The induction of microphthalmia, encephalocele, and other head defects following hyperthermia during the gastrulation process in the rat

The aim of this study was to ascertain whether there is a period during early embryonic development of the rat that is particularly sensitive to hyperthermia. Pregnant Sprague-Dawley rats were partially immersed in a water bath at 43.5 degrees C until their core temperatures, monitored by a rectal thermistor probe, were elevated to 43.5 degrees C. The procedure was repeated 6 hours later. The regimen of two heatings was performed over a range of development from early gastrulation (8 days 18 hours) to about the 12 somite stage (10 days 18 hours). The rats were killed on days 17-19 and the fetuses were examined. Each group contained a minimum of five litters. The main teratogenic effect of the hyperthermia was the induction of one or more head defects, notably microphthalmia, encephalocele (either a single, large, parietal encephalocele or multiple small protuberances), and maxillary hypoplasia. Microphthalmia was the most common defect with approximately 90% of surviving fetuses having small eyes when heating occurred between 9 days 6 hours and 10 days 0 hours (9.06 and 10.00). Encephaloceles were induced by heating between 9.00 and 10.00 with a peak sensitivity between 9.12 and 9.18 when 57% of surviving fetuses were affected. Maxillary hypoplasia resulted from heating between 9.06 and 10.06 with up to 20% of surviving fetuses being affected. Control rats were exposed to the same experimental procedure in a water bath at 38 degrees C on 9.12 and 9.18, the gestational time most sensitive to hyperthermia induced malformations. There were no abnormal fetuses in the controls. The critical period identified spans 9 days 6 hours to 10 days 0 hours gestational age. In developmental terms this includes a large proportion of the gastrulation process.     

Effects of acute exposures to elevated temperatures on rat embryo growth and development in vitro

Day 10 rat embryos (8-12 somites) cultured in vitro were exposed to elevated temperatures (41-43 degrees C) for varying lengths of time. A 15-minute exposure to a temperature of 43 degrees C (109.4 degrees F) was sufficient to produce malformed embryos when observed on day 11. Longer exposures at this temperature produce higher incidences of malformed embryos and also more severely affected embryos. Temperatures of 42 degrees C (107.6 degrees F) or 41 degrees C (105.8 degrees F) also produced malformed embryos, but the required length of exposure was increased compared to 43 degrees C. The minimal length of exposure at 42 degrees C was 60 minutes, while at 41 degrees C it was increased to 4 hours. The central nervous system was particularly sensitive to increased temperatures, and embryos exposed to "teratogenic doses" of hyperthermia exhibited primarily microcephaly and microphthalmia. In addition, histological analyses revealed that at 4.5 hours after a 30-minute exposure to 43 degrees C, necrotic debris was prevalent in the neuroepithelium, less prevalent in the surrounding mesenchyme and surface ectoderm, and absent in the tissues of the heart.     

Accumulation of heat shock protein 72 (hsp 72) in postimplantation rat embryos after exposure to various periods of hyperthermia (40 degrees -43 degrees C) in vitro: evidence that heat shock protein 72 is a biomarker of heat-induced embryotoxicity.

A monoclonal antibody to the 72 kDa heat shock protein and Western blot analysis were used to determine the induction, accumulation and turnover of hsp 72 after day 10 rat embryos were exposed to elevated temperatures (40 degrees-43 degrees C) for various lengths of time (2.5 minutes to 18 hours). Embryos exposed to temperatures that exceed the normal culture temperature (37 degrees C) by 4 degrees C or more for as little as 2.5 minutes (43 degrees C) or 15 minutes (41, 42 degrees C) synthesized and accumulated detectable amounts of heat-inducible hsp 72. Hsp 72 could not be detected by Western blot analysis of proteins from embryos cultured at 40 degrees C or below. Once induced, hsp 72 can be detected in embryos for 24-48 hours after they are removed from the hyperthermic conditions and returned to normothermic conditions. Our results also indicate that hsp 72 is induced by all hyperthermic exposures that induce alterations in rat embryo growth and development; therefore, hsp 72 is a potential biomarker for heat-induced embryotoxicity.     

