Spontaneous Pathology of the Laboratory Non-human Primate

Spontaneous Pathology of the Laboratory Non-human Primate
Copyright
Contributors
Introduction
1. Choice of the non-human primate for biomedical research
	1. Introduction
		1.1 Non-human primate models in biomedical research
	2. Non-human primates as disease models
		2.1 Non-human primates as infectious disease models
		2.2 Non-human primates as noninfectious disease models
	3. Non-human primates as models of aging and reproduction
	4. Non-human primates in drug and biopharmaceutical discovery and development
	5. Challenges for the use of non-human primates in research
	6. The future of non-human primates in biomedical research
		6.1 Transgene models
		6.2 Stem cell–based regenerative models
		6.3 Comparative systems biology models
	7. Conclusion
	References
2. Regulations and ethics concerning the use of non-human primates in research
	1. Introduction
	2. Regulatory considerations for the use of non-human primates in research
	3. Ethical considerations for the use of non-human primates in research
		3.1 Implementation of the ``3Rs''
		3.2 ``3Rs'' and the opportunities for the use of non-human primates in research
		3.3 NHP housing and care management
	4. Conclusion
	References
3. Infectious diseases of non-human primates
	1. Introduction
	2. Viruses
		2.1 Retroviruses
			2.1.1 Betaretroviruses
			2.1.2 Lentiviruses-simian immunodeficiency viruses (SIV)
			2.1.3 Deltaretrovirus-simian T-lymphotropic viruses (STLV)
		2.2 Paramyxoviruses (measles virus)
		2.3 Herpesviruses
			2.3.1 Macacine herpesvirus 1 (B virus) and saiminiine herpesvirus 1 (Herpes T)
			2.3.2 Herpesvirus 2: HVP-2: cercopithecine herpesvirus 16; (previously cercopithecine SA8)
			2.3.3 Herpesvirus 6, 7, and 9: cercopithecine herpesvirus (simian varicella virus)
			2.3.4 Cytomegalovirus
			2.3.5 Gammaherpesviruses
				2.3.5.1 Lymphocryptovirus
				2.3.5.2 Rhadinoviruses
			2.3.6 Herpes simplex: (human herpesvirus 1 and 2; herpes simplex virus 1)
		2.4 Hepatitis viruses
			2.4.1 Hepatitis A virus (infectious hepatitis)
			2.4.2 Hepatitis E
		2.5 Adenovirus
		2.6 Polyomaviruses (SV40, SV12, CPV)
		2.7 Simian parvovirus
		2.8 Papillomavirus
		2.9 Lymphocytic choriomeningitis virus (Callitrichid Hepatitis virus)
		2.10 Flaviviruses
			2.10.1 West Nile virus
			2.10.2 GB agent viruses
		2.11 Parainfluenza viruses
		2.12 Simian hemorrhagic fever viruses
		2.13 Lyssavirus (rabies virus)
		2.14 Enteroviruses (poliovirus)
		2.15 Encephalomyocarditis virus
		2.16 Monkeypox
	3. Bacteria
		3.1 Shigella
		3.2 Campylobacter
		3.3 Salmonellosis
		3.4 Helicobacter spp.
		3.5 Mycobacterium spp.
			3.5.1 Mycobacterium tuberculosis
			3.5.2 Mycobacterium avium complex (MAC)
			3.5.3 Mycobacterium leprae
		3.6 Moraxella (Branhamella; Neisseria) catarrhalis
		3.7 Escherichia coli
		3.8 Rhodococcus equi
		3.9 Bordetella bronchiseptica
		3.10 Klebsiella pneumoniae
		3.11 Yersinia spp.
		3.12 Chromobacterium violaceum
		3.13 Francisella tularensis
		3.14 Corynebacterium spp.
		3.15 Streptococcus spp.
		3.16 Staphylococcus aureus
		3.17 Listeria monocytogenes
		3.18 Morganella morganii
		3.19 Nonpathogenic bacteria commonly noted in non-human primate tissue
	4. Parasites
		4.1 Protozoa
			4.1.1 Cryptosporidium sp.
			4.1.2 Giardia intestinalis
			4.1.3 Trypanosoma spp.
			4.1.4 Sarcocystis spp.
			4.1.5 Plasmodium spp.
			4.1.6 Balantidium coli
			4.1.7 Trichomonas spp.
			4.1.8 Toxoplasma gondii
			4.1.9 Amebae
		4.2 Metazoa
			4.2.1 Nematodes
				4.2.1.1 Trichospirura leptostoma
				4.2.1.2 Oesophagostomum spp.
				4.2.1.3 Strongyloides sp.
				4.2.1.4 Nochtia nochti
				4.2.1.5 Angiostrongylus sp.
				4.2.1.6 Lungworms
				4.2.1.7 Gongylonema sp.
				4.2.1.8 Trichuris sp.
				4.2.1.9 Anatrichosoma spp.
				4.2.1.10 Capillaria spp.
				4.2.1.11 Baylisascaris sp.
			4.2.2 Acanthocephala
			4.2.3 Cestodes
				4.2.3.1 Taenia spp.
				4.2.3.2 Echinococcus sp.
		4.3 Arthropods
			4.3.1 Pneumonyssus
			4.3.2 Skin mites
	5. Opportunistic fungal infections
		5.1 Pneumocystis carinii
		5.2 Candida albicans
		5.3 Cryptococcus neoformans
		5.4 Coccidioides sp.
		5.5 Dermatophytosis
		5.6 Rare opportunistic fungal infections
		5.7 Nonpathogenic fungal organisms-gastric megabacteria
	6. Microsporidians
		6.1 Enterocytozoon bieneusi
		6.2 Encephalitozoon cuniculi
	7. Other pathogens of non-human primates—Pentastomida
	8. Conclusion
	References
4. Clinical examination of the non-human primate
	1. Introduction
	2. The clinical exam of the non-human primate
		2.1 The physical exam
		2.2 Screening procedures
			2.2.1 Clinical pathology
			2.2.2 Radiology
			2.2.3 Parasitology and bacteriology
			2.2.4 Serology
	3. Prophylactic therapy
	4. Conclusion
	References
5. Routes of administration for the non-human primate
	1. Introduction
	2. Selecting the right dose route
	3. Commonly used routes of administration in NHP research
		3.1 Enteral administration (oral route)
		3.2 Local administration (topical route)
		3.3 Parenteral administration
			3.3.1 Intravenous route
			3.3.2 Subcutaneous route
			3.3.3 Intramuscular route
			3.3.4 Intranasal route
			3.3.5 Inhalation administration
	4. Other routes of administration
		4.1 Rectal route
