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Integrated Physiological Mechanisms of Exercise Performance, Adaptation, and Maladaptation to Heat Stress

Michael N. Sawka, Lisa R. Leon, Scott J. Montain, Larry A. Sonna

10.1002/cphy.c100082

Source: Volume 1, Issue 4, October 2011

Published online: October 2011

Full Article on Wiley Online Library



Abstract

This article emphasizes significant recent advances regarding heat stress and its impact on exercise performance, adaptations, fluid electrolyte imbalances, and pathophysiology. During exercise‐heat stress, the physiological burden of supporting high skin blood flow and high sweating rates can impose considerable cardiovascular strain and initiate a cascade of pathophysiological events leading to heat stroke. We examine the association between heat stress, particularly high skin temperature, on diminishing cardiovascular/aerobic reserves as well as increasing relative intensity and perceptual cues that degrade aerobic exercise performance. We discuss novel systemic (heat acclimation) and cellular (acquired thermal tolerance) adaptations that improve performance in hot and temperate environments and protect organs from heat stroke as well as other dissimilar stresses. We delineate how heat stroke evolves from gut underperfusion/ischemia causing endotoxin release or the release of mitochondrial DNA fragments in response to cell necrosis, to mediate a systemic inflammatory syndrome inducing coagulopathies, immune dysfunction, cytokine modulation, and multiorgan damage and failure. We discuss how an inflammatory response that induces simultaneous fever and/or prior exposure to a pathogen (e.g., viral infection) that deactivates molecular protective mechanisms interacts synergistically with the hyperthermia of exercise to perhaps explain heat stroke cases reported in low‐risk populations performing routine activities. Importantly, we question the “traditional” notion that high core temperature is the critical mediator of exercise performance degradation and heat stroke. Published 2011 This article is a U.S. Government work and is in the public domain in the USA. Compr Physiol 1:1883‐1928, 2011.

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Figure 1. Figure 1.

Active (vastus medialis) and inactive (triceps brachii) muscle temperatures relative to core and mean skin temperature changes during exercise.

Reprinted (with permission) from Jay et al. 186
Figure 2. Figure 2.

Core (rectal and esophageal) temperature during rest and aerobic exercise in the heat.

Reprinted (with permission) from Sawka and Wenger 358
Figure 3. Figure 3.

Possible core temperatures steady‐state during aerobic exercise at metabolic rates of 200, 350, 500, and 1000 W at different environmental conditions.

Reprinted (with permission) from Sawka et al. 360
Figure 4. Figure 4.

Schematic diagram of the thermoregulatory control system. Tsk represents skin temperature and Tc represents core temperature.

Reprinted (with permission) from Sawka et al. 360
Figure 5. Figure 5.

Schematic diagram of thermoregulatory effector (e.g., sweating rate and skin blood flow) responses (forcing function analysis with linear plots) to: (A) increased load error (LE), (B) parallel shift in threshold temperature suggesting change in “set point,” and (C) slope or sensitivity changes suggesting peripheral modifications. LE, load error; D, decrease; and I, increase.

Reprinted (with permission) from Gisolfi and Wenger 138
Figure 6. Figure 6.

Differences between the elevation of core temperature in fever and during exercise.

Reprinted (with permission) from Sawka and Wenger 358; redrawn (with permission) from Stitt 394 and Gisolfi and Wenger 138
Figure 7. Figure 7.

Schematic description of the thermoregulatory control of skin blood flow as modified by moderately intense exercise.

Reprinted (with permission) from Gonzalez‐Alonso et al. 147
Figure 8. Figure 8.

Cardiovascular responses during sustained moderate intensity (70% ) exercise in temperate and hot conditions. BF, blood flow; PV, plasma volume; SV, stroke volume; CO, cardiac output; Tsk, skin temperature; Tes, esophageal temperature; and Ta, ambient temperature. Drawn 138 (with permission) from data presented by Nadel et al. 279.
Figure 9. Figure 9.

The impact of high skin temperature on elevating heart rate during light‐intensity exercise.

Reprinted (with permission) from Cheuvront et al. 77
Figure 10. Figure 10.

The impact of graded exercise intensity on cardiovascular responses during hot (triangle) and temperate (circle) conditions.

Reprinted (with permission) from Rowell 338
Figure 11. Figure 11.

Nomogram examining the potential performance decrement (y‐axis) based on projected marathon finishing time (x‐axis) with increasing Wet Bulb Globe Temperature.

Reprinted (with permission) from Ely et al. 111
Figure 12. Figure 12.

Maximum aerobic power values for the pre‐ and postacclimation tests in both environments.

Reprinted (with permission) from Sawka et al. 361
Figure 13. Figure 13.

The percent decrement in time trial performance from euhydration at each skin temperature.

Reprinted (with permission) from Kenefick et al. 198
Figure 14. Figure 14.

A comparison of the benefits from an aerobic training program with a heat acclimation program on reducing physiological strain and improving performance during exercise‐heat stress.

Reprinted (with permission) from Sawka and Young 360. Original data adapted (with permission) from Cohen and Gisolfi 82
Figure 15. Figure 15.

Cardiorespiratory and performance changes as a percent change from the preacclimation trials in both environmental conditions.

Reprinted (with permission) from Lorenzo et al. 240. *P < .05 vs. the preacclimation trials in both environments
Figure 16. Figure 16.

(A) Comparison of baseline heat shock protein (HSP) values between day 1 and day 10 of heat acclimation (HA). (B) Quantification of Western blot analysis in densitometry units representing ratio of HSP:β‐tubulin. Values are means and standard deviation with correlation between post‐HA (day 10 vs. day 1) increase in HSP72 and HSP90 expression.

Reprinted (with permission) from McClung et al. 253
Figure 17. Figure 17.

Predictions of daily water requirements as function of daily energy expenditure and air temperature. Figure adapted (with permission) from Institute of Medicine 181.
Figure 18. Figure 18.

Predictions of daily sodium requirements as function of daily energy expenditure and air temperature. Figure adapted (with permission) from Institute of Medicine 181.
Figure 19. Figure 19.

Predicted body mass loss (due to water deficit; left panel) for two 70‐kg people of different body composition, running at 8.5 km·h−1 in temperate weather (18°C), and drinking water at three rates [400 ml·h−1 (solid line), 600 ml·h−1 (broken line), 800 ml·h−1 (broken dotted line)]. The yellow‐shaded areas indicate when water loss would be sufficient to modestly degrade performance, and when water loss would substantially degrade performance (red). Also predicted are plasma sodium concentrations for three rates sweat sodium loss. Two lines sharing the same line style are the predicted outcomes for people of two different body compositions; with total body water accounting for 50% and 63% (leaner) of body mass. The hatched shaded areas denote the presence of hyponatremia (plasma sodium concentration <130 mEq·liter−1) into the range where symptoms develop.
Figure 20. Figure 20.

Distribution of relative risk among male Marine Corps recruits and distribution of exertional heat stroke at Parris Island, SC, for years 1988 to 1992. High risk = body mass index (BMI) ≥22 kg·m−2, 1.5 mi run time ≥12 min; medium risk = BMI ≥26 kg·m−2, 1.5 mi run time <12 min or BMI <22 kg·m−2, 1.5 mi run time ≥12 min; low risk = BMI <26 kg·m−2, 1.5 mi run time <12 min. Adapted (with permission) from Gardner et al. 131.
Figure 21. Figure 21.

Core temperature of a male Marine Corp recruit during normal physical training and when incurring exertional heat stroke, conducted on two different days. Note the rapid development of hyperthermia on the day of heat stroke despite performing the same activity as the day that heat stroke was not observed. Wenger et al. (unpublished data).
Figure 22. Figure 22.

Summary of exertional heat stroke pathophysiological responses that culminate in multiorgan system failure. During exercise heat stress, there is an increase in cutaneous blood flow and decrease in splanchnic blood flow. Gut epithelial membrane ischemia induces oxidative and nitrosative stress that increases tight junction permeability and allows endotoxin to leak into the systemic and portal circulation. Toll‐like receptors (e.g., TLR4) detect pattern‐associated molecular patterns (PAMPs) on the cell membrane of endotoxin and stimulate pro‐ and anti‐inflammatory cytokine production. Heat is toxic to several organs and stimulates the secretion of heat shock proteins (HSPs) that interact with cytokines and other proteins to mediate the systemic inflammatory response syndrome of the host. A shift of the cytokine milieu from anti‐inflammatory (Th2) to a pro‐inflammatory (Th1) balance (a process known as anergy) is thought to mediate many of the adverse consequences of the heat stroke syndrome that lead to multiorgan system failure and death.
Figure 23. Figure 23.

