Spontaneous polar anterior subcapsular lenticular opacity in Sprague-Dawley rats.

A spontaneous focal polar anterior subcapsular lenticular opacity characterized by focal epithelial proliferation was found in Charles River Sprague-Dawley rats from various breeding facilities around the world (France, Japan, and the United States). The incidence of this change slightly increased with age up to a maximal incidence of 9.8% in 28- to 35-week-old male rats (French source). Over that period, there was little change in the size of the opacity; however some rats that were examined over longer periods (more than 2 years of age) developed secondary anterior cortical changes, and rarely, histologic findings of pigmentation and/or mineralization. The lenticular change was present throughout the life of the animals and had no sex predilection; mode of inheritance was not investigated. Due to its small size, this lens opacity is more easily identified by use of slit lamp biomicroscopy than by use of indirect ophthalmoscopy, and serial sections of the eye aid in locating it for histologic evaluation.

Effect of alendronate on fracture healing and bone remodeling in dogs.

To examine the effect of alendronate (4-amino-1-hydroxybutylidene bisphosphonate) on fracture repair, the drug was given to mature beagle dogs orogastrically at 2 mg/kg/day for 9 weeks preceding fracture. 16 weeks after fracture, or both before and after fracture (25 weeks). A transverse mid-diaphyseal fracture of the right radius was surgically induced and was stabilized by external coaptation splinting. Fracture healing and bone remodeling were evaluated by radiography, gross and histological examination, and bone histomorphometry. The mechanical properties of the fracture callus were determined by a four-point bending test. Radiographs and gross and microscopic examination demonstrated normal bone healing at the fracture site in all dogs. In dogs that received alendronate during the fracture healing period, at 16 weeks the calluses were approximately 2-3 times larger than those in dogs that received a placebo during the healing period. This is consistent with slower callus bone remodeling, an expected pharmacological effect of the compound. Bone histomorphometry demonstrated that treatment with alendronate did not inhibit bone formation or mineralization. Mechanical testing showed that the ultimate load at failure and the flexural rigidity of both the fractured and contralateral intact bone were unaffected by treatment with alendronate. Therefore, in this study, treatment with alendronate before or during fracture healing, or both, resulted in no adverse effects on the union, strength, or mineralization of bone in mature beagle dogs.

Short-term carcinogenesis bioassay of genotoxic procarcinogens in PIM transgenic mice.

E mu-pim-1 transgenic mice, which overexpress the pim-1 oncogene in lymphoid tissues, have shown increased susceptibility to induction of T cell lymphomas by N-ethyl-N-nitrosourea, a direct-acting chemical carcinogen (Nature, 340, 61-63, 1989). We sought to further evaluate E mu-pim-1 transgenic mice as a potential test animal for a short-term carcinogenesis bioassay. We chose to test four genotoxic procarcinogens; 2-acetylaminofluorene (2-AAF), N-nitro-sodiethylamine (NDEA), 1,2-dichloroethane (1,2-DCE) and benzene (BEN). These compounds require metabolic activation and, with the exception of benzene, are not mouse lymphomagens. Compounds were administered by gavage daily for 38 (NDEA and 2-AAF) or 40 (BEN and 1,2-DCE) weeks to groups of 25-29 male and female PIM mice at 1 and 3 mg/kg for NDEA, 50 and 100 mg/kg for BEN, 25-100 mg/kg for 2-AAF and 100-300 mg/kg for 1,2-DCE. Small but statistically significant increases in the incidence of malignant lymphoma were seen for three of the four carcinogens tested; in high dose males treated with 2-AAF, high and low dose females treated with NDEA and high dose females treated with 1,2-DCE. Results for BEN, the only mouse lymphomagen tested, did not show a statistically significant increase in the incidence of malignant lymphomas in transgenic mice within the 40 week duration of the study. NDEA also produced a high incidence (> 70%) of hepatic hemangiosarcomas in both sexes at the low and high dose levels. These results demonstrate that over-expression of the pim-1 oncogene in lymphoid tissue can confer susceptibility of this tissue to chemical carcinogenesis by genotoxic procarcinogens. However, whereas potent genotoxic carcinogens produced only small increases in the incidence of lymphoma and since BEN, a mouse lymphomagen, was negative, PIM transgenic mice may lack sufficient sensitivity to established carcinogens to justify their routine use in a short-term carcinogenesis screening assay.

Reversal of cholinesterase inhibition and clinical signs and the postmortem findings in mice after intraperitoneal administration of anatoxin-a(s), paraoxon or pyridostigmine.