		4.2 Buccal/sublingual route
		4.3 Intraosseous route
		4.4 Epidural and intrathecal route
		4.5 Ocular route
		4.6 Intratracheal route
		4.7 Intraperitoneal route
	5. Conclusion
	References
6. The alimentary system of the non-human primate
	1. Introduction
	2. Anatomy and histology of the alimentary system
		2.1 The oral cavity and salivary glands
		2.2 Esophagus and stomach
		2.3 The small and large intestines
	3. Embryology of the non-human primate alimentary tract
	4. Congenital lesions of the alimentary tract
		4.1 Congenital lesions of the teeth and oral cavity
			4.1.1 Oral salivary gland hamartoma
		4.2 Congenital lesions of the small and large intestines
			4.2.1 Omphalocele
			4.2.2 Meckel's diverticulum
			4.2.3 Ectopic pancreas
			4.2.4 Foregut duplication cyst
	5. Degenerative lesions of the alimentary tract
		5.1 Degenerative lesions of the oral cavity and salivary glands
			5.1.1 Dental caries
			5.1.2 Salivary gland degranulation
		5.2 Degenerative lesions of the stomach
			5.2.1 Smooth muscle degeneration and regeneration
		5.3 Degenerative lesions of the small and large intestines
			5.3.1 Primary systemic amyloidosis
			5.3.2 Lymphangectasia and lymphatic cysts
			5.3.3 Brunner's gland ectasia
	6. Inflammatory lesions of the alimentary tract
		6.1 Inflammatory lesions of the teeth and gingiva
			6.1.1 Dentoalveolar abscesses
			6.1.2 Gingivitis
			6.1.3 Necrotizing stomatitis (noma; cancrum oris)
		6.2 Inflammatory lesions of the salivary gland
		6.3 Inflammatory lesions of the tongue
		6.4 Inflammatory lesions of the esophagus
		6.5 Inflammatory and vascular lesions of the stomach
			6.5.1 Gastritis
			6.5.2 Gastric erosion, ulceration, and hemorrhage
			6.5.3 Gastric infarction
		6.6 Inflammatory and vascular lesions of the small and large intestines
			6.6.1 Enterocolitis and idiopathic diarrhea
			6.6.2 Erosive enteritis and intestinal hemorrhage
			6.6.3 Idiopathic colitis in cotton-top tamarins
			6.6.4 Chronic idiopathic colitis of macaques
			6.6.5 Muciphages of the large intestine
	7. Hyperplastic lesions of the alimentary tract
		7.1 Hyperplastic lesions of the oral cavity
			7.1.1 Gingival hyperplasia (gingival fibromatosis)
		7.2 Hyperplastic lesions of the stomach
		7.3 Hyperplastic lesions of the small and large intestines
			7.3.1 Adenomatous hyperplasia of Brunner's glands
			7.3.2 Goblet cell hyperplasia and smooth muscle hypertrophy of the small intestine
	8. Neoplastic lesions of the alimentary tract
		8.1 Neoplastic lesions of the salivary gland
			8.1.1 Salivary gland adenoma and adenocarcinoma
		8.2 Neoplastic lesions of the teeth and oral cavity
			8.2.1 Dental neoplasms
			8.2.2 Oral squamous cell carcinoma
			8.2.3 Oral papilloma
		8.3 Neoplastic lesions of the stomach
			8.3.1 Gastric adenoma and adenocarcinoma
			8.3.2 Gastrointestinal stromal tumor
			8.3.3 Miscellaneous neoplasms of the stomach
		8.4 Neoplastic lesions of the small and large intestines
			8.4.1 Carcinoma and adenocarcinoma
			8.4.2 Colorectal adenocarcinoma in cotton-top tamarins
			8.4.3 Large intestinal adenocarcinomas in rhesus macaques
			8.4.4 Benign intestinal epithelial tumors
			8.4.5 Mesenchymal tumors
				8.4.5.1 Leiomyomas and leiomyosarcomas
				8.4.5.2 Other mesenchymal tumors
			8.4.6 Round cell tumors
				8.4.6.1 Lymphoma
				8.4.6.2 Mast cell tumors
	9. Toxicologic lesions of the alimentary tract
		9.1 Polychlorinated biphenyls
		9.2 Experimental gastric carcinogenesis
		9.3 Chemotherapy
		9.4 Sunitinib malate
		9.5 Human epidermal growth factor
		9.6 Irradiation
	10. Miscellaneous conditions of the alimentary tract
		10.1 Gastric dilatation syndrome (gastric bloat)
		10.2 Obstructive disorders of the gastrointestinal tract
		10.3 Diverticulosis
		10.4 Rectal prolapse
		10.5 Anorectal fistula
		10.6 Intussusception
		10.7 Megacolon
		10.8 Metabolic diseases of the oral cavity
			10.8.1 Hypovitaminosis C (scurvy)
			10.8.2 Cheilosis (angular cheilitis) due to folic acid deficiency
		10.9 Small intestine mucosal vacuolation
	11. Non-human primate models of disease of the alimentary tract
		11.1 Non-human primate model of gluten-sensitive enteropathy
	12. Conclusion
	References
7. The hepatobiliary system of the non-human primate
	1. Introduction
	2. Anatomy, microanatomy, and function of the liver and gallbladder
		2.1 Gross and subgross anatomy of the liver and gallbladder
		2.2 Microanatomy of the liver and gallbladder
		2.3 Liver function and critical biologic roles
			2.3.1 Immune function
				2.3.1.1 Production of acute phase proteins
				2.3.1.2 Nonspecific phagocytosis and pinocytosis
				2.3.1.3 Nonspecific cell killing
				2.3.1.4 Disposal of waste molecules
				2.3.1.5 Deletion of activated T cells
				2.3.1.6 Induction of tolerance to ingested and self-antigens
				2.3.1.7 Extrathymic proliferation of T cells
		2.4 Gallbladder function
	3. Effects of age on liver structure and function
		3.1 Aging effects on hepatocytes
		3.2 Aging effects on vascular structures
	4. Congenital lesions of the hepatobiliary system
		4.1 Ectopic adrenal glandular tissue
		4.2 Accessory liver
		4.3 Extrahepatic biliary atresia
		4.4 Ductal plate malformation
		4.5 Diaphragmatic hernia with liver lobe hypoplasia
