Prevention of spontaneous tumours in female rats by fadrozole hydrochloride, an aromatase inhibitor.

Mammary tumours are oestrogen dependent in female Sprague-Dawley rats and in a significant proportion of women, so pharmacological treatment to inhibit oestrogen production is a valuable therapeutic measure to prevent or slow the progression of disease. Here we show that a non-steroidal aromatase inhibitor, which competitively inhibits the conversion of androstenedione to oestrone, prevents the development of both benign and malignant spontaneous mammary neoplasms in female Sprague-Dawley ats. It also slows the spontaneous development of pituitary pars distalis adenomas in female rats, and reduces the incidence of spontaneous hepatocellular tumours in male and female rats.

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.

Neoplasms and related proliferative lesions in control Sprague-Dawley rats from carcinogenicity studies. Historical data and diagnostic considerations.

Historical data are presented for neoplasms and related proliferative lesions from 1,170 Sprague-Dawley rats that served as controls in 9 carcinogenicity (2 year) studies conducted in the Safety Evaluation Facility of Ciba-Geigy Corporation, Summit, New Jersey. The most common neoplasm was pituitary adenoma, which occurred in 62.2% of the male and 84.7% of the female rats. Incidences of other neoplasms that occurred in more than 6.0% of the rats were, for males, benign pheochromocytoma (19.0%), cutaneous keratoacanthoma (7.9%), pancreatic islet cell adenoma (7.5%), benign testicular interstitial cell tumor (6.5%), and thyroid C-cell adenoma (6.5%). For females these incidences were mammary fibroadenoma (31.3%), mammary adenocarcinoma (16.8%), and mammary adenoma (6.5%). Focal cortical hypertrophy/cystic degeneration of the adrenal, a focal nonneoplastic lesion of zona fasciculata cells that often degenerate into large cysts, was present in 23.4% of all male and 82.7% of all female rats. Criteria for the differential diagnoses of selected neoplasms and related lesions are presented.

Sudden death attributable to exercise-induced pulmonary hemorrhage in racehorses: nine cases (1981-1983).

Pathologic changes are described in 11 horses that died during racing or training; 9 died of acute pulmonary hemorrhage (exercise-induced pulmonary hemorrhage), 1 died of exsanguination, and 1 died of CNS trauma. Cardiac lesions were not found in any horse. Severe engorgement of pulmonary vessels, with hemorrhage into alveoli, airways, interstitium, and subpleural tissues, was observed in all 9 horses that died of exercise-induced pulmonary hemorrhage. Infiltration of eosinophils and/or lymphocytes around vessels and airways was seen in 6 horses. Focally extensive fibrosis was observed in the pleura and interstitium of 6 horses, and collections of siderophages were seen in the fibrous tissue and in the airways. Focal occlusion of bronchioles with inspissated mucus, such as that associated with small airway disease, was found in 4 horses. Underlying respiratory tract lesions, particularly those associated with small airway disease or bronchiolitis, may have a role in fatal pulmonary hemorrhage.

The effects of natural exposure to high levels of zinc and cadmium in the immature pony as a function of age.

To study the effects of environmental exposure to zinc and cadmium in immature foals, five pregnant ponies were raised within 2.9 km of the New Jersey Zinc Smelter in Palmerton, Pennsylvania. The mares and their foals were kept outdoors on timothy hay and orchard grass. The foals were examined daily for signs of illness and blood samples were taken monthly for estimation of serum zinc, copper, and ceruloplasmin levels. The foals were sacrificed at 2.5, 4.5, 8.5, 13.5, and 18.5 months of age. Necropsy revealed generalized osteochondrosis in joints of the limbs and cervical vertebrae, lymphoid hyperplasia, and eosinophilia. Two of the foals had developed mild lameness. The concentrations of zinc, cadmium, copper, lead, magnesium, and calcium were determined in liver, kidney cortex, and pancreas. The concentration of cadmium and zinc were the only elements that were greatly elevated in all three tissues as compared to control animals. The concentration of cadmium was directly correlated with age in the three tissues (e.g., 23.9 to 212.7 micrograms/g wet wt in kidney cortex), whereas zinc was significantly increased (range 132 to 954 micrograms/g wet wt in liver) but there was no correlation with age. It was concluded that the development of osteochondrosis is associated with increased exposure to zinc and possibly cadmium. The classical signs of cadmium toxicosis, such as renal damage and osteomalacia, were not observed.

Some unusual features of mesangioproliferative glomerulonephritis in horses.

Seven horses ranging from three to 15 years of age had nephrotic syndrome; at necropsy, renal tissue of all seven horses had the morphologic lesions of mesangioproliferative glomerulonephritis (membranoproliferative glomerulonephritis). Homogeneous eosinophilic material which filled the glomerular capillary lumina was found in five horses. Ultrastructurally, this material primarily consisted of electron-dense deposits with a fibrillar pattern in five horses and in one horse, rhomboid crystalline deposits which resembled deposits seen in human cryoglobulinemia. The association of mesangioproliferative glomerulonephritis with cryoglobulinemia is well documented in man. The presence of intracapillary deposits, with the histologic and ultrastructural lesion of mesangioproliferative glomerulonephritis, suggests a similar association in these horses.

Dermal collagen degradation and phagocytosis. Occurrence in a horse with hyperextensible fragile skin.

