Endotoxin and prostaglandin fever of newborn guinea pigs at different ambient temperatures.

At an ambient temperature (Ta) of 30 degrees C, injection of 0.2 micrograms E. coli endotoxin into the lateral cerebral ventricle (icv) of three-day-old or younger guinea pigs was followed by a biphasic febrile rise in body temperature (Tc) and oxygen consumption (VO2), interrupted by a transient fall. At Ta 20 degrees C the change in Tc and VO2 was still biphasic, the first rise was similar as that seen at Ta 30 degrees C, but the subsequent fall was more pronounced. Thus, Tc became lower than before endotoxin and remained below the pre-injection level during and after the second rise. Injection of 10 ng PGE1 icv caused sustained monophasic hyperthermia at both Ta-s. Icv injection of 0.9% NaCl did not affect Tc and VO2 at either Ta. Accordingly, prostaglandins might contribute to, but cannot account for, the whole febrile response to endotoxin.     

Dynamics of endotoxin fever in the rabbit

To analyze the dynamic properties of body temperature and effector mechanisms during endotoxin fever, both experimental and mathematical procedures were applied. Experiments were carried out on rabbits in a climatic chamber at various ambient temperatures. Salmonella typhosa endotoxin (0.1 microgram/kg) was injected into an ear vein. A biphasic core temperature increase evoked by different effector mechanisms depending on ambient temperature was observed. A mathematical model based on experimental results with nonfebrile rabbits predicts the effector behavior at all ambient temperatures. From a comparison of experimental results with the model prediction, it is concluded that the increase of core temperature during fever is essentially caused by a dynamic shift of the controller characteristics. The effect of the pyrogen may be simulated by a resultant fever-controlling signal that is biphasic but increases more steeply than does core temperature. The analysis suggests that the three possible fever-driving effectors, metabolism, ear blood flow, and respiratory evaporative heat loss, should be controlled by the same resultant signal, although the time courses of the effectors and of core temperature vary distinctly at different air temperatures. The model uses an additive controller structure.     

Endotoxin fever in capsaicin treated rats.

The fever elicited by 10 micrograms/kg intravenous E. coli endotoxin was significantly higher in capsaicin desensitized rats than in controls, but there was an upper limit to the rise in body temperature in both groups. Capsaicin desensitization permitted the participation of various heat producing mechanisms even if the initial body temperature was high. The fever course was characteristically biphasic, similar as in control rats, thus desensitization did not alter the factors mediating the various phases of the endotoxin response.     

Nutritional state and endotoxin fever of newborn rabbits.

At thermoneutral environments 6-10 day-old well-fed rabbits responded to 20 microgram/kg I.V. E. coli endotoxin with biphasic fever: temperature peaks at 60 and 120-150, and a transient fall between 60 and 90 min after endotoxin injection. In rabbits starved for 24 hours, and in runt rabbits body temperature did not rise, but a decline started 60 min after endotoxin administration, corresponding to the transient fall observed in well-fed animals and continuing until about the 100-120th min; thereafter body temperature tended to stabilize at the low level.     

Respiration of conscious kittens in acute hypoxia and effect of almitrine bismesylate

Respiration was measured noninvasively in conscious kittens at an ambient temperature of 28-32 degrees C. Inspired O2 fraction (FIO2) was reduced abruptly from 0.21 to 0.12, 0.10, or 0.08 for 5 min on the day of birth and then on days 4, 7, 14, and 28. The ventilatory response to hypoxia was biphasic, as reported previously in anesthetized kittens, with minute ventilation (VE) increasing in the first minute and then falling towards control over the next 4 min. The fall in VE was due to a consistent fall in tidal volume, the changes in frequency during the second phase being more variable. The size of the first phase of the response increased up to 14 days, but the time at which the peak increase in VE occurred was not correlated with age. The degree of the secondary fall in VE was similar at each age and at each FIO2 studied. The degree of the biphasic response was significantly reduced after administration of almitrine (2 mg/kg ip) on days 1 and 4, but almitrine did not affect the response in older kittens.     

