C. T. M. van Duin

Fever and changes in plasma zinc and iron concentrations in the goat. The effects of interferon inducers and recombinant IFN-α2a

Inflammation or invasion by pathogenic micro-organisms induces systemic changes, collectively known as the acute phase response. Among the varied alterations that together produce this response are fever, hypoferraemia and hypozincaemia. It is likely that these responses are mediated, in part, by production and release of cytokines such as interleukin-1 (Il-1), interferons (IFN-alpha) and tumour necrosis factor (TNF). The present report describes a comparative study in dwarf goats on recombinant human IFN-alpha 2a (0.5 x 10(5) IU per kg intravenously (i.v.) and 0.5 x 10(6) IU per kg intramuscularly (i.m.], Poly I:Poly C (an interferon inducer; 30 micrograms per kg i.v.), Newcastle disease virus La Sota strain (an interferon inducer; 0.5 ml per kg i.v.) and Escherichia coli endotoxin (an Il-1 and TNF inducer; 0.1 microgram per kg i.v.). The i.v. injection of recombinant IFN-alpha 2a caused characteristic monophasic febrile reactions, but no significant changes in plasma zinc and iron concentrations. The temperature responses were not due to endotoxin contamination because polymyxin B, which blocks endotoxin, had no inhibitory effect on the pyrogenicity of IFN-alpha 2a. In contrast, the IFN-alpha 2a-induced fever was completely prevented by flurbiprofen pretreatment (1 mg per kg i.v.). In contrast to the i.v. administration, i.m. injection of IFN-alpha 2a caused fever, hypoferraemia and hypozincaemia. Similar results were obtained after E. coli endotoxin, NCD La Sota strain and Poly I:Poly C injection. However, the shapes of the temperature curves and the changes in trace metal concentrations were markedly different. These data support the theory that fever and the changes in plasma zinc and iron concentrations are regulated by different mechanisms.

Fever and changes in plasma zinc and iron concentrations in the goat: The role of leukocytic pyrogen

In goats with trypanosomiasis (T. vivax or T. congolense) no marked fall in plasma zinc concentration was seen despite high temperature peaks, whereas plasma concentrations of iron tended to undergo some decline. In goats infected with Ehrlichia phagocytophila, there was a marked decline in plasma zinc and iron to low values on the 3rd and 4th day, respectively. Circulating endogenous pyrogen (EP) or leukocytic endogenous mediator (LEM) could not be detected in plasma from febrile goats with tick-borne fever. The intravenous injection of leukocytic pyrogen (LP) in kids caused characteristic monophasic febrile reactions, whereas no significant changes in plasma trace metals were found. So, previous evidence purporting to show that LP is similar to or may be identical with LEM is demonstrably inconclusive. Intravenous injection of E. coli lipopolysaccharide (LPS) or staphylococcal enterotoxin B (SEB) induced fever and lowering of plasma zinc and iron concentrations. The decrease in those trace metal values was more persistent in goats given SEB than in those given E. coli LPS. After intramammary infusion of SEB or E. coli LPS, fever and significant decreases in plasma zinc and iron concentrations were observed but no clear relationship was found between the temperature responses and the alterations in plasma trace metal concentrations. Furthermore, the decrease in plasma iron concentration developed more rapidly in goats given SEB than in those given E. coli LPS, whereas the decrease in plasma zinc concentrations in the former was more delayed. These data support the theory that the concentrations of zinc and iron in plasma are regulated by different mechanisms, whereas febrile reactions are mediated by another type of endogenous protein.

Clinical, haematological and blood biochemical changes in goats after experimental infection with tick-borne fever.

Tick-borne fever in goats caused by Ehrlichia (Cytoecetes) phagocytophila was characterised by high fever, dullness, anorexia, tachycardia and a slight to moderate inhibition of rumen motility. The animals developed a gradual decline in the total number of circulating white blood cells. There was a decrease in lymphocytes over a short period, followed by an increase. The number of neutrophils was higher on the 3rd day, causing considerable change in the lymphocyte:neutrophil ratios. The number of eosinophils increased slightly. Serum alkaline phosphatase (ALP) decreased during the febrile episodes, and a marked decline was observed in both plasma zinc and iron concentrations. Furthermore, there was a small but progressive decrease of haemoglobin and haematocrit values. Circulating endogenous pyrogen/leucocyte endogenous mediator could not be detected in plasma from febrile goats. Tick-borne fever was passively transmitted to kids with plasma obtained from these febrile animals.