		4.6 Congenital jaundice
		4.7 Biliary hamartoma
		4.8 Gallbladder hypoplasia
		4.9 Intrahepatic congenital liver cyst
	5. Degenerative lesions of the hepatobiliary system
		5.1 Hepatocellular degeneration
		5.2 Focal hepatocellular necrosis
		5.3 Hepatic pigmentation
			5.3.1 Hemosiderosis
			5.3.2 Secondary hemochromatosis
		5.4 Cholelithiasis
		5.5 Crystalloid structures in endothelial cells
		5.6 Hepatocellular vacuolation: lipid and/or glycogen accumulation
			5.6.1 Glycogen accumulation
			5.6.2 Hepatic lipid accumulation
			5.6.3 Tension lipidosis
			5.6.4 Stellate cell lipidosis
			5.6.5 Nonalcoholic fatty liver disease
		5.7 Sinusoidal dilation
		5.8 Hepatic capsular fibrosis
	6. Inflammatory lesions of the hepatobiliary system
	7. Hypertrophic and hyperplastic lesions of the hepatobiliary system
		7.1 Hepatocellular hypertrophy and hyperplasia
		7.2 Bile duct hyperplasia
	8. Neoplastic lesions
	9. Miscellaneous conditions in non-human primates
		9.1 Extramedullary hematopoiesis
		9.2 Multinucleated hepatocytes
		9.3 Liver lobe torsion
		9.4 Eosinophilic hepatocellular inclusions
	10. Metabolic and nutritional conditions affecting the hepatobiliary system
		10.1 Fatal fasting macaque syndrome
	11. Non-human primate models of liver disease
		11.1 Obesity
		11.2 Alcoholic liver disease
		11.3 Fibrosis
		11.4 Acetaminophen-induced hepatotoxicity
	12. Toxicologic lesions of the hepatobiliary system
	13. Conclusion
	References
8. The exocrine pancreas of the non-human primate
	1. Introduction
	2. Normal anatomy, histology, and physiology
		2.1 Anatomy of the exocrine pancreas
		2.2 Histology of the exocrine pancreas
		2.3 Physiology of the exocrine pancreas
	3. Congenital lesions of the exocrine pancreas
		3.1 Ectopic tissues
		3.2 Ciliated forgut cyst
		3.3 Acinar ectasia
	4. Degenerative and regenerative lesions of the exocrine pancreas
	5. Inflammatory lesions of the exocrine pancreas
	6. Hyperplastic lesions of the exocrine pancreas
	7. Neoplastic lesions of the exocrine pancreas
	8. Miscellaneous lesions of the exocrine pancreas
	9. Toxicologic lesions
	10. Conclusion
	References
	Further reading
9. The urinary system of the non-human primate
	1. Introduction
	2. Embryology and fetal development of the urinary system
	3. Structure and function of the urinary system
		3.1 Gross and subgross anatomy of the non-human primate kidney
		3.2 Microscopic and ultrastructural anatomy of the non-human primate kidney
			3.2.1 The proximal tubules
			3.2.2 The loop of Henle
			3.2.3 Distal tubules and collecting ducts
			3.2.4 Renal pelvis
			3.2.5 Glomerulus and juxtaglomerular apparatus
			3.2.6 Vascular supply
		3.3 Microscopic anatomy of the urinary bladder, ureter and urethra
	4. Congenital lesions of the urinary system
		4.1 Hydronephrosis and hydroureter
		4.2 Renal cysts and polycystic kidney disease
		4.3 Tubular metaplasia of Bowman's capsule
		4.4 Ectopic tissues
			4.4.1 Ectopic adrenal gland in the kidney
			4.4.2 Ectopic intestinal mucosal tissue in the urinary bladder
			4.4.3 Intrathoracic kidney
		4.5 Renal hypoplasia, aplasia, and agenesis
		4.6 Umbilical remnants
	5. Degenerative lesions of the urinary system
		5.1 Glomerulopathy and glomerulointerstitial sclerosis
		5.2 Tubular degeneration
		5.3 Tubular or glomerular casts
		5.4 Vacuolar changes
		5.5 Amyloidosis
		5.6 Pigmentary nephropathy
	6. Inflammatory and vascular lesions of the urinary system
		6.1 Mononuclear cell infiltrates and inflammation
		6.2 Renal infarcts
	7. Hyperplastic and metaplastic lesions of urinary system
		7.1 Tubular epithelial hyperplasia/hypertrophy
		7.2 Urinary bladder mucosa squamous or glandular metaplasia
		7.3 Osseous metaplasia of the kidney
		7.4 Fat metaplasia of the glomerulus
	8. Neoplastic lesions of the urinary system
	9. Miscellaneous lesions of the urinary system
		9.1 Urolithiasis
		9.2 Crystalline nephropathy
		9.3 Retrograde sperm ejaculation
		9.4 Pigments and mineralization
		9.5 Cytoplasmic inclusions
		9.6 Multinucleated cells of the renal tubules
	10. Toxicologic lesions of the urinary system
	11. Conclusion
	References
10. The nervous system of the non-human primate
	1. Introduction
	2. Anatomy and histology of the nervous system
	3. Congenital lesions of the nervous system
		3.1 Anencephaly
		3.2 Hydrocephalus
		3.3 Porencephaly
		3.4 Cerebral deformation
		3.5 Squamous cyst and ependymal cyst
		3.6 Craniorachischisis and omphalocele
		3.7 Neurocutaneous melanosis
		3.8 Cerebellar hypoplasia
		3.9 Ceroid-lipofuscinosis
	4. Degenerative lesions of the nervous system
		4.1 Cerebromalacia
		4.2 Obstructive hydrocephalus
		4.3 Periventricular leukomalacia
		4.4 Pigments
			4.4.1 Lipochromes (lipofuscin and ceroid pigments)
			4.4.2 Neuronal eosinophilic granules and inclusions of noninfectious origin
		4.5 Mineralization
		4.6 Autophagy of sensory neurons
		4.7 Cerebral atrophy
		4.8 Myelin sheath degeneration
		4.9 Cerebral tauopathy
		4.10 Cerebral amyloid plaques and vascular amyloidosis
		4.11 Corpora amylacea of the central nervous system
		4.12 Axonal degeneration of the central and peripheral nervous system
			4.12.1 Axonal dystrophy
			4.12.2 Never fiber degeneration