Teratogenicity of 27.12-MHz radiation in rats is related to duration of hyperthermic exposure

Five groups of pregnant Sprague-Dawley rats were either sham exposed or were irradiated in a 27.12-MHz radiofrequency (RF) field at 55 A/m and 300 V/m on gestation day 9. The absorbed power (approximately 11 W/kg) caused a relatively rapid increase in the rat's colonic temperature. Rats in group I were sham irradiated for 2.5 h at 0 A/m, 0 V/m. In group II RF irradiation was terminated after the rat's colonic temperature reached 41.0 degrees C. In group III the 41.0- degrees C temperature was maintained an additional 2 h by manually varying the incident field strength. In group IV irradiation was terminated after the rat's colonic temperature reached 42.0 degrees C. In group V the 42.0- degrees C temperature was maintained an additional 15 min by varying the field strength. At both temperatures the teratogenic and embryotoxic effects of the RF-induced hyperthermia increased as the exposure duration increased, but the increase was especially noticeable at 42.0 degrees C. The results indicate that the teratogenic and embryotoxic effects of RF-induced hyperthermia are related to both the temperature of the dam during exposure and the length of time the dam's temperature remains elevated.     

Effects of raised body temperature on reasoning, memory, and mood

Volunteers' body core temperatures were raised to 38.80-39.05 degrees C within a few minutes by immersion in water at 41 degrees C. Tests were then made with the subjects insulated and cooling slowly. Control immersions were made in water at 37 degrees C when core temperatures remained at 36.60-37.40 degrees C. Neither memory registration nor recall of memories registered an hour earlier, nor immediate ability to recall digit spans forward or backward was affected by the increase in core temperature. The increase in temperature did not have any significant effect on accuracy of performance of verbal logic problems or of two-digit subtractions. However, the increase in core temperature was associated with a significant increase in the speed of performance of the tests, by 11 and 10%, respectively. The warm immersions also induced a significant decrease in alertness and an increase in irritability as assessed subjectively by the volunteers; control immersions had no such effects.     

Association of microwaves and ionizing radiation: potentiation of teratogenic effects in the rat

Pregnant Wistar rats were exposed to either microwave-induced hyperthermia or gamma radiation or a combination of both. In microwave-induced hyperthermia, a core temperature of 42 degrees C was slightly teratogenic and a core temperature greater than or equal to 43 degrees C was highly teratogenic. Gamma radiation at 40 cGy was subteratogenic, while a dose of 75 cGy was highly teratogenic. A combination of microwave-induced hyperthermia up to 42 degrees C with 40 cGy of gamma radiation was highly teratogenic, indicating a mutual potentiation of the embryotoxic action of these two teratogens.     

Improved preferential tumor hyperthermia with regional heating and systemic blood cooling: a balanced heat transfer method

Absorption of power in large body volumes can occur with some approaches used for hyperthermia treatment of cancer. A systemic heat absorption rate exceeding the heat dissipation rate can lead to systemic temperature elevation that limits the magnitude and duration of application of power and hence the degree of preferential tumor temperature rise. We describe a hyperthermia approach consisting of regional electromagnetic power absorption and extracorporeal blood cooling with regulation of both systemic heat absorption and dissipation rates ("balanced heat transfer"). A test of this approach in five dogs with nonperfused tumor models demonstrated intratumoral temperatures greater than 42 degrees C, while systemic temperature remained at 33 degrees C and visceral temperatures within the heated region equilibrated between 33 and 42 degrees C. Solutions of the bioheat transfer equation were obtained for a simplified model with a tumor perfusion rate lower than surrounding normal tissue perfusion rate. In this model, the use of arterial blood temperatures less than 37 degrees C allowed higher power densities to be used, for given normal tissue temperatures, than when arterial temperature was greater than or equal to 37 degrees C. As a result, higher intratumoral temperatures were predicted. Control of arterial blood temperature using extracorporeal cooling may thus (1) limit systemic temperature rise produced by regional heating devices and (2) offer a means of improving intratumoral temperature elevations.     

Pharmacological evidence for adrenergic activation of hyperthermic responses associated with psychosocial stimulation

1. Brief social encounters between strange voles living adjacent compartments of a population cage lead to rapid increases of more than 1 degrees C in their core temperatures. 2. Socially induced core temperature responses remain elevated for more than 1 hr following social contact, and are of greater amplitude and duration than can be elicited by handling, noise or exercise. 3. Pretreatment of opponents with adrenergic blockers reduces the amplitude and duration of hyperthermic response proportional to drug intake; both alpha and beta blocking effects are completely reversed within 24 hr. 4. The dynamics of the hyperthermic response and effects of the drugs suggest that the rapid rise in core temperature is due to both vasoconstrictor (alpha) heat conservation and metabolic (beta) heat generating mechanisms, and that the protracted elevation of core temperature is primarily due to (beta) metabolic activation.     

