entity for humans. Major selection criteria for animal models should include approximating the human as closely as possible on the basis of present anatomic and physiologic knowledge. Additionally, projects should use whatever animal will provide a usable manifestation of the normal physiological / metabolic process or disease state under study. While not as important, but just as consequential, there are other selection criteria for animal models that include: Sufficient availability of the species under consideration; The data obtained must be extrapolatable to man; The animal should be available to multiple investigators; The animal should be handled easily by most investigators; It must survive long enough to be functional; It must fit available animal housing facilities; It should be of sufficient size to provide multiple samples; And it should be polytocous (multiparous) so that multiple offspring are produced for each gestation. Consideration of Non-animal Models: Not simply because of the current situation of animal activism, but also in our quest for good research and medical achievements at minimal cost we need to consider non-animal replacement systems whenever possible. However, non-animal replacement systems do require animal studies for validation. Examples of these alternative systems include: Physicochemical Techniques ... in which you identify tissue responses to physical or chemical agents; Computer or mathematical models may be useful when a biological effect can be represented by a known equation, such as occurs in irradiation studies. Microbiological models use microbes for specific responses to chemicals. It should be noted that the reliability of microbiological models is still under debate. Cell / tissue cultures are useful as screening tests for chemicals, however, often they do not represent the whole animal effect, and sometimes yield false positives or false negatives. The single most significant problem with non-animal replacements is that they cannot mimic the complicated processes that occur in humans or animals in which multiple organs act in concert for an ultimate effect. As we have briefly addressed animal models in general, we shall now turn our attention to the rabbit: models and research applications. HISTORY OF RABBIT USE IN RESEARCH The rabbit was discovered is Spain about 100 B.C. by the Phoenicians, and although some attempts at domestication were made during the Greek and Roman eras, true domestication was not initiated until about the l6th century. Investigations of various aspects of this animal's ocular anatomy occurred as far back as the 17th century, but it was not until the 18th century that standardization of breeds was accomplished. Although there is little record of initial attempts to use rabbits as laboratory animals, scattered reports began to appear by the middle of the 19th century. ln 1852 an Austrian physician reported that rabbits were able to thrive on a diet consisting solely of belladonna leaves, the deadly nightshade. Today, it is known that one-third of randomly selected domesticated rabbits, possess the enzyme DL-hyoscyamine and are capable of hydrolyzing atropine. The discovery of endogenous atropinesterase represents the first fully documented observation of a heritable modification of a pharmacologic response. This characteristic is controlled by a pair of allelic genes. As a model of infectious disease processes, the rabbit has an extensive resume. Pasteur, in 1884, demonstrated that dogs could be protected against rabies by the injection of suspensions of dried spinal cord from rabbits experimentally infected with the disease. For nearly a century, Pasteur's vaccine was the only post-exposure treatment available for rabies in humans. The first embryo transfer work was performed by Walter Heape in 1891 using rabbits to answer a basic scientific question concerning the influence of the uterine environment on the phenotype of the developing embryo. Rabbits were the first animals to be used as models of atherosclerosis. In 1908, Ignatowsky produced intimal lesions resembling human atherosclerosis by feeding diets of milk, meat, and eggs to rabbits. His conclusion that the lesions were due to the high level of animal protein in the rabbits' diet was later refuted by a number of workers who incriminated the fat portion of the diet. It is now recognized that cholesterol is the atherogenic component of the diet. In 1928 the first demonstration of intranuclear development of virus was made in studies of rabbits with herpetic lesions. The early work in the transmission of tuberculosis was done in the rabbit. The first direct observation of the rupture of a Graafian follicle was observed in rabbits. The utilization of the domestic rabbit as a research animal for genetic studies dates from the dawn of Mendelism, with the various coat colors affording ready material for confirmation of the generalities of Mendelian inheritance. The rabbit was also used extensively by the early immunologists, Bordet, Ehrlich, and others. It is still the most widely used research animal in immunologic studies primarily because of the high quality and quantity of its antibodies. Rabbits, because of their hypersensitivity to irritants, continue to be used for testing primary skin irritants, rubefacients, counterirritants, photosensitizers, eye irritants, and other allergens. It should be noted however, that recent announcements by Revlon and Avon indicate they have decreased/eliminated animal (rabbit) testing of new cosmetics and will rely upon "... the judgement of pharmacological, toxicological, medical experts, non- animal test methods and the past safety history of formulations and ingredients to determine product safety ..." The rabbit has also been used in all types of basic science studies, including nutrition, reproduction, and embryology and monoclonal gammopathies. The rabbit is one of the principal laboratory animals used in eye research. Historically, the rabbit has been the test animal for diagnosis of human pregnancy (Friedman test), and it has become the basic test animal for pyrogen testing as well as other pharmacologic research. The limbus amelocyte lysate test is a alternate assay to the pyrogen test. The rabbit has been used extensively in parasite research. A variety of parasites in man and other animals have been observed in rabbits. Studies have directed attention in areas of natural infection. Examples of studied parasites include: Fasciola hepatica (ruminants); Ascaris suum (swine); Angiostrongylus cantonensis (rat); Taenia piriformis (dog); Schistosoma japonica (man). Rabbits are a commonly used research aniaml, ranking just behind mice and rats in numbers used. The Institute of Laboratory Animal Resources and the Animal and Plant Health Inspection Service reports that over 400,000 lagomorphs have been used annually in biomedical research, with New Zealand White being the most commonly used breed. A comprehensive literature review done in 1956 provided over 8,000 references covering a variety of subjects which used rabbits as models dating back to the late 1800's. MEDLARS II, the National Library of Medicine's Medical Literature Analysis and Retrieval System, had in its data bank for the period l966 - 1987 over 130,000 bibliographic citations linking the rabbit to virtually all areas in biomedical research. From January 1988 to the present 821 citations, under the search criteria of rabbit, model, and human disease, are listed in MEDLARS further illustrating the continued usefulness of the rabbit in biomedical research. In summary, the rabbit has been used in almost all areas of biomedical research and has been a significant contributor in many specialized areas of scientific investigation. ADVANTAGES AND DISADVANTAGES IN BIOMEDICAL RESEARCH The rabbit is large enough to provide adequate quantities of tissue for experimental work without pooling of samples but its small size makes it more economical than dogs or monkeys and it does not have the emotional stigma often encountered with the use of dogs or monkeys in research. Blood samples can be taken from birth onward in sufficient quantity to study the effect of age during the development of a particular pathological condition. The rabbit is especially suited for use as a laboratory animal because of certain characteristics. The intermediate body and skeletal size, timed ovulatory response, nest-building phenomena, immobility reflex, response to presumptive teratogenic drugs, and the simplicity of care relative to the larger animals have given the rabbit a unique importance in biomedical research. It is docile, and easy to handle, and varies considerably in weight and conformation; according to breed. This affords a range of sizes with which to work. Its size, rate of maturity, prolificacy, and feeding habits permit statistically satisfactory samples without excessive cost. The large ear veins provide easy access to the circulatory system and have made the rabbit a valuable resource in serological and immunological research. The quality and quantity of rabbit antibodies are often considered superior to all other laboratory animals. Many workers prefer rabbit complement over that of the guinea pig because of the more rapid lysis of sensitized red cells. The lower molecular weight and solubility of rabbit sera give it a greater precipitating power than that from other frequently used animal sources, specifically the horse and the chicken. Since the female ovulates only after mating, the time of ovulation can be determined accurately, and embryologic material specifically timed can be easily obtained in teratologic studies. Superovulation may be stimulated in the female rabbit with possible recovery of up to 100 viable eggs. Research such as this has provided significant information on embryo development. Sperm can be readily collected from males and artificial insemination techniques are easily accomplished, as described in a recent LAS article. These features have been used in studies of spermatogenesis, sperm capacitance, and reproduction. The rabbit reproduces easily, and large numbers of offspring can be readily obtained for experimental studies. There are two main disadvantages to the use of the rabbit in the laboratory: (1) Most rabbit colonies are virtual storehouses of various diseases, and (2) The rabbit is extremely variable in its responses to most general anesthetics. Much work, however, is being done to develop healthy, disease-free stocks and to maintain them under experimental conditions. In fact, several specific pathogen free rabbit colonies are in operation. As an experimental animal, the rabbit is an excellent compromise between the relatively large and slow-breeding domestic animals on the one hand and the relatively small and rapidly breeding rodents on the other. RESEARCH USES AND TECHNIQUES RITARD = Removable Intestinal Tie - Adult Rabbit Diarrhea. The abdomen is opened surgically, the cecum is permanently ligated near the ileocecal junction, and a slip knot is used to occlude the terminal ileum. A 10ml sample of Campylobacter fetus ssp. jejuni (1 X 109 CFU) is injected into the mid small bowel. The incision is closed, and the loose ends of the slip knot are brought out through the incision. Four hours after surgery, the slip knot is released, and intestinal patency is restored. These rabbits usually have a mucus diarrhea lasting 10 days. Organisms are present in the feces. THIRY-VELLA LOOP TV loops are constructed by isolating a loop of intestine (jejunum) with intact blood vasculature and nerve supply. The intestinal segment is fistulated to the skin and the continuity of the jejunum is restored with end-to-end anastomosis. TV loops have been used extensively in the rabbit as an aid to obtain pure intestinal secretion which is free from other digestive secretions and food. They have also been use for studying mucosal immunity and pathogenesis of intestinal organisms. APPENDICULAR CATHETERIZATION The rabbit is a primary model for the study of immunologic function. This model provides a means of bypassing the upper gastrointestinal tract and the effects of gastric and upper gi secretions. The catheter is placed in the tip of the appendix, tunneled subcutaneously to a buried injection port in the dorsocervical neck. The model has been developed for both the adult NZW and the neonate (7 day old) animal. PLACENTATION The rabbit provides an excellent mammalian model system to investigate placental transfer of drugs, metabolites and steroids. Both rabbits and humans have the same type of placentation (hemochorial), allowing the