	5. Inflammatory and vascular lesions of the nervous system
		5.1 Inflammatory cell infiltrates and gliosis of the nervous system
		5.2 Vascular lesions of the nervous system
			5.2.1 Hemorrhage and edema
			5.2.2 Cerebral thrombosis and infarction
			5.2.3 Polyarteritis nodosa
	6. Neoplastic lesions of the nervous system
		6.1 Meningioma
		6.2 Neuroblastic tumors
			6.2.1 Primitive neuroectodermal tumors
			6.2.2 Ganglioneuroma
		6.3 Paraganglioma
		6.4 Ependymoma
		6.5 Glial cell tumors
		6.6 Vascular tumors
		6.7 Lipoma of the choroid plexus
	7. Miscellaneous spontaneous and artifactual findings of the nervous system
		7.1 Melanocytic foci of the central nervous system
		7.2 Ganglion dysplasia
		7.3 Findings associated with intrathecal catheterization
		7.4 Eosinophilic deposits of the meninges and dura mater
		7.5 Vacuolation artifact of the central nervous system
		7.6 Vacuolation of dorsal root ganglia neurons
		7.7 Neuronal shrinkage artifact (dark neurons)
	8. Toxicological findings of the nervous system
		8.1 Findings in the nervous system due to biologic-induced immune-mediated processes
		8.2 Findings associated with adeno-associated viral vectors (AAV)
		8.3 Findings associated with polyethylene glycol (PEG)
		8.4 Findings associated with antisense oligonucleotides (ASO)
		8.5 Neurotoxic metals, chemicals, and drugs
			8.5.1 Methylmercury, lead, and manganese
			8.5.2 Neurotoxic chemicals
			8.5.3 Excitatory neurotoxins
			8.5.4 Neurotoxic medications
	9. Conclusion
	Acknowledgments
	References
11. The eye and ocular adnexa of the non-human primate
	1. Introduction
	2. Embryology
	3. Anatomy and histology
		3.1 Orbital anatomy
		3.2 Eye anatomy
			3.2.1 General eye anatomy
			3.2.2 Cornea
			3.2.3 Lens
			3.2.4 Uvea (iris, ciliary body, choroid) and aqueous humor outflow system
				3.2.4.1 Iris
				3.2.4.2 Ciliary body
				3.2.4.3 Choroid
				3.2.4.4 Aqueous humor outflow system
			3.2.5 Retina
				3.2.5.1 Retinal phototransductive neurons
				3.2.5.2 Cone opsins and color vision in macaques and marmosets
				3.2.5.3 Retinal nonphototransductive neurons
				3.2.5.4 Retinal glial cells
				3.2.5.5 Retinal layers
				3.2.5.6 Retinal topography
					3.2.5.6.1 Fovea centralis and macula lutea
					3.2.5.6.2 Visual streak
				3.2.5.7 Retinal vasculature
			3.2.6 Retinal pigment epithelium (RPE)
			3.2.7 Vitreous
			3.2.8 Sclera
			3.2.9 Optic nerve and optic nerve head (ONH)
		3.3 Ocular adnexa
			3.3.1 Eyelids, eyelid glands, and conjunctiva
			3.3.2 Plica semilunaris and lacrimal caruncle
			3.3.3 Lacrimal gland and lacrimal drainage apparatus
			3.3.4 Extraocular muscles
	4. Congenital lesions
		4.1 Persistent fetal hyaloid vasculature
		4.2 Retinal and optic nerve head myelination
		4.3 Retinal nodular gliosis
		4.4 Oculocutaneous albinism
		4.5 Miscellaneous congenital lesions of the eye
		4.6 Heritable color vision deficits
		4.7 Congenital lesions of the ocular adnexa
	5. Inflammatory lesions
		5.1 Mononuclear cell infiltrates and inflammation
		5.2 Cornea, anterior chamber, and uveal tract inflammation
		5.3 Retinal inflammation
		5.4 Vitreal inflammation
		5.5 Optic nerve inflammation
		5.6 Conjunctival and lacrimal gland inflammation
	6. Degenerative lesions
		6.1 Degenerative lesions of the eye
			6.1.1 Corneal degenerative lesions
			6.1.2 Lens degenerative lesions
				6.1.2.1 Cataract
			6.1.3 Uvea (ciliary body, iris, choroid) degenerative lesions
			6.1.4 Retinal degenerative lesions
				6.1.4.1 Retinal peripheral microcystoid degeneration
				6.1.4.2 Subretinal displacement of rod and cone photoreceptor nuclei
				6.1.4.3 Retinal detachment
				6.1.4.4 Retinal edema
			6.1.5 Retinal pigment epithelium degenerative lesions
				6.1.5.1 Drusen, drusenoid lesions, and acquired macular degeneration (AMD)-like lesions
			6.1.6 Optic nerve and optic nerve head (ONH) degenerative lesions
				6.1.6.1 Idiopathic bilateral optic atrophy
				6.1.6.2 Glaucoma
	7. Proliferative lesions
		7.1 Proliferative lesions of the eye
		7.2 Proliferative lesions of the ocular adnexa
	8. Toxicologic lesions
		8.1 Corneal epithelial necrosis and increased mitosis
		8.2 Iris hyperpigmentation
		8.3 Eyelid meibomian gland squamous metaplasia
	9. Miscellaneous lesions and artifacts
		9.1 Miscellaneous lesions
			9.1.1 Keratoconus
			9.1.2 Refractive and oculomotor disorders
			9.1.3 Orbital lesions
		9.2 Artifacts
	10. Conclusion
	References
12. Musculoskeletal system of the non-human primate
	1. Muscle
		1.1 Introduction
		1.2 Embryology and histology of muscle
		1.3 Congenital lesions of muscle
			1.3.1 Diaphragmatic hernia
		1.4 Degenerative lesions of muscle
			1.4.1 Muscle necrosis and degeneration
			1.4.2 Muscle atrophy
		1.5 Inflammatory and vascular lesions of muscle
			1.5.1 Muscle inflammatory cell infiltrates
		1.6 Metabolic and nutritional lesions of muscle
			1.6.1 Sarcopenia, oxidative stress and calorie restriction
			1.6.2 Vitamin deficiencies
			1.6.3 Marmoset Wasting Syndrome (MWS)
		1.7 Neoplastic lesions of muscle
		1.8 Toxicologic lesions of muscle
			1.8.1 Adjuvants
			1.8.2 Radiation therapy
			1.8.3 Delayed-type hypersensitivity (DTH) induction site inflammation of muscle
			1.8.4 Steroid muscle atrophy