Anorexia during febrile conditions in dwarf goats. The effect of diazepam, flurbiprofen and naloxone

The most common sign of febrile diseases is anorexia, which develops at a time when adequate caloric and micronutrient availability may be critical. In order to study the relationship of fever and anorexia, feed intake in dwarf goats was studied under conditions of fever and antipyresis. Furthermore, experiments were done to establish whether a feed intake stimulant would override the anorexia during febrile conditions. Infection with Ehrlichia phagocytophila and i.v. injection of Escherichia coli endotoxin (0(111) B4, 0.1 microgram/kg body weight) both resulted in increased rectal temperatures and significant reductions in feed intake. Administration of the antipyretic drug flurbiprofen (1 mg/kg) to febrile animals inhibited the temperature responses, but food intake was still suppressed. Diazepam (0.06 mg/kg), a feed intake stimulant, did not override the anorexia associated with fever. Blocking the febrile response of E. coli LPS-injected goats with flurbiprofen plus diazepam or with flurbiprofen plus naloxone (0.1 mg/kg) did not antagonise their reduced feed intake either. The effects of these drugs and of endotoxin on rumen motility adds an interesting aspect to their activities in the CNS, since the CNS has been shown to regulate various aspects of forestomach motility, which in turn could alter feeding behaviour. Moreover, our findings are consistent with the hypothesis that the suppression of feed intake might depend on the release of interleukin-1.

Pathophysiological aspects ofE. coli mastitis in ruminants

It is a common theory that the systemic signs in cows suffering from coliform mastitis would be caused by absorption of endotoxin from the udder into the circulation. However, definite proof to validate this hypothesis is as yet not available. Therefore, the effects on some clinical and clinical-chemical parameters of administering either intravenously or intramammarilyE. coli endotoxin to normal and endotoxin-tolerant ruminants were comparatively examined. The absence of marked effects on rumen motility following the intramammary administration of endotoxin was striking. Moreover, in cows the intramammary administration of one fifth of the dose of endotoxin to which the animals were made tolerant produced a maximum effect on body temperature and plasma zinc concentrations. These observations suggest the release of inflammatory endogenous mediators in the udder and their subsequent absorption into the circulation rather than the absorption of endotoxin. However, attempts to validate this hypothesis failed. Further research for detection methods more sensitive than the bioassay used in this study is recommended.

Feed intake and rumen motility in dwarf goats. Effects of some α-adrenergic agonists, prostaglandins and posterior pituitary hormones

The purpose of the present investigation was to test the hypothesis that drug-induced changes in rumen contractions influence feed intake in dwarf goats. Intravenous (i.v.) administration of clonidine (1 μg kg-1 min-1 for 10 min), xylazine (1 μg kg-1 min-1 for 10 min), and PGF-2α (10 μg kg-1 min-1 for 15 min) caused bradycardia and inhibition of rumen contractions. However, no appetite-stimulating effect of these drugs was observed. Other clinical changes induced by the α2-adrenergic agonists included slight sedation and a decrease in body temperature; all clinical effects of clonidine and xylazine were partly antagonized by tolazoline pretreatment (10 μg kg-1 min-1 for 30 min). These results suggest that the CNS control of feeding differs in ruminants and monogastric species.In dwarf goats fasted for 2 h, i.v. administration of oxytocin (0.01 IU kg-1 min-1 for 15 min), vasopressin (0.01 IU kg-1 min-1 for 15 min), octapressin (0.003 IU kg-1 min-1 for 15 min) or PGE (0.8 μg kg-1 min-1 for 15 min) did not change feeding behaviour during the two observation periods (0–30 min and 180–210 min after drug infusion, respectively). In previous studies, similar doses of these drugs induced changes in heart rate and inhibition of rumen contraction in goats. These findings demonstrate that drug-induced changes in forestomach contractions do not simply cause changes in feeding behaviour. The i.v. infusion of the PGF2α analogues etiproston (10 μg kg-1 min-1 for 15 min), luprostiol (30 μg kg-1 min-1 for 15 min), cloprostenol (1 μg kg-1 min-1 for 15 min) and tiaprost (1 μg kg-1 min-1 for 15 min) induced hypophagic effects and stimulated intestinal propulsion.

The effect of testosterone on the plasma disappearance rates of sulphadimidine and antipyrine in castrated dwarf goats.

Plasma disappearance of sulphadimidine and antipyrine was studied in adult castrated dwarf goats before and following pretreatment with testosterone. Comparison was made with entire males before and after castration. Testosterone pretreatment caused a significant increase in the apparent elimination half-life in castrates, whilst in entire males castration caused a significant decrease.