closest contact between maternal and fetal circulations. Maternal and fetal blood are separated by only one layer of tissue. The fetal tissues of the chorion, mesenchyme and endothelium lie or bathe in a "lake" of maternal blood, since all maternal tissues have been removed. This arrangement also exists in the rodent, primate and human. To contrast the state of the rabbit, rodent and human to other animals, a chart has been provided: ÉÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍ» º EPITHELIOCHORIAL ENDOTHELIOCHORIAL HEMOCHORIAL º º º º FETUS FETUS FETUS º º º º Endothelium Endothelium Endothelium º º Mesenchyme Mesenchyme Mesenchyme º º Chorion Chorion Chorion º º Epi. of Endometrium º º Connective Tissue º º Endothelium Endothelium º º º º MATERNAL MATERNAL MATERNAL º º º º º ÈÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍÍͼ DRAIZE The Draize eye-irritancy test, developed in 1944 by J. H. Draize, provides an experimental procedure and scoring system for the assessment of the eye irritancy potential of several products used in man. The four primary groups which require eye irritancy assessment studies are: 1) Pharmaceuticals (eye therapeutics) 2) Cosmetics and toiletries (make-up, shampoo, soap) 3) Consumer products (Household detergents and chemicals) 4) Industrial chemicals (hazardous chemicals) The albino rabbit is the most frequently used animal model for eye-irritancy testing. The rabbit eye is highly sensitive, more so than human or monkey, and is considered the best in maximizing the probability of detecting an irritanting substance. The Draize eye- irritancy test procedure involves the instillation of approximately 0.1 ml liquid or 0.1 g solid material into the conjuctival sac of 4 to 6 rabbits while using the other eye for control. Tissue changes are noted as they develop in the iris, cornea and conjunctiva over the course of a specified time period. Scores are developed based on the nature of the change and on the maximal response produced in the rabbit eye. Several advantages and disadvantages have been identified with regard to the use of the Draize eye-irritancy test. Some of the rationale for the use of this test procedure are: 1) Provides a whole animal and organ evaluation 2) Complete products or specific chemicals can be tested in concentrated or dilute form 3) Observation of the recovery and healing process 4) Several acts require eye-irritation test 5) Yields quantitative and qualitative information under the Draize scoring system 6) The test is easy modified 7) A rabbit is easy to handle 8) The ocular surface area of the albino rabbit eye is large and easy to interpret the degree of inflammatory response 9) The Draize test is a conservative estimate of the eye- irritation that err's in favor of man. The Draize test has been severely criticized by animal welfare groups and scientist for: 1) Lack of reproducibility of results from laboratory to laboratory 2) The subjectiveness of scoring and lack of fine discrimination of differences 3) Lack of applicability to man based on basic physiological differences between the human and rabbit eye 4) The ethical unacceptibility of the test itself Although the Draize eye-irritancy test has undergone modifications to reduce pain, ethical unacceptibility in conjunction with concern for animal activists and reported inconsistency of results has motivated scientists to search for in vitro alternatives. Several types of in vitro tests have been developed to assess different aspects of irritancy. Cell toxicity, or cytotoxicity, allow measurement of parameters such as adherence, membrane integrity and metabolic changes associated with irritancy. Organ culture, the isolation and maintenance of animal or human organs is another in vitro alternative that may be utilized for irritation assessment. Other tests include the Water Flea Assay, Sperm Motility Assay, Chorioallantoic Membrane Irritancy, or Tetrahymena thermophila. However, of the in vitro alternatives currently under the development it appears that no single procedure provides a comprehensive evaluation of irritation potential. Rather, a battery of tests may be required to measure the different responses associated with eye-irritancy, e.g. injury/healing and inflammatory response. POLYCLONAL ANTIBODIES Granting the mouse as the primary animal used for the production of polyclonals, rabbits are also heavily used to produce copious quantities of polyclonal antibodies throughout the world. SERA PRODUCTION The rabbit is used extensively for production of rabbit anti- goat, rabbit anti-sheep, or other antibodies. ACQUIRED IMMUNODEFICIENCY SYNDROME (Model Number 320 in Fascicles) Human Disease: Acquired Immunodeficiency Syndrome. Pathogenesis: Profound immune dysfunction, opportunistic infection and the appearance and spread of a malignant tumor. T cells are the major target cell. Animal Disease: Malignant Rabbit Fibroma Syndrome. Pathogenesis: Malignant Rabbit Fibroma virus (MV) is a poxvirus related to Shope Fibroma Virus and the Rabbit Myxoma Virus. MV induces a syndrome of severe immunodeficiency, disseminated tumors, and opportunistic infections. The affected rabbits are profoundly immunosuppressed affecting both the T and B cells. Neither the human or animal lymphocytes respond to mitogens in culture, and these cultures produce factors (Lymphokines) that actually inhibit the proliferative and antibody production responses of normal lymphocytes. Both diseases are transmitted by direct contact and not by the airborne route. ACUTE ACALCULOUS CHOLECYSTITIS (Model Number 336 in Fascicles) Human Disease: Acute Acalculous Cholecystitis. Pathogenesis: A serious and fatal disease seen in patients post surgery or trauma involving inflammation of the gall bladder in the absence of gallstones. It is more commonly seen in females with precedent events such as multiple transfusions, child birth, bacterial sepsis and SLE. The etiology of this condition is unclear and may be multifactorial. Theories regarding pathogenesis include bile stasis, sepsis or ischemia. Animal Disease: Acute Acalculous Cholecystitis Induced by Lysophosphatidylcholine in Rabbits. Pathogenesis: Perfusion of the rabbit gall bladder with lysophosphatidylcholine causes histologic changes identical to man. Lesions included mucosal damage, vascular dilatation, edema and erosion of the normal epithelial cells. ACUTE RESPIRATORY DISTRESS SYNDROME (Model Number 275 in Fascicles) Human Disease: Acute Respiratory Distress Followed by Pulmonary Interstitial Pneumonitis and Pulmonary Fibrosis. Pathogenesis: Both acute and chronic alveolar injury characterized by interstitial inflammation, hemorrhage, edema, infiltration of macrophages and plasma cells. Animal Disease: Pulmonary Artery Injury Induced by Phorbol Myristate Acetate Following Intravenous Administration in Rabbits. Pathogenesis: A single dose of phorbol myristate acetate induces chronic neutropenia and thrombocytopenia, acute respiratory distress, and hemorrhagic pneumonitis. Features seen are strikingly similar to the disease in man. Pathogenic mechanisms are not yet known. ANENCEPHALY (ACLAM Text) Human Disease: Anencephaly. Pathogenesis: Anencephaly is defined as partial or total absence of the forebrain. It is the most common congenital malformation of the human brain and is reported to occur at an incidence of 1 to 2 per 1000 births. Exencephaly is a defect of the calvarium with extroversion of the brain. It is only rarely seen in human births because the condition usually proceeds to anencephaly by the time of birth. While the actual etiology is obscure, predisposing factors may include the previous birth of an anencephalic, consanguinity of the parents, ancestors whose posterity contained other deformed children, and poor maternal nutrition. Animal Disease: Anencephaly. Pathogenesis: In lagomorphs, which have shorter gestation periods, there is less time for anencephaly to develop and exencephaly is seen more frequently. A genetic basis for anencephaly is supported by a 3% incidence in siblings of anencephalics. Affected females outnumber males three to seven times. The possibility of environmental influences, especially those affecting the maternal diet, playing a part in the etiology cannot be overlooked. Periodic fluctuations in incidence rates also point to a possible environmental influence. Anencephaly has been noted occasionally in the strain of Dutch Belted rabbit that carries the gene for spina bifida (sb). ATHEROSCLEROSIS (ACLAM Text) Human Disease: Atherosclerosis. Pathogenesis: Deposits of yellowish plaques (atheromas) containing cholesterol, lipoid material, and lipophages are formed within the intima and inner media of the large and medium sized arteries of the abdomenal aorta. Animal Disease: Atherosclerosis. Pathogenesis: The physiological and pathological dissimilarities between rabbit disease and the disease in man causes them to be looked upon with disfavor by many comparative pathologists. Young rabbits undergo two different types of arterial changes, one being a spontaneously occurring medial mineralization with the lesions primarily in the aortic arch and thoracic aorta. In addition to the arterial lesions, rabbits also deposit fat and cholesterol in most organs, particularly the liver, adrenal glands, spleen, bone marrow, and eyes, resulting in a syndrome more nearly resembling a lipid storage disorder than atherosclerosis. Coronary atherosclerosis in rabbits occurs after feeding a cholesterol and fat diet for 1 month. The distribution of coronary lesions in rabbits is quite different from those of man. Large proximal coronary arteries are relatively spared; the small intramyocardial branches are affected, with their lumens occluded by masses of intimal foam cells. The carotid arteries of the rabbit are affected only in the proximal portion. The distal portion and the cerebral arteries appear to remain free of atherosclerotic changes. Also unlike man, plagues are present in the pulmonary arteries and veins. Rabbits appear to be particularly useful for research on the interrelationships of hypercholesterolemia, immune complex damage to the endothelium, and the pathogenesis of atherosclerosis. The Wantanabe heritable hyperlipidemia rabbit (WHHL) is a model for familial hypercholesterolemia. There is a single gene mutation for the low density lipoprotein in this rabbit. CAMPYLOBACTER ENTERlTlS (Model Number 329 in Fascicles) Human Disease: Campylobacter Enteritis. Pathogenesis: Campylobacter fetus ssp. jejuni is a major cause of bacterial diarrhea worldwide. Infections usually are self-limited, lasting 3-5 days beyond an incubation period of 2-7 days. Profuse watery diarrhea or a dysentery-like syndrome with stools containing mucus, polymorphonuclear leukocytes, and blood. Animal Disease: Campylobacter Enteritis in Rabbits. Pathogenesis: The RITARD technique is used to prepare the model. After a 2-7 day incubation period, the stools are fluid, containing gross mucus but rarely show blood. Mortality results from dehydration. Biopsies contain edema of lamina propria with acute inflammatory infiltrates of varying severity, crypt abscesses, mucin depletion, and an increased mitotic index in the glandular epithelium. Lesions ranged from inflammatory infiltration to epithelial necrosis. CARDIOMYOPATHY (ACLAM Text) Human Disease: Cardiomyopathy. Pathogenesis: Cardiomyopathy is nonspecific term applied to conditions in which the lesions are located in the myocardium rather than the other anatomic structures of the heart. Although cardiomyopathy in man is much less common than ischemic myocardial disease associated with coronary atherosclerosis, the condition is an important cause of myocardial failure, often leading to severe functional decompensation and death. Animal Disease: Cardiomyopathy. Pathogenesis: Cardiomyopathy has been reported in rabbits due to stress associated with severe crowding. Animals were crowded 4 to a cage for 2-week periods alternating with 1 week alone in a cage. During the first month, 20 of 44 rabbits died and 15 died between 2 and 9 months of this crowding regimen. The animals exhibited aggressive behavior during the confinement. At necropsy, heart weight was normal, but there was dilation of the ventricles in most animals. Histologically, there was myocardial edema with both myocytolysis and coagulative necrosis of myofibers. Although this model is not strictly a spontaneously occurring condition, it may be useful for structural and functional studies of the diseased myocardium. There are similarities with idiopathic endomyocardiopathy as seen in southern Africa, but the model differs