	2. Bone
		2.1 Introduction
		2.2 Embryology, anatomy and histology of bone and joints
		2.3 Congenital lesions of bones and joints
		2.4 Degenerative lesions of bones and joints
			2.4.1 Osteopenia
			2.4.2 Degenerative joint disease
		2.5 Inflammatory and vascular lesions of bones and joints
		2.6 Hyperplastic lesions of bones and joints
			2.6.1 Increased thickness of the physis
		2.7 Neoplastic lesions of bones
		2.8 Other findings in the skeletal system
			2.8.1 Traumatic lesions of the bone and joint
		2.9 Toxicologic lesions of bones and joints
	3. Conclusion
	References
13. The integumentary system of the non-human primate
	1. Introduction
	2. Integumentary anatomy and histology
		2.1 Epidermis
		2.2 Dermis
		2.3 Subcutis
		2.4 Adnexa and hair follicles
	3. Evaluation and diagnosis of dermatological disease
	4. Congenital and developmental lesions of skin
	5. Degenerative lesions of skin
		5.1 Calcinosis circumscripta
		5.2 Atrophy of skin or adnexa
	6. Inflammatory and vascular lesions
		6.1 Inflammatory lesions and patterns of skin injury
			6.1.1 Superficial dermatitis of the macaque
			6.1.2 Erythema multiforme (EM) and toxic epidermal necrolysis (TEN)
			6.1.3 Lupus
			6.1.4 Other interface dermatoses
			6.1.5 Psoriasiform dermatoses
			6.1.6 Contact dermatitis
			6.1.7 Seborrheic dermatitis
			6.1.8 Foreign body reactions
			6.1.9 Panniculitis
		6.2 Vascular lesions of skin
			6.2.1 Gangrenous necrosis
			6.2.2 Urticaria
	7. Hyperplastic and neoplastic lesions of skin
		7.1 Proliferative epithelial and adnexal lesions
			7.1.1 Papilloma
			7.1.2 Squamous cell carcinoma
			7.1.3 Basal cell carcinoma
			7.1.4 Trichoepithelioma
			7.1.5 Keratoacanthoma
			7.1.6 Apocrine gland tumors
			7.1.7 Epidermal inclusion cysts and comedonal cysts
			7.1.8 Sebaceous adenoma
		7.2 Proliferative lesions of the dermis and subcutis
			7.2.1 Cutaneous fibroepithelial polyp
			7.2.2 Lipoma, liposarcoma, and adipose hamartoma
		7.3 Melanin-rich foci
		7.4 Vascular neoplasms
			7.4.1 Hemangioma
			7.4.2 Hemangiosarcoma
			7.4.3 Angiofibroma
		7.5 Other neoplasms
			7.5.1 Lymphoma
			7.5.2 Cutaneous osseous neoplasia
			7.5.3 Mast cell tumor
	8. Other dermatological conditions of non-human primates
		8.1 Amyloidosis
		8.2 Paraneoplastic cutaneous manifestations
		8.3 Nutritional deficiencies
		8.4 Dermatological changes due to hormonal influence
		8.5 Thermal injury
		8.6 Trauma
		8.7 Grooming alopecia
	9. Non-human primate models with dermatologic manifestations
		9.1 Non-human primate delayed type hypersensitivity (DTH) model
		9.2 Dermatological manifestations of the non-human primate xenotransplantation model
	10. Toxicologic lesions of the integument
		10.1 Vaccine injection sites
		10.2 T cell–dependent antibody response (TDAR) model induction site
		10.3 Administration sites for biologic test articles
		10.4 Sustained-release buprenorphine administration site reaction
		10.5 Carcinogen-induced neoplasia
		10.6 Steroid-induced dermal atrophy
		10.7 Antibody-drug conjugate skin toxicity
	11. Fish skin grafting for non-human primate skin lesions
	12. Conclusion
	References
14. The mammary gland of the non-human primate
	1. Introduction
	2. Anatomy, histology, and embryology of the non-human primate mammary gland
		2.1 Gross anatomy
		2.2 Microscopic anatomy
		2.3 Embryology and developmental stages
	3. Congenital lesions of the non-human primate mammary gland
	4. Degenerative lesions of the non-human primate mammary gland
	5. Inflammatory and vascular lesions of the non-human primate mammary gland
	6. Hyperplastic and neoplastic lesions of the non-human primate mammary gland
		6.1 Lobular hyperplasia of the mammary gland
		6.2 Ductal hyperplasia
	7. Neoplastic lesions of the non-human primate mammary gland
		7.1 Fibroadenoma
		7.2 Ductal carcinoma in situ (DCIS)
		7.3 Invasive ductal carcinoma (IDC)
		7.4 Lobular carcinoma in situ (LCIS)
		7.5 Infiltrating lobular carcinoma
	8. Miscellaneous lesions of the non-human primate mammary gland
	9. Toxicologic lesions of the non-human primate mammary gland
	10. Conclusion
	References
15. The respiratory system of the non-human primate
	1. Introduction
	2. Anatomy and histology of the respiratory system
		2.1 Nasal cavity
		2.2 Larynx
		2.3 Tracheobronchial tree
		2.4 Lung
	3. Congenital lesions of the respiratory system
	4. Degenerative lesions of the respiratory system
		4.1 Degeneration of the respiratory epithelium
		4.2 Pleural or interstitial fibrosis and adhesions
	5. Inflammatory and vascular lesions of the respiratory system
		5.1 Mixed or mononuclear cell infiltrates of the respiratory system
		5.2 Eosinophilic airway inflammation
		5.3 Foreign body granulomas and aspirated materials
		5.4 Vasculitis
		5.5 Thrombosis and thromboembolism
	6. Hyperplastic, metaplastic, and neoplastic lesions of the respiratory system
		6.1 Goblet cell hyperplasia and metaplasia
		6.2 Osseous or cartilaginous metaplasia of the lung
		6.3 Alveolar epithelial hyperplasia
		6.4 Smooth muscle hypertrophy and hyperplasia
		6.5 Pulmonary neoplasia
	7. Miscellaneous lesions of the respiratory system
		7.1 Pulmonary mineralization
		7.2 Extramedullary hematopoiesis
		7.3 Pulmonary pigments