The effects of ACTH, prednisolone and Escherichia coli endotoxin on some clinical haematological and blood biochemical parameters in dwarf goats

ACTH (microgram kg-1 i.v.) and prednisolone (1 microgram-1 i.v.) caused a moderate but statistically significant inhibition of rumen contractions, whereas no effects on heart rate and body temperature were observed. Both hormones induced hyperglycaemia and leucocytosis, characterised by moderate lymphopenia and a profound increase in the number of circulating neutrophils. A significant decrease in plasma iron and increase in plasma zinc concentrations were observed. After 3 daily i.m. injections of ACTH (10 micrograms-1 day-1) decreases were seen in both serum Alkaline phosphatase (ALP) activity and plasma trace metal concentrations; heart rate was significantly higher. Intraveneous injection of E. coli endotoxin (0.1 microgram kg-1) caused shivering, fever, inhibition of rumen contractions, changes in heart rate, lymphopenia, neutropenia followed by neutrophilic leucocytosis, hypoferraemia, hypozincaemia, hypoglycaemia and a decline in serum ALP activity. ACTH, given i.m. for 3 days, reduced the febrile responses to E. coli endotoxin, modified the changes in heart rate, intensified the inhibition of rumen contractions, and induced a more marked decrease in the number of circulating neutrophils. ACTH pretreatment did not affect the endotoxin-induced decrease in blood glucose concentrations nor the drop in plasma zinc and iron values. These results suggest that glucocorticosteroids are not primarily involved in the fall in plasma iron and zinc concentrations during E. coli endotoxin-induced fever, the effects of endotoxin released glucocorticosteroids on white blood cells and blood glucose are masked by some other effect(s) of endotoxin, and in dwarf goats, ACTH has antipyretic properties without influencing normal body temperature. This effect is probably not dependent on adrenal cortical activity.

FOOD INTAKE AND RUMEN MOTILITY IN DWARF GOATS. EFFECTS OF ATIPAMEZOLE ON THE INHIBITORY EFFECTS INDUCED BY DETOMIDINE, MEDETOMIDINE AND ROMIFIDINE

The effects of some α2-adrenoceptor agonists and of the α2-adrenoceptor antagonist atipamezole on food intake and ruminal contractions were studied in dwarf goats. Detomidine, 0.2 µg/kg per min for 10 min, failed to modify food intake during either the first or second observation period (0–30 min and 180–210 min after drug infusion, respectively). Given at a higher dose rate (0.4 µg/kg per min for 10 min), the drug inhibited food consumption during the first observation period, but stimulated food intake during the second period. A similar pattern was observed after IV infusion with medetomidine (0.2 µg/kg per min for 10 min), romifidine (0.4 µg/kg per min for 10 min) or xylazine (1 µg/kg per min for 10 min). The α2-antagonist atipamezole (2 µg/kg per min for 10 min) failed to modify food intake during either the first or second observation period. After treatment with atipamezole, the effects of α2-agonists on feeding behaviour were completely antagonized.The α2-agonists administered at similar dose rates to those used in the food intake experiments induced bradycardia, decreases in body temperature and inhibition of ruminal contractions. The inhibition of ruminal contractions induced by romifidine was partly antagonized by atipamezole pre-treatment. These findings demonstrate that the α2-agonist-induced changes in ruminal contractions do not simply cause changes in feeding behaviour. The drop in body temperature induced by α2-agonists was prevented by atipamezole pre-treatment, whereas the induced bradycardia was not modified by this α2-antagonist.

Effects of flurbiprofen on recombinant human IL‐1α induced fever and associated clinical, haematological and blood biochemical changes in the dwarf goat

Flurbiprofen, a potent NSAID, was given as an intravenous infusion (1 mg/kg) to dwarf goats. After drug administration, no significant changes were observed in heart rate and rumen motility, whereas rectal temperature increased slightly; mean plasma glucose and creatinine concentrations gradually increased during the observation period. Plasma iron concentration and the number of circulating lymphocytes were significantly lower after flurbiprofen infusion. Intravenous injection of recombinant human interleukin-1 alpha (r. HuIL-1 alpha: 0.5 microgram/kg) caused shivering, fever, inhibition of rumen contractions, tachycardia, hypoferraemia, hypozincaemia, hyperglycaemia followed by hypoglycaemia, changes in plasma urea and creatinine values, lymphopaenia and neutropaenia followed by neutrophilic leukocytosis. Pretreatment with flurbiprofen partly antagonized the febrile reactions to r.HuIL-1 alpha. The r.HuIL-1 alpha-induced tachycardia and inhibition of rumen contractions were only delayed. The drug prevented the initial hyperglycaemia but did not abolish the secondary hypoglycaemia. Furthermore, flurbiprofen delayed the decline in plasma zinc and iron concentrations, whereas plasma creatinine values were significantly lower. Finally, after drug pretreatment the changes in circulating neutrophils were more pronounced. These data demonstrate that most of the haematological, blood biochemical, and clinical effects of r.HuIL-1 alpha cannot be blocked by flurbiprofen, suggesting that an increased synthesis of prostaglandins is not involved in these r.HuIL-1 alpha-induced effects.