Growth failure after recurrent fever in young guinea pigs.

Infection causes fever and suppression of appetite, a combination of effects which threatens normal growth in infected children. We have used an animal model to study the effects on growth of recurrent simulated Gram-positive bacterial infection. After weaning, 10 guinea pig pups underwent surgery under general anaesthesia for the implantation of temperature-sensitive radiotelemeters and thereafter were assigned to receive intramuscular injections of either 50 microg/kg muramyl dipeptide (MDP), or sterile saline. During a 30-day period corresponding to their rapid growth phase, the pups were given eight injections. MDP resulted in fevers of about 1.5 degrees C on each occasion, but no significant change in body temperature occurred after saline injections. Food intake was suppressed during each febrile episode such that 24-h intake was significantly lower on days of injections of MDP, compared to days between MDP injections in the same animals, and compared to that of animals injected with saline. The rate of weight gain of the MDP-injected guinea pigs was significantly lower than that of the control group and failed even to achieve a rate similar to the saline-injected group in their more adult-like growth phase. Plasma zinc concentration was significantly lower in MDP-compared to saline-injected animals sampled 8 days after the last injection. Our results show that recurrent fever during the growth phase of young guinea pigs results in irreversible growth failure, and that reduced food intake on days when the animals were febrile was at least partly responsible for this reduced rate of growth.

Fever and lethargy induced by subcutaneous pyrogen infusion in unrestrained rats.

We have investigated the effects of continuous subcutaneous infusion of lipopolysaccharide (LPS), muramyldipeptide (MDP), or saline on abdominal temperature and voluntary activity in unrestrained rats. Both pyrogens were infused via osmotic pumps at a rate of approximately 2 microg.kg-1.min-1 for 7 d. LPS infusion evoked a 3-d and MDP a 1-d elevation in body temperature. Night-time activity was suppressed on days 1 and 2 during LPS infusion and on day 1 of MDP infusion. Body mass was significantly decreased on infusion day 4 in rats receiving either LPS or MDP; however, the rate of weight gain had been restored by day 8 (1 d after cessation of pyrogen infusion). We further tested the body temperature response of the same experimental animals to a single subcutaneous bolus injection (250 microg/kg) of the same pyrogen that had been infused for 7 d, 2 d after cessation of pyrogen infusion (day 9). The fever response in rats receiving a bolus injection of either LPS or MDP was significantly attenuated in rats that had previously been infused with the same pyrogen. These data suggest that tolerance developed to continuous infusion of both Gram-negative and Gram-positive pyrogens, and that mechanisms of tolerance development set in early during the 7-d infusion period of both pyrogens and persisted for at least 2 d after the cessation of pyrogen infusion. We propose that cytokine intermediates were involved or required in inducing these responses to continuous infusion of both LPS and MDP.

Effects of nitric oxide synthase inhibitors on the febrile response to muramyl dipeptide and lipopolysaccharide in rats.

We have administered aminoguanidine, a relatively specific inhibitor of inducible nitric oxide synthase, and N-nitro-L-arginine methyl ester (L-NAME), an unspecific nitric oxide synthase inhibitor, to rats made febrile with the gram-positive pyrogen, muramyl dipeptide and gram-negative pyrogen, lipopolysaccharide. Sprague-Dawley rats, housed individually at approximately 25 degrees C with a 12:12 h light:dark cycle (lights on 0700 hours), were injected (at 0900 hours) intraperitoneally with 50 mg/kg aminoguanidine, 25 mg/kg or 50 mg/kg L-NAME, and intramuscularly with 500 microg/kg muramyl dipeptide or 100 microg/kg lipopolysaccharide. Pyrogen injections were spaced at least 14 days apart. Body temperature was measured throughout the study in unrestrained animals using radio-telemetry. Neither muramyl dipeptide nor lipopolysaccharide-induced fevers were affected by aminoguanidine. However, L-NAME administration inhibited muramyl dipeptide and lipopolysaccharide-induced fevers, but only for the 1st 2-4 h of the fevers (two-way ANOVA, P<0.05). After the initial inhibition, lipopolysaccharide fevers developed normally. Therefore, constitutively expressed nitric oxide synthase appears to be involved in the initial phases of fever genesis of gram-negative and gram-positive fevers in rats. On the other hand, inducible nitric oxide synthase appears not to play a role in these fevers.