Investigating the warming and cooling rates of human cadavers by development of a gel-filled model to validate core temperature

Tissue Services (within NHS Blood and Transplant) plans to bring deceased donors to its state of the art retrieval suite at its new centre in Speke, Liverpool in air-conditioned transport at circa 20 degrees C but without dedicated active cooling. The aim of this study was to determine how quickly a refrigerated body would warm at different ambient temperatures using a gel-filled model. Two models of a human body were prepared consisting of neoprene wetsuits filled with approximately 7 or 18 l of a viscous solution, which once set has similar properties to ballistics gel. This gel consisted of 47.5% distilled water, 47.5% glycerol and 5% agar. Final "dummy" weights were 7.4 and 18.6 kg respectively, representing "virtual" weights of approximately 40 kg and 70 kg. A K-class thermocouple probe was then inserted into a "rectal" position within each model and the models were cooled to a series of different core temperatures: 5 degrees C, 10 degrees C and 15 degrees C and then were placed in an orbital incubator set at 20 degrees C or 30 degrees C ambient temperature. The rate of temperature increase, in the dummy, was measured, until the model's core temperature was close to the ambient temperature. This was done in triplicate for each size model and ambient temperature. Data indicate that increase in core temperature depends on the size of the model and the initial core temperature. For an equivalent donor weight of 70 kg and background temperature of 20 degrees C, core temperature rises from 5 degrees C to 9.2 degrees C; 10 degrees C to 13.3 degrees C and 15 degrees C to 15.5 degrees C after 2 h. The final core temperatures after 2 h are likely to retard bacterial growth, movement or contamination during transport. Cooling rate data indicated that a 70 kg donor equivalent cooled from 37 degrees C to 15 degrees C within 6 h in a cold room at 4 degrees C. This work has shown that a body can be transported without refrigeration and not cause further tissue deterioration as a result.     

Effect of different factors on the germination of spores in S and P- variants of Bacillus brevis]

The effect of temperature, duration of heating and the presence of L-alanine and L-glutamine in the medium on the spore germination was studied with the S and P- variants of Bacillus brevis which did not contain gramicidin S and with the R and P+ varants obtained on a defined medium with beta-phenyl-beta-alanine, an inhibitor of the biosynthesis of gramicidin S. The experiments were carried out according to the scheme of complete factor experiment. Germination of the spores was found upon their incubation in a defined medium with L-alanine within two hours after their preliminary heating at 80 degrees C during 45 minutes (S variant), at 60 degrees C during 45 minutes (R variant+trace amounts of gramicidin S), at 80 degrees C during 15 minutes (P+ variant/trace amounts of gramicidin S). Germination of the spores of the P- variant was best upon heating to 60 degrees C during 45 minutes. Gramicidin S is presumed to inhibit, to a certain extent, germination of the spores of its producing culture.     

A second postcooling afterdrop: more evidence for a convective mechanism.

An attempt was made to demonstrate the importance of increased perfusion of cold tissue in core temperature afterdrop. Five male subjects were cooled twice in water (8 degrees C) for 53-80 min. They were then rewarmed by one of two methods (shivering thermogenesis or treadmill exercise) for another 40-65 min, after which they entered a warm bath (40 degrees C). Esophageal temperature (Tes) as well as thigh and calf muscle temperatures at three depths (1.5, 3.0, and 4.5 cm) were measured. Cold water immersion was terminated at Tes varying between 33.0 and 34.5 degrees C. For each subject this temperature was similar in both trials. The initial core temperature afterdrop was 58% greater during exercise (mean +/- SE, 0.65 +/- 0.10 degrees C) than shivering (0.41 +/- 0.06 degrees C) (P < 0.005). Within the first 5 min after subjects entered the warm bath the initial rate of rewarming (previously established during shivering or exercise, approximately 0.07 degrees C/min) decreased. The attenuation was 0.088 +/- 0.03 degrees C/min (P < 0.025) after shivering and 0.062 +/- 0.022 degrees C/min (P < 0.025) after exercise. In 4 of 10 trials (2 after shivering and 2 after exercise) a second afterdrop occurred during this period. We suggest that increased perfusion of cold tissue is one probable mechanism responsible for attenuation or reversal of the initial rewarming rate. These results have important implications for treatment of hypothermia victims, even when treatment commences long after removal from cold water.     