in the extent of myocardial degeneration and fibrosis as usually encountered in Western countries. CHAGAS' DISEASE (Model Number 334 in Fascicles) Human Disease: Chagas' Disease. Pathogenesis: Trypanosoma cruzi infection, a flagellate protozoan. Macrophages and muscle cells are easily penetrated, but any cell type can be parasitized. Acute infections are clinically silent in over 2/3 of the individuals. Lesions include induration at the port of entry, fever, splenomegaly, lymphadenopathy, electrocardiographic abnormalities, myositis, and ganglioneuritis. Animal Disease: Trypanosoma cruzi infection of inbred III/J rabbits. Pathogenesis: Lesions observed in the rabbit were almost identical to those seen in humans. Persistent electrocardiographic changes were recorded in 90% of the rabbits. Cardiomegaly and dilatation of the chambers were also conspicuous findings. CLEFT PALATE (PALATOSCHISIS) AND CLEFT LIP (CHEILOSCHISIS) (ACLAM Text) Human Disease: Cleft palate (palatoschisis) and cleft lip cheiloschisis). Pathogenesis: Palatoschisis is characterized by a cleft of variable size extending through the hard palate, soft palate, or both. It may be V-shaped or ovoid depending on whether it is open or closed posteriorly. Cheiloschisis (hare lip) presents as a unilateral, bilateral, or median cleft of the upper lip which may extend superiorly to involve the nose. These malformations are clefts left between the various parts caused by failure of normal fusion of the maxillary processes and the median and lateral portions of the frontonasal processes during organogenesis. The precise anatomic location and severity of the resultant cleft determines the clinical entity which may be cheiloschisis, palatoschisis, or a combination of both. The more severely affected babies die so that associated defects are much less common in children surviving 1 year. The etiology of these abnormalities is unknown; however, hereditary, environmental, or interaction of hereditary and environmental factors are likely to be involved. Some are thought to be single gene syndromes while those unassociated with other syndromes are hypothesized to be polygenic. Animal Disease: Cleft palate (palatoschisis) and cleft lip cheiloschisis). Pathogenesis: Palatoschisis associated with hydrocephalus occurred in 148 rabbits representing 13% of those born in an inbred colony over a 2 year period. The condition was thought to be due to a complicated interaction of genetic and environmental influences. Palatoschisis with or without cheiloschisis is closely associated with spina bifida and dwarfism, occurring in 53% of achondroplastic and 97% of chondrodystrophic rabbits. CHOLERA OR CYSTIC FIBROSIS (ACLAM Text) Human Disease: Cholera or Cystic Fibrosis. Pathogenesis: In cholera, the patient hypersecretes electrolytes, water, and mucus from a histologically healthy epithelium. Cystic fibrosis (CF) is recognized as a generalized derangement of transport of electrolytes and production of mucus. The electrolytes are lost excessively in sweat, salivary and lacrimal glands, and excessive tenacious mucus is produced in intestine, pancreatic ducts, bile ducts, salivary glands, trachea and bronchi. Animal Disease: Mucoid Enteropathy (ME). Pathogenesis: ME in the rabbit appears to be a subacute enterotoxin-induced secretory disease. As is the case with cholera, affected rabbits hypersecrete electrolytes, water, and mucus from a histologically healthy epithelium. The fluid-filled small bowel loops in ME appear morphologically similar to the isolated loops produced by enterotoxin. ME may represent a link in pathogenesis, at the cellular level, between two previously unrelated human diseases. CRYPTOCOCCAL MENINGITIS (Model Number 318 in Fascicles) Human Disease: Cryptococcal Meningitis. Pathogenesis: Cryptococcus neoformans is a low-grade pathogen that occasionally causes subacute or chronic meningitis in man. Gray glistening exudate and the packing of the subarachnoid space with organisms or mononuclear cells is a consistent finding. Animal Disease: Cryptococcal Meningitis in Rabbits. Pathogenesis: Rabbits appear innately resistent to cryptococcal infections and require an immunosuppressive event for a chronic infection to occur. The lesions seen are the same as observed in man. CYSTIC DISORDERS OF THE KIDNEY (ACLAM Text) Human Disease: Cystic Disorders of the Kidney. Pathogenesis: Cystic disorders of the kidney may be unilateral or bilateral and involve the cortex, medulla or both, occurring in children or adults. These disorders vary from large polycystic kidneys, which usually result in morphological changes and reduced renal function to small cortical, benign "simple" cysts. The mode of inheritance for polycystic kidneys appears to be autosomal dominant for the adult type and autosomal recessive for the juvenile form. Animal Disease: Polycystic Disease of Rabbits. Pathogenesis: An autosomal recessive model for the "simple cysts" has been reported in Strain IIIvo rabbits. Both sexes are affected. Cysts are not usually observed until the animals are 1 month of age or older. Analysis of serum and urine show no pathological changes. The cysts appear to be of tubular origin and are found in the cortex. DEFICIENCY OF C6 (ACLAM Text) Human Disease: Deficiency of C6. Pathogenesis: Inherited as an autosomal recessive (codominant) trait and associated with increased susceptibility to gonococcal and meningococcal infections. Animal Disease: Deficiency of C6. Pathogenesis: A strain of rabbits has been described with a deficiency of the sixth component of complement. This condition is inherited as an autosomal recessive trait. These rabbits exhibited the same rate of blood clearance of S. typhi as normal rabbits. A study of the hemostatic properties of the blood of these animals showed prolonged clotting times and retarded prothrombin consumption. The clotting defect in these rabbits, which are more pronounced than those described for C4-deficient guinea pigs, can be corrected by the addition of purified C6. It is of interest that similar studies of C6-deficients human showed no evidence of coagulation abnormality. DIABETES MELLITUS (Model Number 266 in Fascicles) Human Disease: Diabetes mellitus. Pathogenesis: Insulin dependent (children). Insulin independent (adult) usually associated with obesity. Animal Disease: Diabetes mellitus of NZW rabbits. Pathogenesis: A spontaneous condition in the NZW Rabbit exhibiting polydipsia and polyuria. Specific lesions are limited to the beta- cells with a marked accumulation of membrane-associated secretory granules. No increase in atherosclerosis or in peripheral capillary basement membrane alterations have been found in diabetic rabbits. ENDOCARDITIS (ACLAM Text) Human Disease: Endocarditis. Pathogenesis: Defined as inflammation of the endocardium, this disease is generally associated with rheumatic fever or other febrile disease. It may present as acute or chronic, non-bacterial (verrucous or rheumatic) and bacterial (mycotic, fungal, or bacterial). Animal Disease: Endocarditis. Pathogenesis: Endocarditis can be induced in the rabbit by placing a catheter tip at the entrance to, or in, the right side of the heart, and then infusing as few as 100 microorganisms. It is a good model to study the bacteriological, pathological and immunologic aspects of bacterial endocarditis. This model reproduces some of the complications of indwelling catheters in humans. ENDOMETRIAL ADENOCARCINOMA (Model Number 21 in Fascicles) Human Disease: Endometrial Adenocarcinoma. Pathogenesis: Cessation of menstruation is related to the incidence of endometrial adenocarcinoma. Hormonal dysfunctions such as the Stein-Leventhal syndrome, have been associated with endometrial carcinoma in young patients. Generally, human endometrial carcinoma is associated with glandular hyperplasia, diabetes, obesity and hypertension. Animal Disease: Endometrial Adenocarcinoma. Pathogenesis: Among known mammalian species, the incidence of endometrial adenocarcinoma is especially high in rabbits. Breed incidence has been reported as: Tan, 50%; French Silver, 25%; Havana, 22%; Dutch Belted, 20%. Incidence in other breeds ranged from 8 to 17%. Female rabbits 4 to 7 years old have the highest incidence. The adenocarcinomas are often multicentric, involving both uterine horns, with frequent central ulcerations. Uterine horns are often distended with the tumor, hydrometra and pyometra. The tumors usually originates from the deeper glandular portion of the epithelium. In both humans and rabbits, there appears to be a relationship between loss of estrogen and the increasing incidence of tumors in the older female. Males are peculiarly resistant to tumor development. GLAUCOMA (ACLAM Text) Human Disease: Glaucoma. Pathogenesis: One of the three major causes of blindness in humans. Glaucoma is actually a group of eye diseases characterized by an increase in intraocular pressure which causes pathological changes in the optic disk and typical defects in the field of vision. Pathogenesis dependent upon specific type of glaucoma. Animal Disease: Glaucoma. Pathogenesis: The inherited glaucoma of the rabbit (NZW) has been studied more extensively than that in any other species. Unfortunately, this trait in the rabbit is linked with a semilethal trait that results in small litters, poor viability and lower fertility. Certain pressure-reducing drugs that work in humans have no effect in rabbits. HERPES SIMPLEX ENCEPHALITIS (Model Number 352 in Fascicles) Human Disease: Herpes Simplex Encephalitis. Pathogenesis: Herpes Simplex Type 1 (HSV-1) is ubiquitous among humans. The infection is manifest by fever, seizures, hemiparesis, speech and behavioral disturbances. Left untreated, HSE has a mortality in excess of 70%. HSV-1 preferentially attacks ectodermal tissue in the immunocompetent adult causing herpes labialis, herpes keratitis, and herpes simplex encephalitis. The virus may become latent in the ganglia and recur after latency. The potential for viral latency in human brain tissue is largely unknown. Although it is assumed that herpes labialis are spread by contact, the pathway by which HSV-1 gains access to the brain in cases of HSE remains controversial. Animal Disease: Focal Herpes Simplex in New Zealand White Rabbit. Pathogenesis: New Zealand White rabbits are injected in the left olfactory bulb. Animals appear well for at least the first two days after inoculation, after which an encephalitic disease becomes clinically evident. Approximately 30% of rabbits will develop seizures. Microscopic findings are identical with human HSE. The only major differences between the rabbit model and the human disease are absence of documentable dysphagia and confusion in the rabbit. HYPERCALCEMIA OF MALIGNANCY (Model Number 168 in Fascicles) HYPERCALCEMIC NEPHROPATHY (ACLAM Text) Human Disease: Hypercalcemic Nephropathy. Pathogenesis: The hypercalcemia which develops is insidious and progressive and results in nephrocalcinosis. The development of the hypercalcemia has been associated with production of Prostaglandins (and metabolites thereof) by neoplastic cells. One of the earliest and most significant clinical manifestations of hypercalcemia is an impaired ability to concentrate urine which is unresponsive to antidiuretic hormone. Animal Disease: VX-2 Carcinoma of rabbits. Pathogenesis: The VX-2 carcinoma is the result of a malignant transformation of the viral-induced Shope papilloma. A transplantable carcinoma (VX2 carcinoma) has been reported in rabbits that produced profound hypercalcemia and calcium nephropathy 3 to 4 weeks after transplantation. The carcinoma grows rapidly with local infiltration and metastases to regional lymph nodes and lungs. Results of in vitro and in vivo studies suggest that VX2 carcinoma produces prostaglandin E2, a potent bone resorption-stimulating agent. Hypercalcemia occurred in the apparent absence of bone metastases, and was reversed by excision of the primary tumor and was prevented and reversed by administration of indomethacin. Death occurs predominantly at 4 to 8 weeks, with evidence of pulmonary metastases, hypercalcemia, nephrocalcinosis, and renal failure. Necropsies fail to note any distant metastasis to bone. HYDROCEPHALUS (Model Number 38 in Fascicles) (ACLAM Text) Human Disease: Congenital Communicating Hydrocephalus. Pathogenesis: Hydrocephalus is a disorder in which there is an increased quantity of cerebrospinal fluid (CSF) in the ventriculosubarachnoid system. Hydrocephalus can be classified as communicating and noncommunicating. In the latter type, CSF does not enter the subarachnoid space due to an