Route of administration differentially affects fevers induced by Gram-negative and Gram-positive pyrogens in rabbits.

We have investigated the febrile responses of New Zealand White rabbits to a Gram-negative pyrogen (bacterial lipopolysaccharide (LPS) from Salmonella typhosa), commonly associated with systemic infection, and a Gram-positive pyrogen (Staphylococcus aureus), more frequently associated with superficial soft tissue infection, each administered via one of four different routes (intravenous, intramuscular, subcutaneous or intraperitoneal) at each of three different doses (LPS: 0.1, 1 and 10 microg kg(-1); S. aureus: 1.5 x 10(7), 1.5 x 10(8) and 1.5 x 10(9) cell walls kg(-1)). Intravenous administration of LPS evoked rapid, dose-dependent biphasic fever. Injection of LPS by the other routes also evoked dose-dependent fever. However, these fevers were monophasic, had increased latency of onset, and were of lower amplitude. It is important to note that a dose of approximately 10 and 100 times that of the standard intravenous dose was required to produce a similar peak rise in temperature when administered subcutaneously and intraperitoneally, respectively. Intravenous injection of the highest dose of S. aureus evoked dose-dependent biphasic fever, with short latency of onset, which was very similar to that induced by intravenous LPS. At lower doses, intravenous S. aureus induced monophasic fever. No fever occurred when the same doses of S. aureus were administered by any other route. We conclude that any of the four routes may be used for the study of LPS-induced fever, provided that the doses are adjusted. However, studies of S. aureus-induced fever, and detection of contamination with either pyrogen, requires intravenous injection.

Feto-maternal relationships in goats during heat and cold exposure.

Maternal and fetal body temperatures were measured in five Boer goats, of mean mass 64 +/- 8 kg, using temperature-sensitive radiotelemeters implanted intra-abdominally. Body temperatures were recorded every 5 min. Throughout the last month of gestation, fetal temperature was approximately 0.6 (o)C higher than that of the mother, in normal laboratory conditions (ambient air temperature: 21-24 (o)C). This feto-maternal temperature difference between the goat fetus and its mother is similar to that found in other mammals, including sheep. When the pregnant goats were subjected to short-term heating and cooling, the difference between maternal and fetal body temperatures changed. Thus the mean difference between fetal and maternal body temperatures decreased from 0.4 to 0.2 (o)C during 2 h of heating, while it widened from 0.3 to 0.7 (o)C during 6 h of cooling. These data support the idea that the fetus is thermally protected from excursions of body temperature during changes in the mother's thermal environment. Reports of goat stock losses and abortions during cold spells in their natural habitats may be the result of more severe and/or prolonged cold exposures that not only adversely affect fetal or maternal body temperature, but also influence other aspects of metabolism. Experimental Physiology (2001) 86.2, 199-204.

Fever and motor activity in rats following day and night injections of Staphylococcus aureus cell walls.

Body temperature and physical activity are affected by both circadian cycles and pyrogens. We injected intraperitoneally 2.5 x 10(9) cell walls of the gram-positive organism Staphylococcus aureus or sterile saline at three different times in the circadian temperature and activity rhythm of Sprague-Dawley rats. Irrespective of whether pyrogen injections were made when the rats were inactive (injection at 0900), just before the nighttime rise in activity and body temperature (1630), or during high activity (2100), the peak body temperature attained and the time to reach peak temperature were indistinguishable. The fever response, as measured by the thermal-response index, was greatest, however, when body temperature and activity were in the lowest phase. Physical activity was inhibited by night but not day injection of S. aureus. Our results provide the first description of experimental fever resulting from a gram-positive pyrogen in rats and the first time an aspect of sickness behavior (suppressed motor activity) has been associated with fever resulting from simulated gram-positive bacterial infection.

Activity, blood temperature and brain temperature of free-ranging springbok.