A 2-year-old female horse had large areas of hyperextensible, fragile skin that were interspersed with areas of normal skin. Affected skin tore easily and contained reduced amounts of dermal collagen. Collagen fibers were fragmented and disorganized, and in trichrome-stained sections, many fibers had abnormal red-stained centers. Electron microscopy showed that many collagen fibers had discrete foci of degradation in which the fibrils were fragmented, loosely packed, and widely separated by granular material. Collagen fibril fragments were present in secondary lysosomes in dermal fibroblasts, but there were no degranulated mast cells or inflammatory cells in these areas. This suggested that a noninflammatory degradation and phagocytosis of collagen had occurred in the areas of hyperextensible fragile skin in this horse. Unaffected skin had no signs of collagen degradation or phagocytosis; uniformly cylindrical collagen fibrils were densely packed into morphologically normal fibers.

Abortion and stillbirth associated with Chlamydia psittaci var ovis in dairy goats with high titers to Toxoplasma gondii.

During two consecutive breeding seasons in a brucellosis-free dairy goat herd, approximately 40% to 70% of the does (mean herd size, 14.5) had stillbirths or aborted. None of the does aborted or had stillbirths twice. In the first breeding season, 9 of 13 does aborted in the last 2 months of gestation. Three fetuses and 2 fetal placentas from 2 does were examined. Microscopic findings included severe multifocal hepatic necrosis, mild pneumonia, and mild multifocal necrosis in the brain. Cultures for Listeria monocytogenes, Chlamydia psittaci, and Coxiella burnetii were negative. Paired sera from 3 of the does that had aborted or had stillbirths were tested for antibodies to Toxoplasma gondii. On the basis of high titers, a tentative diagnosis of toxoplasmosis was made. During the following breeding season, 6 of 16 does aborted during the last 2 months of gestation. A total of 6 fetuses and 4 fetal placentas from 5 of these does were examined. Microscopic findings included infiltration of mononuclear cells around hepatic vessels and multifocal necrosis and gliosis in the brain. Chlamydia psittaci was isolated from the tissues of 1 fetus, 2 aborting does had persistent, high antibody titers against C psittaci (1:160 and 1:320), and all except 2 other does in the herd had C psittaci titers of 1:20 to 1:40. All but 2 does had T gondii titers of 1:32 to 1:4096. Evidently there was mixed infection with C psittaci and T gondii in this herd, but the former organism probably was responsible for the abortions and stillbirths.

Ulcerative duodenitis in foals.

Seven foals aged 18 days to 3 1/2 months had either single or multiple full-circumference segments or long antimesenteric bands of necrotizing duodenitis, sharply delineated from adjacent viable duodenum. Perforation of the necrotic wall had occurred in all foals, leading to acute fibrinous peritonitis. On the mucosal surface severe diffuse, acute inflammation and ulceration involved the anterior half of the duodenum. Two further foals, aged 28 and 30 days, had lesions that are believed to be a chronic form of this disease. Both foals had a thickened duodenal wall, with large areas of mucosa replaced by granulation tissue. In addition one had several strictures associated with firm adhesions between the duodenal serosa and adjacent structures, together with ascending cholangiohepatitis and pancreatitis. Eight foals had gastric ulcers that were considered to be of less significance than the duodenal lesions. No etiologic agent could be found by aerobic or anaerobic bacterial culturing, negative contrast electron microscopy for viruses, or immunofluorescence staining for equine herpesvirus 1, equine adenovirus, or equine coronavirus. The possible involvement of non-steroidal anti-inflammatory drugs is discussed.

Renal papillary necrosis in horses after phenylbutazone and water deprivation.

Acute renal papillary necrosis occurred in five horses given normal therapeutic doses of phenylbutazone and deprived of water for 36 to 48 hours prior to euthanasia. Five horses given phenylbutazone alone and four horses subjected to water deprivation alone did not develop papillary necrosis. Urinalyses were normal prior to water deprivation, and also after water deprivation in the horses that did not receive phenylbutazone, but the water-deprived, phenylbutazone-treated horses had many red blood cells, transitional epithelial cells, and large numbers of oxalate crystals in their urine. Ulceration of the alimentary tract was seen in more than 50% of these horses. Tongue ulceration was present in one of five horses given phenylbutazone and one of five horses which had phenylbutazone and water deprivation. Ulceration of the gastric mucosa was seen in two of the five phenylbutazone-treated horses, four of five horses with phenylbutazone treatment and water deprivation, and one of four horses with water deprivation alone. Severe colonic ulceration with perforation and peritonitis was present in one horse given phenylbutazone for three months. No other significant changes in the small or large intestine were seen in the other 13 horses.

Environmental zinc and cadmium pollution associated with generalized osteochondrosis, osteoporosis, and nephrocalcinosis in horses.

Several suspect causes of chronic zinc/cadmium toxicosis in horses near a zinc smelter were investigated following observations of lameness, swollen joints, and unthriftiness, particularly in foals. Two foals born and raised near the smelter were lame and had joint swellings that were attributable to severe generalized osteochondrosis. Zinc and cadmium concentrations were markedly increased in the pancreas, liver, and kidney. The serum of 1 foal, zinc and potassium concentrations were high, whereas calcium and magnesium concentrations were low. Marked nephrocalcinosis and osteoporosis were observed in this foal. Nephrocalcinosis also was observed in his dam, who died of a punctured lung following rib fractures, though there was no history of trauma. The joint cartilage lesions were similar to those induced experimentally in animals fed high-zinc diets and may have been the result of zin-induced abnormality of copper metabolism. The osteoporosis and nephrocalcinosis were consistent with chronic cadmium toxicosis.