Representative light micrographs of histological damage (hematoxylin and eosin stain) to inverted rat small‐intestinal sac tissue exposed to 41.5 to 42°C over a 60‐min time course. Villi appear normal at 15 min compared with the initial sloughing of epithelia from the villous tips at 30 min of exposure. At 45 min, there is significant lifting of villi epithelial linings at the top and sides, which is completed denuded by 60 min of exposure. Bars represent 100 μM. N = 2 to 4 rats per time point.

Reprinted (with permission) from Lambert et al. 218
Figure 24. Figure 24.

Computer tomography (CT) scans of a 45‐year‐old man that collapsed from exertional heat stroke on a hot summer day. He was unconscious and hyperthermic (42°C) with convulsion at the time of hospital admission. The patient remained unconscious for 5 days. (A) Normal CT scan of the cerebellum 2 weeks following collapse (B) and (C). Progression of cerebellar atrophy from 10 weeks (B) to 11 months (C). Note that hypothalamic damage was not reported in this patient.

Reprinted (with permission) from Albukrek et al. 6
Figure 25. Figure 25.

Time course of core temperature (A; °C; radiotelemetry), metabolic rate (B; oxygen consumption, ), and respiratory exchange ratio (C; RER) of control and mild heat stroke mice during heat stroke and recovery in an indirect calorimeter. Time 0 represents the start of recovery following heat stroke collapse. Note that mice developed hypothermia immediately following collapse that was preceded by ∼35% reduction in . Despite reliance on fatty acid oxidation (RER∼0.7) during hypothermia, mice developed fever (∼1°C), which was associated with ∼20% increase in from 20 to 32 h of recovery. Note that hypothermia and fever were observed in heat‐stroked mice in the absence of histological damage (hematoxylin and eosin) to the preoptic area of the hypothalamus. Data are 1‐h averages. Black horizontal bars indicate lights‐off periods. *represents significant difference between heat stroke and control animals at P < 0.05.

Reprinted (with permission) from Leon et al. 228
Figure 26. Figure 26.

Mechanisms of disseminated intravascular coagulation (DIC). Heat injury to the vascular endothelium initiates the coagulation and fibrinolysis pathways. Excess fibrin deposition may lead to vascular thrombosis in the arterioles and capillaries and lead to occlusion of the blood supply to the organ bed. As coagulation proceeds, platelets and coagulation proteins are consumed at a faster rate than they are produced resulting in blood loss from multiple tissue sites (e.g., venipuncture wounds and gums). The combined effects of vessel occlusion and excess blood loss result in coagulopathies leading to multiorgan dysfunction.

Reprinted (with permission) from Leon and Helwig 229
Figure 27. Figure 27.

IL‐6 receptor signaling pathways. Classic signaling involves IL‐6 binding to the membrane‐bound IL‐6 receptor (IL‐6R), which stimulates an interaction between the IL‐6:IL‐6R complex and the membrane‐bound gp130 to initiate intracellular signaling. Transignaling occurs when the extracellular domain of the membrane‐bound IL‐6R is proteolytically cleaved to generate the soluble IL‐6R (sIL‐6R) that binds IL‐6. The IL‐6:sIL‐6R complex can stimulate cells that only express gp130 (i.e., do not normally possess the transmembrane IL‐6R) to transmit an intracellular signal. Cells that express gp130 only would not be able to respond to IL‐6 in the absence of the sIL‐6R.

Reprinted (with permission) from Leon and Kenefick 230
Figure 28. Figure 28.

Representative photomicrographs of histological damage (hematoxylin and eosin; 200×) to the kidney of a normothermic (A) and passively heat‐stroked mouse (core temperature = 42.7°C). (B) Arrows indicate identified tissue lesions which included renal tubular necrosis in the straight tubules of the kidney lower cortex. This was observed as shrunken, acidophilic, and fragmented epithelial cells with pyknotic nuclei. Renal damage was first detected at the time of heat stroke collapse with progressively greater damage from hypothermia to 24 h of recovery (time of fever).

Reprinted (with permission) from Leon et al. 226
Figure 29. Figure 29.

Fatty liver change observed in a heat‐stroked mice (right) ∼72 h following heat stroke collapse (core temperature = 42.7°C). Liver from a nonheated control (left) and heat stroke nonsurvivor (right) are shown.

Reprinted (with permission) from Leon 225
Figure 30. Figure 30.

Representative data showing that common clinical measures do not always accurately reflect the presence of peripheral organ damage. Core temperature (radiotelemetry; ±0.1°C) of male Fischer 344 rats was recorded at 1‐min intervals during 10 days of heat stroke recovery. On day 10, circulating levels of blood urea nitrogen (BUN), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were compared with gross morphology and histological damage (hematoxylin and eosin) to the kidney and liver. Representative core temperature tracings (top row), kidney pathology and BUN levels (middle row), and liver pathology, AST and ALT levels (bottom row) from one control (left panel) and two heat stroke rats (middle and right panel; core temperature = 42.0°C) are shown. Left panel: Nonheated control rat displayed a normal circadian core temperature profile through 10 days with low daytime (∼37°C) and high nighttime (∼38°C) values. The kidney and liver showed normal gross and histological appearance, and circulating levels of BUN, AST, and ALT were within the normal range. Middle panel: Following heat stroke collapse, profound hypothermia (∼34‐35°C) was observed through 5 days of recovery and then the animal re‐warmed to ∼37°C by day 10 of recovery, but failed to re‐establish a normal circadian rhythm. Gross appearance of the kidney and liver indicated damage, which was confirmed by histological analysis. The kidney showed bilateral renal tubular degeneration with protenuria and multifocal necrosis of hepatocytes was evident in the liver (indicated by black arrows in representative photomicrographs). High circulating BUN, AST, and ALT levels accurately reflected the extensive histological damage to these organs. Right panel: Following heat stroke collapse, hyperthermia (∼39°C) was observed through day 3 and then the animal re‐established a normal circadian core temperature profile through 10 days of recovery. Gross appearance of the kidney and liver suggested residual damage in these organs, which was confirmed histologically as bilateral mineralization and protenuria in the kidney and extramedullary hematopoiesis with mineralization of hepatocytes (indicated by black arrows in representative photomicrographs). Circulating levels of BUN, AST, and ALT levels were virtually identical to controls and did not accurately reflect the presence of organ damage in this animal. These data demonstrate that traditional clinical biomarkers of organ function lack specificity and sensitivity to detect damage in all animals following heat stroke collapse. Gray shading in core temperature graphs represents 12‐h lights‐off, active period. *Indicates values elevated above control.

Adapted (with permission) from Leon and Helwig 229
Figure 31. Figure 31.

Interpretation of Venn diagram for gene expression experiments.
Figure 32. Figure 32.

Gene expression responses to physical exercise, heat injury, and heat shock.


Figure 1.

Active (vastus medialis) and inactive (triceps brachii) muscle temperatures relative to core and mean skin temperature changes during exercise.

Reprinted (with permission) from Jay et al. 186


Figure 2.

Core (rectal and esophageal) temperature during rest and aerobic exercise in the heat.

Reprinted (with permission) from Sawka and Wenger 358


Figure 3.

Possible core temperatures steady‐state during aerobic exercise at metabolic rates of 200, 350, 500, and 1000 W at different environmental conditions.

Reprinted (with permission) from Sawka et al. 360


Figure 4.

Schematic diagram of the thermoregulatory control system. Tsk represents skin temperature and Tc represents core temperature.

Reprinted (with permission) from Sawka et al. 360


Figure 5.

Schematic diagram of thermoregulatory effector (e.g., sweating rate and skin blood flow) responses (forcing function analysis with linear plots) to: (A) increased load error (LE), (B) parallel shift in threshold temperature suggesting change in “set point,” and (C) slope or sensitivity changes suggesting peripheral modifications. LE, load error; D, decrease; and I, increase.

Reprinted (with permission) from Gisolfi and Wenger 138


Figure 6.

Differences between the elevation of core temperature in fever and during exercise.

Reprinted (with permission) from Sawka and Wenger 358; redrawn (with permission) from Stitt 394 and Gisolfi and Wenger 138


Figure 7.