obstruction within the ventricular system. Such an obstruction may be due to developmental abnormalities, inflammatory lesions, or neoplasm that cause stenosis or obliteration of the aqueduct or foramina. Communicating hydrocephalus can be caused by an imbalance of CSF secretion-absorption within the ventricles or to absorptive dysfunction in the subarachnoid space. Animal Disease: Vitamin A Deficiency Hydrocephalus. Pathogenesis: Congenital hydrocephalus can be induced in a number of rabbit strains by feeding does a vitamin A deficient diet. Hydrocephalus has also been reported to be the result of an autosomal recesive gene (hy) and is frequqently associated with dwarfing. Clinical signs of the genetic form is identical to the vitamin A deficient form. It has been postulated that there is a defect in vitamin A metabolism. If present at birth, there is a distinct bulging over the frontal lobes of the brain and a general distortion of the head. If the newborn appears normal but develops the condition postnatally, the general anatomic alterations develop in a predictable pattern culminating in characteristic post natal hydrocephaly. Affected rabbits appeared to have a functional block at the level of the aqueduct or lateral apertures (foramina of Luschka). Signs of vitamin A deficiency hydrocephalus in newborn rabbits are essentially the same as the signs observed in human infant for the congenital communicating type. INFLAMMATORY BOWEL DISEASE (Model Number 205 in Fascicles) Human Disease: Ulcerative colitis and Krohn's Disease. Pathogenesis: Exogenous antigens initiate a cellular immune reaction in the colon and the immune response to the exogenous antigen may be responsible for the pathogenesis of disease in some patients. Animal Disease: New Zealand white rabbit. Immunologic Model of Inflammatory Bowel Disease. Pathogenesis: Dinitrochlorobenzene (DNCB) used to sensitize animals by placing it on their skin. The animal is then challenged by placing a drop of DNCB intrarectal. An anamnestic response occurs with the rapid accumulation of mononuclear cells, edema, and tissue necrosis. KYPHOSIS (ACLAM Text) Human Disease: Kyphosis. Pathogenesis: In man, kyphosis is rarely encountered as a single entity but is associated with several syndromes. These are usually inherited syndromes such as metatrophic dwarfism, enzyme or metabolic defects, and other rare conditions. Scoliosis may be present in the same individual. Animal Disease: Kyphosis. Pathogenesis: The precise cause is unknown, but kyphosis occurs in most rabbits with the recessive trait spina bifida. Marked kyphotic curvature occurs in the majority of achondroplasia stock with spina bifida; only those with minimal spina bifida are free of kyphosis. The condition mimics some human cases associated with spina bifida. MANDIBULAR PROGNATHISM (ACLAM Text) Human Disease: Mandibular prognathism. Pathogenesis: Mandibular prognathism is a condition wherein the lower jaw is either larger than normal or protrudes to a position forward to that which is normal. The condition has been noted in man since earliest times. Its etiology may lie in genetic patterns as was noted historically in the royalty of the Hapsburgs, or it may be the result of an over secretion of the pituitary gland as in acromegaly. Although it is stated that malocclusion affects a large segment of the population, it is difficult to find specific statistical data on the occurrence of the various types of malocclusion. Animal Disease: Mandibular prognathism, Malocclusion, Buck Teeth, Walrus Teeth. Pathogenesis: Mandibular prognathism (mp/mp) has been reported in the rabbit and is due to facial shortening as reflected in a decreased length of the maxillary diastema. A similar cause has been reported for man. A hereditary basis for the occurrence of prognathia in the rabbit is strongly suggested. Mandibular prognathism is inherited as an inherited autosomal recessive trait with incomplete penetrance. NEPHROBLASTOMA (Model Number 193 in Fascicles) Human Disease: Wilms' Tumor, Embryonal Nephroma, Embryoma, Embryonal Adenosarcoma, Mixed Teratoid Tumor, Adenomyosarcoma. Pathogenesis: Rare tumor usually appearing during the first decade of life. Average age is 3 years. Accounts for about 20 of all solid malignancies in childhood. Characterized by a close association of epithelial and mesenchymal tissue elements. Animal Disease: Experimentally induced (transplacental ethylnitrosourea) tumors in the rabbit. Pathogenesis: Experimentally induced (transplacental ethylnitrosourea) tumors in the rabbit do metastasize and share many important characteristics with the human counterpart. Rabbits lose weight and tumors become palpable. Rabbits may develop renal insufficiency. Growth is invasive and tumor can almost totally replace kidney. Good model in which to study chemotherapy or combined surgical and radiological treatments of the developing animal. OSTEOPETROSIS (ACLAM Text) Human Disease: Osteopetrosis, Marble Bone Disease, Alber-Schonberg Disease. Pathogenesis: Human osteopetrosis is a rare inherited disorder characterized by severe generalized osteosclerosis. The bony abnormality may be associated with frequent fractures, abnormal dentition, delayed growth, recurrent osteomyelitis, and encroachment on cranial foramina leading to cranial nerve damage. Bone marrow transplantation completely corrects hematologic, skeletal, and immunologic abnormalities and arrests neurologic effects of infantile osteopetrosis. Animal Disease: Osteopetrosis. Pathogenesis: A hereditary condition transmitted by an autosomal recessive gene (os) and phenotypically resembling Albers- Schonberg's disease exists in rabbits. The original mutation was discovered in the Dutch-Belted breed of rabbits. The disease is evident at birth in the eruption of the incisors is usually delayed, and radiographs reveal a marked increase in the density of the bone with limited internal details. Growth rate is relatively normal for the first week, declines in the second, and ceases thereafter. Maximum life span of the mutants in strain OS/J is 4-5 weeks of age. Histologic examination of the long bones reveals a delicate, open latticework of calcified cartilage extending the length of the diaphysis. Unlike all of the other osteopetrotic mutants, the os rabbit is deficient in bone. Transplantation of parathyroid and thyroid glands from normal rabbits to os/os siblings has had no corrective influence on the disease. Administration of parathyroid extract and thyroxine also fail to reverse osteopetrosis. Jax Labs use to maintain the OS strain. OTITIS MEDIA (ACLAM Text) Human Disease: Otitis media. Pathogenesis: Inflammation of the ear, which may be marked by pain, fever, abnormalities of hearing, deafness, tinnitus, and vertigo. This disease is of major significance to young children during the speech development phase, it is often seen as a painless accumulation of the middle ear due to an obstruction (inflammation) of the eustachian tube. Animal Disease: Otitis media, Torticollis, Wry neck. Pathogenesis: In the rabbit, it is often reported to be associated with Pasteurella multocida infection. Since this is a common pathogen in many rabbit colonies, models for studying this condition are readily available. Susceptibility in the rabbit appears to be under genetic control. PELGER-HUET ANOMALY (Model 278 in Fascicles) Human Disease: Pelger-Huet Anomaly, Hereditary Hyposegmentation of Granulocytes. Pathogenesis: This benign anomaly of leukocytes is inherited as a nonsex-linked dominant trait. It is characterized by distinctive shapes of the nucleus of leukocytes, by a reduced number of nuclear segments, best seen in neutrophils. As a result, the granulocyte nucleus appears young in shape, but old in structure i.e., nuclear chromatin pattern is coarse, clumped, and similar to the chromatin pattern of a polymorphonuclear leukocyte. Originally described by Pelger in 1928, the condition was considered to be one of the hematologic features of tuberculosis. Huet later described the genetic features of the anomaly. It has since been found to be transmitted as a simple autosomal dominant in at least 1 out of 6000 people. This abnormal nuclear development is not associated with any other congenital abnormality and does not appear to affect neutrophil function. The Pelger-Huet cells are able to phagocytize microorganisms and survive normally. The Pelger-Huet anomaly may be a feature of pre-leukemia. Animal Disease: Pelger-Huet Anomaly of Rabbits. Pathogenesis: A benign anomaly of leukocytes is inherited as a non-sex linked dominant trait. In rabbits this condition, if homozygous, is lethal (only 18% of the feti are delivered), and the individual is called a "super-Pelger". Most homozygotes die in utero, but those that survive often have skeletal malformations. No one seems to know the significance of this condition, other than that it may be pre-leukemic. SCOLIOSIS (ACLAM Text) Human Disease: Scoliosis. Pathogenesis: Defined as latereal curvature of the spine, in man scoliosis is mainly acquired postnatally but also occurs congenitally. The acquired condition was frequently attributed to nutritional deficiencies, thoracic lesions, unilateral muscular spasms, or paralysis and poliomyelitis. Congenital scoliosis is frequently associated with other abnormalities such as arthrogryposis, dwarfism, club hand, club foot, or as a partial manifestation of one of several syndromes, particularly defects of the central nervous system and skin. Hemivertebra is commonly associated with scoliosis. An extreme form of scoliosis recently described is an autosomal recessive trait. Animal Disease: Scoliosis Pathogenesis: Two unrelated strains of rabbits exhibited scoliosis in the proportion of 1 affected to every 15 normal, suggesting, but not proving that two recessive genes were involved. Severe scoliosis involves all areas of the axial skeleton and is characterized by an extremely jumbled vertebral column caused by many mismatched vertebrae or hemisegments. The condition is characterized by reduced, missing, or extra half-vertebral units. Severity and anatomic location of the defect varies with the strain of rabbit. Scoliosis associated with hemivertebra resembles some human congenital forms, but differs due to absence of associated defects. SPINA BIFIDA (ACLAM Text) Human Disease: Spina Bifida. Pathogenesis: Spina bifida is characterized by a spectrum of patterns. The symptoms can be related to the severity of the pathological events; however, the determinants of this condition in man are puzzling and virtually unknown. There is considerable speculation on the mechanism of neural tube malformations. Animal Disease: Spina bifida. Pathogenesis: Spina bifida was first reported in the AC strain of Dutch rabbit. Its genetic pattern was reported to be a lethal autosomal recessive gene (sb). The affected animals are stillborn. The bifid spine often extends from the caudal part of calvarium to the tail. The open spine, in most cases, is covered by a thin layer of skin. Some associated congenital defects include harelip, cleft palate, severe kyphosis, and a ventral deviation of the tail. Other defects were reported in the cardiovascular, respiratory, or urogenital systems. The frequency of spontaneous spina bifida is high in the rabbit and predictable; however, the lethality of this disease limits the rabbit as a useful model. STAPHYLOCOCCAL BLEPHARITIS (Model Number 361 in Fascicles) Human Disease: Staphylococcal Blepharitis. Pathogenesis: Blepharitis is an inflammatory disorder of the eyelids which is one of the most common diseases in humans. It is characterized by dilated blood vessels of the lid margin, crust around the lashes, loss of lashes and lash pigmentation, and misdirected lashes. It is not known whether this blepharitis is a direct infection of the lids by Staphylococcus aureus, the result of exotoxin, or a hypersensitivity response to its antigens. Animal Disease: Staphylococcal Blepharitis in Rabbits. Pathogenesis: New Zealand White rabbits are immunized with either a Staphylococcus aureus cell wall preparation or one of its three major components. Topical challenge with a suspension of S. aureus is started after a 90 day immunization period (18 injections at 5 day intervals). Rabbit studies suggest there to be hypersensitivity as the cause of the condition. The blepharitis in rabbits predominately involves the lid tissues beneath the epidermis and palpebral conjunctival epithelium with sparing of the meibomian glands. SYSTEMIC HYPERTENSION (ACLAM Text) Human Disease: Systemic Hypertension. Pathogenesis: There are many factors, most of which