The effects of coliform endotoxin (E) and recombinant ovine tumor necrosis factor a (TNF) were compared with respect to clinical signs of disease and changes in plasma metabolite and pituitary and pancreatic hormone concentrations in calves. In addition, changes in plasma TNF concentration during each challenge exposure were quantitated by use of radioimmunoassay. Healthy Holstein bull calves with mean body weight of 90 kg were each given, in order, on different days, saline solution (5.0 ml, IV, day 1, n = 4), E (type 055:B5, 1.0 microgram/kg of body weight IV, day 2, n = 4) and TNF (5.0 microgram/kg IV, day 9, n = 3). Jugular venous blood samples, rectal temperature reading, and PCV were obtained at hourly intervals before (2 hours) and after challenge exposure. The PCV increased (P < 0.05) after E and TNF administrations for the first 5 hours, then returned to normal in calves given E, but decreased and remained low in calves given TNF through 24 hours. Plasma triglyceride and nonesterified free fatty acids concentrations were increased through 10 hours (P < 0.05) after E administration, whereas triglyceride and nonesterified free fatty acids concentrations were not significantly affected by TNF administration. Increase in blood glucose concentration at 1 hour after administration of E and TNF was followed by prolonged hypoglycemia that lasted through 6 hours. Changes in plasma insulin concentration paralleled the observed changes in glucose concentration, initially increased at 2 hours after E and TNF (P < 0.05) administrations, but then tended to decrease below control values thereafter. Plasma growth hormone and luteinizing hormone concentrations decreased after E and TNF administrations to almost nondetectable values through 4 hours after dosing, returning to normal values by 8 hours. The data indicate similarities in physiologic response of calves to E and TNF and suggest a role for acute production of TNF as a mediator of E responses.

The purpose of this in vitro study was to determine whether Pasteurella haemolytica capsular extract (CE) damages bovine pulmonary endothelial cells (EC) directly or through neutrophil-mediated mechanisms. Chromium 51-labeled EC were treated with the following variables: CE (1, 10, and 100 ng of protein/ml), CE and bovine neutrophils (10(6) cells/well), and CE and polymyxin B (500 U/ml). Although only minimal damage to EC occurred by 5 hours after treatment, by 22 hours after treatment, the 10-ng and 100-ng CE dose produced severe damage to EC, as indicated by 51Cr release, cellular detachment, and loss of monolayer confluency. The component in the CE that was toxic to the EC was lipopolysaccharide, evidenced by effective neutralization of the toxic effect with polymyxin B. Neutrophils inhibited the CE-mediated EC toxicity and were activated, as indicated by shape change and adhesion to EC monolayers. We concluded that the lipopolysaccharide component of CE causes direct damage to EC, which can be attenuated by neutrophils and polymyxin B.

Progressive changes in serum enzyme activity and liver histologic features were monitored in calves fed tansy ragwort (Senecio jacobaea)-contaminated pellets. The experiments were designed to simulate natural intoxicant ingestion conditions in relationship to the dose and duration of exposure to the toxic plant to correlate early laboratory diagnostic changes with the natural progression of the disease, thereby facilitating early diagnosis and intervention by veterinary clinicians. Eight calves were fed tansy ragwort and 4 additional calves served as controls. In group 1, 4 calves were continuously fed dried tansy ragwort mixed in a pelleted feed at a 5% concentration by dry weight until terminal liver disease developed. Serum liver enzyme (alkaline phosphatase, glutamate dehydrogenase, and gamma-glutamyltransferase) activities were monitored at weekly intervals in these calves and in the 2 controls. In group 2, 4 calves were fed the same contaminated feed for only 60 days, with return to normal feed for the duration of the trial. Two additional calves served as controls. Their liver enzyme activities were monitored every other week in conjunction with percutaneous liver biopsies. All 8 calves fed tansy ragwort-contaminated pellets developed terminal hepatopathy in either a chronic pattern (n = 6) or a chronic-delayed pattern (n = 2), with the onset of a moribund state or sudden death at 11 to 17 weeks and 27 to 51 weeks, respectively. The calves were euthanatized when classic terminal signs of hepatic encephalopathy first became evident. The clinicopathologic patterns of chronic and chronic-delayed toxicoses were typical of over 5,000 cases of field tansy toxicosis diagnosed at the diagnostic laboratory. Serum glutamate dehydrogenase was the first enzyme to increase in most animals, with a short-term increase to peak values followed by a rapid return to normal. This enzyme change was followed by increases in alkaline phosphatase and gamma-glutamyltransferase. Serum enzyme changes preceded development of recognizable histologic lesions. Vacuolar changes in hepatocyte nuclei, biliary hyperplasia, and fibrosis sequentially developed in liver biopsy specimens from each animal, whereas megalocytosis was not a predominant feature until necropsy. On the basis of our finding we suggest that the optimal tests for diagnosis of pyrrolizidine alkaloid intoxication should consist of liver biopsy and determination of concurrent serum liver-enzyme activities.