Numeric Estimates of Teratogenic Severity from Embryo–Fetal Developmental Toxicity Studies

A developing organism exposed to a toxicant will have a response that ranges from none to severe (i.e., death or malformation). The response at a given dosage may be termed teratogenic (or developmental toxic) severity and is dependent on exposure conditions. Prenatal/embryo–fetal developmental (EFD) toxicity studies in rodents and rabbits are the most consistent and definitive assessments of teratogenic severity, and teratogenesis screening assays are best validated against their results. A formula is presented that estimates teratogenic severity for each group, including control, within an EFD study. The developmental components include embryonic/fetal death, malformations, variations, and mean fetal weight. The contribution of maternal toxicity is included with multiplication factors to adjust for the extent of mortality, maternal body weight change, and other parameters deemed important. The derivation of the formula to calculate teratogenic severity is described. Various EFD data sets from the literature are presented to highlight considerations to the calculation of the various components of the formula. Each score is compared to the concurrent control group to obtain a relative teratogenic severity. The limited studies presented suggest relative scores of two‐ to <fivefold higher than control have detectable but a low level of teratogenic severity, and scores ≥fivefold higher than control have increasingly more severe teratogenicity. Such scores may help refine the concept of an exposure‐based validation list for use by proponents of screening assays (Daston et al., 2014) by estimating the severity of “positive” exposures, or in other situations by defining the severity of a LOAEL (lowest observed adverse effect level)     

Teratogenic interaction of ethanol and hyperthermia in mice

Alcohol and maternal hyperthermia have been implicated in human birth defects. Both ethanol and heat can induce neural tube defects (NTDs) and other developmental abnormalities in mice when large doses are given during pregnancy. To explore the teratogenic interaction of both agents, pregnant ICR mice were injected with a single dose of 25% ethanol and/or were heat-stressed in a water bath at 42 degrees C on the morning of Day 8 of gestation. Combined treatment with ethanol (0.01-0.02 ml/g) and heat (10 min), when they were given concurrently or 1 hr apart, resulted in a significant increase of resorptions and externally malformed fetuses. Skeletal malformations and visceral variations also increased significantly following a concurrent exposure to both agents. These results indicate that ethanol and heat can be synergistically teratogenic in mice when the doses of each agent are below the teratogenic threshold. It was also suggested that pretreatment with a small dose of ethanol may not enhance the teratogenicity of heat when the hyperthermic stress is strong enough and teratogenic by itself.     

Body temperature set-point and the conscious perception of skin temperature in obese women

Obese and control women were immersed in a bath of water kept at 37 degrees C. Oral temperature was measured. The subjects left hand was placed outside the bath for the local application of thermal stimuli between 20 degrees and 45 degrees C, subjects reporting the most pleasant temperature. The lower oral temperatures and lower levels of skin temperature rated as pleasant by obese women as compared with women of normal body weight or less suggests that in obesity the set-point of body temperature is lowered.     

Duration of the mitotic cycle of Chinese hamster cells cultured at 30--39 degrees]

The duration of the mitotic cycle (T) at temperatures of 30, 33, 36 and 39 degrees C was studied in subline 237 of Chinese hamster cells with the aid of the radioautographic method. T was the least at 39 degrees C and increased with reduction of the cultivation temperature. At the temperature range of 33--39 degrees C prolongation of T and its periods was "proportional" to the temperature under study. The characteristic curve gradient of T dependence on the temperature showed a sharp change in the direction of greater figures with the temperature reduction from 33 to 30 degrees C. Analysis of the results of other studies on T duration of the human amniotic cells demonstrated that such sharp elevation of the duration of the mitotic cycle occurred with the change from 39 to 40--41 degrees C. The G1 period was the most and G2--THE LEAST Sensitive to changes of the cultivation temperature.     