are poorly understood, which control blood pressure. Both genetic and environmental factors must be considered, and the distinction is not always easy. Hypertension is an increase in blood pressure above levels normally expected in the general population. Systolic blood pressure normally increases with advancing age, but diastolic pressure does not. 85 to 90 percent of hypertension is essential, meaning that no specific etiology can be identified. The remaining small percentage of hypertensive patients have definite conditions known to result in an increase in blood pressure. Animal Disease: Systemic Hypertension. Pathogenesis: Selected strains of rabbits have been shown to have increased systolic blood pressure of about 30 to 40 mm Hg above normotensive animals, and the incidence of hypertension could be increased in succeeding generations by selective breeding (heritability = 20%). However, little information is available concerning other characteristics of these rabbits, and how they been used for studies of hypertension other than to demonstrate the genetic relationship. VESICOURETERAL REFLUX (ACLAM Text) Human Disease: Vesicoureteral Reflux. Pathogenesis: Efflux of urine from the peristaltic activity of the ureter fills the bladder. In humans, when detrusor activity empties the bladder, a valvular mechanism prevents the urine from reentering the ureter. When the mechanism is ineffective, urine is refluxed back up the ureter during voiding. It is generally believed that reflux in humans is abnormal. However, a high incidence of vesicoureteral reflux is found in children with urinary tract infections. The possible relation between urinary tract infection, vesicoureteral reflux, and pyelonephritis is the stimulus for much interest and research on reflux. Animal Disease: Vesicoureteral Reflux. Pathogenesis: Reflux occurs in 40 - 80% of rabbits. Specific strains and sex differences may be the cause of variation since many investigators are not specific. Little has been done on the relation between bacteria, reflux, and pyelonephritis; perhaps because of endemic chronic nephritis in rabbits caused by Nosema cuniculi which might be confused with bacterial nephritis. VON WILLEBRAND'S DISEASE (ACLAM Text) Human Disease: Von Willebrand's disease. Pathogenesis: Von Willebrand's disease (VWD) is a complex, multifaceted disorder of hemostasis first described by von Willebrand in 1926. A hemorrhagic diathesis with autosomal inheritance; bleeding is mainly purpuric, affecting mucous membranes and the skin, the most common symptom is epistaxis. Gingival bleeding and menorrhagia are other frequent manifestations of the disease, as are occasional gastrointestinal bleeding, hemarthroses, and hematuria. Affected patients have prolonged bleeding times. Animal Disease: Von Willebrand's disease. Pathogenesis: Discovered in 1975 in a line of Flemish Giant- Chinchilla rabbits by Dr. Dodds in New York. The main features of this defect are autosomal inheritance with variable penetrance, mild to moderate bleeding tendency involving mucosal surfaces and exacerbated by trauma or surgery; markedly prolonged bleeding time, especially from central-ear arterial puncture. Development of this model of VWD has progressed to the fifth generation. By planned matings of affected and normal family members, two distinct lines have been developed, one selected for and the other away from the defect. The trait is consequently becoming more severely expressed in the affected line and minimally carried in the normal line. OTHER MODELS USING THE RABBIT Albinism. An inherited disorder of melanin metabolism in humans. In the rabbit, there is a graded series of alleles at the C locus providing a step-wise reduction in color, thus giving a gradual system to help unravel the etiology. B-adrenergic response. Rabbit-based research has shown that decreased B-adrenergic responsiveness, the common pharmacological effect on the ciliary body following the use of either topical timolol or epinephrine, may be responsible for the decrease in aqueous humor formation observed in humans treated with these medications. Contact Dermatitis. Two clinical entities are included in the syndrome, allergic and irritant. The rabbit is one of the few species commonly used to illustrate and study these two conditions. Emphysema. A condition of the lung characterized by an increase beyond the normal size of air spaces distal to the terminal bronchiole with destructive changes in their walls. Fairly common in older rabbits (over 2.5 years), it is irregularly distributed in the lung, and largely of the panlobar type. It seems to be asymptomatic until an advanced stage of the disease. Endometriosis has been experimentally induced in the rabbit. Considering that the cost to obtain and keep non-human primates (the only spontaneously occurring animal model of this disease) is so high, the ability to induce this disease in rabbits is a very cost effective way to study it. Endometrium from one horn can be surgically implanted into the peritoneum. There it grows and functions as normal endometrial tissue. Endometriosis may be induced by the injection of estradiol cypionate. Entropion. Primary congenital entropion is relatively common in rabbits. It is probably under genetic control, so it is a good animal model for surgical intervention and other treatments. Hypogonadia. Causes partial or complete sterility in both sexes of rabbits. Gonad size is markedly reduced. Associated changes in secondary sex characteristics and histological changes in the gonad evident. The rabbit is a model for some forms of gonadal dysgenesis. The disease in humans may be spontaneous or have a familial basis. Found in ACEP strain at JAX Labs. Immune damage. A rabbit model of hypersensitivity pneumonitis exists that allows study of the pathogenesis of this condition and elaboration of the role played by the lung in various types of immune damage. The model induced with ovalbumin in Complete Freund's Adjuvant. Abnormalities include thickening of alveolar septa and increased numbers of mononuclear cells, lymphocytes, phagocytic macrophages and eosinophilic granulocytes within alveolar walls and spaces. Lysozyme deficiency. A genetic disorder of NZW rabbits. It is an autosomal recessive trait. Although not the model of a human disease, these rabbits may be useful in the delineation of the role of lysozyme in mammalian tissues. These rabbits have less than 1% of the lysozyme usually present in all tissues in the body, except that the thymus has normal levels. Osteoarthritis. An induced model in the rabbit involving IV infection of Staphylococcus aureus allows study of the pathogenesis and radiological appearances, which are similar to the less frequent human occurrences. Osteoarthritis can be induced in rabbits by injecting papain into the hip joint. This condition is sufficiently similar to the human condition that it is a useful model to study the pathogenesis and treatments of the human disease. Xanthomas with hyperlipoproteinemia have been induced in rabbits by feeding a high cholesterol diet, but the only naturally occurring xanthomatosis seen with any regularity is in the chicken. Xanthomas are defined as a papule, nodule, or plaque of a yellow color in the skin, due to deposits of lipids. Microscopically the lesions show light cells with foamy protoplasm (foam cells, or xanthoma cells). REFERENCES 1. Health Benefits of Animal Research. Edited by William I.. Gay, DVM. Foundation for Biomedical Research. Chapter entitled: The Rabbit as a Research Subject. by Richard R. Fox. 2. Spontaneous Animal Models of Human Disease, Volumes I. Edited by Edwin J. Andrews, Billy C. Ward, and Norman H. Altman. 1979. The American College of Laboratory Animal Medicine Series. Academic Press. 3. Spontaneous Animal Models of Human Disease, Volumes II. Edited by Edwin J. Andrews, Billy C. Ward, and Norman H. Altman. 1979. The American College of Laboratory Animal Medicine Series. Academic Press. 4. Handbook: Animal Models of Human Disease. (The AFIP Fascicles 1 through 16). Registry of Comparative Pathology, AFIP, Wash. D.C. 5. Laboratory Animal Medicine. Edited by James G. Fox, Bennett J. Cohen, Franklin M. Loew. 1984. The American College of Laboratory Animal Medicine Series. Academic Press. 6. Reproduction of Laboratory Animals. Kevin Ohair, USAMRIID Seminar Series. 1986. 7. Rabbit: Animal Models of Human Disease. Jim McMillian, USAMRIID Seminar Series. 1986. 8. Species Reference Briefs: Alternatives to the use of Animals in Research and Education. National Agricultural Library. NAL SRB 88-11. September 1988. 9. Species Reference Briefs: Alternatives to the use of Animals in Research and Education. National Agricultural Library. NAL SRB 89-02. November 1988. 10. Terahymena thermophila as an Indicator of Ocular Irritancy in Rabbits. Jerald Silverman, Stephan Pennisi. Alternative Methods in Toxicology. Volume 3. 1985. 11. The Rabbit Eye Irritancy Test - Are there In Vitro Alternatives?. Michael Scaife. ATLA Volume 12. 1985. ACQUIRED IMMUNODEFICIENCY SYNDROME (Model Number 320 in Fascicles) Human Disease: Acquired Immunodeficiency Syndrome. Pathogenesis: Profound immune dysfunction, opportunistic infection and the appearance and spread of a malignant tumor. T cells are the major target cell. Animal Disease: Malignant Rabbit Fibroma Syndrome. Pathogenesis: Malignant Rabbit Fibroma virus (MV) is a poxvirus related to Shope Fibroma Virus and the Rabbit Myxoma Virus. MV induces a syndrome of severe immunodeficiency, disseminated tumor, and opportunistic infections. The affected rabbits are profoundly immunosuppressed affecting both the T and B cells. Neither the human or animal lymphocytes respond to mitogens in culture, and these cultures produce factors (Lymphokines) that actually inhibit the proliferative and antibody production responses of normal lymphocytes. Both diseases are transmitted by direct contact and not by the airborne route. ACUTE ACALCULOUS CHOLECYSTITIS (Model Number 336 in Fascicles) Human Disease: Acute Acalculous Cholecystitis. Pathogenesis: A serious and fatal disease seen in patients post surgery or trauma involving inflammation of the gall bladder in the absence of gallstones. It is more commonly seen in females with precedent events such as multiple transfusions, child birth, bacterial sepsis and SLE. The etiology of this condition is unclear and may be multifactorial. Theories regarding pathogenesis include bile stasis, sepsis or ischemia. Animal Disease: Acute Acalculous Cholecystitis Induced by Lysophosphatidylcholine in Rabbits. Pathogenesis: Perfusion of the rabbit gall bladder with lysophosphatidylcholine causes histologic changes identical to man. Lesions included mucosal damage, vascular dilatation, edema and erosion of the normal epithelial cells. ACUTE RESPIRATORY DISTRESS SYNDROME (Model Number 275 in Fascicles) Human Disease: Acute Respiratory Distress Followed by Pulmonary Interstitial Pneumonitis and Pulmonary Fibrosis. Pathogenesis: Both acute and chronic alveolar injury characterized by interstitial inflammation, hemorrhage, edema, infiltration of macrophages and plasma cells. Animal Disease: Pulmonary Artery Injury Induced by Phorbol Myristate Acetate Following Intravenous Administration in Rabbits. Pathogenesis: A single dose of phorbol myristate acetate induces chronic neutropenia and thrombocytopenia, acute respiratory distress, and hemorrhagic pneumonitis. Features seen are strikingly similar to the disease in man. Pathogenic mechanisms are not yet known. ATHEROSCLEROSIS (ACLAM Text) Human Disease: Atherosclerosis. Pathogenesis: Deposits of yellowish plaques (atheromas) containing cholesterol, lipoid material, and lipophages are formed within the intima and inner media of the large and medium sized arteries. Animal Disease: Atherosclerosis. Pathogenesis: The physiological and pathological dissimilarities between rabbit disease and the disease in man causes them to be looked upon with disfavor by many comparative pathologists. Young rabbits undergo two different types of arterial changes, one being a spontaneously occurring medial mineralization in rabbits. These lesions occur primarily in the aortic arch and thoracic aorta, consist of mineralization of the media, and resemble Monkeyberg's mineral sclerosis of man. Rabbits have been selectively bred for the presence or absence of these arterial lesions. In addition to the arterial lesions induced, rabbits also deposit fat and cholesterol in most organs, particularly in the liver, adrenal glands, spleen, bone marrow, and eyes, resulting in a syndrome more nearly resembling a lipid storage