Gentamicin sulfate-induced nephrotoxicosis was compared in 2 groups of horses fed different rations. Four horses were fed only alfalfa hay, and 4 other horses were fed only whole oats. Seven days after initiation of the diet, all horses were given gentamicin IV (5 mg/kg of body weight) every 12 hours for 22 days. Urinary gamma-glutamyltransferase to urinary creatinine (UGGT:UCr) ratio was calculated daily, and serum concentration of gentamicin was measured at 1 and 12 hours after drug administration. Results indicated that horses fed oats had greater renal tubular damage than did horses fed alfalfa. Mean UGGT:UCr for horses fed alfalfa was 47.1 +/- 18.8 and was 100.0 +/- 19.0 for horses fed oats (P = 0.007). The UGGT:UCr in horses fed oats was > 100 for a total of 54 days; horses fed alfalfa had UGGT:UCr > 100 for only 7 days. Two horses not given gentamicin were fed only oats and 2 were fed only alfalfa. These horses had mean UGGT:UCr of 17.6 +/- 2.2 and 30.5 +/- 3.0, respectively. Mean peak and trough concentrations of gentamicin were statistically different for horses fed oats and those fed alfalfa (peak 23.16 +/- 1.87 and 14.07 +/- 1.79 microgram/ml, respectively [P = 0.0001], and trough, 1.81 +/- 0.69 and 0.71 +/- 0.70 microgram/ml, respectively [P = 0.02701)]. Mean half-lives of gentamicin (estimated from peak and trough concentrations) for horses fed alfalfa (2.58 +/- 0.26 hours) and horses fed oats (2.88 +/- 0.27 hours) were not significantly different. Horses fed only oats had greater degree of gentamicin-induced nephrotoxicosis than did those fed only alfalfa.

The Escherichia coli heat-stable enterotoxin (STb) is the most prevalent toxin associated with diarrheagenic E coli isolates of porcine origin. Unequivocal biological activity of this toxin has been observed only in swine intestine. In this study, when endogenous protease activity was blocked with soybean trypsin inhibitor, intestinal secretion was stimulated by STb in jejunal loops of rats, mice, calves, and rabbits. Compared with pigs, rats, mice, and calves, rabbits were relatively insensitive to STb. These data demonstrate that the activity of STb is not a species-specific toxic activity; there is species variation in sensitivity to STb, and some common laboratory animals may have potential to be used to measure biological activity Of STb.

Hydrated sodium calcium aluminosilicate (HSCAS), an anticaking agent for mixed feed, was added to the diets of growing wethers (mean body weight, 34.0 kg) and was evaluated for its ability to diminish the clinical signs of aflatoxicosis. The experimental design consisted of 4 treatment groups of 5 wethers each, consuming concentrations of 0 g of HSCAS and 0 g of aflatoxin (AF)/kg of feed (control; group 1); 20 g of HSCAS/kg (2.0%; group 2), 2.6 mg of AF/kg (group 3); or 20 g of HSCAS (2.0%) plus 2.6 mg of AF/kg (group 4). Wethers were maintained in indoor pens, with feed and water available ad libitum for 42 days. Lambs were observed twice daily and weighed weekly, and blood samples were obtained every 2 weeks for hematologic and serum biochemical analyses and for measurement of mitogen-induced lymphocyte-stimulation index. At the termination of the study, wethers were euthanatized and necropsied. Body weight gain was diminished significantly (P less than 0.05) by consumption of 2.6 mg of AF/kg of feed, whereas body weight of lambs consuming HSCAS plus AF did not differ from that of control wethers. The AF-alone treatment increased serum aspartate transaminase and gamma-glutamyltransferase activities, prothrombin time, and cholesterol, uric acid, and triglyceride values and decreased albumin, glucose, and urea nitrogen values, and urea-to-creatine ratio. A 27% decrease in lymphocyte stimulation index, increased spleen weight (as a percentage of body weight), and decreased liver weight were induced by AF-alone treatment. Results indicate that HSCAS may be a high-affinity sorbent for AF, that 2.6 mg of AF/kg of feed induces signs of aflatoxicosis in growing wethers, that lambs may not be as resistant to the effects of AF as previously thought, that 2.0% HSCAS can substantially reduce the toxic effects of 2.6 mg of AF/kg, and that sorbent compounds may offer a novel approach to the preventive management of aflatoxicosis in livestock.

