Hyperthermia in humans enhances interferon-gamma synthesis and alters the peripheral lymphocyte population.

Induction of hyperthermia (39 degrees C) in human volunteers by immersion in warm water (41-45 degrees C) rapidly alters the cell populations in the peripheral blood. In addition to granulocytosis, there is an alteration of the normal ratios among T-lymphocyte subsets. Following in vitro mitogen stimulation, lymphocytes from hyperthermic individuals produce as much as 10-fold more interferon-gamma (IFN-gamma) than cells withdrawn at basal core temperatures from the same individuals. A temperature threshold of 39 degrees C for this response suggests potential relevance to fever. No change was noted in the activity of the macrophage population. The possible involvement of interleukin-2 (IL-2) in this enhanced production is discussed. No changes were noted in the circulating levels of IFN-gamma.

In vivo hyperthermia enhances plasma antiviral activity and stimulates peripheral lymphocytes for increased synthesis of interferon-gamma.

The effect of in vivo hyperthermia on plasma interferon (IFN) activity and on the induction of IFN-gamma by phytohemagglutinin (PHA) or staphylococcal enterotoxin B (SEB) in isolated leukocyte cultures was investigated. Adult rhesus monkeys (Macaca mulatta) were placed in a climatic chamber maintained at 45 degrees C until their core body temperatures increased 2 degrees C above control levels. Peripheral blood samples were withdrawn both prior to core temperature elevation and at the time of peak body temperature. Plasma IFN-alpha increased slightly from a control value of 12 U/ml to 16 U/ml at the elevated core temperature. However, this alteration of plasma IFN levels appears to be a complex process that includes the loss of certain circulating IFN-alpha subtypes and the influx of acid-labile (Type II) IFN-alpha. Additionally, a non-IFN antiviral factor present in the plasma was elevated 10-fold at the higher body temperature. When mononuclear cells were isolated and cultured at 37 degrees C in the presence of PHA or SEB, those cells isolated from animals at the peak of body temperature showed a 4- to 16-fold increase in IFN-gamma activity relative to cells isolated from the same animal before the temperature increase. Similar results were obtained with cells isolated when fever was induced by the systemic injection of nonviable Escherichia coli. These results demonstrate that increased body temperature results in a circulating lymphocyte pool which is "primed" for the production of elevated levels of IFN-gamma activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise in a cold environment after sleep deprivation.

Seven subjects exercised to thermal comfort in a cold environment (O degrees C, 2.5 m X s-1) after normal sleep (control) and following a 50-h period of sleep deprivation. Resting core temperature (rectal) taken before the subject entered the cold environment was significantly lower (-0.5 degrees C, P less than 0.05) following the 50-h period of wakefulness. However, rectal temperature was not different after 15 min of exercise during the two exposures, suggesting that the subjects stored heat more rapidly during the first 15 min of exercise after sleep deprivation. No significant differences in self-chosen exercise intensity, significant differences in self-chosen exercise intensity, heart rate, metabolic rate, or exercise time were evident between the control and sleep deprived exposures. Fifty hours of sleep deprivation failed to alter the core temperature response during exercise in severe cold stress, and subjects chose identical work rates to minimize fatigue and cold sensation. The results suggest that the 50-h sleep deprivation period was not a true physiological stress during exercise in a cold environment. (Supported by Contract #DAMD 17-81-C1023.)

Thermoregulation in Erythrocebus patas: a thermal balance study.

A thermal balance study over an ambient temperature (Ta) range of 15-40 degrees C was performed on six nonacclimated patas monkeys (Erythrocebus patas) weighing between 3.9 and 6.0 kg. O2 consumption, CO2 production, mean weighted skin temperature (Tsk), rectal temperature (Tre), respiratory evaporative water loss (Eresp), and total evaporative water loss (Etot) were measured continuously after equilibration at each Ta. Tsk increased as Ta increased, whereas Tre was maintained between 37.6 and 38.4 degrees C at Ta from 15 to 40 degrees C. Total evaporative heat losses increased with increasing Ta to a mean value of 76 W/m2 at 40 degrees C. Eresp was relatively constant and increased from 1.0 to 8.0 W/m2 at 15 and 40 degrees C, respectively. Whole-body conductance was similar to that previously reported for Macaca mulatta except at the highest Ta (40 degrees C), where the values for the patas monkey were significantly lower than those reported for the rhesus monkey (rhesus = 72 W/m2; patas = 33 W/m2). The data demonstrate that the patas monkey can maintain its core temperature within a narrow range over a wide range of Ta values. Additionally, Etot in the patas monkey is significantly higher than what has been reported in other nonhuman primates and approaches that reported in humans.