disorder than atherosclerosis. When fed atherogenic diets, rabbits tend to develop atherosclerotic lesions in the area of the aortic arch and thoracic aorta, rather than in the abdominal aortas as is seen in man. Coronary atherosclerosis in rabbits occurs after feeding a cholesterol and fat diet for 1 month. The distribution of coronary lesions in rabbits is quite different from those of man. Large proximal coronary arteries are relatively spared; the small intramyocardial branches are affected, with their lumens occluded by masses of intimal foam cells. Atherosclerotic lesions also occur in many other anatomic sites. The carotid arteries of the rabbit, unlike man, are affected but only in the proximal portion; the distal portion and the cerebral arteries appear to remain free of atherosclerotic changes. Also unlike man, plagues are present in the pulmonary arteries and veins. Repeated injections of foreign serum proteins, along with an atherogenic diet has produced coronary artery lesions that were more cellular, located in the larger coronary arteries, and more comparable to the usual lesions in man. Rabbits appear to be particularly useful for research on the interrelationships of hypercholesterolemia, immune complex damage to the endothelium, and the pathogenesis of atherosclerosis. CAMPYLOBACTER ENTERlTlS (Model Number 329 in Fascicles) Human Disease: Campylobacter Enteritis. Pathogenesis: Campylobacter fetus ssp. jejuni is a major cause of bacterial diarrhea worldwide. Infections usually are self-limited, lasting 3-5 days beyond an incubation period of 2-7 days. Profuse watery diarrhea or a dysentery-like syndrome with stools containing mucus, polymorphonuclear leukocytes, and blood. Animal Disease: Campylobacter Enteritis in Rabbits. Pathogenesis: The RITARD technique is used to prepare the model. After a 2-7 day incubation period, the stools are fluid, containing gross mucus but rarely show blood. Mortality results from dehydration. Biopsies contain edema of lamina propria with acute inflammatory infiltrates of varying severity, crypt abscesses, mucin depletion, and an increased mitotic index in the glandular epithelium. Lesions ranged from inflammatory infiltration to epithelial necrosis. CHAGAS' DISEASE (Model Number 334 in Fascicles) Human Disease: Chagas' Disease. Pathogenesis: Trypanosoma cruzi infection, a flagellate protozoan. Macrophages and muscle cells are easily penetrated, but any cell type can be parasitized. Acute infections are clinically silent in over 2/3 of the individuals. Lesions include induration at the port of entry, fever, splenomegaly, lymphadenopathy, electrocardiographic abnormalities, myositis, and ganglioneuritis. Animal Disease: Trypanosoma cruzi infection of inbred III/J rabbits. Pathogenesis: Lesions observed in the rabbit were almost identical to those seen in humans. Persistent electrocardiographic changes were recorded in 90% of the rabbits. Cardiomegaly and dilatation of the chambers were also conspicuous findings. CRYPTOCOCCAL MENINGITIS (Model Number 318 in Fascicles) Human Disease: Cryptococcal Meningitis. Pathogenesis: Cryptococcus neoformans is a low-grade pathogen that occasionally causes subacute or chronic meningitis in man. Gray glistening exudate and the packing of the subarachnoid space with organisms or mononuclear cells is a consistent finding. Animal Disease: Cryptococcal Meningitis in Rabbits. Pathogenesis: Rabbits appear innately resistent to cryptococcal infections and require an immunosuppressive event for a chronic infection to occur. The lesions seen are the same as observed in man. DIABETES MELLITUS (Model Number 266 in Fascicles) Human Disease: Diabetes mellitus. Pathogenesis: Insulin dependent (children). Insulin independent (adult) usually associated with obesity. Animal Disease: Diabetes mellitus of NZW rabbits. Pathogenesis: A spontaneous condition in the NZW Rabbit exhibiting polydipsia and polyuria. Specific lesions are limited to the beta- cells with a marked accumulation of membrane-associated secretory granules. No increase in atherosclerosis or in peripheral capillary basement membrane alterations have been found in diabetic rabbits. ENDOMETRIAL ADENOCARCINOMA (Model Number 21 in Fascicles) Human Disease: Endometrial Adenocarcinoma. Pathogenesis: Cessation of menstruation is related to the incidence of endometrial adenocarcinoma. Hormonal dysfunctions such as the Stein-Leventhal syndrome, have been associated with endometrial carcinoma in young patients. Generally, human endometrial carcinoma is associated with glandular hyperplasia, diabetes, obesity and hypertension. Animal Disease: Endometrial Adenocarcinoma. Pathogenesis: Among known mammalian species, the incidence of endometrial adenocarcinoma is especially high in rabbits. Breed incidence has been reported as: Tan, 50%; French Silver, 25%; Havana, 22%; Dutch Belted, 20%. Incidence in other breeds ranged from 8 to 17%. Female rabbits 4 to 7 years old have the highest incidence. The adenocarcinomas are often multicentric, involving both uterine horns. Tumors are polypous, with frequent central ulcerations. Uterine horns are often distended with the tumor, hydrometra and pyometra. The tumors usually originates from the deeper glandular portion of the epithelium. In both humans and rabbits, there appears to be a relationship between loss of estrogen and the increasing incidence of tumors in the older female. Males are peculiarly resistant to tumor development. HERPES SIMPLEX ENCEPHALITIS (Model Number 352 in Fascicles) Human Disease: Herpes Simplex Encephalitis. Pathogenesis: Herpes Simplex Type 1 (HSV-1) is ubiquitous among humans. The infection is manifest by fever, seizures, hemiparesis, speech and behavioral disturbances. Left untreated, HSE has a mortality in excess of 70%. HSV-1 preferentially attacks ectodermal tissue in the immunocompetent adult causing herpes labialis, herpes keratitis, and herpes simplex encephalitis. The virus may become latent in the ganglia and recur after latency. The potential for viral latency in human brain tissue is largely unknown. Although it is assumed that herpes labialis are spread by contact, the pathway by which HSV-1 gains access to the brain in cases of HSE remains controversial. Animal Disease: Focal Herpes Simplex in New Zealand White Rabbit. Pathogenesis: New Zealand White rabbits are injected in the left olfactory bulb. Animals appear well for at least the first two days after inoculation, after which an encephalitic disease becomes clinically evident. Approximately 30% of rabbits will develop seizures. Microscopic findings are identical with human HSE and include Cowdry type `A' inclusion bodies, perivascular cuffing, leptomeningeal inflammation, brain tissue infiltration and necrosis. The only major differences between the rabbit model and the human disease are absence of documentable dysphagia and confusion in the rabbit. HYPERCALCEMIA OF MALIGNANCY (Model Number 168 in Fascicles) Human Disease: Hypercalcemia of Malignancy Pathogenesis: Animal Disease: Pathogenesis: HYDROCEPHALUS (Model Number 38 in Fascicles) (ACLAM Text) Human Disease: Congenital Communicating Hydrocephalus. Pathogenesis: Hydrocephalus is a disorder in which there is an increased quantity of cerebrospinal fluid (CSF) in the ventriculosubarachnoid system. Hydrocephalus can be classified as communicating and noncommunicating. In the latter type, CSF does not enter the subarachnoid space due to an obstruction within the ventricular system. Such an obstruction may be due to developmental abnormalities, inflammatory lesions, or neoplasm that cause stenosis or obliteration of the aqueduct or foramina. Communicating hydrocephalus can be caused by an imbalance of CSF secretion-absorption within the ventricles or to absorptive dysfunction in the subarachnoid space. Animal Disease: Vitamin A Deficiency Hydrocephalus. Pathogenesis: Congenital hydrocephalus can be induced in a number of rabbit strains by feeding does a vitamin A deficient diet. If present at birth, there is a distinct bulging over the frontal lobes of the brain and a general distortion of the head. If the newborn appears normal but develops the condition postnatally, the general anatomic alterations develop in a predictable pattern culminating in characteristic post natal hydrocephaly. Affected rabbits appeared to have a functional block at the level of the aqueduct or lateral apertures (foramina of Luschka). Signs of vitamin A deficiency hydrocephalus in newborn rabbits are essentially the same as the signs observed in human infant for the congenital communicating type. INFLAMMATORY BOWEL DISEASE (Model Number 205 in Fascicles) Human Disease: Ulcerative colitis and Krohn's Disease. Pathogenesis: Exogenous antigens initiate a cellular immune reaction in the colon and the immune response to the exogenous antigen may be responsible for the pathogenesis of disease in some patients. Animal Disease: New Zealand white rabbit. Immunologic Model of Inflammatory Bowel Disease. Pathogenesis: Dinitrochlorobenzene (DNCB) used to sensitize animals by placing it on their skin. The animal is then challenged by placing a drop of DNCB intrarectal. An anamnestic response occurs with the rapid accumulation of mononuclear cells, edema, and tissue necrosis. NEPHROBLASTOMA (Model Number 193 in Fascicles) Human Disease: Wilms' Tumor, Embryonal Nephroma, Embryoma, Embryonal Adenosarcoma, Mixed Teratoid Tumor, Adenomyosarcoma. Pathogenesis: Rare tumor usually appearing during the first decade of life. Average age is 3 years. Accounts for about 20 of all solid malignancies in childhood. Characterized by a close association of epithelial and mesenchymal tissue elements. Animal Disease: Experimentally induced (transplacental ethylnitrosourea) tumors in the rabbit. Pathogenesis: Experimentally induced (transplacental ethylnitrosourea) tumors in the rabbit do metastasize and share many important characteristics with the human counterpart. Rabbits lose weight and tumors become palpable. Rabbits may develop renal insufficiency. Growth is invasive and tumor can almost totally replace kidney. Good model in which to study chemotherapy or combined surgical and radiological treatments of the developing animal. PELGER-HUET ANOMALY (Model 278 in Fascicles) Human Disease: Pelger-Huet Anomaly, Hereditary Hyposegmentation of Granulocytes. Pathogenesis: This benign anomaly of leukocytes is inherited as a nonsex-linked dominant trait. It is characterized by distinctive shapes of the nucleus of leukocytes, by a reduced number of nuclear segments, best seen in neutrophils, and by coarseness of the nuclear chromatin of neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Rodlike, dumb-bell-shaped, peanut- shaped, and spectacle-like ("pince-nez") nuclei with smooth, round, or oval individual lobes contrast with the irregular lobes seen in normal neutrophils. As a result, the granulocyte nucleus appears young in shape, but old in structure i.e., nuclear chromatin pattern is coarse, clumped, and similar to the chromatin pattern of a polymorphonuclear leukocyte. Originally described by Pelger in 1928, the condition was considered to be one of the hematologic features of tuberculosis. Huet later described the genetic features of the anomaly. It has since been found to be transmitted as a simple autosomal dominant in at least 1 out of 6000 people. This abnormal nuclear development is not associated with any other congenital abnormality and does not appear to affect neutrophil function. The Pelger-Huet cells are able to phagocytize microorganisms and survive normally. The Pelger-Huet anomaly may be a feature of pre-leukemia. Animal Disease: Pelger-Huet Anomaly of Rabbits. Pathogenesis: A benign anomaly of leukocytes is inherited as a non-sex linked dominant trait. This syndrome is a non-inflammatory disorder in which the granulocytes mature without normal segmentation of the nucleus. It is characterized by distinctive shapes of the nucleus of leukocytes, by a reduced number of nuclear segments, best seen in the neutrophils, and by coarseness of the nuclear chromatin of neutrophils, eosinophils, basophils, lymphocytes and monocytes. In rabbits this condition, if homozygous, is lethal, and the individual is called a "super- Pelger". Most homozygotes die in utero, but those that survive often have skeletal malformations. No one seems to know the significance of this condition, other than that it may be pre- leukemic. STAPHYLOCOCCAL BLEPHARITIS (Model Number 361 in Fascicles) Human Disease: Staphylococcal Blepharitis. Pathogenesis: Blepharitis is an inflammatory disorder of the eyelids which is one of the most