		7.4 Continuous infusion pneumonitis
	8. Toxicologic lesions of the respiratory system
		8.1 Upper respiratory tract response to toxic injury
		8.2 Toxic inflammation and hemorrhage of the lung
		8.3 Lung findings due to PEGylation of test articles
		8.4 Acute respiratory distress syndrome
		8.5 Drug-induced hypersensitivity reactions
			8.5.1 Immune complex vasculitis
			8.5.2 Anaphylaxis and anaphylactoid reactions
		8.6 Antibody drug conjugates
		8.7 Increased leukocyte trafficking
	9. Non-human primate models of respiratory disease
		9.1 Macaque model of SARS-CoV-2 infection
		9.2 Models of airway hypersensitivity and asthma
	10. Conclusion
	References
16. The hematolymphoid system of the non-human primate
	1. Introduction
	2. Anatomy of the hematolymphoid system
		2.1 Development of the hematolymphoid system of non-human primates
			2.1.1 Chronology of lymphoid tissue development
			2.1.2 Lymphocyte development
			2.1.3 Development of populations of antigen presenting cells and their tissue distribution
			2.1.4 Development, subgross anatomy, and histology of lymph nodes
			2.1.5 Functional anatomy of the lymph node: cell trafficking and antigen presentation
			2.1.6 Development, anatomy, and function of the spleen
			2.1.7 Development and functional anatomy of the monkey thymus
	3. Congenital lesions of the hematolymphoid system
		3.1 Thymus ectopia and parathyroid gland ectopia within the thymus
		3.2 Congenital thymic cysts
		3.3 Ectopic spleen
		3.4 Ectopic salivary gland in the mandibular lymph node
		3.5 Other congenital findings in non-human primates
	4. Degenerative lesions of the hematolymphoid system of the non-human primate
		4.1 Capsular and trabecular fibrosis of the spleen
		4.2 Degenerative cysts of the thymus
		4.3 Stress-induced changes in the hematolymphoid system
		4.4 Other degenerative findings of the hematolymphoid system
	5. Inflammatory and vascular lesions of the hematopoietic system
		5.1 Inflammatory cell infiltrates
			5.1.1 Increased granulocyte content of lymphoid tissues
			5.1.2 Lymph node sinus histiocytosis
			5.1.3 Lymph node lymphoplasmacytosis
			5.1.4 Lymph node inflammation
		5.2 Lymph node sinus erythrocytosis and erythrophagocytosis
		5.3 Thrombosis
		5.4 Hemorrhage
	6. Hyperplastic and neoplastic lesions of the hematolymphoid system
		6.1 Hyperplastic and neoplastic diseases of the thymus
			6.1.1 Thymoma
		6.2 Hyperplastic and neoplastic lesions of the spleen
			6.2.1 Reticuloendothelial hypertrophy or hyperplasia of the splenic red pulp
			6.2.2 Nodular and mass-like lesions of the spleen
			6.2.3 Neoplastic lesions of the spleen
		6.3 Hyperplastic/neoplastic lesions of the lymph nodes
			6.3.1 Lymphoproliferation
		6.4 Systemic neoplastic diseases: lymphomas and leukemias
	7. Miscellaneous findings in the hematolymphoid system of non-human primates
		7.1 Splenosis
		7.2 Tertiary lymphoid structures
		7.3 Trabecular fibrosis
		7.4 Extramedullary hematopoiesis of lymph nodes and spleen
		7.5 Nonheme pigments in lymph nodes and spleen
			7.5.1 Tattoo ink
			7.5.2 Melanin pigment
		7.6 Warthin Finkeldey giant cells and Reed-Sternberg cells of the lymphoid follicles
		7.7 Tissue artifact
	8. Toxicologic findings of the hematolymphoid system
		8.1 Lymphoid tissues—spleen, lymph nodes, thymus, and bone marrow
		8.2 Toxicologic lesions produced by small molecules
		8.3 Toxicologic lesions produced by biotherapeutics
		8.4 Toxicologic findings of hemopoietic tissue—bone marrow
	9. Conclusion
	References
17. The female reproductive tract of the non-human primate
	1. Introduction
	2. Normal anatomy and biology
		2.1 Anatomy
			2.1.1 Macaca species
			2.1.2 Callithrix species
		2.2 Cyclic changes of the female reproductive system
			2.2.1 Macaca species
			2.2.2 Callithrix species
		2.3 Pregnancy
			2.3.1 Macaca species
			2.3.2 Callithrix species
		2.4 Immaturity and senescence
			2.4.1 Macaca species
			2.4.2 Marmoset species
		2.5 Social and seasonal effects
			2.5.1 Macaque species
			2.5.2 Marmoset species
	3. Congenital lesions of the female reproductive system
		3.1 Ectopic ovarian tissue
		3.2 Para-ovarian cysts
		3.3 Disorders of sexual development
		3.4 Imperforate vagina and fused labia
		3.5 Mullerian duct anomalies
		3.6 Uterine hypoplasia
		3.7 Uterocervical malformation
	4. Degenerative lesions
		4.1 Ovarian follicular mineralization
		4.2 Polyovular follicles
		4.3 Ovarian follicular cysts and rete ovarii cysts
		4.4 Uterine endometrial cysts and cervical cysts
	5. Vascular lesions
		5.1 Pregnancy-associated vascular change
		5.2 Uterine infarction
		5.3 Serosal hemorrhage of the uterus
	6. Inflammatory lesions
		6.1 Ovary and oviducts
		6.2 Uterus
		6.3 Cervix, vagina, and vulva
			6.3.1 Condylomatous eosinophilic vulvovaginitis
	7. Hyperplastic and neoplastic lesions
		7.1 Ovaries and oviducts
			7.1.1 Ovarian surface epithelial hyperplasia
			7.1.2 Teratoma/dermoid cyst
			7.1.3 Ovarian epithelial carcinoma
			7.1.4 Sex cord stromal tumors
			7.1.5 Trophoblastic tumors
			7.1.6 Ectopic oviduct epithelium
		7.2 Uterus
			7.2.1 Epithelial plaque response
			7.2.2 Decidual change/deciduosis
			7.2.3 Endometrial polyps
			7.2.4 Leiomyomas
			7.2.5 Uterine hemangiomas