We used miniature data loggers to record temperature and activity in free-ranging springbok (Antidorcas marsupialis) naturally exposed to severe nocturnal cold and moderate diurnal heat. The animals were active throughout the day and night, with short rests; the intensity of activity increased during daylight. Arterial blood temperature, averaged over many days, exhibited a circadian rhythm with amplitude < 1 degree C, but with a wide range which resulted from sporadic rapid deviations of body temperature. Peak blood temperature occurred after sunset. Environmental thermal loads had no detectable effect on blood temperature, even though globe temperature varied by > 10 degrees from day to day and > 20 degrees C within a day. Brain temperature increased approximately linearly with blood temperature but with a slope < 1, so that selective brain cooling tended to be activated at high body temperature, but without a precise threshold for the onset of brain cooling. Low activity attenuated selective brain cooling and high activity abolished it, even at high brain temperature. Our results support the concept that selective brain cooling serves to modulate thermoregulation rather than to protect the brain against heat injury.

Extracts of rhinoceros horn are not antipyretic in rabbits.

We administered extracts of the horn of the African Black rhinoceros intragastrically to 7 rabbits, at the same time as injecting bacterial lipopolysaccharide (LPS) intravenously into the rabbits to produce fever. At a dose of horn (50 mg/kg) similar to that allegedly used to reduce human fever, and at ten times that dose, the fever response to LPS was not significantly different (P > 0.05, t-test) to the response to LPS injection when boiled water was administered instead of horn extract. The known antipyretic indomethacin, however, at a dose of 10 mg/kg significantly reduced the response to LPS.

Blood and brain temperatures of free-ranging black wildebeest in their natural environment.

Using miniature data loggers, we measured the temperatures of carotid blood and brain in four wildebeest (Connochaetes gnou) every 2 min for 3 wk and every 5 min, in two of the animals, for a further 6 wk. The animals ranged freely in their natural habitat, in which there was no shelter. They were subject to intense radiant heat (maximum approximately 1,000 W/m2) during the day. Arterial blood temperature showed a circadian rhythm with low amplitude (< 1 degree C) and peaked in early evening. Brain temperature was usually within 0.2 degrees C of arterial blood temperature. Above a threshold between 38.8 and 39.2 degrees C, brain temperature tended to plateau so that the animals exhibited selective brain cooling. However, selective brain cooling sometimes was absent even when blood temperature was high and present when it was low. During helicopter chases, selective brain cooling was absent, even though brain temperature was near 42 degrees C. We believe that selective brain cooling is controlled by brain temperature but is modulated by sympathetic nervous system status. In particular, selective brain cooling may be abolished by high sympathetic activity even at high brain temperatures.

Body temperatures of lambs and their mothers measured by radio-telemetry during parturition.

Using temperature-sensitive radio-telemeters chronically implanted in the abdomens of 8 fetal lambs and their mothers, we measured body temperature changes induced by parturition. Maternal body temperature rose at 0.70 +/- 0.06 degrees C/hour (mean +/- SEM) in the final stages of labour. Fetal body temperature also rose, but at a significantly lower rate, 0.45 +/- 0.06 degrees C/hour (p < 0.05). The fetus appears to be protected from excessive hyperthermia during the birth process.

Fetal and maternal body temperatures measured by radiotelemetry in near-term sheep during thermal stress.

Using implanted radiotelemeters, we have measured amniotic temperature and fetal lamb and pregnant ewe body temperatures continuously over the last 34 days of gestation and during conditions of thermal stress. Body temperature of the fetus was approximately 0.6 degrees C higher than that of the mother, and the fetomaternal temperature difference remained constant over the last 25 days of gestation, until the immediate prepartum period, when it rose. During exposure to mild heat stress (35 degrees C dry-bulb temperature, 24 degrees C wet-bulb temperature), ewe and fetal body temperatures rose, but fetal temperature rose at a slower rate. Thus the fetomaternal temperature gradient fell significantly in the initial exposure period. In an environment of 4 degrees C, body temperature of the pregnant ewes fell, but the fetomaternal gradient did not change significantly. During maternal fever, heat loss from the fetus was compromised; body temperature of the fetus rose more than that of the mother, and the fetomaternal temperature gradient rose significantly. We suggest that mild heat or cold exposure in pregnant animals constitutes little risk of fetal thermal stress. During maternal fever, however, the fetus may be at risk of thermal injury.