Schematic description of the thermoregulatory control of skin blood flow as modified by moderately intense exercise.

Reprinted (with permission) from Gonzalez‐Alonso et al. 147


Figure 8.

Cardiovascular responses during sustained moderate intensity (70% ) exercise in temperate and hot conditions. BF, blood flow; PV, plasma volume; SV, stroke volume; CO, cardiac output; Tsk, skin temperature; Tes, esophageal temperature; and Ta, ambient temperature. Drawn 138 (with permission) from data presented by Nadel et al. 279.



Figure 9.

The impact of high skin temperature on elevating heart rate during light‐intensity exercise.

Reprinted (with permission) from Cheuvront et al. 77


Figure 10.

The impact of graded exercise intensity on cardiovascular responses during hot (triangle) and temperate (circle) conditions.

Reprinted (with permission) from Rowell 338


Figure 11.

Nomogram examining the potential performance decrement (y‐axis) based on projected marathon finishing time (x‐axis) with increasing Wet Bulb Globe Temperature.

Reprinted (with permission) from Ely et al. 111


Figure 12.

Maximum aerobic power values for the pre‐ and postacclimation tests in both environments.

Reprinted (with permission) from Sawka et al. 361


Figure 13.

The percent decrement in time trial performance from euhydration at each skin temperature.

Reprinted (with permission) from Kenefick et al. 198


Figure 14.

A comparison of the benefits from an aerobic training program with a heat acclimation program on reducing physiological strain and improving performance during exercise‐heat stress.

Reprinted (with permission) from Sawka and Young 360. Original data adapted (with permission) from Cohen and Gisolfi 82


Figure 15.

Cardiorespiratory and performance changes as a percent change from the preacclimation trials in both environmental conditions.

Reprinted (with permission) from Lorenzo et al. 240. *P < .05 vs. the preacclimation trials in both environments


Figure 16.

(A) Comparison of baseline heat shock protein (HSP) values between day 1 and day 10 of heat acclimation (HA). (B) Quantification of Western blot analysis in densitometry units representing ratio of HSP:β‐tubulin. Values are means and standard deviation with correlation between post‐HA (day 10 vs. day 1) increase in HSP72 and HSP90 expression.

Reprinted (with permission) from McClung et al. 253


Figure 17.

Predictions of daily water requirements as function of daily energy expenditure and air temperature. Figure adapted (with permission) from Institute of Medicine 181.



Figure 18.

Predictions of daily sodium requirements as function of daily energy expenditure and air temperature. Figure adapted (with permission) from Institute of Medicine 181.



Figure 19.

Predicted body mass loss (due to water deficit; left panel) for two 70‐kg people of different body composition, running at 8.5 km·h−1 in temperate weather (18°C), and drinking water at three rates [400 ml·h−1 (solid line), 600 ml·h−1 (broken line), 800 ml·h−1 (broken dotted line)]. The yellow‐shaded areas indicate when water loss would be sufficient to modestly degrade performance, and when water loss would substantially degrade performance (red). Also predicted are plasma sodium concentrations for three rates sweat sodium loss. Two lines sharing the same line style are the predicted outcomes for people of two different body compositions; with total body water accounting for 50% and 63% (leaner) of body mass. The hatched shaded areas denote the presence of hyponatremia (plasma sodium concentration <130 mEq·liter−1) into the range where symptoms develop.



Figure 20.

Distribution of relative risk among male Marine Corps recruits and distribution of exertional heat stroke at Parris Island, SC, for years 1988 to 1992. High risk = body mass index (BMI) ≥22 kg·m−2, 1.5 mi run time ≥12 min; medium risk = BMI ≥26 kg·m−2, 1.5 mi run time <12 min or BMI <22 kg·m−2, 1.5 mi run time ≥12 min; low risk = BMI <26 kg·m−2, 1.5 mi run time <12 min. Adapted (with permission) from Gardner et al. 131.



Figure 21.

Core temperature of a male Marine Corp recruit during normal physical training and when incurring exertional heat stroke, conducted on two different days. Note the rapid development of hyperthermia on the day of heat stroke despite performing the same activity as the day that heat stroke was not observed. Wenger et al. (unpublished data).



Figure 22.

Summary of exertional heat stroke pathophysiological responses that culminate in multiorgan system failure. During exercise heat stress, there is an increase in cutaneous blood flow and decrease in splanchnic blood flow. Gut epithelial membrane ischemia induces oxidative and nitrosative stress that increases tight junction permeability and allows endotoxin to leak into the systemic and portal circulation. Toll‐like receptors (e.g., TLR4) detect pattern‐associated molecular patterns (PAMPs) on the cell membrane of endotoxin and stimulate pro‐ and anti‐inflammatory cytokine production. Heat is toxic to several organs and stimulates the secretion of heat shock proteins (HSPs) that interact with cytokines and other proteins to mediate the systemic inflammatory response syndrome of the host. A shift of the cytokine milieu from anti‐inflammatory (Th2) to a pro‐inflammatory (Th1) balance (a process known as anergy) is thought to mediate many of the adverse consequences of the heat stroke syndrome that lead to multiorgan system failure and death.



Figure 23.

Representative light micrographs of histological damage (hematoxylin and eosin stain) to inverted rat small‐intestinal sac tissue exposed to 41.5 to 42°C over a 60‐min time course. Villi appear normal at 15 min compared with the initial sloughing of epithelia from the villous tips at 30 min of exposure. At 45 min, there is significant lifting of villi epithelial linings at the top and sides, which is completed denuded by 60 min of exposure. Bars represent 100 μM. N = 2 to 4 rats per time point.

Reprinted (with permission) from Lambert et al. 218


Figure 24.

Computer tomography (CT) scans of a 45‐year‐old man that collapsed from exertional heat stroke on a hot summer day. He was unconscious and hyperthermic (42°C) with convulsion at the time of hospital admission. The patient remained unconscious for 5 days. (A) Normal CT scan of the cerebellum 2 weeks following collapse (B) and (C). Progression of cerebellar atrophy from 10 weeks (B) to 11 months (C). Note that hypothalamic damage was not reported in this patient.

Reprinted (with permission) from Albukrek et al. 6


Figure 25.

Time course of core temperature (A; °C; radiotelemetry), metabolic rate (B; oxygen consumption, ), and respiratory exchange ratio (C; RER) of control and mild heat stroke mice during heat stroke and recovery in an indirect calorimeter. Time 0 represents the start of recovery following heat stroke collapse. Note that mice developed hypothermia immediately following collapse that was preceded by ∼35% reduction in . Despite reliance on fatty acid oxidation (RER∼0.7) during hypothermia, mice developed fever (∼1°C), which was associated with ∼20% increase in from 20 to 32 h of recovery. Note that hypothermia and fever were observed in heat‐stroked mice in the absence of histological damage (hematoxylin and eosin) to the preoptic area of the hypothalamus. Data are 1‐h averages. Black horizontal bars indicate lights‐off periods. *represents significant difference between heat stroke and control animals at P < 0.05.

Reprinted (with permission) from Leon et al. 228


Figure 26.

Mechanisms of disseminated intravascular coagulation (DIC). Heat injury to the vascular endothelium initiates the coagulation and fibrinolysis pathways. Excess fibrin deposition may lead to vascular thrombosis in the arterioles and capillaries and lead to occlusion of the blood supply to the organ bed. As coagulation proceeds, platelets and coagulation proteins are consumed at a faster rate than they are produced resulting in blood loss from multiple tissue sites (e.g., venipuncture wounds and gums). The combined effects of vessel occlusion and excess blood loss result in coagulopathies leading to multiorgan dysfunction.

Reprinted (with permission) from Leon and Helwig 229


Figure 27.

IL‐6 receptor signaling pathways. Classic signaling involves IL‐6 binding to the membrane‐bound IL‐6 receptor (IL‐6R), which stimulates an interaction between the IL‐6:IL‐6R complex and the membrane‐bound gp130 to initiate intracellular signaling. Transignaling occurs when the extracellular domain of the membrane‐bound IL‐6R is proteolytically cleaved to generate the soluble IL‐6R (sIL‐6R) that binds IL‐6. The IL‐6:sIL‐6R complex can stimulate cells that only express gp130 (i.e., do not normally possess the transmembrane IL‐6R) to transmit an intracellular signal. Cells that express gp130 only would not be able to respond to IL‐6 in the absence of the sIL‐6R.