			7.2.6 Endometrial carcinoma
			7.2.7 Trophoblastic neoplasms
		7.3 Cervix, vagina, and vulva
			7.3.1 Cervical squamous metaplasia
			7.3.2 Intraepithelial neoplasia (papillomavirus)
			7.3.3 Squamous cell carcinoma
	8. Miscellaneous spontaneous, experimental and iatrogenic lesions of the female reproductive system
		8.1 Endometriosis
		8.2 Adenomyosis
		8.3 Hydrosalpinx
		8.4 Obstetric fistulas
		8.5 Vaginal prolapse
		8.6 Endometrial pigmentation
		8.7 Ovarian smooth muscle metaplasia
	9. Toxicologic lesions
		9.1 Estrogen, progestogen, and androgen effects on the female reproductive system
			9.1.1 Prenatal testosterone (T) effects on the hypothalamic-pituitary-gonadal axis (HPG)
			9.1.2 Bisphenol A
			9.1.3 Clitoromegaly
			9.1.4 Endometrial stromal hyperplasia
			9.1.5 Endometrial glandular hyperplasia
		9.2 Teratogenic research models
	10. Conclusion
	Acknowledgments
	References
18. The male reproductive system of the non-human primate
	1. Introduction
	2. Anatomy and histology
		2.1 Testis, rete testis
		2.2 Efferent ducts, epididymis, and vas deferens
		2.3 Accessory sex glands, penis, and scrotum
	3. Physiology
		3.1 Endocrinology
	4. Congenital lesions
		4.1 Hypospadias
		4.2 Cryptorchidism
		4.3 Testicular and epididymal appendages
		4.4 Increased stromal collagen
		4.5 Tubular hypoplasia
		4.6 Ectopic adrenal gland
	5. Degenerative lesions
		5.1 Introduction
		5.2 Testes
			5.2.1 Tubular dilatation/degeneration
			5.2.2 Tubular degeneration/atrophy
			5.2.3 Hypospermatogenesis
			5.2.4 Tubular necrosis
		5.3 Efferent ducts, epididymis, and vas deferens
			5.3.1 Epithelial degeneration
			5.3.2 Epithelial apoptosis and/or atrophy
			5.3.3 Cellular debris and reduced sperm
		5.4 Accessory sex glands
			5.4.1 Atrophy
			5.4.2 Other degenerative changes
	6. Inflammatory and vascular lesions
		6.1 Introduction
		6.2 Testis and epididymis
			6.2.1 Orchitis
			6.2.2 Epididymitis and sperm granuloma
			6.2.3 (Peri)vasculitis
		6.3 Accessory sex glands
	7. Hyperplastic and neoplastic lesions
		7.1 Testis
		7.2 Accessory sex glands
		7.3 Penis
	8. Toxicologic lesions
		8.1 Testis
			8.1.1 Germ cell effects
			8.1.2 Sertoli cell toxicity
			8.1.3 Hormonal effects
		8.2 Efferent ducts, epididymis, and vas deferens
		8.3 Accessory sex glands
	9. Conclusion
	References
19. The cardiovascular system of the non-human primate
	1. Introduction
	2. Anatomy of the cardiovascular system
	3. Congenital lesions of the cardiovascular system
		3.1 Congenital defects of the heart and vasculature
		3.2 Congenital proliferative vascular lesions
		3.3 Congenital epicardial cysts and epithelial plaques
		3.4 Ectopic thyroid tissue
	4. Degenerative lesions of the cardiovascular system
		4.1 Arteriosclerosis
		4.2 Degeneration of the arterial tunica media
		4.3 Aortic Dissection
		4.4 Vascular and myocardial associated pigments
		4.5 Vascular and cardiac mineralization
		4.6 Myocardial degeneration, necrosis, and fibrosis
			4.6.1 Small foci of myocardial degeneration
			4.6.2 Large foci of myocardial degeneration (idiopathic cardiomyopathy)
			4.6.3 Cardiac fibrosis
		4.7 Mucinous change of the myocardium and arteries
		4.8 Valvular myxomatous degeneration
		4.9 Valvular vascular ectasia and hematocysts
		4.10 Epicardial adipose atrophy
	5. Inflammatory and vascular lesions of the cardiovascular system
		5.1 Mononuclear or mixed cell infiltrates of the heart
		5.2 Vasculitis (Polyarteritis Nodosa-PAN)
		5.3 Granulomatous epicarditis
		5.4 Hemorrhage
	6. Hyperplastic lesions of the cardiovascular system
		6.1 Cardiomyocyte hypertrophy
		6.2 Mesothelial hyperplasia
		6.3 Vascular endothelial hypertrophy and hyperplasia
	7. Neoplastic lesions of the cardiovascular system
		7.1 Mesothelioma
		7.2 Other cardiac neoplasms
		7.3 Hemangioma and hemangiosarcoma
		7.4 Other vascular neoplasms
	8. Miscellaneous findings of the cardiovascular system
		8.1 Findings associated with indwelling catheters
		8.2 Findings associated with continuous infusion
		8.3 Cardiac contraction band artifact
		8.4 Perfusion fixation—induced findings
		8.5 Fatty infiltration of the myocardium
		8.6 Intranuclear and intracytoplasmic inclusions of noninfectious nature
		8.7 Antidrug antibody—associated immune complex disease
	9. Toxicologic lesions of the cardiovascular system
		9.1 Xenobiotic-induced congenital defects
		9.2 Atherosclerosis models
		9.3 Anthracycline-induced cardiotoxicity
		9.4 Propofol-induced pulmonary edema
		9.5 Antisense oligonucleotide-associated vasculitis
	10. Conclusion
	References
20. The endocrine system of the non-human primate
	1. Introduction
	2. Anatomy, histology, and embryology of the endocrine system
		2.1 Adrenal gland
		2.2 Thyroid and parathyroid glands
		2.3 Pituitary gland and hypothalamus
		2.4 Endocrine pancreas
		2.5 Pineal gland (epiphysis cerebri)
	3. The hypothalamic endocrine axes
	4. Congenital lesions of the endocrine system
		4.1 Adrenal gland
			4.1.1 Adrenohepatic fusion and liver embedded adrenal gland
			4.1.2 Ectopic adrenal gland
			4.1.3 Ectopic bone in the adrenal gland
			4.1.4 Retained fetal adrenal cortex
		4.2 Thyroid and parathyroid glands
			4.2.1 Congenital thyroid gland cysts