Amitriptyline attenuates the febrile response to a pyrogen in rabbits.

We investigated the effect of a tricyclic antidepressant (TCA) agent on fever in rabbits. In the first series of experiments, the TCA agent amitriptyline hydrochloride (AMI) was administered intraperitoneally (i.p.) at a dose of 1 mg/kg or 10 mg/kg daily for three weeks. The rabbit's response to intravenous (i.v.) injection of 0.1 micrograms/kg of the lipopolysaccharide (LPS) of Salmonella typhosa was tested on a weekly basis. In the second series of experiments, rabbits were given simultaneous i.v. injections of either 1 mg/kg or 10 mg/kg of AMI together with 0.1 microgram/kg of LPS. After two weeks of chronic i.p. administration of 10 mg/kg AMI, and for the remainder of the experimental period, the rabbit's response to the LPS was significantly attenuated when compared to control animals. When AMI was administered simultaneously with the LPS, a significant dose-dependent antipyresis was observed from 50 minutes after injection, compared to the response of control animals. AMI had no effect on the body temperature of afebrile animals.

Effects of tracheostomy breathing on brain and body temperatures in hyperthermic sheep.

1. We measured rectal and hypothalamic temperature in sheep breathing nasally and via a tracheostomy, during hyperthermia resulting from exposure to a hot environment, exercise and fever. 2. In normothermic and hyperthermic sheep hypothalamic temperature was up to 1.0 degree C lower than rectal temperature when the sheep breathed nasally. Tracheostomy breathing abolished the rectal-hypothalamic temperature difference. 3. In sheep breathing via the tracheostomy and exposed to a dry-bulb temperature of 45-50 degrees C for 2 h, hypothalamic temperature exceeded rectal temperature by about 0.4 degrees C, and was significantly higher than that in sheep breathing nasally in the same environment. 4. During exercise on a treadmill and in the post-exercise period, the difference between hypothalamic and rectal temperature was abolished in the sheep while breathing through the tracheostomy, and rectal temperature rose to higher levels compared to those evident in the same activity while breathing nasally. 5. After an I.V. injection of 0.4 micrograms/kg lipopolysaccharide (LPS), the difference between hypothalamic and rectal temperature again was abolished in the sheep when breathing through the tracheostomy, but rectal temperature rose significantly less compared to when breathing nasally. 6. Our results indicate that selective brain cooling depends on upper respiratory tract cooling in normo- and hyperthermic states in sheep.

Sodium aurothiomalate does not block interleukin 1 production in rabbits.

Gold salts may attenuate inflammatory processes by inhibiting interleukin 1 production. It is shown that sodium aurothiomalate does not act as an antipyretic after intravenous injection of two pyrogens into rabbits. Consequently, it cannot suppress interleukin 1 production, a conclusion confirmed by an in vitro lymphocyte activating factor assay. Chronic sodium aurothiomalate treatment, however, did depress the blood leucocyte count significantly.

Circadian temperature rhythm blunting and sleep composition.

The sleep patterns of nine male subjects were studied on four consecutive nights comprising two baseline nights, one night on which environmental temperature was elevated from 21 degrees C to 30 degrees C one hour after lights out, and a recovery night. There was a suppression of stage 4 sleep during the initial three hours of sleep on the hot night. A significant increase in stage 4 sleep with a decrease in stage 2 sleep occurred during the first three hours of the recovery sleep. There was a shortening in sleep onset latency and an increase in sleep efficiency on the recovery night. There were no changes in REM latency or REM sleep time. Rectal temperature rose after the increase in ambient temperature on the hot night. These results indicate that elevations in environmental temperature during sleep affect sleep patterns in a manner opposite to elevations of body temperature occurring prior to sleep onset. The curtailing of the usual circadian temperature drop during the first few hours of sleep reduces slow-wave sleep during this period. These findings have implications for those conditions with both altered sleep and altered temperature rhythms, for example, depression.