Reprinted (with permission) from Leon and Kenefick 230


Figure 28.

Representative photomicrographs of histological damage (hematoxylin and eosin; 200×) to the kidney of a normothermic (A) and passively heat‐stroked mouse (core temperature = 42.7°C). (B) Arrows indicate identified tissue lesions which included renal tubular necrosis in the straight tubules of the kidney lower cortex. This was observed as shrunken, acidophilic, and fragmented epithelial cells with pyknotic nuclei. Renal damage was first detected at the time of heat stroke collapse with progressively greater damage from hypothermia to 24 h of recovery (time of fever).

Reprinted (with permission) from Leon et al. 226


Figure 29.

Fatty liver change observed in a heat‐stroked mice (right) ∼72 h following heat stroke collapse (core temperature = 42.7°C). Liver from a nonheated control (left) and heat stroke nonsurvivor (right) are shown.

Reprinted (with permission) from Leon 225


Figure 30.

Representative data showing that common clinical measures do not always accurately reflect the presence of peripheral organ damage. Core temperature (radiotelemetry; ±0.1°C) of male Fischer 344 rats was recorded at 1‐min intervals during 10 days of heat stroke recovery. On day 10, circulating levels of blood urea nitrogen (BUN), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were compared with gross morphology and histological damage (hematoxylin and eosin) to the kidney and liver. Representative core temperature tracings (top row), kidney pathology and BUN levels (middle row), and liver pathology, AST and ALT levels (bottom row) from one control (left panel) and two heat stroke rats (middle and right panel; core temperature = 42.0°C) are shown. Left panel: Nonheated control rat displayed a normal circadian core temperature profile through 10 days with low daytime (∼37°C) and high nighttime (∼38°C) values. The kidney and liver showed normal gross and histological appearance, and circulating levels of BUN, AST, and ALT were within the normal range. Middle panel: Following heat stroke collapse, profound hypothermia (∼34‐35°C) was observed through 5 days of recovery and then the animal re‐warmed to ∼37°C by day 10 of recovery, but failed to re‐establish a normal circadian rhythm. Gross appearance of the kidney and liver indicated damage, which was confirmed by histological analysis. The kidney showed bilateral renal tubular degeneration with protenuria and multifocal necrosis of hepatocytes was evident in the liver (indicated by black arrows in representative photomicrographs). High circulating BUN, AST, and ALT levels accurately reflected the extensive histological damage to these organs. Right panel: Following heat stroke collapse, hyperthermia (∼39°C) was observed through day 3 and then the animal re‐established a normal circadian core temperature profile through 10 days of recovery. Gross appearance of the kidney and liver suggested residual damage in these organs, which was confirmed histologically as bilateral mineralization and protenuria in the kidney and extramedullary hematopoiesis with mineralization of hepatocytes (indicated by black arrows in representative photomicrographs). Circulating levels of BUN, AST, and ALT levels were virtually identical to controls and did not accurately reflect the presence of organ damage in this animal. These data demonstrate that traditional clinical biomarkers of organ function lack specificity and sensitivity to detect damage in all animals following heat stroke collapse. Gray shading in core temperature graphs represents 12‐h lights‐off, active period. *Indicates values elevated above control.

Adapted (with permission) from Leon and Helwig 229


Figure 31.

Interpretation of Venn diagram for gene expression experiments.



Figure 32.

Gene expression responses to physical exercise, heat injury, and heat shock.