Sympathoadrenal responses to cold and ketamine anesthesia in the rhesus monkey.

The effect of cold exposure on the sympathoadrenal system in primates was studied with and without ketamine anesthesia in eight adult rhesus monkeys. Each monkey was placed in a primate chair at a thermoneutral temperature (25 degrees C) for 1 h (control) followed by cold exposure (12 degrees C) for 3 h or placed in a circulating water bath (28 degrees C) to induce a decrease in core temperature (Tre) to 35 and 33 degrees C. Plasma catecholamines were analyzed by high-pressure liquid chromatography with electrochemical detection (60-65% recovery, coefficient of variation = 15%). The 3-h cold exposure was associated with a 175% increase above control levels of norepinephrine (NE) and a 100% increase in epinephrine (E). Decreases were evident in Tre (0.5 degree C), mean skin temperature (Tsk, 5.5 degrees C), and mean body temperature (Tb, 2.0 degrees C). Continuous infusion of ketamine (0.65 mg . kg-1 . min-1) resulted in no change in the plasma levels of NE and E from the control levels. Tre, Tsk, and Tb all showed greater declines with the addition of ketamine infusion to the cold exposure. Water exposure (28 degrees C) under ketamine anesthesia resulted in a drop in Tre to 33 degrees C within 1 h. Plasma levels of NE and E were unchanged from control values at Tre of 35 and 33 degrees C. The data suggest that the administration of ketamine abolished both the thermoregulatory response and the catecholamine response to acute cold exposure.

Body fluid and hematologic adjustments during resting cold acclimation in rhesus monkey.

The purpose of this study was to examine body fluid adjustments during prolonged cold exposure in primates. Six male rhesus monkeys were acclimated for 35 days and 6 degrees C and 80% rh. Red cell mass, extracellular fluid volume, and total body water (TBW) were determined with 51Cr, 35SO4, and 3H2O, respectively, prior to and at various intervals during the cold stress. TBW was increased throughout the exposure, whereas changes in extravascular compartments had occurred within the 1st wk of cold exposure, after which they returned to control values. An increased concentration of blood constituents on day 1 was not accompanied by a decrease in cardiovascular volume. Blood volume and plasma volume in relation to TBW were significantly increased on day 3 and remained increased during the remainder of the exposure. These cardiovascular volume changes were accompanied by a significant hemodilution on day 3 and a gradual return to control values. An increased plasma osmolality and expansion of the erythrocytes (decrease in mean corpuscular hemoglobin concentration) were observed throughout the cold stress. These data suggest that the rhesus monkey may be an adequate primate model for studies of body fluid adjustments, especially during prolonged cold exposure, in primates in general, including the human.

Thermal balance in ketamine-anesthetized rhesus monkey Macaca mulatta.

A partitional calorimetry study compared thermoregulatory responses of unanesthetized adult rhesus monkeys (4 female, 1 male) to those anesthetized with ketamine HCl and exposed to ambient temperature (Ta) of 18, 29, 38 degrees C. Steady-state metabolic heat production (M), mean skin temperature (Tsk), rectal temperature (Tre), respiratory evaporative heat loss (Eres), and total evaporative heat loss (Etot) were measured at each Ta. Average Tre of anesthetized animals was reduced by approximately 1 degree C at Ta 18 degrees C, but thermal balance in anesthetized and control animals was maintained by reflexly decreased tissue conductance and shivering. For anesthetized animals, the average M increased 1.8 times over the lowest value of 40.13 W/m2 at Ta 29 degrees C, compared to a 1.5-fold increase for controls. Responses for both groups were not different at Ta 29 degrees C, both groups regulated body temperatures by vasodilation and increased sweating, but with ketamine sweating was reduced (35%). Effective tissue thermal conductance (K) was lowest at Ta 18 (10.8 W/m2 . degrees C) and increased to 39.4 W/m2 . degrees C at Ta 38 degrees C. No significant difference in K was found between ketamine and control groups at other Ta's.

Dentin Apposition rates as markers of primate growth.

The incremental lines of von Ebner frequently have been described as ultradian markers of dentin calcification. To determine the relationship between these lines and the quantity of dentin formed, reference was made to an in vivo marker of calcification, tetracycline. These markers were produced by injecting four juvenile monkeys periodically over a period of 175 days. These animals had been subjects in the heat stress study and were exposed to a series of heat stresses and cortisone injections. At the end of the study, undecalcified thin sections of premolars and second molars were prepared by standard histological techniques. We found that linear apposition rates increased in a gradient toward the pulp chamber. These rates varied within each tooth but not in corresponding parts of different teeth. Also, we determined that dentin apposition can be temporarily depressed by certain metabolic stresses. Heat load and cortisone significantly slowed dentin formation. Each depression, however, was followed by a "catch-up" period. Incremental line distances also increased as a function of the distance from the dentoenamel junction. There was, however, no systematic relationship between apposition rates and incremental line distance; these distances did not deviate from the observed trends during periods of slowed apposition. Incremental lines may by interpreted, not as natural growth markers, but as structural phenomena which are a function of dentin geometry and tubule bending.