The effects of ligation of the oesophagus on body and brain temperature in pigeons.

1. We measured brain and colonic temperatures in adult pigeons (Columba livia) with or without oesophageal ligation, and with or without simultaneous eye covering at ambient temperatures between 24 degrees C and 45 degrees C. 2. Colonic and brain temperatures rose at the higher ambient temperatures; the temperature elevations were no different in pigeons with oesophageal ligation, compared to sham-operated controls. The presence of simultaneous eye covering also had no effect on colonic or brain temperatures. 3. Oesophageal inflation decreased from a rate of 2.8 +/- 1.4 per minute (mean +/- SEM) to zero, in anaesthetized pigeons when warmed from a colonic temperature of 40.5 degrees C to 43.8 degrees C. 4. In pigeons oesophageal inflation plays no significant part in body temperature regulation or in the maintenance of a lower brain than body temperature even in hot ambient conditions.

Is prostaglandin E the neural mediator of the febrile response? The case against a proven obligatory role.

We have reviewed the evidence in favor of a prostaglandin mediator of the thermal responses in fever and found that PGE injected into the hypothalamus does not always cause fever, that cerebrospinal fluid concentrations of PGE are not reliable reflections of hypothalamic events, and that antipyretic drugs may act in ways other than inhibiting PGE synthesis. Fever is not blocked by prostaglandin antagonists, nor by ablation of PGE-sensitive areas of the brain. There is poor correlation between the effects of pyrogens and of PGE on cerebral neurons. There is evidence that at least one prostanoid other than prostaglandin is a mediator of fever, but the prostanoid has not been identified yet. We conclude that PGE may contribute to the neural responses in fever but is not essential.

Pyrogens fail to produce fever in a cordylid lizard.

We investigated the effects on body temperature of the lizard Cordylus cataphractus of intracardiac injections of leucocyte pyrogen (LP) synthesized from rabbit blood and of killed Aeromonas hydrophila, a gram-negative bacterium reputed to be pathogenic in lizards. Lizards were placed in a photothermal gradient that allowed them to select a preferred body temperature following the injections. Neither injection of 0.5 ml rabbit LP nor of 4 X 10(9) organisms of A. hydrophila in 0.2 ml sterile saline caused body temperature of lizards to differ from that of control lizards injected with sterile saline. Following injection of these solutions in the lizards placed in a thermal gradient where ambient temperature ranged from 20-88 degrees C, body temperature was maintained between 32 and 34 degrees C. Pyrogens failed to elevate body temperature even when body temperature was elevated artificially to 36 degrees C before injection. We conclude that C. cataphractus does not respond with fever to either rabbit LP or A. hydrophila. Fever may not be ubiquitous even among lizards.

A dissociation between temperature regulation and fever in the rabbit.

1. The role of 5-hydroxytryptamine (5-HT) in temperature regulation and in fever in the rabbit has been investigated. 2. Intrahypothalamic microinjections of 5-HT in the conscious rabbit alters body temperature in a dose-dependent manner. 3. Low doses (5-5nmol) of 5-Ht and control saline injections produced a small, non-significant increase in temperature, with a long latency. 4. Doses of 14 nmol 5-HT produce a hyperthermia with a 45 min delay; while microinjections of 28 nmol result in a biphasic response; an initial short hypothermia is followed later by a hyperthermia. 5. Depleting the rabbit's brain of 5-HT by pretreatment with p-chlorophenylalanine (PCPA) fails to affect its body temperature at thermoneutral temperatures but significantly impairs the ability to thermoregulate against a cold stress. 6. PCPA pretreatment did not, however, impair the febrile response to bacterial pyrogen and prostaglandin E1. 7. These results reveal a dissociation between the effects of 5-HT depletion on temperature regulation, and on fever. The site of action of 5-HT in temperature regulation must be proximal to the fever input, but distal to the convengence of peripheral and hypothalamic temperature inputs.