The control of thermoregulation in the developing lamb during slow wave sleep

This study investigates the mechanisms involved in adjusting metabolic rate in response to acute changes in ambient temperature close to thermoneutrality during postnatal development. Twelve lambs were prepared for sequential studies at 4, 14, 30, 45 and 55 days of age. During each study they were maintained at ambient temperatures of 5, 10, 15, 20, 25 and 30 degrees C for at least 1 h and until a slow wave sleep epoch was established. Eight lambs completed all studies. In these there was a significant fall in oxygen consumption with age which was independent of ambient temperature. This effect was closely related to a decrease in plasma triiodothyronine concentration that was greatest between 4- and 14-days old lambs and was not associated with a change in the plasma concentration of thyrotrophin or thyroxine. In 4-days old lambs oxygen consumption was increased at ambient temperatures of 5 and 10 degrees C by non-shivering thermogenesis, whilst in 14- and 30-days old lambs this effect was achieved by shivering. On the basis of significant changes in oxygen consumption and/or the occurrence of shivering (lower critical temperature) and panting (upper critical temperature) we have shown that there is a fall in both upper and lower critical temperature with age and a widening of the thermoneutral zone. This was associated with a decrease in the plasma cortisol concentration and heart rate as measured at thermoneutrality, whilst rectal temperature increased from 4 to 30 days of age. The other 4 lambs, 3 of which died between 7 and 17 days of age, had low plasma triiodothyronine concentrations when studied at 4 and/or 14 days of age and their oxygen consumption at thermoneutrality was significantly lower than the normal group at 14 days. Shivering thermogenesis occurred at an earlier age and control of body temperature was less effective. It is concluded that triiodothyronine has an important role in the control of metabolic rate in the developing lamb even to meet modest changes in ambient temperature, and possibly directly in survival.     

Effect of temperature on the induction of interferons by endotoxin and virus

Postic, Bosko (University of Pittsburgh, Pittsburgh, Pa.), Catherine DeAngelis, Mary K. Breinig, and Monto Ho. Effect of temperature on the induction of interferons by endotoxin and virus. J. Bacteriol. 91:1277-1281. 1966.-The effect of ambient and body temperature on interferon formation in rabbits injected intravenously with virus differed from that seen after injection of endotoxin. Newcastle disease virus-induced interferon (VII) was elevated by increasing ambient temperature to 35 C, whereas cooling of the rabbit at 4 C resulted in low VII levels. Neither of these conditions affected the titers of endotoxin-induced interferon (EII). However, a significant enhancement of EII levels was found in sera of shorn rabbits, in which the body temperature was lower than in unshorn animals by 1.0 to 1.5 F and the pyrogenic response to endotoxin was less by about 2 F. This enhancement of EII by relatively low body temperatures was also in striking contrast to the reported enhancing effect of high body temperature of the rabbit on the lethal action of endotoxin. It is suggested that the temperature optimum for formation of EII is lower than for formation of VII.     

Comparison of the effector mechanisms during endotoxin fever in the adult rabbit.

In unanaesthetized adult rabbits an intravenous dose of E. coli endotoxin evoked a febrile rise in colonic temperature at ambient temperatures of 9 to 31 degrees C. The rise in colonic temperature and oxygen consumption did not depend on the ambient temperature, while, among the heat loss effectors, in warmer environments only the depression of respiratory heat loss and in cooler environments only ear skin vasoconstriction contributed to the febrile rise in colonic temperature. In moderately warm environments the endotoxin first induced a maximum inhibition of respiratory frequency and this was followed by vasoconstriction. Later, a transient rise in oxygen consumption occurred. During defervescence the timing of the effectors was reversed. The results showed that a febrile response is not necessarily characterized by simultaneous changes in the thermoregulatory effector mechanisms.     