References
 1. Abello PA, Buchman TG. Heat shock‐induced cell death in murine microvascular endothelial cells depends on priming with tumor necrosis factor‐alpha or interferon‐gamma. Shock 2: 320‐323, 1994.
 2. Aderka D, Engelmann H, Maor Y, Brakebusch C, Wallach D. Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors. J Exp Med 175: 323‐329, 1992.
 3. Adolph EF, Dill DB. Observations on water metabolism in the desert. Am J Physiol 123: 369‐378, 1938.
 4. Adolph EF. Physiology of Man in the Desert. New York: Interscience Publishers, 1947a.
 5. Adolph EF. Tolerance to heat and dehydration in several species of mammals. Am J Physiol 151: 564‐575, 1947b.
 6. Albukrek D, Bakon M, Moran DS, Faibel M, Epstein Y. Heat‐stroke‐induced cerebellar atrophy: Clinical course, CT and MRI findings. Neuroradiology 39: 195‐197, 1997.
 7. Allan JR, Wilson CG. Influence of acclimatization on sweat sodium concentration. J Appl Physiol 30: 708‐712, 1971.
 8. Almond CS, Shin AY, Fortescue EB, Mannix RC, Wypij D, Binstadt BA, Duncan CN, Olson DP, Salerno AE, Newburger JW, Greenes DS. Hyponatremia among runners in the Boston Marathon. N Engl J Med 352: 1550‐1556, 2005.
 9. Alzeer AH, el‐Hazmi MA, Warsy AS, Ansari ZA, Yrkendi MS. Serum enzymes in heat stroke: Prognostic implication. Clin Chem 43: 1182‐1187, 1997.
 10. Armstrong CG, Kenney WL. Effects of age and acclimation on responses to passive heat exposure. J Appl Physiol 75: 2162‐2167, 1993.
 11. Armstrong LE, De Luca JP, Hubbard RW. Time course of recovery and heat acclimation ability of prior exertional heatstroke patients. Med Sci Sports Exerc 22: 36‐48, 1990.
 12. Armstrong LE, Pandolf KB. Physical training, cardioresiratory physical fitness and exercise‐heat tolerance. In: Pandolf KB, Sawka MN, Gonzalez RR, editors. Human Performance Physiology and Environmental Medicine at Terrestrial Extremes. Indianapolis, IN: Benchmark, 1988, chapt. 5, p. 199‐226.
 13. Arngrimsson SA, Stewart DJ, Borrani F, Skinner KA, Cureton KJ. Relation of heart rate to percent V·o2max peak during submaximal exercise in the heat. J Appl Physiol 94: 1162‐1168, 2003.
 14. Asakura H, Suga Y, Yoshida T, Ontachi Y, Mizutani T, Kato M, Ito T, Morishita E, Yamazaki M, Miyamoto K, Nakao S. Pathophysiology of disseminated intravascular coagulation (DIC) progresses at a different rate in tissue factor‐induced and lipopolysaccharide‐induced DIC models in rats. Blood Coagul Fibrinolysis 14: 221‐228, 2003.
 15. Astrand I. Aerobic work capacity in men and women with special reference to age. Acta Physiol Scand Suppl 49: 1‐92, 1960.
 16. Avellini BA, Shapiro Y, Fortney SM, Wenger CB, Pandolf KB. Effects on heat tolerance of physical training in water and on land. J Appl Physiol 53: 1291‐1298, 1982.
 17. Ayus JC, Achinger SG, Arieff A. Brain cell iume regulation in hyponatremia: Role of sex, age, vasopressin, and hypoxia. Am J Physiol 295: F619‐F624, 2008.
 18. Backer HD, Shopes E, Collins SL, Barkan H. Exertional heat illness and hyponatremia in hikers. Am J Emerg Med 17: 532‐539, 1999.
 19. Bagley WH, Yang H, Shah KH. Rhabdomyolysis. Intern Emerg Med 2: 210‐218, 2007.
 20. Baker LB, Dougherty KA, Chow M, Kenney WL. Progressive dehydration causes a progressive decline in basketball skill performance. Med Sci Sports Exerc 39: 1114‐1123, 2007.
 21. Barbui T, Falanga A. Disseminated intravascular coagulation in acute leukemia. Semin Thromb Hemost 27: 593‐604, 2001.
 22. Bassett DR Jr, Howley ET. Limiting factors for maximum oxygen uptake and determinants of endurance performance. Med Sci Sports Exerc 32: 70‐84, 2000.
 23. Beller GA, Maher JT, Hartley LH, Bass DE, Wacker WE. Changes in serum and sweat magnesium levels during work in the heat. Aviat Space Environ Med 46: 709‐712, 1975.
 24. Below PR, Mora‐Rodriguez R, Gonzalez‐Alonso J, Coyle EF. Fluid and carbohydrate ingestion independently improve performance during 1 h of intense exercise. Med Sci Sports Exerc 27: 200‐210, 1995.
 25. Bergeron MF. Heat cramps: Fluid and electrolyte challenges during tennis in the heat. J Sci Med Sport 6: 19‐27, 2003.
 26. Bergeron MF, Maresh CM, Armstrong LE, Signorile JF, Castellani JW, Kenefick RW, LaGasse KE, Riebe DA. Fluid‐electrolyte balance associated with tennis match play in a hot environment. Int J Sport Nutr 5: 180‐193, 1995.
 27. Bianchi L. Liver biopsy in elevated liver functions tests? An old question revisited. J Hepatol 35: 290‐294, 2001.
 28. Bianchi L, Ohnacker H, Beck K, Zimmerli‐Ning M. Liver damage in heatstroke and its regression. A biopsy study. Hum Pathol 3: 237‐248, 1972.
 29. Biary N, Madkour MM, Sharif H. Post‐heatstroke parkinsonism and cerebellar dysfunction. Clin Neurol Neurosurg 97: 55‐57, 1995.
 30. Bigard AX, Sanchez H, Claveyrolas G, Martin S, Thimonier B, Arnaud MJ. Effects of dehydration and rehydration on EMG changes during fatiguing contractions. Med Sci Sports Exerc 33: 1694‐1700, 2001.
 31. Blatteis CM. The onset of fever: New insights into its mechanism. Prog Brain Res 162: 3‐14, 2007.
 32. Bouchama A, al‐Hussein K, Adra C, Rezeig M, al‐Shail E, al‐Sedairy S. Distribution of peripheral blood leukocytes in acute heatstroke. J Appl Physiol 73: 405‐409, 1992.
 33. Bouchama A, al‐Sedairy S, Siddiqui S, Shail E, Rezeig M. Elevated pyrogenic cytokines in heatstroke. Chest 104: 1498‐1502, 1993.
 34. Bouchama A, Bridey F, Hammami MM, Lacombe C, al‐Shail E, al‐Ohali Y, Combe F, al‐Sedairy S, de‐Prost D. Activation of coagulation and fibrinolysis in heatstroke. Thromb Haemost 76: 909‐915, 1996.
 35. Bouchama A, Hammami MM, al‐Shail E, DeVol E. Differential effects of in vitro and in vivo hyperthermia on the production of interleukin‐10. Intensive Care Med 26: 1646‐1651, 2000.
 36. Bouchama A, Knochel JP. Heat stroke. N Engl J Med 346: 1978‐1988, 2002.
 37. Bouchama A, Parhar RS, el‐Yazigi A, Sheth K, al‐Sedairy S. Endotoxemia and release of tumor necrosis factor and interleukin 1 alpha in acute heatstroke. J Appl Physiol 70: 2640‐2644, 1991.
 38. Bouchama A, Roberts G, Al Mohanna F, El‐Sayed R, Lach B, Chollet‐Martin S, Ollivier V, Al Baradei R, Loualich A, Nakeeb S, Eldali A, de Prost D. Inflammatory, hemostatic, and clinical changes in a baboon experimental model for heatstroke. J Appl Physiol 98: 697‐705, 2005.
 39. Boulant JA. Hypothalamic neurons regulating body temperature. In:Blatteis CM, Fregley MJ, editors. Handbook of Physiology. Environmental Physiology. Bethesda, MD: American Physiological Society, 1996, sect. 4, vol. I, chapt. 6, p. 105‐126.
 40. Bowers WD Jr, Hubbard RW, Leav I, Daum R, Conlon M, Hamlet MP, Mager M, Brandt P. Alterations of rat liver subsequent to heat overload. Arch Pathol Lab Med 102: 154‐157, 1978.
 41. Brengelmann GL, Johnson JM, Hermansen L, Rowell LB. Altered control of skin blood flow during exercise at high internal temperatures. J Appl Physiol 43: 790‐794, 1977.
 42. Brengelmann GL, Savage MV, Avery DH. Reproducibility of core temperature threshold for sweating onset in humans. J Appl Physiol 77: 1671‐1677, 1994.
 43. Broad EM, Burke LM, Cox GR, Heeley P, Riley M. Body weight changes and voluntary fluid intakes during training and competition sessions in team sports. Int J Sport Nutr 6: 307‐320, 1996.
 44. Brothers RM, Bhella PS, Shibata S, Wingo JE, Levine BD, Crandall CG. Cardiac systolic and diastolic function during whole body heat stress. Am J Physiol 296: H1150‐H1156, 2009.
 45. Brothers RM, Wingo JE, Hubing KA, Del CJ, Crandall CG. Effect of whole body heat stress on peripheral vasoconstriction during leg dependency. J Appl Physiol 107: 1704‐1709, 2009.
 46. Brothers RM, Zhang R, Wingo JE, Hubing KA, Crandall CG. Effects of heat stress on dynamic cerebral autoregulation during large fluctuations in arterial blood pressure. J Appl Physiol 107: 1722‐1729, 2009.