			4.2.2 Ectopic thymus in the thyroid gland or parathyroid gland
			4.2.3 Ectopic thyroid or parathyroid gland
			4.2.4 Ectopic salivary gland in the thyroid gland
			4.2.5 Thyroid gland hypoplasia or agenesis
			4.2.6 Congenital goiter
		4.3 Pituitary gland
			4.3.1 Congenital cysts of the pituitary gland
		4.4 Endocrine pancreas
			4.4.1 Giant islets of Langerhans
	5. Degenerative lesions of the endocrine system
		5.1 Adrenal gland
			5.1.1 Adrenal gland pigment
			5.1.2 Adrenal gland necrosis
		5.2 Thyroid and parathyroid glands
			5.2.1 Degenerative cysts of the thyroid and parathyroid glands
			5.2.2 Thyroid gland follicular atrophy and degeneration
			5.2.3 Follicular epithelial vacuolation
			5.2.4 Thyroid gland and parathyroid gland fibrosis
			5.2.5 Fat infiltration of the thyroid gland or parathyroid gland
		5.3 Pituitary gland
			5.3.1 Pituitary gland fibrosis and mineralization
			5.3.2 Vacuolar degeneration of the pituitary gland
			5.3.3 Degenerative cysts of the pars distalis or pars intermedia
		5.4 Endocrine pancreas
			5.4.1 Islet of Langerhans atrophy
		5.5 Pineal gland
			5.5.1 Fibrosis and mineralization of the pineal gland
	6. Inflammatory and vascular lesions of the endocrine system
		6.1 Mononuclear cell infiltrates of endocrine organs
		6.2 Adrenal gland
			6.2.1 Adrenalitis
			6.2.2 Adrenal gland hemorrhage
		6.3 Thyroid and parathyroid glands
			6.3.1 Thyroiditis
		6.4 Pituitary gland and pineal gland
		6.5 Endocrine pancreas
			6.5.1 Inflammation of the islets of Langerhans
			6.5.2 Vascular ectasia of the islets of Langerhans
	7. Hyperplastic lesions of the endocrine system
		7.1 Adrenal gland
		7.2 Thyroid and parathyroid glands
		7.3 Pituitary gland
			7.3.1 Hypertrophy and hyperplasia of the pars distalis
		7.4 Endocrine pancreas
	8. Neoplastic lesions of the endocrine system
		8.1 Adrenal gland
			8.1.1 Pheochromocytoma
			8.1.2 Adrenal cortical adenoma
			8.1.3 Adrenal hemangioma
			8.1.4 Other tumors of the adrenal gland
		8.2 Thyroid and parathyroid glands
			8.2.1 C-cell neoplasia
			8.2.2 Thyroid follicular adenoma and follicular adenocarcinoma
		8.3 Pituitary gland
			8.3.1 Pituitary adenoma
		8.4 Endocrine pancreas
			8.4.1 Pancreatic neuroendocrine tumors (PanNETs)
	9. Other findings in endocrine organs of non-human primates
		9.1 Adrenal gland multinucleated cells
		9.2 Euthanasia artifact
		9.3 Fat metaplasia of the adrenal gland
	10. Toxicologically induced lesions of the endocrine system
		10.1 Immune-mediated hypersensitivity reactions
		10.2 Postvaccination bacille Calmette-Guérin (BCG) granulomas
		10.3 General toxicity of the adrenal gland
		10.4 General toxicity of the thyroid and parathyroid glands
		10.5 General toxicity of the pituitary gland and hypothalamus
		10.6 General toxicity of the endocrine pancreas
	11. Conclusion
	References
21. Clinical pathology of the non-human primate
	1. Introduction
	2. Challenges and rationale for clinical pathology evaluations of non-human primates in biomedical research
	3. Clinical pathology sample collection and analysis
	4. Hematology
		4.1 Erythrocytes
			4.1.1 Decreases in red cell mass
			4.1.2 Increases in red blood cell mass
		4.2 Leukocytes
			4.2.1 Neutrophils
			4.2.2 Eosinophils
			4.2.3 Basophils
			4.2.4 Lymphocytes
			4.2.5 Monocytes
		4.3 Platelets
	5. Hemostasis: factors, tests, and interpretation
		5.1 Coagulation times
			5.1.1 Prolongation of PT and/or APTT times
			5.1.2 Shortening of PT and/or APTT
			5.1.3 Thrombin time
		5.2 Fibrinogen
			5.2.1 Decreased fibrinogen
			5.2.2 Increased fibrinogen
			5.2.3 Fibrin degradation products and D-dimer
		5.3 Coagulation factors
		5.4 Bleeding time
		5.5 Platelet dysfunction assays
	6. Clinical chemistry: collection, analysis, and interpretation
		6.1 Principles of clinical chemistry testing
		6.2 Routine and nonroutine testing
		6.3 Assessment of the liver
		6.4 Assessment of the kidney
		6.5 Assessment of muscle and the heart
		6.6 Assessment of proteins
		6.7 Assessment of metabolism and lipids
		6.8 Assessment of electrolytes and minerals
	7. Urinalysis: general overview and interpretation
	8. Bone marrow smear evaluation
	9. Conclusion
	References
22. Immunohistochemistry for the non-human primate
	1. Introduction
	2. Why use immunohistochemistry
	3. Methodology
		3.1 Tissue preparation and fixation
		3.2 Antigen retrieval
		3.3 Positive and negative controls
		3.4 Antibody controls
		3.5 Other controls
		3.6 Selection of detection method
		3.7 Selection of markers and antibodies
	4. Slide evaluation
	5. Potentially useful immunohistochemical stains
		5.1 Cell proliferation
		5.2 Endothelium/vasculogenesis
		5.3 Apoptosis
		5.4 Immune complexes
		5.5 Complement fixation
		5.6 Neoplasia
		5.7 Digestive system
		5.8 Urinary system
		5.9 Nervous system
		5.10 Eye and associated glands
		5.11 Bone, joints, skeletal muscle
		5.12 Skin and subcutis
		5.13 Cardiovascular system
		5.14 Respiratory
		5.15 Lymphoid and hematopoietic systems
		5.16 Male reproductive tract
		5.17 Female reproductive tract
		5.18 Mammary gland
		5.19 Endocrine system
		5.20 Liver and gall bladder
	6. Conclusion
	References
Index
	A
	B
	C
	D
	E
	F
	G
	H
	I
	J
	K
	L
	M
	N
	O
	P
	Q
	R
	S
	T
	U
	V
	W
	X
	Y
	Z