Role of dopamine and arterial chemoreceptors in thermal tachypnea in conscious cats

In mammals submitted to a warm environment, intracerebral injection of dopamine (DA) produces no change or an increase in body temperature accompanied by an increase in metabolic heat production, but its effect on heat loss mechanisms such as vasodilation and tachypnea is not clear. Because the principal mechanism of heat loss in the conscious cat is thermal tachypnea, we studied the influence of DA on thermal tachypnea in response to heat stress (ambient temperature = 33-36 degrees C) in five conscious cats. We first studied the steady-state response to a DA agonist, apomorphine, which crosses the blood-brain barrier. Intravenous injection of apomorphine greatly reduced thermal tachypnea by decreasing respiratory frequency (from 94.9 to 52.5 breaths/min) and increasing tidal volume (from 13.2 to 20.4 ml). The subsequent injection of the DA antagonist haloperidol, which also crosses the blood-brain barrier, restored the initial tachypnea. To further investigate the mechanism involved in thermal tachypnea, we studied the influence of peripheral chemoreceptors by transiently stimulating or inhibiting carotid body (CB) activity during tachypneic breathing. CB stimulation by intravenous injection of NaCN or domperidone reduced thermal tachypnea mainly by decreasing the respiratory frequency, whereas CB inhibition by DA tended to increase frequency and thus tachypnea. It is concluded that 1) in a warm environment, central DA receptors are also greatly involved in heat loss mechanisms, 2) arterial chemoreceptor input appears to counteract this tachypneic breathing, and 3) thermal and hypoxic tachypnea may be controlled by the same mechanism in which a DA-like system has a key role.     

Characteristics of body temperature, vasopressin, and oxytocin responses to endotoxin in the rat

Several physiological variables were measured after endotoxin administration in the rat to examine the relationship between these variables. Rats responded to endotoxin with a biphasic body temperature response, an initial decrease and a subsequent increase in body temperature. Plasma vasopressin and oxytocin levels increased markedly after endotoxin administration. Diarrhea occurred in some animals. There was a strong negative correlation between increase in body temperature and base-line body temperature, and weak correlations between body weight and plasma vasopressin release and between base-line body temperature and minimum body temperature reached. Plasma vasopressin and oxytocin levels were correlated if samples from all time points were analyzed together, whereas they were not correlated if data from each time point were analyzed separately or if total peptide release for each rat was evaluated. These data suggest similar regulation for the release of vasopressin and oxytocin, that is, release by a common stimulus, but the magnitude of release of vasopressin and oxytocin appears to be independent, probably reflecting differences in synthesis and storage of these two peptides.     

Effect of alterations in ambient temperature on blood flow in the skin.

The effect of changing ambient temperature on skin temperature was recorded in human subjects; also, its effect on blood flow was measured using venous occlusion and optical plethysmography. When cold stimulus was removed in stages using a heating cabinet, it was found that a biphasic flow response occurred in the fingers with each step change in temperature. There was a rapid transient rise followed by a decline to an equilibrium flow level. The transient rise occurred even when the temperature rose from 37 to 40 degrees C, although at this level the equilibrium remained unchanged. It is suggested that the transient rise was due to stimulation of Hensel's dynamic warmth receptors, whereas the rise in equilibrium temperature was due to removal of cold stimulus, which at low ambient temperatures maintains reflex vasoconstriction through activation of static cold receptors. Upper arm skin responded to removal of cold stimulus by a fall in temperature. Immersion of a different limb in cold water produced vasoconstriction in fingers but vasodilatation in the upper arm skin. It is suggested that this may be due to neurogenic vasodilatation, though the present work gives no indication as to pathways.     

Radiant heat affects thermoregulation and energy expenditure during rewarming from torpor

The high expenditure of energy required for endogenous rewarming is one of the widely perceived disadvantages of torpor. However, recent evidence demonstrates that passive rewarming either by the increase of ambient temperature or by basking in the sun appears to be common in heterothermic birds and mammals. As it is presently unknown how radiant heat affects energy expenditure during rewarming from torpor and little is known about how it affects normothermic thermoregulation, we quantified the effects of radiant heat on body temperature and metabolic rate of the small (body mass 25 g) marsupial Sminthopsis macroura in the laboratory. Normothermic resting individuals exposed to radiant heat were able to maintain metabolic rates near basal levels (at 0.91 ml O(2) g(-1) h(-1)) and a constant body temperature down to an ambient temperature of 12 degrees C. In contrast, metabolic rates of individuals without access to radiant heat were 4.5-times higher at an ambient temperature of 12 degrees C and body temperature fell with ambient temperature. During radiant heat-assisted passive rewarming from torpor, animals did not employ shivering but appeared to maximise uptake of radiant heat. Their metabolic rate increased only 3.2-times with a 15- degrees C rise of body temperature (Q(10)=2.2), as predicted by Q(10) effects. In contrast, during active rewarming shivering was intensive and metabolic rates showed an 11.6-times increase. Although body temperature showed a similar absolute change between the beginning and the end of the rewarming process, the overall energetic cost during active rewarming was 6.3-times greater than that during passive, radiant heat-assisted rewarming. Our study demonstrates that energetic models assuming active rewarming from torpor at low ambient temperatures can substantially over-estimate energetic costs. The low energy expenditure during passive arousal provides an alternative explanation as to why daily torpor is common in sunny regions and suggests that the prevalence of torpor in low latitudes may have been under-estimated in the past.     