 47. Brouns F. Heat–sweat–dehydration–rehydration: A praxis oriented approach. J Sports Sci 9 Spec No: 143‐152, 1991.
 48. Brown D, Winter EM. Fluid loss during international standard match‐play in squash. In: Lees A, Maynard I, Hughes M, Reilly T, editors. Science and Racquet Sports II. London: E & FN Spon, 1998, 8, p. 56‐59.
 49. Buchanan JB, Peloso E, Satinoff E. Thermoregulatory and metabolic changes during fever in young and old rats. Am J Physiol 285: R1165‐R1169, 2003.
 50. Buchanan JB, Peloso E, Satinoff E. A warmer ambient temperature increases the passage of interleukin‐1beta into the brains of old rats. Am J Physiol 295: R361‐R368, 2008.
 51. Buchanan TA, Cane P, Eng CC, Sipos GF, Lee C. Hypothermia is critical for survival during prolonged insulin‐induced hypoglycemia in rats. Metabolism 40: 330‐334, 1991.
 52. Buono MJ, Heaney JH, Canine KM. Acclimation to humid heat lowers resting core temperature. Am J Physiol 274: R1295‐R1299, 1998.
 53. Buskirk ER, Iampietro PF, Bass DE. Work performance after dehydration: Effects of physical conditioning and heat acclimatization. J Appl Physiol 12: 189‐194, 1958.
 54. Butkow N, Mitchell D, Laburn H, Kenedi E. Heat stroke and endotoxemia in rabbits. In: Hales JR, editor. Thermal Physiology. New York: Raven Press, 1984, p. 511‐514.
 55. Bynum G, Brown J, Dubose D, Marsili M, Leav I, Pistole TG, Hamlet M, LeMaire M, Caleb B. Increased survival in experimental dog heatstroke after reduction of gut flora. Aviat Space Environ Med 50: 816‐819, 1979.
 56. Bynum GD, Pandolf KB, Schuette WH, Goldman RF, Lees DE, Whang‐Peng J, Atkinson ER, Bull JM. Induced hyperthermia in sedated humans and the concept of critical thermal maximum. Am J Physiol 235: R228‐R236, 1978.
 57. Byrne C, Lee JK, Chew SA, Lim CL, Tan EY. Continuous thermoregulatory responses to mass‐participation distance running in heat. Med Sci Sports Exerc 38: 803‐810, 2006.
 58. Cabanac M. Sensory pleasure optimizes muscular work. Clin Invest Med 29: 110‐116, 2006.
 59. Cadarette BS, Sawka MN, Toner MM, Pandolf KB. Aerobic fitness and the hypohydration response to exercise‐heat stress. Aviat Space Environ Med 55: 507‐512, 1984.
 60. Camus G, Poortmans J, Nys M, Deby‐Dupont G, Duchateau J, Deby C, Lamy M. Mild endotoxaemia and the inflammatory response induced by a marathon race. Clin Sci (Lond) 92: 415‐422, 1997.
 61. Carter R III, Cheuvront SN, Sawka MN. A case report of idiosyncratic hyperthermia and review of U.S. Army heat stroke hospitalizations. J Sport Rehabil 16: 238‐243, 2007.
 62. Carter R III, Cheuvront SN, Vernieuw CR, Sawka MN. Hypohydration and prior heat stress exacerbates decreases in cerebral blood flow velocity during standing. J Appl Physiol 101: 1744‐1750, 2006.
 63. Carter R III, Cheuvront SN, Williams JO, Kolka MA, Stephenson LA, Sawka MN, Amoroso PJ. Epidemiology of hospitalizations and deaths from heat illness in soldiers. Med Sci Sports Exerc 37: 1338‐1344, 2005.
 64. Casa DJ, Becker SM, Ganio MS, Brown CM, Yeargin SW, Roti MW, Siegler J, Blowers JA, Glaviano NR, Huggins RA, Armstrong LE, Maresh CM. Validity of devices that assess body temperature during outdoor exercise in the heat. J Athl Train 42: 333‐342, 2007.
 65. Chao TC, Sinniah R, Pakiam JE. Acute heat stroke deaths. Pathology 13: 145‐156, 1981.
 66. Charkoudian N. Mechanisms and modifiers of reflex induced cutaneous vasodilation and vasoconstriction in humans. J Appl Physiol 109: 1221‐1228, 2010.
 67. Charkoudian N, Halliwill JR, Morgan BJ, Eisenach JH, Joyner MJ. Influences of hydration on post‐exercise cardiovascular control in humans. J Physiol 552: 635‐644, 2003.
 68. Chensue SW, Shmyr‐Forsch C, Otterness IG, Kunkel SL. The beta form is the dominant interleukin 1 released by murine peritoneal macrophages. Biochem Biophys Res Commun 160: 404‐408, 1989.
 69. Cheung SS, Sleivert GG. Multiple triggers for hyperthermic fatigue and exhaustion. Exerc Sport Sci Rev 32: 100‐106, 2004.
 70. Cheuvront SN, Bearden SE, Kenefick RW, Ely BR, Degroot DW, Sawka MN, Montain SJ. A simple and valid method to determine thermoregulatory sweating threshold and sensitivity. J Appl Physiol 107: 69‐75, 2009.
 71. Cheuvront SN, Carter R III, Castellani JW, Sawka MN. Hypohydration impairs endurance exercise performance in temperate but not cold air. J Appl Physiol 99: 1972‐1976, 2005.
 72. Cheuvront SN, Carter R III, Haymes EM, Sawka MN. No effect of moderate hypohydration or hyperthermia on anaerobic exercise performance. Med Sci Sports Exerc 38: 1093‐1097, 2006.
 73. Cheuvront SN, Carter R III, Montain SJ, Sawka MN. Daily body mass variability and stability in active men undergoing exercise‐heat stress. Int J Sport Nutr Exerc Metab 14: 532‐540, 2004.
 74. Cheuvront SN, Ely BR, Kenefick RW, Sawka MN. Biological variation and diagnostic accuracy of dehydration assessment markers. Am J Clin Nutr 92: 565‐573, 2010.
 75. Cheuvront SN, Goodman DA, Kenefick RW, Montain SJ, Sawka MN. Impact of a protective vest and spacer garment on exercise‐heat strain. Eur J Appl Physiol 102: 577‐583, 2008.
 76. Cheuvront SN, Kenefick RW, Montain SJ, Sawka MN. Mechanisms of aerobic performance impairment with heat stress and dehydration. J Appl Physiol 109: 1989‐1995, 2010.
 77. Cheuvront SN, Kolka MA, Cadarette BS, Montain SJ, Sawka MN. Efficacy of intermittent, regional microclimate cooling. J Appl Physiol 94: 1841‐1848, 2003.
 78. Cheuvront SN, Montain SJ, Goodman DA, Blanchard L, Sawka MN. Evaluation of the limits to accurate sweat loss prediction during prolonged exercise. Eur J Appl Physiol 101: 215‐224, 2007.
 79. Cheuvront SN, Sawka MN. Hydration assessment of athletes. Sports Sci Exch 18: 1‐6, 2005.
 80. Chinevere TD, Kenefick RW, Cheuvront SN, Lukaski HC, Sawka MN. Effect of heat acclimation on sweat minerals. Med Sci Sports Exerc 40: 886‐891, 2008.
 81. Chorley J, Cianca J, Divine J. Risk factors for exercise‐associated hyponatremia in non‐elite marathon runners. Clin J Sport Med 17: 471‐477, 2007.
 82. Cohen JS, Gisolfi CV. Effects of interval training on work‐heat tolerance of young women. Med Sci Sports Exerc 14: 46‐52, 1982.
 83. Cohen O, Kanana H, Zoizner R, Gross C, Meiri U, Stern MD, Gerstenblith G, Horowitz M. Altered Ca2 +handling and myofilament desensitization underlie cardiomyocyte performance in normothermic and hyperthermic heat‐acclimated rat hearts. J Appl Physiol 103: 266‐275, 2007.
 84. Connolly PH, Caiozzo VJ, Zaldivar F, Nemet D, Larson J, Hung SP, Heck JD, Hatfield GW, Cooper DM. Effects of exercise on gene expression in human peripheral blood mononuclear cells. J Appl Physiol 97: 1461‐1469, 2004.
 85. Consolazio CF, Johnson RE, Pecora LJ. The computation of metabolic balances. In: Physiological Measurements of Metabolic Functions in Man. New York: McGraw‐Hill, 1963, p. 313‐339.
 86. Consolazio CF, Matoush LO, Nelson RA, Hackler LR, Preston EE. Relationship between calcium in sweat, calcium balance, and calcium requirements. J Nutr 78: 78‐88, 1962.
 87. Costill DL. Sweating: Its composition and effects on body fluids. Ann N Y Acad Sci 301: 160‐174, 1977.
 88. Costill DL, Cote R, Miller E, Miller T, Wynder S. Water and electrolyte replacement during repeated days of work in the heat. Aviat Space Environ Med 46: 795‐800, 1975.
 89. Cox GR, Broad EM, Riley MD, Burke LM. Body mass changes and voluntary fluid intakes of elite level water polo players and swimmers. J Sci Med Sport 5: 183‐193, 2002.
 90. Craig EN, Cummings EG. Dehydration and muscular work. J Appl Physiol 21: 670‐674, 1966.
 91. Crandall CG. Carotid baroreflex responsiveness in heat‐stressed humans. Am J Physiol 279: H1955‐H1962, 2000.
 92. Crandall CG, Shibasaki M, Wilson TE. Insufficient cutaneous vasoconstriction leading up to and during syncopal symptoms in the heat stressed human. Am J Physiol 299: H1168‐H1173, 2010.
