Spontaneous thymoma in a juvenile cynomolgus macaque (Macaca fascicularis).

A single, solid, yellow-white thymic mass was found at necropsy of a two-year-old female cynomolgus macaque from a four-week, repeat-dose toxicity and immunogenicity study. Microscopically, the mass was multilobular and well encapsulated, surrounded by a thick connective tissue capsule, and composed of dense sheets of elongate or spindle-shaped cells and large cystic cavities separated by thick connective tissue stroma. Normal thymus was adjacent to the mass, but it was compressed. Within the mass were abundant interspersed Hassall's corpuscles; individual and small clusters of mature, small lymphocytes; scattered eosinophils; large areas of necrosis; focal mineralization; and cholesterol clefts. An interesting feature was the presence of large multinucleated giant cells, which varied widely in size and nuclear number. Immunohistochemical staining for two lymphocyte markers and two structural proteins confirmed the identity of the neoplastic spindle cells and other cellular components. There was no evidence of vascular invasion or metastasis. Features of the thymoma indicated it was a pre-existing condition and not treatment related.

Definition of a production specification for xenotransplantation. A European perspective.

In the absence of regulatory guidance on animal production for xenotransplantation and the need to conform to European, U.K. and international standards of animal health and welfare, Imutran set up a forum of experts in 1994 to assess the risks associated with the possible transmission of diseases from pig to man after transplantation of porcine tissue. This risk assessment set the specification for Qualified Pathogen-Free pig production and the animal testing required to demonstrate that the specification has been achieved. The invasive sampling required for detailed health monitoring of individual source animals is in conflict with the aim of producing healthy, normal animals that are not subject to undue stress, and produces predominantly retrospective data on a donor. Imutran has developed a sampling regime that qualifies age-class cohorts and the whole herd by the routine testing of representative sentinel animals. Imutran set up a pilot production unit in 1995 and this unit has remained populated beyond a 30-month period and has received in excess of 20 cohorts of animals by hysterectomy re-derivation. Rigorous testing of sentinels and noninvasive testing of individuals have demonstrated that this pilot unit has achieved the required specification on a routine basis in a system that has been designed to meet European ethical and animal welfare concerns, within the constraints of the strict U.K. animal research laws and an ISO 9001 quality environment.

Functional and morphological characterization of neuropathy induced with 5-lipoxygenase inhibitor CGS 21595.

Peripheral toxic neuropathy induced in rats with a 5-lipoxygenase inhibitor CGS 21,595 was characterized using special functional tests and pathological procedures. Functional tests included measurement of grip strength, landing foot splay, assessment of sensorimotor and autonomic functions and monitoring of motor activity. Pathological procedures consisted of perfusion fixation, embedding in plastic, teasing of isolated nerve fibers, and light and electron microscopy. Male and female albino rats received the test article orally by gavage on 5 days per week. To characterize the development of the lesion animals treated with 1000 mg/kg were examined and sacrificed at 2-week intervals until termination at 10 weeks. In a separate study, the dose-effect relationship was examined in groups of animals treated with 50,200 or 1000 mg/kg for 10 weeks. Neurotoxicity occurred only in animals treated with 1000 mg/kg and was first detected following 4 weeks of treatment. Although there were no overt clinical signs of neurotoxicity, functional examination detected a reduction of grip strength, increased landing foot splay and reduced motor activity. Neuropathological examination revealed peripheral segmental demyelination affecting predominantly the Schwann cells in the ventral spinal nerve roots. Owing to its unusual localization in the nervous system and to subtlety of functional signs, peripheral segmental demyelination represents a special diagnostic challenge in toxicological safety studies.

Toxic peripheral neuropathy with demyelination in Sprague-Dawley rats given CGS 21595--a 5-lipoxygenase inhibitor.