Redefining physiological responses of moose (Alces alces) to warm environmental conditions

We tested the concept that moose (Alces alces) begin to show signs of thermal stress at ambient air temperatures as low as 14 °C. We determined the response of Alaskan female moose to environmental conditions from May through September by measuring core body temperature, heart rate, respiration rate, rate of heat loss from exhaled air, skin temperature, and fecal and salivary glucocorticoids. Seasonal and daily patterns in moose body temperature did not passively follow the same patterns as environmental variables. We used large changes in body temperature (≥1.25 °C in 24hr) to indicate days of physiological tolerance to thermal stressors. Thermal tolerance correlated with high ambient air temperatures from the prior day and with seasonal peaks in solar radiation (June), ambient air temperature and vapor pressure (July). At midday (12:00hr), moose exhibited daily minima of body temperature, heart rate and skin temperature (difference between the ear artery and pinna) that coincided with daily maxima in respiration rate and the rate of heat lost through respiration. Salivary cortisol measured in moose during the morning was positively related to the change in air temperature during the hour prior to sample collection, while fecal glucocorticoid levels increased with increasing solar radiation during the prior day. Our results suggest that free-ranging moose do not have a static threshold of ambient air temperature at which they become heat stressed during the warm season. In early summer, body temperature of moose is influenced by the interaction of ambient temperature during the prior day with the seasonal peak of solar radiation. In late summer, moose body temperature is influenced by the interaction between ambient temperature and vapor pressure. Thermal tolerance of moose depends on the intensity and duration of daily weather parameters and the ability of the animal to use physiological and behavioral responses to dissipate heat loads.     

Endotoxin inactivation via steam‐heat treatment in dilute simethicone emulsions used in biopharmaceutical processes

Simethicone emulsion is used to regulate foaming in cell culture operations in biopharmaceutical processes. It is also a potential source of endotoxin contamination. The inactivation of endotoxins in dilute simethicone emulsions was assessed as a function of time at different steam temperatures using a Limulus amebocyte lysate kinetic chromogenic technique. Endotoxin inactivation from steam‐heat treatment was fit to a four‐parameter double exponential decay model, which indicated that endotoxin inactivation was biphasic, consisting of fast and slow regimes. In the fast regime, temperature‐related effects were dominant. Transitioning into the slow regime, the observed temperature dependence diminished, and concentration‐related effects became increasingly significant. The change in the Gibbs free energy moving through the transition state indicated that a large energy barrier must be overcome for endotoxin inactivation to occur. The corresponding Arrhenius pre‐exponential factor was >>10¹² s^?1 suggesting that endotoxins in aqueous solution exist as aggregates. The disorder associated with the endotoxin inactivation reaction pathway was assessed via the change in entropy moving through the transition state. This quantity was positive indicating that endotoxin inactivation may result from hydrolysis of individual endotoxin molecules, which perturbs the conformation of endotoxin aggregates, thereby modulating the biological activity observed. Steam‐heat treatment decreased endotoxin levels by 1–2 logarithm (log) reduction (LRV), which may be practically relevant depending on incoming raw material endotoxin levels. Antifoam efficiency and cell culture performance were negligibly impacted following steam‐heat treatment. The results from this study show that steam‐heat treatment is a viable endotoxin control strategy that can be implemented to support large‐scale biopharmaceutical manufacturing. © 2014 American Institute of Chemical Engineers Biotechnol. Prog., 30:1145–1160, 2014     