The role of L-asparaginase (L-ASP) in limiting signs of methotrexate (MTX) toxicosis was studied. Eight dogs were randomly allotted to 2 groups of 4 dogs. All dogs were given 400 IU of L-ASP/kg of body weight IM, on day 1. On day 10, group-1 dogs were given 3 mg of MTX/kg, IV, and group-2 dogs were given 6 mg of MTX/kg, IV. All dogs were given 400 IU of L-ASP/kg, IM, 24 hours later (on day 11). One group-2 dog was euthanatized on day 16 because of severe gastrointestinal signs that were unresponsive to treatment. A second dose of MTX, identical to that given on day 10, was given on day 20 to each surviving dog, followed by L-ASP on day 21. On day 67, the 7 surviving dogs were given 3 mg gf MTK/kg, IV. Adverse reactions observed were vomiting diarrhea, and weight loss. Gastrointestinal side effects of MTX were not attenuated with L-ASP and would be a serious limitation to use of MTX administered at an intermediate dose in the treatment of lymphoma in dogs.

Phosphonoformate (PFA), a noncompetitive inhibitor of reverse transcriptase (RT), inhibited feline leukemia virus FeLV) infection of 2 feline cell lines and inhibited progeny virus RT activity in a chronically FeLV-infected cell line. Feline leukemia virus infection of 3201 cells, an FeLV-negative lymphoma cell line, was inhibited by > 70% at a concentration of only 1 micromole PFA and by > 90% at concentrations of 64 to 256 micromole PFA, as evidenced by RT activity. However, FeLV antigen expression by 3201 cells remained relatively constant over noncytotoxic concentrations of PFA. Because the persistence of viral antigen expression with concomitant suppression of RT activity appears to be unique and because 3201 cells express small amounts of an endogenous retrovirus (RD and 114) contain endogenous FeLV proviral sequences, a possible role of endogenous retroviruses acting as helper viruses was suggested. Feline leukemia virus infection of 81C cells, a sarcoma-positive, leukemia-negative fibroblast cell line, was inhibited by > 50% at a concentration of 64 micromole PFA and by > 98% at concentrations of 256 to 512 micromole PFA, as indicated by suppression of focus formation. The feline lymphoid cell line FL-74 is a large producer of FeLV. When FL-74 cells were cultured in the presence of 256 micromole PFA, virus production (virus budding and viral antigen) was not affected, but progeny virus lost RT activity and infectivity. Direct addition of PFA (256 micromole to FeLV also reduced RT activity and infectivity. These data indicate that PFA can directly and rapidly inactivate retrovirus independent of cellular processing, presumably by inhibiting RT. Long-term PFA administration may curtail spread of retroviral infections within and between hosts via extracellular inactivation of newly produced virus particles. Results of this study also suggest that PFA might be used prophylactically to treat materials potentially contaminated with retroviruses.

Ototoxicosis was evaluated in 6 healthy ponies given 5 mg of gentamicin/kg of body weight, q 8 h, IM. Ponies 1, 2, and 3 were dosed for 7 days and ponies 4, 5, and 6 were dosed for 14 days. Serum peak and trough concentrations of gentamicin were measured by radioimmunoassay at regular intervals. Brain stem auditory-evoked responses were recorded every 5 days up to 60 days after the first dose to monitor auditory function. Although serum gentamicin concentrations were within or above the accepted clinical therapeutic range, loss of auditory function was not observed at the frequency range (1 to 4 kHz) tested. Serum chemical values remained within the accepted clinical range and no evidence of nephrotoxicosis was observed. Seemingly, gentamicin given IM to healthy ponies was safe and had minimal risk of side effects.

Five groups of Hereford steers were monitored for 293 days. One group of 3 was not given selenium supplementation; the other 4 groups of 3 steers each were given 2, 4, 6, or 8 reticulorumen selenium pellets. Health, body weight, and blood selenium concentration were monitored during the study. At the finish, steers were slaughtered, and various tissues from the carcasses were analyzed for selenium content. Initial blood selenium concentration did not differ significantly among groups. However, significant (alpha = 0.01) difference among means was detected during the early period of rapid increase in blood selenium concentration in steers of supplemented groups. Means of maximal blood selenium concentration also differed among groups; however, even the highest value, 0.253 microgram/g, was lower than the 3 microgram/ml reported in chronic clinical cases of toxicosis in the literature. Carcass analysis indicated significant (alpha = 0.05) differences in selenium concentrations among treatment groups for almost all tissues tested. Only kidney samples (7.9 microgram/g) from steers of the 8-pellet treatment group exceeded published normal values (7.6 microgram/g). Health variables for most dates were not significantly different among groups, and selenium toxicosis was not evident in any steer. Analysis did not indicate risk to human beings consuming tissues from these steers.