common diseases in humans. It is characterized by dilated blood vessels of the lid margin, crust around the lashes, loss of lashes and lash pigmentation, and misdirected lashes. It is not known whether this blepharitis is a direct infection of the lids by Staphylococcus aureus, the result of exotoxin, or a hypersensitivity response to its antigens. Animal Disease: Staphylococcal Blepharitis in Rabbits. Pathogenesis: New Zealand White rabbits are immunized with either a Staphylococcus aureus cell wall preparation or one of its three major components. Topical challenge with a suspension of S. aureus is started after a 90 day immunization period (18 injections at 5 day intervals). Rabbit studies suggest there to be hypersensitivity as the cause of the condition. The blepharitis in rabbits predominately involves the lid tissues beneath the epidermis and palpebral conjunctival epithelium with sparing of the meibomian glands. ANENCEPHALY (ACLAM Text) Human Disease: Anencephaly. Pathogenesis: Anencephaly is defined as partial or total absence of the forebrain and is most frequently associated with malformations of the brain stem and spinal cord. It is the most common congenital malformation of the human brain and is reported to occur at an incidence of 1 to 2 per 1000 births, although there is considerable variation in incidence in different geographic areas. Exencephaly is a defect of the calvarium with extroversion of the brain. It is only rarely seen in human births because the condition usually proceeds to anencephaly by the time of birth. While the actual etiology is obscure, predisposing factors may include the previous birth of an anencephalic, consanguinity of the parents, apparently descended from ancestors whose posterity contained other deformed children, and poor maternal nutrition. Animal Disease: Anencephaly. Pathogenesis: In lagomorphs, which have shorter gestation periods, there is less time for anencephaly to develop and exencephaly is seen more frequently. Pseudo-encephaly is the term used for massive "area cerebrovasculosa" imitating the shape of the brain that it replaces and is probably also a stage in the development of anencephaly. A genetic basis for anencephaly is supported by a 3% incidence in siblings of anencephalics. Affected females outnumber males three to seven times. Twinning does not affect the rate of anencephaly except when the twins are monozygotic, in which case the rate is estimated to be nearly twice as great. The possibility of environmental influences, especially those affecting the maternal diet, playing a part in the etiology cannot be overlooked. Periodic fluctuations in incidence rates also point to a possible environmental influence. Acephaly has been noted occasionally in the strain of Dutch Belted rabbit that carries the gene for spina bifida (sb). Spina bifida is an autosomal recessive characteristic, but is complicated by the presence of the gene for achondroplasia (ac) in the same stock. In the New Zealand White rabbit a very low incidence (2/1000) of anencephaly is reported by Cozens. CARDIOMYOPATHY (ACLAM Text) Human Disease: Cardiomyopathy. Pathogenesis: Cardiomyopathy is nonspecific term applied to conditions in which the lesions are located in the myocardium rather than the other anatomic structures of the heart, and not secondary to lesions primarily involving other cardiac structures, The term is very broad, encompassing a wide variety of etiologic agents. Although cardiomyopathy in man is much less common than ischemic myocardial disease associated with coronary atherosclerosis, the condition is an important cause of myocardial failure, often leading to severe functional decompensation and death. Animal Disease: Cardiomyopathy. Pathogenesis: Cardiomyopathy has been reported in rabbits due to stress associated with severe crowding. Animals were crowded 4 to a cage for 2-week periods alternating with 1 week alone in a cage. During the first month, 20 of 44 rabbits died and 15 died between 2 and 9 months of this crowding regimen. The animals exhibited aggressive behavior during the confinement. At necropsy, heart weight was normal, but there was dilation of the ventricles in most animals. Histologically, there was myocardial edema with both myocytolysis and coagulative necrosis of myofibers. The multifocal areas of necrosis were replaced with fibrous connective tissue, and basophilic mucinous degeneration was a common finding in the longer-term survivors. The endocardium was thickened with collagen and elastic fibers in animals surviving over 1 month; the thickening tended to be focal, concentrated at the apex of the ventricles. Although this model is not strictly a spontaneously occurring condition, it may be useful for structural and functional studies of the diseased myocardium. There are similarities with idiopathic endomyocardiopathy as seen in southern Africa, but the model differs in the extent of myocardial degeneration and fibrosis from myocardial degeneration and fibrosis from myocardiopathy as usually encountered in Western countries. CHOLERA OR CYSTIC FIBROSIS (ACLAM Text) Human Disease: Cholera or Cystic Fibrosis. Pathogenesis: In cholera, the patient hypersecretes electrolytes, water, and mucus from a histologically healthy epithelium. Cystic fibrosis (CF) is recognized as a generalized derangement of transport of electrolytes and production of mucus. The electrolytes are lost excessively in sweat, salivary and lacrimal glands, and excessive tenacious mucus is produced in intestine, pancreatic ducts, bile ducts, salivary glands, trachea and bronchi. Animal Disease: Mucoid Enteropathy (ME). Pathogenesis: ME in the rabbit appears to be a subacute enterotoxin-induced secretory disease. As is the case with cholera, affected rabbits hypersecrete electrolytes, water, and mucus from a histologically healthy epithelium. The fluid-filled small bowel loops in ME appear morphologically similar to the isolated loops produced by enterotoxin. The hypersecretion of tenacious mucus in the neonate is known as meconium ileus. ME may represent a link in pathogenesis, at the cellular level, between two previously unrelated human diseases. CLEFT PALATE (PALATOSCHISIS) AND CLEFT LIP (CHEILOSCHISIS) (ACLAM Text) Human Disease: Cleft palate (palatoschisis) and cleft lip cheiloschisis). Pathogenesis: Palatoschisis is characterized by a cleft of variable size extending through the hard palate, soft palate, or both. It may be V-shaped or ovoid depending on whether it is open or closed posteriorly. Cheiloschisis (hare lip) presents as a unilateral, bilateral, or median cleft of the upper lip which may extend superiorly to involve the nose. These malformations are clefts left between the various parts caused by failure of normal fusion of the maxillary processes and the median and lateral portions of the frontonasal processes during organogenesis. The precise anatomic location and severity of the resultant cleft determines the clinical entity which may be cheiloschisis, palatoschisis, or a combination of both. The more severely affected babies die so that associated defects are much less common in children surviving 1 year. The etiology of these abnormalities is unknown; however, hereditary, environmental, or interaction of hereditary and environmental factors are likely to be involved. Some are thought to be single gene syndromes while those unassociated with syndromes are hypothesized to be polygenic. Animal Disease: Cleft palate (palatoschisis) and cleft lip cheiloschisis). Pathogenesis: Palatoschisis associated with hydrocephalus occurred in 148 rabbits representing 13% of those born in an inbred colony over a 2 year period. The condition was thought to be due to a complicated interaction of genetic and environmental influences. Palatoschisis with or without cheiloschisis is closely associated with spina bifida and dwarfism, occurring in 53% of achondroplastic and 97% of chondrodystrophic rabbits. CYSTIC DISORDERS OF THE KIDNEY (ACLAM Text) Human Disease: Cystic Disorders of the Kidney. Pathogenesis: Cystic disorders of the kidney may be unilateral or bilateral and involve the cortex, medulla or both, occurring in children or adults. These disorders vary from large polycystic kidneys, which usually result in morphological changes and reduced renal function to small cortical, benign "simple" cysts. The mode of inheritance for polycystic kidneys appears to be autosomal dominant for the adult type and autosomal recessive for the juvenile form. Animal Disease: Polycystic Disease of Rabbits. Pathogenesis: An autosomal recessive model for the "simple cysts" has been reported in rabbits. Both sexes are affected. Cysts are not usually observed until the animals are 1 month of age or older. Analysis of serum and urine show no pathological changes. The cysts appear to be of tubular origin and are found in the cortex. DEFICIENCY OF C6 (ACLAM Text) Human Disease: Deficiency of C6. Pathogenesis: Inherited as an autosomal recessive (codominant) trait ans associated with increased susceptibility to gonococcal and meningococcal infections. Animal Disease: Deficiency of C6. Pathogenesis: A strain of rabbits has been described with a deficiency of the sixth component of complement. This condition is inherited as an autosomal recessive trait. These rabbits exhibited the same rate of blood clearance of S. typhi as normal rabbits. A study of the hemostatic properties of the blood of these animals showed prolonged clotting times and retarded prothrombin consumption. The clotting defect in these rabbits, which are more pronounced than those described for C4-deficient guinea pigs, can be corrected by the addition of purified C6. It is of interest that similar studies of C6-deficients human showed no evidence of coagulation abnormality. ENDOCARDITIS (ACLAM Text) Human Disease: Endocarditis. Pathogenesis: Defined as inflammation of the endocardium, this disease is generally associated with rheumatic fever or other febrile disease. It may present as acute or chronic, non-bacterial (verrucous or rheumatic) and bacterial (mycotic, fungal, or bacterial). Animal Disease: Endocarditis. Pathogenesis: Endocarditis can be induced in the rabbit by placing a catheter tip at the entrance to, or in, the right side of the heart, and then infusing as few as 100 microorganisms. It is a good model to study the bacteriological, pathological and immunologic aspects of bacterial endocarditis. This model reproduces some of the complications of indwelling catheters in humans. GLAUCOMA (ACLAM Text) Human Disease: Glaucoma. Pathogenesis: One of the three major causes of blindness in humans. Glaucoma is actually a group of eye diseases characterized by an increase in intraocular pressure which causes pathological changes in the optic disk and typical defects in the field of vision. Pathogenesis dependent upon specific type of glaucoma. Animal Disease: Glaucoma. Pathogenesis: The inherited glaucoma of the rabbit (NZW) has been studied more extensively than that in any other species. Unfortunately, this trait in the rabbit is linked with a semilethal trait that results in small litters, poor viability and lower fertility. Certain pressure-reducing drugs that work in humans have no effect in rabbits. HYPERCALCEMIC NEPHROPATHY (ACLAM Text) Human Disease: Hypercalcemic Nephropathy. Pathogenesis: The hypercalcemia which develops is insidious and progressive and results in nephrocalcinosis. The development of the hypercalcemia has been associated with production of Prostaglandins (and metabolites thereof) by neoplastic cells in human carcinomas associated with hypercalcemia. One of the earliest and most significant clinical manifestations of hypercalcemia is an impaired ability to concentrate urine which is unresponsive to antidiuretic hormone. Impairment in the ability to concentrate urine is related to several factors, including calcium inhibition of binding vasopressin to renal plasma membranes, calcium inhibition of adenylate cyclase, and calcium influence on medullary hyperosmolality by altering intrarenal flow. Animal Disease: VX-2 Carcinoma of rabbits. Pathogenesis: The VX-2 carcinoma is the result of a malignant transformation of the viral-induced Shope papilloma. A transplantable carcinoma (VX2 carcinoma) has been reported in rabbits that produced profound hypercalcemia and calcium nephropathy 3 to 4 weeks after transplantation. The carcinoma grows rapidly with local infiltration and metastases to regional lymph nodes and lungs. Results of in vitro and in vivo studies suggest that VX2 carcinoma produces prostaglandin E2, a potent bone resorption-stimulating agent. Hypercalcemia