Ambient temperature effect on changes in heat exchange and skin and coat thermoisolation induced with nembutal in guinea pigs

The experiment was carried out on adult male guinea pigs not adapted to cold at temperatures of 29 degrees, 20 degrees and 12 degrees C. During 150 minutes after nembutal injection the following values were recorded: oxygen consumption, subcutaneous, cutaneous and hair-coat temperatures. Using Hatfield's disc heat loss from the body surface by radiation and convection was measured. Nembutal not only inhibited thermogenetic processes at low ambient temperature, but decreased also heat production in a thermoneutral environment. This effect increased with decreasing ambient temperature. At the same time, there was a reduction in heat loss, although in a lower degree. The final result was a fall of the rectal temperature (even by 10 degrees C in a cold environment). Following nembutal administration skin thermoinsulation decreased slightly but the thermoinsulating activity of the hair-coat increased (the pilomotor response was more pronounced than in waking animals). Thermoregulation disturbances induced by nembutal included mainly thermogenesis impairment. The effect of general anaesthesia on heat loss was without any greater importance for maintenance of thermic homeostasis of the organism.     

Thermoregulatory differences in African mole-rat species from disparate habitats: Responses and limitations

Individuals and populations possess physiological adaptations to survive local environmental conditions. To occur in different regions where ambient temperature varies, animals must adopt appropriate thermoregulatory mechanisms. Failure to adjust to environmental challenges may result in species distributional range shifts or decreased viability. African mole-rats (Bathyergidae) occupy various habitats in sub-Saharan Africa from deserts to montane regions to mesic coastal areas. We examined thermoregulatory characteristics of three African mole-rat species originating from disparate (montane, savannah, and arid/semi-arid) habitats. Animals were exposed to various ambient temperatures, whilst core body temperature and the surface temperature of different body parts were measured. Oxygen consumption was determined as a measure of heat production. Core body temperatures of Natal (montane) mole-rats (Cryptomys hottentotus natalensis) increased significantly at ambient temperatures >24.5 °C, while those of the highveld (Cryptomys hottentotus pretoriae) (savannah) and Damaraland (Fukomys damarensis) (arid/semi-arid) mole-rats remained within narrower ranges. In terms of surface temperature variation, while pedal surfaces were important in regulating heat loss in Natal and Damaraland mole-rats at high ambient temperatures, the ventral surface was important for heat dissipation in Damaraland and highveld mole-rats. This study provides evidence of the variation and limitations of thermo-physiological mechanisms for three mole-rat species relative to their habitats. Information on physiological adaptations to particular habitats may inform predictive modelling of species movements, declines, and extinctions in response to a changing environment, such as climate change.     

Endotoxin fever in the newborn kitten. The role of prostaglandins and monoamines.

In 5--10 day-old kittens at thermoneutral environmental temperature cerebroventricular injections of 10 microgram serotonin or noradrenaline caused hyperthermia and hypothermia, respectively. Central injections of 20 and 200 ng prostaglandin E1 induced hyperthermia. Monophasic fever followed the cerebroventricular injections of 0.2 or 0.002 microgram E. coli endotoxin, both in thermoneutral and moderately cool environments. In kittens pretreated with para-chlorophenylalanine (PCPA) the endotoxin induced rise in body temperature was attenuated within 60 to 90 min after the endotoxin. Indomethacin pretreatment prevented the first part of the febrile response and only a slight temperature rise occurred after a long latency. Central injections of phentolamine did not modify the fever response, while centrally applied propranolol modified the fever course so that it resembled that seen in PCPA treated kittens. The central mediation of endotoxin fever in the kitten is complex, despite that the pattern of the temperature change is simple (monophasic). Arachidonic acid metabolites and serotonin of the central nervous system may be involved in the reaction, while the activation of central noradrenergic mechanisms does not seem to be indispensable for the response. The changes in mediators are similar to those in newborn guinea pigs, although the fever course is different in the two species.     