Regional heterothermy and conservation of core temperature in emperor penguins diving under sea ice

Temperatures were recorded at several body sites in emperor penguins (Aptenodytes forsteri) diving at an isolated dive hole in order to document temperature profiles during diving and to evaluate the role of hypothermia in this well-studied model of penguin diving physiology. Grand mean temperatures (+/-S.E.) in central body sites during dives were: stomach: 37.1+/-0.2 degrees C (n=101 dives in five birds), pectoral muscle: 37.8+/-0.1 degrees C (n=71 dives in three birds) and axillary/brachial veins: 37.9+/-0.1 degrees C (n=97 dives in three birds). Mean diving temperature and duration correlated negatively at only one site in one bird (femoral vein, r=-0.59, P<0.05; range <1 degrees C). In contrast, grand mean temperatures in the wing vein, foot vein and lumbar subcutaneous tissue during dives were 7.6+/-0.7 degrees C (n=157 dives in three birds), 20.2+/-1.2 degrees C (n=69 in three birds) and 35.2+/-0.2 degrees C (n=261 in six birds), respectively. Mean limb temperature during dives negatively correlated with diving duration in all six birds (r=-0.29 to -0.60, P<0.05). In two of six birds, mean diving subcutaneous temperature negatively correlated with diving duration (r=-0.49 and -0.78, P<0.05). Sub-feather temperatures decreased from 31 to 35 degrees C during rest periods to a grand mean of 15.0+/-0.7 degrees C during 68 dives of three birds; mean diving temperature and duration correlated negatively in one bird (r=-0.42, P<0.05). In general, pectoral, deep venous and even stomach temperatures during diving reflected previously measured vena caval temperatures of 37-39 degrees C more closely than the anterior abdominal temperatures (19-30 degrees C) recently recorded in diving emperors. Although prey ingestion can result in cooling in the stomach, these findings and the lack of negative correlations between internal temperatures and diving duration do not support a role for hypothermia-induced metabolic suppression of the abdominal organs as a mechanism of extension of aerobic dive time in emperor penguins diving at the isolated dive hole. Such high temperatures within the body and the observed decreases in limb, anterior abdomen, subcutaneous and sub-feather temperatures are consistent with preservation of core temperature and cooling of an outer body shell secondary to peripheral vasoconstriction, decreased insulation of the feather layer, and conductive/convective heat loss to the water environment during the diving of these emperor penguins.     

Some teratogenic properties of ethanol and acetaldehyde in C57BL/6J mice: implications for the study of the fetal alcohol syndrome

To investigate the teratogenic effect of acute alcohol exposure, pregnant C57BL/6J mice were exposed to 25% ethanol (either two doses of 2.9g/kg or one dose 5.8g/kg) during the organogenic period either by intraperitoneal injections or by intubation. The incidence of malformations varied according to (1) the stage of embryonic development at the time of exposure, (2) the route of administration of the alcohol, and (3) the amount of alcohol given and the time period over which it was administered. Oral doses of alcohol were teratogenic although less so than the same dose given intraperitoneally, and two intraperitoneal doses four hours apart produced significantly more malformation than the same two doses six hours apart. The primary metabolite of alcohol, acetaldehyde, was also investigated for its teratogenicity. It was found that one or two doses of four percent acetaldehyde (0.32g/kg), administered intraperitoneally were teratogenic. A further attempt was made to raise blood acetaldehyde levels by exposing mice to disulfiram, an inhibitor of acetaldehyde dehydrogenase, prior to administration of alcohol. The disulfiram pretreatment did not increase the malformation rate. Treatment with alcohol on day 7 or 8 caused a variety of facial abnormalities, some of which were comparable to those seen in children with fetal alcohol syndrome. Exposure on day 9 or 10 resulted in limb defects. The results suggest that one or more episodes of heavy maternal drinking at critical periods in pregnancy may severely damage the embryo and may produce many features of the fetal alcohol syndrome.     