The reversibility of inhibition of plasma, red blood cell (RBC), and diaphragm cholinesterase (ChE) and clinical signs in mice given anatoxin-a(s) [antx-a(s)], a ChE inhibitor from Anabaena flos-aquae NRC-525-17, were characterized and compared with the effects of 2 known ChE inhibitors, the organophosphorus compound paraoxon and the carbamate pyridostigmine bromide. To follow recovery of ChE activity, mice were given either a control solution or an LD40 dose of one of the toxicants ip and killed at time points up to 8 d postdosing. After dosing, mice were monitored for diarrhea, fasciculations, respiratory difficulty, salivation, and tremors. In general, clinical signs in mice given antx-a(s) persisted longer than in mice given pyridostigmine and were more similar in duration to the clinical signs in mice given paraoxon. Histologic lesions were not detected in tissues of mice killed after administration of antx-a(s). Anatoxin-a(s) inhibited lesions were diaphragm ChE for greater than 1 but less than 2 d and RBC ChE for 8 d. The time required for recovery from Antx-a(s)-induced inhibition of ChE in plasma, RBC, and diaphragm was similar to or longer than that with paraoxon and longer than that with pyridostigmine. Based on the duration of antx-a(s) induced clinical signs and ChE inhibition in mice, antx-a(s) appears to be an in vivo irreversible inhibitor of ChE.

Pathophysiologic effects of anatoxin-a(s) in anaesthetized rats: the influence of atropine and artificial respiration.

The pathophysiologic effects of anatoxin-a(s) from the cyanobacterium Anabaena flos-aquae NRC-525-17 were investigated in anaesthetized adult male Sprague Dawley rats given the toxin by continuous intravenous infusion until death. Rats (n = 6) pretreated with atropine sulfate (50 mg/kg) intraperitoneally survived significantly longer (P less than 0.05) than non-atropinized rats (n = 6), suggesting that the muscarinic effects of anatoxin-a(s) were important in the lethal syndrome. In contrast to rats only given toxin, rats that were pretreated with atropine had a decrease in heart rate and mean blood pressure that followed profound reductions in respiratory tidal and minute volume, suggesting that neuromuscular blockade of the muscles of respiration was the cause of death. Even when survival time of rats was increased by pretreatment with atropine, phrenic nerve amplitude increased, indicating a lack of a depressive effect of anatoxin-a(s) on central mediation of respiration. Rats (n = 3) continuously ventilated during toxin infusion survived a dose more than 4 fold greater than a consistently lethal dose of the toxin. Thus, the cardiovascular effects of anatoxin-a(s) alone could not account for the death of rats. Electromyographic activity recorded from the diaphragms of rats (n = 5) during continuous toxin administration revealed an increase in muscular electrical activity that became more random and finally decreased prior to death, suggesting a toxin-induced neuromuscular blockade in vivo which ultimately was the cause of death of the anatoxin-a(s) dosed rats.

Effect of anatoxin-a(s) from Anabaena flos-aquae NRC-525-17 on blood pressure, heart rate, respiratory rate, tidal volume, minute volume, and phrenic nerve activity in rats.

The effects of anatoxin-a(s) [antx-a(s)] from the cyanobacterium Anabaena flos-aquae NRC-525-17 on mean arterial blood pressure, heart rate, respiratory rate, tidal volume, minute volume, and phrenic nerve activity were evaluated in anesthetized Sprague-Dawley rats. Anatoxin-a(s) was administered by continuous intravenous infusion. The initial effect of the toxin was to slow the heart rate and reduce arterial blood pressure, followed by much more pronounced reductions in these parameters. The marked decline in heart rate and blood pressure frequently occurred before there was a large decrease in respiratory minute volume [reduced by only 15.4 +/- 3% (mean +/- S.E.) compared to the predose period], suggesting that antx-a(s) has an important muscarinic action on the cardiovascular system in vivo. Phrenic nerve amplitude increased, but, nevertheless, tidal and minute volumes decreased progressively, indicating that antx-a(s), unlike most low-molecular-weight organophosphorus cholinesterase inhibitors, does not have any remarkable inhibitory action on central mediation of respiration.

Regional brain cholinesterase activity in rats injected intraperitoneally with anatoxin-a(s) or paraoxon.

Adult male Long-Evans rats were injected intraperitoneally with 1.5, 3.0 or 9.0 micrograms/kg of anatoxin-a(s) that had been extracted from laboratory-grown Anabaena flos-aquae NRC-525-17, 800 micrograms/kg of paraoxon, or a control solution. Blood, anterior spinal cord, and brain cerebellar, cortical, medullary, midbrain, hippocampal, hypothalamic, olfactory and striatal cholinesterase activity was determined in rats that died prior to 2 hours or were anesthetized and killed at 2 hours. Unlike paraoxon, anatoxin-a(s) did not cause detectable inhibition of cholinesterase in the central nervous system, but did cause inhibition of cholinesterase in blood, suggesting that anatoxin-a(s) is strictly a peripheral cholinesterase inhibitor.

Algae intoxication in livestock and waterfowl.