Energetic Optimisation of Foraging Honeybees: Flexible Change of Strategies in Response to Environmental Challenges

Heterothermic insects like honeybees, foraging in a variable environment, face the challenge of keeping their body temperature high to enable immediate flight and to promote fast exploitation of resources. Because of their small size they have to cope with an enormous heat loss and, therefore, high costs of thermoregulation. This calls for energetic optimisation which may be achieved by different strategies. An ‘economizing’ strategy would be to reduce energetic investment whenever possible, for example by using external heat from the sun for thermoregulation. An ‘investment-guided’ strategy, by contrast, would be to invest additional heat production or external heat gain to optimize physiological parameters like body temperature which promise increased energetic returns. Here we show how honeybees balance these strategies in response to changes of their local microclimate. In a novel approach of simultaneous measurement of respiration and body temperature foragers displayed a flexible strategy of thermoregulatory and energetic management. While foraging in shade on an artificial flower they did not save energy with increasing ambient temperature as expected but acted according to an ‘investment-guided’ strategy, keeping the energy turnover at a high level (∼56–69 mW). This increased thorax temperature and speeded up foraging as ambient temperature increased. Solar heat was invested to increase thorax temperature at low ambient temperature (‘investment-guided’ strategy) but to save energy at high temperature (‘economizing’ strategy), leading to energy savings per stay of ∼18–76% in sunshine. This flexible economic strategy minimized costs of foraging, and optimized energetic efficiency in response to broad variation of environmental conditions.     

Fever in rats during normal and dehydrated conditions

The effect of endogenous pyrogen (EP, from rabbit) and endotoxin (Salmonella typhosa) on rectal temperature (Tre) was investigated in normal and dehydrated rats of both sexes. Intraperitoneal injection of either EP or endotoxin did not affect body temperature. In addition, no changes in Tre were observed when endotoxin was injected intravenously in normally hydrated male rats, but significant falls in Tre occurred in normal female rats. However, intravenous injection of EP produced fever in both sexes, but females generally showed smaller responses. A second intravenous injection of endotoxin, given 3 days after the first injection, always produced fever in normally hydrated rats. The pattern of this febrile response was monophasic. In contrast to the response in normal rats, intravenous endotoxin produced significant fevers with a biphasic pattern in dehydrated rats of either sex, but the febrile responses of male rats were greater than those of female rats. On the other hand, there were no significant differences between febrile responses to intravenous EP exhibited by normal and dehydrated animals. These results show that rats of both sexes possess physiological mechanisms capable of producing a fever following intravenous injections of EP.     

Thermoregulatory responses to preoptic-anterior hypothalamic heating and cooling in the bat,Eptesicus fuscus

Summary The central nervous control of temperature regulation in the bat, Eptesicus fuscus, was evaluated by heating the preoptic-anterior hypothalamus (PO/AH) of active, unanaesthetized bats. Because bats are metabolically very variable, change in body temperature was used as the criterion of change in heat balance in response to change in brain temperature and change in wing temperature as an indicator of vasomotor changes.Heating the preoptic-anterior hypothalamic area (PO/AH) of the bat Eptesicus fuscus caused an average increase in wing temperature due to vasodilation of 1.0° C and an average increase in body temperature of 0.4° C. Conversely, cooling the PO/AH led to an average decline in wing temperature due to vasoconstriction of 0.9° C and an average decline in body temperature of 0.4° C.Bats were heat-stressed to augment the responsiveness of the PO/AH. Heat-stress alone causes a rise in body temperature and wing temperature. Release from heat stress causes a fall in body temperature and a fall in wing temperature. When the PO/AH is heated following a period of high heat-stress, the body temperature continues to fall but wing temperature reverses its direction of change and rises. When bats are given a low heat-stress and simultaneous heating of the PO/AH, wing temperature rises in response to PO/AH temperature and the body temperature stabilizes. When the PO/AH is cooled in bats under high heat-stress, body temperature stabilizes and wing temperature falls. When bats are cold-stressed, body temperature and wing temperature fall regardless of heating of the PO/AH.These responses are related to the life habits of the bat.It is concluded that the PO/AH of the bat Eptesicus fuscus may be less thermally sensitive than the PO/AH in other vertebrates studied, and that other central nervous structures have acquired an increased thermoregulatory function.We thank Mrs. Ruth Chalmers for her excellent histological preparstions.This work was supported, in part, by National science Foundation grant GB 6303 and GB 13797.