 93. Crandall CG, Zhang R, Levine BD. Effects of whole body heating on dynamic baroreflex regulation of heart rate in humans. Am J Physiol 279: H2486‐H2492, 2000.
 94. Davies CT, Brotherhood JR, Zeidifard E. Temperature regulation during severe exercise with some observations on effects of skin wetting. J Appl Physiol 41: 772‐776, 1976.
 95. Davis DP, Videen JS, Marino A, Vilke GM, Dunford JV, Van Camp SP, Maharam LG. Exercise‐associated hyponatremia in marathon runners: A two‐year experience. J Emerg Med 21: 47‐57, 2001.
 96. Devlin LH, Fraser SF, Barras NS, Hawley JA. Moderate levels of hypohydration impairs bowling accuracy but not bowling velocity in skilled cricket players. J Sci Med Sport 4: 179‐187, 2001.
 97. di Prampero PE. Factors limiting maximal performance in humans. Eur J Appl Physiol 90: 420‐429, 2003.
 98. Dietrich WD, Kuluz JW. New research in the field of stroke: Therapeutic hypothermia after cardiac arrest. Stroke 34: 1051‐1053, 2003.
 99. Dill DB, Hall FG, Edwards HT. Changes in composition of sweat during acclimatization to heat. Am J Physiol 123: 412‐419, 1938.
 100. Dokladny K, Wharton W, Lobb R, Ma TY, Moseley PL. Induction of physiological thermotolerance in MDCK monolayers: Contribution of heat shock protein 70. Cell Stress Chaperones 11: 268‐275, 2006.
 101. Dougherty KA, Baker LB, Chow M, Kenney WL. Two percent dehydration impairs and six percent carbohydrate drink improves boys basketball skills. Med Sci Sports Exerc 38: 1650‐1658, 2006.
 102. Drexler AM. Tumor necrosis factor: Its role in HIV/AIDS. STEP Perspect 7: 13‐15, 1995.
 103. Dubois M, Sato S, Lees DE, Bull JM, Smith R, White BG, Moore H, Macnamara TE. Electroencephalographic changes during whole body hyperthermia in humans. Electroencephalogr Clin Neurophysiol 50: 486‐495, 1980.
 104. DuBose DA, Wenger CB, Flinn SD, Judy TA, Dubovtsev AI, Morehouse DH. Distribution and mitogen response of peripheral blood lymphocytes after exertional heat injury. J Appl Physiol 95: 2381‐2389, 2003.
 105. Edelman IS, Leibman J, O'Meara MP, Birkenfeld LW. Interrelations between serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water. J Clin Invest 37: 1236‐1256, 1958.
 106. Eichna LW, Beam WB, Ashe WF, Nelson N. Performance in relation to environmental temperature. Bull John Hopkins Hosp 76: 25‐58, 1945.
 107. Eichna LW, Park CR, Nelson N, Horvath SM, Palmes ED. Thermal regulation during acclimatization in a hot, dry (desert type) environment. Am J Physiol 163: 585‐597, 1950.
 108. Ekblom B, Greenleaf CJ, Greenleaf JE, Hermansen L. Temperature regulation during exercise dehydration in man. Acta Physiol Scand 79: 475‐483, 1970.
 109. Ely BR, Cheuvront SN, Kenefick RW, Sawka MN. Aerobic performance is degraded, despite modest hyperthermia, in hot environments. Med Sci Sports Exerc 42: 135‐141, 2010.
 110. Ely BR, Ely MR, Cheuvront SN, Kenefick RW, Degroot DW, Montain SJ. Evidence against a 40 degrees C core temperature threshold for fatigue in humans. J Appl Physiol 107: 1519‐1525, 2009.
 111. Ely MR, Cheuvront SN, Roberts WO, Montain SJ. Impact of weather on marathon‐running performance. Med Sci Sports Exerc 39: 487‐493, 2007.
 112. Epstein Y, Moran DS, Shapiro Y, Sohar E, Shemer J. Exertional heat stroke: A case series. Med Sci Sports Exerc 31: 224‐228, 1999.
 113. Evetovich TK, Boyd JC, Drake SM, Eschbach LC, Magal M, Soukup JT, Webster MJ, Whitehead MT, Weir JP. Effect of moderate dehydration on torque, electromyography, and mechanomyography. Muscle Nerve 26: 225‐231, 2002.
 114. Febbraio MA. Does muscle function and metabolism affect exercise performance in the heat? Exerc Sport Sci Rev 28: 171‐176, 2000.
 115. Febbraio MA, Snow RJ, Hargreaves M, Stathis CG, Martin IK, Carey MF. Muscle metabolism during exercise and heat stress in trained men: Effect of acclimation. J Appl Physiol 76: 589‐597, 1994.
 116. Feig PU, McCurdy DK. The hypertonic state. N Engl J Med 297: 1444‐1454, 1977.
 117. Fortney SM, Nadel ER, Wenger CB, Bove JR. Effect of acute alterations of blood volume on circulatory performance in humans. J Appl Physiol 50: 292‐298, 1981a.
 118. Fortney SM, Nadel ER, Wenger CB, Bove JR. Effect of blood volume on sweating rate and body fluids in exercising humans. J Appl Physiol 51: 1594‐1600, 1981b.
 119. Fortney SM, Wenger CB, Bove JR, Nadel ER. Effect of hyperosmolality on control of blood flow and sweating. J Appl Physiol 57: 1688‐1695, 1984.
 120. Francesconi RP. Endocrinological and metabolic responses to acute and chronic heat exposure. In: Blatteis CM, Fregley MJ, editors. Handbook of Physiology. Environmental Physiology. Bethesda, MD: American Physiological Society, 1996, sect. 4, vol. I, chapt. 12, p. 245‐260.
 121. Fritzsche RG, Switzer TW, Hodgkinson BJ, Coyle EF. Stroke volume decline during prolonged exercise is influenced by the increase in heart rate. J Appl Physiol 86: 799‐805, 1999.
 122. Fruth JM, Gisolfi CV. Work‐heat tolerance in endurance‐trained rats. J Appl Physiol 54: 249‐253, 1983.
 123. Gabai VL, Sherman MY. Interplay between molecular chaperones and signaling pathways in survival of heat shock. J Appl Physiol 92: 1743‐1748, 2002.
 124. Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine (Baltimore) 61: 141‐152, 1982.
 125. Gader AM, al‐Mashhadani SA, al‐Harthy SS. Direct activation of platelets by heat is the possible trigger of the coagulopathy of heat stroke. Br J Haematol 74: 86‐92, 1990.
 126. Gagge AP, Gonzalez RR. Mechanisms of heat exchange: Biophysics and physiology. In: Blatteis CM, Fregley MJ, editors. Handbook of Physiology. Environmental Physiology. Bethesda, MD: American Physiological Society, 1996, sect. 4, vol. II, chapt. 4, p. 45‐84.
 127. Gagge AP, Stolwijk JA, Saltin B. Comfort and thermal sensations and associated physiological responses during exercise at various ambient temperatures. Environ Res 2: 209‐229, 1969.
 128. Galloway SD, Maughan RJ. Effects of ambient temperature on the capacity to perform prolonged cycle exercise in man. Med Sci Sports Exerc 29: 1240‐1249, 1997.
 129. Ganio MS, Brown CM, Casa DJ, Becker SM, Yeargin SW, McDermott BP, Boots LM, Boyd PW, Armstrong LE, Maresh CM. Validity and reliability of devices that assess body temperature during indoor exercise in the heat. J Athl Train 44: 124‐135, 2009.
 130. Gardner JW, Kark JA. Clinical diagnosis, management, and surveillance of exertional heat illness. In: Pandolf KB, Burr RE, editors. Medical Aspects of Harsh Environments (Vol.1). Washington, DC: Office of the Surgeon General, US Army Medical Department, 2001, p. 231‐279.
 131. Gardner JW, Kark JA, Karnei K, Sanborn JS, Gastaldo E, Burr P, Wenger CB. Risk factors predicting exertional heat illness in male Marine Corps recruits. Med Sci Sports Exerc 28: 939‐944, 1996.
 132. Garigan TP, Ristedt DE. Death from hyponatremia as a result of acute water intoxication in an Army basic trainee. Mil Med 164: 234‐238, 1999.
 133. Gathiram P, Gaffin SL, Brock‐Utne JG, Wells MT. Time course of endotoxemia and cardiovascular changes in heat‐stressed primates. Aviat Space Environ Med 58: 1071‐1074, 1987.
 134. Gathiram P, Wells MT, Brock‐Utne JG, Gaffin SL. Antilipopolysaccharide improves survival in primates subjected to heat stroke. Circ Shock 23: 157‐164, 1987.
 135. Gauchard GC, Gangloff P, Vouriot A, Mallie JP, Perrin PP. Effects of exercise‐induced fatigue with and without hydration on static postural control in adult human subjects. Int J Neurosci 112: 1191‐1206, 2002.
 136. Georgopoulos C, Welch WJ. Role of the major heat shock proteins as molecular chaperones. Annu Rev Cell Biol 9: 601‐634, 1993.
 137. Giercksky T, Boberg KM, Farstad IN, Halvorsen S, Schrumpf E. Severe liver failure in exertional heat stroke. Scand J Gastroenterol 34: 824‐827, 1999.
 138. Gisolfi CV, Wenger CB. Temperature regulation during exercise: Old concepts, new ideas. Exerc Sport Sci Rev 12: 339‐372, 1984.