Male and female Sprague-Dawley rats were given CGS 21595, a pro-drug that is almost immediately metabolized to CGS 19213, a naphthoquinone that acts as a 5-lipoxygenase inhibitor. The compound was administered by gavage to five groups of Sprague-Dawley rats (group Nos. 1, 5, n = 30; group Nos. 2-4, n = 20) at daily doses of 0, 50, 150, 500, or 1,000 mg/kg for 13 weeks. Rats in the higher dose groups had a reduced weight gain, but significant neurologic signs were not observed. A peripheral neuropathy consisting predominantly of myelin destruction in the spinal nerve roots and sciatic nerves in male rats treated with greater than or equal to 150 mg/kg CGS 21595 and in female rats treated with greater than or equal to 50 mg/kg CGS 21595 for 13 weeks. This lesion was not fully reversible after a recovery period of 4 weeks. Lesions consisted of ballooning of myelin sheaths, infiltration by macrophages, demyelination, and occasional areas of remyelination. Axons were generally preserved, and the brain and spinal cord were not affected. Male and female rats in all treatment groups had cytoplasmic hyaline droplets in the proximal renal tubules. This change was reversible after 4 weeks and was not associated with any other adverse effects on the kidney.

Chromatophoromas in a pine snake.

Iridophoroma and melanophoroma were diagnosed in an adult male pine snake. Light microscopic examination of irregularly thickened white and black portions of abnormal scales demonstrated two distinctive populations of pigment-containing cells. Pigment cells within abnormal-appearing white scales had needle-shaped granules that were dark amber in color while black portions were composed of pigment cells typical of melanophores, with dark black, round granules. Both populations of cells showed junctional activity, and clusters of both neoplastic pigment cell types were found in adjoining areas of the epidermis. By electron microscopy, the pigment cell with amber-colored granules contained reflecting platelet profiles typical of iridophores while pigment cells with dark round granules contained melanosomes. At a junctional area between abnormal white and black scales, mosaic chromatophores containing reflecting platelet profiles and melanosomes were observed. At 1 1/2 years following initial diagnosis, the snake died and neoplastic iridophores were found at multiple visceral sites; there was no evidence of metastases of melanophores to any organ. The two pigment cell tumors are believed to have developed from either stem cells destined to become iridophores and melanophores or from prexisting iridophores and melanophores in the dermis.

Toxicity of 8-methoxypsoralen, 5-methoxypsoralen, 3-carbethoxypsoralen, or 5-methylisopsoralen with ultraviolet radiation in the hairless (HRA/Skh) mouse.

An experimental design to simulate PUVA therapy (oral 8-methoxypsoralen followed by uv radiation) has been tested in a 13-week subchronic study to determine the relative toxicities of 8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP), 5-methylisopsoralen (5-MIP), and 3-carbethoxypsoralen (3-CEP) in inbred hairless mice (HRA/Skh). Drug was administered by 1-hr pulse feedings three times a week after mice were fasted overnight; individually housed animals were then exposed to uv radiation (320-400 nm; less than 2% output less than 320 nm). 8-MOP or 5-MOP administered orally (at doses of approximately 240 or 480 mg/m2 body surface area per week) followed one-half hour later with uv radiation of 2 J/cm2 for 13 weeks were found to cause skin toxicity including inflammation, hyperplasia, ulceration, and cellular atypia. Dose-related toxicity was not seen in other organ systems. Corresponding levels of 5-MIP or 3-CEP with uv radiation did not produce skin toxicity. These studies show that the psoralens with two potential DNA-binding sites (8-MOP and 5-MOP) were more toxic than psoralens with only one photoreactive site (5-MIP and 3-CEP).

Subchronic inhalation of diethylamine vapor in Fischer-344 rats: organ system toxicity.

Male and female Fischer 344 (F-344) rats were exposed at 0,25 or 250 ppm diethylamine (DEA) vapor, 6.5 hr per day, 5 days per week, for 24 weeks in order to assess cardiac and other organ system toxicity. Scheduled sacrifices were performed following 30, 60, and 120 days of exposure. During the first 2 weeks of exposure, the rats exposed at 250 ppm DEA did not gain weight. After 2 weeks, however, the rate of weight gain of these rats was greater than that of controls. Nevertheless, mean body weights for both sexes of rats exposed at 250 ppm DEA remained depressed compared to controls throughout the study. Sneezing, tearing, and reddened noses were seen in rats exposed at 250 ppm DEA. Histopathologic examinations revealed lesions of the nasal mucosa of rats exposed at 250 ppm DEA (rats exposed at 25 ppm were not evaluated). These lesions of the respiratory epithelium consisted of squamous metaplasia, suppurative rhinitis, and lymphoid hyperplasia. There were no pronounced treatment-related effects on organ weights, hematology, or clinical chemistry indices except for blood urea nitrogen which was evaluated in rats of both sexes exposed at 250 ppm DEA for 24 weeks. In contrast to the high-dose animals, no treatment-related effects were observed in rats intermittently exposed at 25 ppm DEA for up to 24 weeks. No evidence of cardiotoxicity was seen in rats exposed to either DEA concentration for up to 24 weeks.