occurred in the apparent absence of bone metastases, and was reversed by excision of the primary tumor and was prevented and reversed by administration of indomethacin. Death occurs predominantly at 4 to 8 weeks, with evidence of pulmonary metastases, hypercalcemia, nephrocalcinosis, and renal failure. Necropsies fail to note any distant metastasis to bone. KYPHOSIS (ACLAM Text) Human Disease: Kyphosis. Pathogenesis: In man, kyphosis is rarely encountered as a single entity but is associated with several syndromes. These are usually inherited syndromes such as metatrophic dwarfism, enzyme or metabolic defects, and other rare conditions. Scoliosis may be present in the same individual. Animal Disease: Kyphosis. Pathogenesis: The precise cause is unknown, but kyphosis occurs in most rabbits with the recessive trait spina bifida. Marked kyphotic curvature occurs in the majority of achondroplasia stock with spina bifida; only those with minimal spina bifida are free of kyphosis. The condition mimics some human cases associated with spina bifida. MANDIBULAR PROGNATHISM (ACLAM Text) Human Disease: Mandibular prognathism. Pathogenesis: Mandibular prognathism is a condition wherein the lower jaw is either larger than normal or protrudes to a position forward to that which is normal. The condition has been noted in man since earliest times. Its etiology may lie in genetic patterns as was noted historically in the royalty of the Hapsburgs, or it may be the result of an over secretion of the pituitary gland as in acromegaly. Although it is stated that malocclusion affects a large segment of the population, it is difficult to find specific statistical data on the occurrence of the various types of malocclusion. Animal Disease: Mandibular prognathism. Pathogenesis: Mandibular prognathism has been reported in the rabbit and is due to facial shortening as reflected in a decreased length of the maxillary diastema. A similar cause has been reported for man. A hereditary basis for the occurrence of prognathia in the rabbit is strongly suggested. OSTEOPETROSIS (ACLAM Text) Human Disease: Osteopetrosis. Pathogenesis: Human osteopetrosis is a rare inherited disorder characterized by severe generalized osteosclerosis. The bony abnormality may be associated with frequent fractures, abnormal dentition, delayed growth, recurrent osteomyelitis, and encroachment on cranial foramina leading to cranial nerve damage. Pyknodysostosis is a variant form of dense bone disease characterized by autosomal recessive inheritance, short stature, persistent open cranial clefts, underdeveloped mandible with abnormal angulation, small hands and feet, and osteolysis of the terminal phalanges and the acromial ends of the clavicles. Bone marrow transplantation completely corrects hematologic, skeletal, and immunologic abnormalities and arrests neurologic effects of infantile osteopetrosis. Animal Disease: Osteopetrosis. Pathogenesis: A hereditary condition transmitted by an autosomal recessive gene (os) and phenotypically resembling Albers- Schonberg's disease exists in rabbits. The original mutation was discovered in the Dutch-Belted breed of rabbits. The disease is evident at birth in the eruption of the incisors is usually delayed, and radiographs reveal a marked increase in the density of the bone with limited internal details. Growth rate is relatively normal for the first week, declines in the second, and ceases thereafter. Maximum life span of the mutants in strain OS/J is 4-5 weeks of age. Histologic examination of the long bones reveals a delicate, open latticework of calcified cartilage extending the length of the diaphysis. Unlike all of the other osteopetrotic mutants, the os rabbit is deficient in bone. Transplantation of parathyroid and thyroid glands from normal rabbits to os/os siblings has had no corrective influence on the disease; however, the strain was not fully inbred at the time these grafts were made. Administration of parathyroid extract and thyroxine also fail to reverse osteopetrosis. OTITIS MEDIA (ACLAM Text) Human Disease: Otitis media. Pathogenesis: Inflammation of the ear, which may be marked by pain, fever, abnormalities of hearing, deafness, tinnitus, and vertigo. This disease is of major significance to young children during the speech development phase, it is often seen as a painless accumulation of the middle ear due to an obstruction (inflammation) of the eustachian tube. Animal Disease: Otitis media. Pathogenesis: In the rabbit, it is often reported to be associated with Pasteurella multocida infection. Since this is a common pathogen in many rabbit colonies, models for studying this condition are readily available. Susceptibility in the rabbit appears to be under genetic control. SCOLIOSIS (ACLAM Text) Human Disease: Scoliosis. Pathogenesis: In man scoliosis is mainly acquired postnatally but also occurs congenitally. The acquired condition was frequently attributed to nutritional deficiencies, thoracic lesions, unilateral muscular spasms, or paralysis and poliomyelitis. The majority of acquired cases are idiopathic; however, they are classified by either clinical signs or morphologic lesions. Congenital scoliosis is frequently associated with other abnormalities such as arthrogryposis, dwarfism, club hand, club foot, or as a partial manifestation of one of several syndromes, particularly defects of the central nervous system and skin. Hemivertebra is commonly associated with scoliosis. Secondary asymmetrical vertebral growth exacerbates the deformity during the period of active growth. In fully grown patients the condition may deteriorate due to degenerative processes in bones, joints, intervertebral discs, or osteoporosis in older individuals. An extreme form of scoliosis recently described is an autosomal recessive trait. Animal Disease: Scoliosis. Pathogenesis: Two unrelated inbred strains of rabbits exhibited scoliosis in the proportion of 1 affected to every 15 normal, suggesting, but not proving that two recessive genes were involved. Severe scoliosis involves all areas of the axial skeleton and is characterized by an extremely jumbled vertebral column caused by many mismatched vertebrae or hemisegments. The condition is characterized by reduced, missing, or extra half-vertebral units. Severity and anatomic location of the defect varies with the strain of rabbit. Scoliosis associated with hemivertebra resembles some human congenital forms, but differs due to absence of associated defects. SPINA BIFIDA (ACLAM Text) Human Disease: Spina Bifida. Pathogenesis: Spina bifida is characterized by a spectrum of patterns. The symptoms can be related to the severity of the pathological events; however, the determinants of this condition in man are puzzling and virtually unknown. There is considerable speculation on the mechanism of neural tube malformations. Animal Disease: Spina bifida. Pathogenesis: Spina bifida was first reported in the AC strain of Dutch rabbit. Its genetic pattern was reported to be a lethal autosomal recessive gene. The affected animals are stillborn. The bifid spine often extends from the caudal part of calvarium to the tail. The open spine, in most cases, is covered by a thin layer of skin. Some associated congenital defects include harelip, cleft palate, severe kyphosis, and a ventral deviation of the tail. Other defects were reported in the cardiovascular, respiratory, or urogenital systems. The frequency of spontaneous spina bifida is high in the rabbit and predictable; however, the lethality of this disease limits the rabbit as a useful model. SYSTEMIC HYPERTENSION (ACLAM Text) Human Disease: Systemic Hypertension. Pathogenesis: There are many factors, most of which are poorly understood, which control blood pressure. Both genetic and environmental factors must be considered, and the distinction is not always easy. Hypertension is an increase in blood pressure above levels normally expected in the general population. Systolic blood pressure normally increases with advancing age, but diastolic pressure does not. 85 to 90 percent of hypertension is essential, meaning that no specific etiology can be identified. The remaining small percentage of hypertensive patients have definite conditions known to result in an increase in blood pressure. Animal Disease: Systemic Hypertension. Pathogenesis: Selected strains of rabbits have been shown to have increased systolic blood pressure of about 30 to 40 mm Hg above normotensive animals, and the incidence of hypertension could be increased in succeeding generations by selective inbreeding. However, little information is available concerning other characteristics of these rabbits, and how they been used for studies of hypertension other than to demonstrate the genetic relationship. VESICOURETERAL REFLUX (ACLAM Text) Human Disease: Vesiculourethral Reflux. Pathogenesis: Efflux of urine from the peristaltic activity of the ureter fills the bladder. In humans, when detrusor activity empties the bladder, a valvular mechanism prevents the urine from reentering the ureter. When the mechanism is ineffective, urine is refluxed back up the ureter during voiding. It is generally believed that reflux in humans is abnormal. However, a high incidence of vesicoureteral reflux is found in children with urinary tract infections. The possible relation between urinary tract infection, vesicoureteral reflux, and pyelonephritis is the stimulus for much interest and research on reflux. Animal Disease: Vesiculourethral Reflux. Pathogenesis: Reflux occurs in 40 - 80% of rabbits. Specific strains and sex differences may be the cause of variation since many investigators are not specific. Little has been done on the relation between bacteria, reflux, and pyelonephritis; perhaps because of endemic chronic nephritis in rabbits caused by Nosema cuniculi which might be confused with bacterial nephritis. VON WILLEBRAND'S DISEASE (ACLAM Text) Human Disease: Von Willebrand's disease. Pathogenesis: Von Willebrand's disease (VWD) is a complex, multifaceted disorder of hemostasis first described by von Willebrand in 1926. A hemorrhagic diathesis with autosomal inheritance; bleeding is mainly purpuric, affecting mucous membranes and the skin. The most common symptom is epistaxis. Gingival bleeding and menorrhagia are other frequent manifestations of the disease, as are occasional gastrointestinal bleeding, hemarthroses, and hematuria. Affected patients have prolonged bleeding times. Decreased platelet retention in glass bead columns can be corrected by addition of fractions of plasma containing factor VIII (FVII). In addition to the platelet abnormality, FVIII coagulant activity (FVII-C) is decreased in VWD. In some forms of VWD it seems likely that VWF is actually absent, but in other variant forms there is evidence of an abnormal, non- functional VWF molecule. Animal Disease: Von Willebrand's disease. Pathogenesis: Discovered in 1975 in a line of Flemish Giant- Chinchilla rabbits by Dr. Dodds in New York. The main features of this defect are autosomal inheritance with variable penetrance, mild to moderate bleeding tendency involving mucosal surfaces and exacerbated by trauma or surgery; markedly prolonged bleeding time, especially from central-ear arterial puncture; variable FVIII-C deficiency (<10-65%); variable platelet retention; and ristocetin aggregation not measurable by standard methods. Many affected rabbits are asymptomatic unless exposed to trauma. Development of this model of VWD has progressed to the fifth generation. By planned matings of affected and normal family members, two distinct lines have been developed, one selected for and the other away from the defect. The trait is consequently becoming more severely expressed in the affected line and minimally carried in the normal line based on FVIII activity levels, over 80 percent of the current offspring of normal parents are also normal, whereas 2 years ago the defect was widespread within this inbred rabbit colony. PELGER-HUET ANOMALY ACQUIRED IMMUNODEFICIENCY SYNDROME ACUTE RESPIRATORY DISTRESS SYNDROME CHAGAS' DISEASE HYDROCEPHALUS HYPERCALCEMIC NEPHROPATHY INFLAMMATORY BOWEL DISEASE MANDIBULAR PROGNATHISM NEPHROBLASTOMA DIABETES MELLITUS VON WILLEBRAND'S DISEASE CARDIOMYOPATHY ATHEROSCLEROSIS DEFICIENCY OF C6 CLEFT PALATE (PALATOSCHISIS) AND CLEFT LIP (CHEILOSCHISIS) CYSTIC DISORDERS OF THE KIDNEY KYPHOSIS CHOLERA OR CYSTIC FIBROSIS ENDOMETRIAL ADENOCARCINOMA VESICOURETERAL REFLUX CAMPYLOBACTER ENTERlTlS SCOLIOSIS ANENCEPHALY ACUTE ACALCULOUS CHOLECYSTITIS OSTEOPETROSIS SPINA BIFIDA SYSTEMIC HYPERTENSION CRYPTOCOCCAL MENINGITIS ENDOCARDITIS GLAUCOMA OTITIS MEDIA