Blue-green algae toxins include (1) hepatotoxic peptides that are known to be toxic to cattle, dogs, swine, waterfowl, and sometimes other species; (2) a nicotinic agonist neurotoxin that appears to be toxic to a wide range of animal species; (3) a peripheral-acting cholinesterase inhibitor that is very toxic to swine, birds, and dogs; (4) toxins that impair nervous transmission by blocking sodium channels in nerve cells; and (5) lipopolysaccharide endotoxins. This article provides current information on the mechanisms of action of the primary toxins recognized to date as well as on procedures important in the diagnosis and management of some of the more common cyanobacterial toxicoses in livestock and waterfowl.

Aflatoxicosis in Iowa swine: eight cases (1983-1985).

During 1983, 1984, and 1985, aflatoxicosis was diagnosed in 8 Iowa swine herds after the herds were fed corn from the 1983 corn crop. As a result of the diagnosis, the associated environmental conditions, clinical signs of aflatoxicosis, macroscopic and microscopic lesions, aflatoxin concentrations detected in feeds, and management of affected swine were reviewed. Concentrations of aflatoxin in shelled corn and complete feed were as high as 2,020 ng and 1,200 ng of aflatoxin (B1 and B2)/g of feed, respectively. Clinical signs of aflatoxicosis included decreased feed consumption and weight loss. Some pigs died acutely, but death often was preceded by a period of clinical disease. Greater morbidity and mortality were observed in swine herds that consumed greater concentrations of aflatoxin.

Comparison of effects of anatoxin-a(s) and paraoxon, physostigmine and pyridostigmine on mouse brain cholinesterase activity.

Anatoxin-a(s), an alkaloid neurotoxin from the freshwater cyanobacterium, Anabaena flos-aquae NRC-525-17, was compared to paraoxon, physostigmine and pyridostigmine for effects on brain cholinesterase after i.p. injection into Balb/c mice. The duration of clinical signs in mice injected with anatoxin-a(s) persisted longer than in mice given the carbamates and was comparable with that of paraoxon. Anatoxin-a(s) did not inhibit brain cholinesterase activity suggesting that this toxin is unable to cross the blood-brain barrier.

Clinical and pathologic changes in acute bovine aflatoxicosis: rumen motility and tissue and fluid concentrations of aflatoxins B1 and M1.

Effects of aflatoxin on bovine rumen motility were determined by radiotelemetric techniques. Aflatoxin altered amplitude and/or frequency of rumen contractions in steers given dosages of 0.2, 0.4, 0.6, or 0.8 mg of aflatoxin/kg of body weight. Effects of aflatoxin on rumen motility were dose dependent. An increase in elimination time of aflatoxin from rumen contents was observed in steers given the aflatoxin dosages of 0.4 to 0.8 mg/kg. The increase in elimination time of this toxin facilitates diagnostic capabilities for detecting bovine aflatoxicosis by obtaining rumen contents for analysis for aflatoxin. Aflatoxin M1 was detected in rumen contents from steers at 2 hours after aflatoxin was administered. Thus, intraruminal metabolism of aflatoxin B1 to M1 may occur.

Ochratoxicosis in Iowa swine.

Ochratoxicosis was diagnosed in 2 Iowa swine herds. In both cases, clinical signs consisted of increased urination and water consumption. Pale tan kidneys were found in affected pigs at necropsy. Histologic examination of renal tissue from an affected pig revealed diffuse tubular nephrosis and interstitial fibrosis. In both cases, ochratoxin A was detected by thin-layer chromatography in extracts of whole corn and ground complete feed. Ochratoxicosis was reproduced in swine with feed obtained in one of the cases.

Levamisole toxicosis in swine.

Levamisole toxicosis occurred in swine in a commercial swine operation after the animals were mistakenly injected intramuscularly with levamisole. Clinical signs consisted of vomition, salivation, ataxia, recumbency and death. Surviving animals recovered completely within 24 to 48 hr.

Fonofos toxicosis and milk residues in dairy cattle.

An organophosphate toxicosis due to fonofos was diagnosed in an Iowa Dairy herd. Fonofos was detected in the feed source and in the rumen contents, liver, and kidney tissue of one cow that died acutely. Bulk tank milk contained detectable levels of fonofos.

Selenium toxicosis in swine.

Selenium toxicosis was diagnosed as the cause of fatal paralytic disease in a group of feeder pigs. Lumbar poliomyelomalacia and coronary band necrosis were the principal lesions. High selenium concentrations were detected in liver and kidney. Excessive selenium was traced to the premix added to the complete ration.

Endrin toxicosis in a cat.

Endrin toxicosis was believed responsible for the sudden death of a cat. Stomach contents contained bird remains, and chemical analysis revealed 233 micrograms of endrin/g. The cat's owner had been using an avicide on the premises just before the cat's death. Endrin is an effective pesticide for control of insects, rodents, and birds. It poses a problem with secondary poisoning in other animals.

A suspected case of endrin toxicosis in a cat.

Endrin toxicosis was diagnosed in a cat after it ingested birds poisoned with endrin. The animal lived next to a feed mill where an avicide was used. Analysis by gas chromatography of vomitus from the cat revealed the presence of endrin.