Polycystic kidney and liver disease in Springbok: I. Morphology of the lesions.

Spontaneous polycystic kidney and liver disease in an inbred herd of Springbok (Antidorcas marsupialis) was studied by light microscopy, transmission electron microscopy, and microdissection. Springbok are a small species of gazelle of the family Bovidae native to South Africa. Since 1976, 18% of all live calves born have had nephromegaly and died within 2 weeks of birth. Examination of kidney and liver from ten calves which had died or were sacrifices since 1978 revealed bilateral, symmetrical nephromegaly due to moderate to marked focal dilatation of tubules predominately in the outer zone of the medulla. Microdissection of renal tissue from three affected calves indicated polycystic kidneys had cysts in all of the bends of Henle's loops, over half of the ascending limbs, and about one fourth of the collecting ducts. All of these calves had proliferation and cystic dilatation of bile ducts in most hepatic portal areas. The bile ducts were irregularly dilated and confluent with only a slight increase in periductular connective tissue. Ultrastructural studies revealed no consistent changes in the basement membranes of either the renal or hepatic cysts. This disease has several features similar to the autosomal recessive form of polycystic kidney disease in man and may prove a useful animal model.

Illness associated with paramyxo-like virus infection in a zoologic collection of snakes.

Of 438 snakes in a zoologic collection, 35 died during a 3-month period; all were members of the family Viperidae. Clinical signs consisted of gaping of the mouth followed within 1 day by convulsions. All necropsied animals had a mucoid exudate throughout the respiratory tract. Histologic evaluation of lung revealed evidence of interstitial pneumonia, with occasional eosinophilic intracytoplasmic inclusions in epithelial cells. A paramyxo-like virus, isolated in viper heart cells from lung tissue, was observed by electron microscopy to be budding from cell membranes. The virus hemagglutinated chicken red blood cells at 5 C, and antibody titers were assayed by hemagglutination inhibition. In a random survey of 22 snakes from the zoologic collection, antibody titers to the virus ranged from 1/20 to 1/2,560.

Exuberant granulation tissue in the stomach of a horse.

A 4-year-old stallion was examined because of a 2-month history of inappetance and weight loss. Diarrhoea had also developed a month before presentation. Abnormal clinical findings were emaciation, diarrhoea, ventral oedema, palpable mesenteric lymph node enlargement and a large mass in the left cranial portion of the abdomen. Significant laboratory findings were anaemia (packed cell volume 0.21 litres/litre), hypoalbuminaemia (16 g/litre) and xylose malabsorption. The horse was euthanased and at necropsy a 10.5 kg pendunculated mass composed of granulation tissue was found within and attached to the stomach. There was villous atrophy diffusely throughout the small intestine. The inciting cause of the gastric mass was not determined.

Obstructive jaundice associated with chronic active hepatitis in a dog.

A cholestatic syndrome was the primary manifestation of chronic active hepatitis in a dog. Enzyme determinations did not differentiate between extrahepatic and intrahepatic cholestasis as the cause of the conjugated hyperbilirubinemia, thus necessitating percutaneous liver biopsy. The dog was treated with prednisolone but developed gastrointestinal hemorrhage and terminal hepatic encephalopathy. Morphologic variations in liver biopsy specimens obtained simultaneously and in the specimen obtained at necropsy demonstrated that the disease activity varied by locales in the liver.

Meningoencephalitis secondary to otitis in a gorilla.

An adult female gorilla died following a 13-day illness and was necropsied. Gross and microscopic findings included a 2-cm straw deep in the external auditory meatus, suppurative otitis media and interna, and suppurative meningoencephalitis. Proteus mirabilis was cultured from the internal acoustic pore.