Survival of Phytophthora ramorum hyphae after exposure to temperature extremes and various humidities

We examined the effect of short-term exposure to high and low temperatures and a range of relative humidity (RH) on survival of Phytophthora ramorum hyphae. Spore-free hyphal colonies were grown on dialysis squares atop V8 medium. Colonies were transferred to water agar plates positioned at 27.5-50 C on a thermal gradient plate and incubated 2.5-480 min. For low temperature trials colonies were transferred to vials of distilled water and incubated in a water bath at -5 to -25 C for 1-24 h. In the relative humidity trials hyphal colonies were transferred to sealed humidity chambers containing various concentrations of glycerin for 1-8 h. Relative humidity was 41-93% at 20 C and 43-86% at 28 C. Survival in all trials was characterized by growth from dialysis squares into V8 medium. Temperatures of 37.5-40 C were lethal to P. ramorum hyphae within several hours, and temperatures of 42.5-50 C were lethal within minutes. Exposure to 32.5 and 35 C resulted in reduced survival over 8 h, while 30 C had no effect on three of four isolates. Hyphal colonies demonstrated considerable tolerance to cold, with all isolates surviving a 24 h exposure to -5 C. Survival diminished over time at lower temperatures, however a few colonies survived 24 h exposure to -25 C. Temperature also affected the ability of hyphal colonies to withstand reduced humidity. A RH of 41-43% was lethal in 2 h at 28 C compared to 8 h at 20 C. Three of four isolates were unaffected by an 8 h exposure to 81 and 95% RH at 20 C, and 73 and 86% RH at 28 C. Isolate differences were apparent in tolerance to freezing temperatures and reduced humidity. From these results it is apparent that the cold temperatures found in the northeastern USA are not likely to prevent the establishment of P. ramorum. There is also the potential for hyphae, and presumably spores, to survive periods of high humidity on the leaf surface in the absence of free water.     

Investigation of the teratogenic potential of ochratoxin A and B using the FETAX system

BACKGROUND: Ochratoxin A (OTA) is a mycotoxin produced by certain Aspergillus and Penicillium species. It has been observed to be teratogenic in a number of animal models including rat, mouse, hamster, and chick, with reduced birth weight and craniofacial abnormalities being the most commonly observed malformations. Neither the potential of OTA to cause malformations in humans nor its teratogenic mode of action is known. The FETAX system is an embryotoxicity assay system, with a high correlation to animal models and epidemiological data. Analysis of OTA-mediated teratogenesis using this system could provide a useful tool for the generation of high numbers of samples for mechanistic studies. METHODS: Using the standard ASTM 96-hr exposure protocol, the effect of OTA and its structural analogue OTB on the development of Xenopus laevis embryos in vitro was assessed. The accumulation of both substances in Xenopus embryos was also examined using tritiated OTA and OTB. RESULTS: Both OTA and OTB caused craniofacial malformations, while OTA also caused reduced embryo growth. As expected, OTA was far more potent in inducing these effects than OTB. This could at least in part be due to greater levels of OTA being accumulated within the embryos. CONCLUSIONS: The ability of FETAX to differentiate between close structural analogues indicates the assay has great potential for the elucidation of the embryotoxic and teratogenic mechanisms of action. Hence, the model could provide a suitable system for the investigation of other known teratogens or for the pre-screening of new agents for teratogenic potential.     

Cell type–specific variations in the induction of hsp70 in human leukocytes by feverlike whole body hyperthermia

Fever has been associated with shortened duration and improved survival in infectious disease. The mechanism of this beneficial response is still poorly understood. The heat-inducible 70-kDa heat shock protein (Hsp70) has been associated with protection of leukocytes against the cytotoxicity of inflammatory mediators and with improved survival of severe infections. This study characterizes the induction of Hsp70 by feverlike temperatures in human leukocytes in vitro and in vivo. Using flow cytometry, Hsp70 expression was determined in whole blood samples. This approach eliminated cell isolation procedures that would greatly affect the results. Heat treatment of whole blood in vitro for 2 hours at different temperatures revealed that Hsp70 expression depends on temperature and cell type; up to 41 degrees C, Hsp70 increased only slightly in lymphocytes and polymorphonuclear leukocytes. However, in monocytes a strong induction was already seen at 39 degrees C, and Hsp70 levels at 41 degrees C were 10-fold higher than in the 37 degrees C control. To be as close as possible to the physiological situation during fever, we immersed healthy volunteers in a hot water bath, inducing whole body hyperthermia (39 degrees C), and measured leukocyte Hsp70 expression. Hsp70 was induced in all leukocytes with comparable but less pronounced cell type-specific variations as observed in vitro. Thus, a systemic increase of body temperature as triggered by fever stimulates Hsp70 expression in peripheral leukocytes, especially in monocytes. This fever-induced Hsp70 expression may protect monocytes when confronted with cytotoxic inflammatory mediators, thereby improving the course of the disease.