Prostaglandins and temperature regulation in the rhesus monkey.

The role of prostaglandins in nonfebrile temperature regulation in the rhesus monkey (Macaca mulatta) was investigated, Indomethacin, a potent inhibitor of prostaglandin synthesis, produced only a slight (less than 0.8 degrees C) fall in core temperature when administered intravenously (2-4 mg/kg) to warm-, cold-, and nonacclimated afebrile rhesus monkeys at ambient temperatures of 18, 27, and 33 degrees C. The fall in the core temperature was independent of the state of temperature acclimation and was brought about by nonregulated means. In addition, cold acclimation in the rhesus monkey was not associated with any change in hypothalamic sensitivity to the hyperthermic effects of exogenous prostaglandin E1. The results indicate that hypothalamic prostaglandins are not involved in normal temperature regulation of the monkey or in the process of temperature acclimation.

Body fluid and hematologic adjustments during resting heat acclimation in rhesus monkey.

The purpose of this study was to examine body fluid adjustments during prolonged resting heat exposure in primates. Rhesus monkeys were acclimated for 35 days at 35 degrees C and 30% rh. Red cell mass, extracellular fluid volume (ECF), and total body water (TBW) were determined with 51Cr, 35SO4, and 3H2O, respectively, prior to and at intervals during heat exposure. Heat acclimation was characterized by a fluid shift from the interstitial compartment. In relation to TBW, interstitial fluid volume and ECF decreased 10.3 and 8.3%, respectively, while plasma volume (PV) and intracellular fluid were increased an average of 5.8 and 3.8%. TBW increased 4.8% during heat exposure. Hematocrit and hemoglobin decreased significantly on day 3 (7.9 and 6.5%) followed by a return toward control values. PV in relation to TBW remained elevated throughout the exposure. An increased drinking (25.0%) was associated with a decrease in caloric intake (30.7%) during heat acclimation. This study has provided a complete body fluid compartment analysis during resting heat acclimation in the rhesus monkey. Our results are consistent with the hypothesis that heat acclimation in primates is characterized by a protein and fluid shift from the interstitial fluid compartment to the cardiovascular system and to the intracellular compartment.

Effect of ambient temperature on development of prostaglandin E1 hyperthermia in the rhesus monkey.

Prostaglandin E1 (PGE1) hyperthermia (fever) was studied at ambient temperatures (Ta) of 18, 27, and 35 degrees C in four male unanesthetized rhesus monkeys (Macaca mulatta) implanted with four guide tubes and one reentrant tube within the preoptic anterior hypothalamus (PO/AH). Rectal, hypothalamic, and mean weighted skin temperatures, O2 consumption, CO2 production, and respiratory and total evaporative water losses were measured continuously before and during PGE1 fever at each Ta. The febrile reponse to PO/AH PGE1 injection was dose responsive and was less at a Ta of 35 degrees C than at the other Ta's. At a Ta of 18 degrees C, fever was brought about primarily by an increase in metabolic rate. At a Ta of 27 degrees C, fever was produced by an increase in metabolic rate and by skin vasoconstriction. At a Ta of 35 degrees C, fever was the result of an increase in metabolic rate and a decrease in sweating evaporative heat loss. At each Ta some generalized skin vasconstriction also occurred. During the plateau phase of the fever, the measured heat losses and gains returned to near control levels. The data indicate that the rhesus monkey shows specific thermoregulatory responses to PO/AH PGE1 injection and would be a good model for the study of thermoregulation during fever in higher primates.

Sweating responses during changes of hypothalamic temperature in the rhesus monkey.

A technique is presented for preparing a durable thermode implant in the hypothalamus of the rhesus monkey. In unanesthetized monkeys implanted with thermodes in the anterior hypothalamic area of the brain, a linear relation was found between local sweat rates on the general body surface and clamped hypothalamic temperature. Changes in skin temperature were found to shift the hypothalamic set-point temperature at which sweating began but did not alter the gain of the hypothalamic temperature-sweat rate relationship. This study provides direct support for the concept that central brain temperature and skin temperature interact additively in the control of sweating in higher primates. Due to the very close similarity between these responses and those seen with indirect measurements of brain temperature in men, the rhesus monkey is seen as an excellent experimental analogue for studying human thermoregulation.