 139. Goddard CJ, Warnes TW. Raised liver enzymes in asymptomatic patients: Investigation and outcome. Dig Dis 10: 218‐226, 1992.
 140. Godek SF, Bartolozzi AR, Godek JJ. Sweat rate and fluid turnover in American football players compared with runners in a hot and humid environment. Br J Sports Med 39: 205‐211, 2005.
 141. Gonzalez RR. Biophysics of heat exchange and clothing: Applications to sports physiology. Med Exerc Nutr Health 4: 290‐305, 1995.
 142. Gonzalez RR, Cheuvront SN, Montain SJ, Goodman DA, Blanchard LA, Berglund LG, Sawka MN. Expanded prediction equations of human sweat loss and water needs. J Appl Physiol 107: 379‐388, 2009.
 143. Gonzalez RR, Gagge AP. Magnitude estimates of thermal discomfort during transients of humidity and operative temperature and their relation to the new ASHRAE effective temperature. ASHRAE Trans 79: 88‐96, 1973.
 144. Gonzalez RR, Gagge AP. Warm discomfort and associated thermoregulatory changes during dry, and humid‐heat acclimatization. Isr J Med Sci 12: 804‐807, 1976.
 145. Gonzalez‐Alonso J, Calbet JA. Reductions in systemic and skeletal muscle blood flow and oxygen delivery limit maximal aerobic capacity in humans. Circulation 107: 824‐830, 2003.
 146. Gonzalez‐Alonso J, Calbet JA, Nielsen B. Muscle blood flow is reduced with dehydration during prolonged exercise in humans. J Physiol 513 (Pt 3): 895‐905, 1998.
 147. Gonzalez‐Alonso J, Crandall CG, Johnson JM. The cardiovascular challenge of exercising in the heat. J Physiol 586: 45‐53, 2008.
 148. Gonzalez‐Alonso J, Dalsgaard MK, Osada T, Volianitis S, Dawson EA, Yoshiga CC, Secher NH. Brain and central haemodynamics and oxygenation during maximal exercise in humans. J Physiol 557: 331‐342, 2004.
 149. Gonzalez‐Alonso J, Mora‐Rodriguez R, Below PR, Coyle EF. Dehydration reduces cardiac output and increases systemic and cutaneous vascular resistance during exercise. J Appl Physiol 79: 1487‐1496, 1995.
 150. Gonzalez‐Alonso J, Mora‐Rodriguez R, Coyle EF. Stroke volume during exercise: Interaction of environment and hydration. Am J Physiol 278: H321‐H330, 2000.
 151. Gonzalez‐Alonso J, Teller C, Andersen SL, Jensen FB, Hyldig T, Nielsen B. Influence of body temperature on the development of fatigue during prolonged exercise in the heat. J Appl Physiol 86: 1032‐1039, 1999.
 152. Goodman DA, Kenefick RW, Cadarette BS, Cheuvront SN. Influence of sensor ingestion timing on consistency of temperature measures. Med Sci Sports Exerc 41: 597‐602, 2009.
 153. Graber CD, Reinhold RB, Breman JG, Harley RA, Hennigar GR. Fatal heat stroke. Circulating endotoxin and gram‐negative sepsis as complications. JAMA 216: 1195‐1196, 1971.
 154. Greenleaf JE, Castle BL. External auditory canal temperature as an estimate of core temperature. J Appl Physiol 32: 194‐198, 1972.
 155. Greiwe JS, Staffey KS, Melrose DR, Narve MD, Knowlton RG. Effects of dehydration on isometric muscular strength and endurance. Med Sci Sports Exerc 30: 284‐288, 1998.
 156. Haber MM, West AB, Haber AD, Reuben A. Relationship of aminotransferases to liver histological status in chronic hepatitis C. Am J Gastroenterol 90: 1250‐1257, 1995.
 157. Hales JRS, Hubbard RW, Gaffin SL. Limitations of heat tolerance. In: Blatteis CM, Fregley MJ, editors. Handbook of Physiology. Environmental Physiology. Bethesda, MD: American Physiological Society, 1996, sect. 4, vol. II, chapt. 15, p. 285‐355.
 158. Hall DM, Buettner GR, Oberley LW, Xu L, Matthes RD, Gisolfi CV. Mechanisms of circulatory and intestinal barrier dysfunction during whole body hyperthermia. Am J Physiol 280: H509‐H521, 2001.
 159. Hammami MM, Bouchama A, al‐Sedairy S, Shail E, AlOhaly Y, Mohamed GE. Concentrations of soluble tumor necrosis factor and interleukin‐6 receptors in heatstroke and heatstress. Crit Care Med 25: 1314‐1319, 1997.
 160. Harden LM, du P I, Poole S, Laburn HP. Interleukin (IL)‐6 and IL‐1 beta act synergistically within the brain to induce sickness behavior and fever in rats. Brain Behav Immun 22: 838‐849, 2008.
 161. Hardy JD, Du Bois EF, Soderstrom GF. The technique of measuring radiation and convection: One figure. J Nutr 15: 461‐475, 1938.
 162. Hashim IA, Al‐Zeer A, Al‐Shohaib S, Al‐Ahwal M, Shenkin A. Cytokine changes in patients with heatstroke during pilgrimage to Makkah. Mediators Inflamm 6: 135‐139, 1997.
 163. Hassanein T, Perper JA, Tepperman L, Starzl TE, Van Thiel DH. Liver failure occurring as a component of exertional heatstroke. Gastroenterology 100: 1442‐1447, 1991.
 164. Hassanein T, Razack A, Gavaler JS, Van Thiel DH. Heatstroke: Its clinical and pathological presentation, with particular attention to the liver. Am J Gastroenterol 87: 1382‐1389, 1992.
 165. Haveman J, Geerdink AG, Rodermond HM. Cytokine production after whole body and localized hyperthermia. Int J Hyperthermia 12: 791‐800, 1996.
 166. Hensel H. Neural processes in thermoregulation. Physiol Rev 53: 948‐1017, 1973.
 167. Herbert JM, Savi P, Laplace MC, Lale A. IL‐4 inhibits LPS‐, IL‐1 beta‐ and TNF alpha‐induced expression of tissue factor in endothelial cells and monocytes. FEBS Lett 310: 31‐33, 1992.
 168. Hew TD, Chorley JN, Cianca JC, Divine JG. The incidence, risk factors, and clinical manifestations of hyponatremia in marathon runners. Clin J Sport Med 13: 41‐47, 2003.
 169. Holowatz LA, Kenney WL. Peripheral mechanisms of thermoregulatory control of skin blood flow in aged humans. J Appl Physiol 109: 1538‐1544, 2010.
 170. Holowatz LA, Thompson‐Torgerson CS, Kenney WL. Altered mechanisms of vasodilation in aged human skin. Exerc Sport Sci Rev 35: 119‐125, 2007.
 171. Horowitz M. Heat acclimation and cross‐tolerance against novel stressors: Genomic‐physiological linkage. Prog Brain Res 162: 373‐392, 2007.
 172. Horowitz M, Eli‐Berchoer L, Wapinski I, Friedman N, Kodesh E. Stress‐related genomic responses during the course of heat acclimation and its association with ischemic‐reperfusion cross‐tolerance. J Appl Physiol 97: 1496‐1507, 2004.
 173. Horowitz M, Kodesh E. Molecular signals that shape the integrative responses of the heat acclimated phenotype. Med Sci Sports Exerc 42: 2164‐2172, 2010.
 174. Hoshi A, Watanabe H, Chiba M, Inaba Y, Kobayashi M, Kimura N, Ito T. Seasonal variation of trace element loss to sweat during exercise in males. Environ Health Prev Med 7: 60‐63, 2002.
 175. Hoshi A, Watanabe H, Kobayashi M, Chiba M, Inaba Y, Kimura N, Ito T. Concentrations of trace elements in sweat during sauna bathing. Tohoku J Exp Med 195: 163‐169, 2001.
 176. Hubbard RW, Criss RE, Elliott LP, Kelly C, Matthew WT, Bowers WD, Leav I, Mager M. Diagnostic significance of selected serum enzymes in a rat heatstroke model. J Appl Physiol 46: 334‐339, 1979.
 177. Huisse MG, Pease S, Hurtado‐Nedelec M, Arnaud B, Malaquin C, Wolff M, Gougerot‐Pocidalo MA, Kermarrec N, Bezeaud A, Guillin MC, Paoletti X, Chollet‐Martin S. Leukocyte activation: The link between inflammation and coagulation during heatstroke. A study of patients during the 2003 heat wave in Paris. Crit Care Med 36: 2288‐2295, 2008.
 178. Hutchison JS, Ward RE, Lacroix J, Hebert PC, Barnes MA, Bohn DJ, Dirks PB, Doucette S, Fergusson D, Gottesman R, Joffe AR, Kirpalani HM, Meyer PG, Morris KP, Moher D, Singh RN, Skippen PW. Hypothermia therapy after traumatic brain injury in children. N Engl J Med 358: 2447‐2456, 2008.
 179. Hutchison VM, Murphy K. Behavioral thermoregulation in the salamander Necturus maculosus after heat stroke. Comp Biochem Physiol 82: 391‐394, 1985.
 180. Ibuka N, Fukumura K. Unpredictable deprivation of water increases the probability of torpor in the Syrian hamster. Physiol Behav 62: 551‐556, 1997.
 181. Institute of Medicine. Water. In: Dietary Reference Intakes for Water, Potassium, Sodium, Chlordie, and Sulfate. Washington, DC: National Academies Press, 2005, p. 73‐185.
 182. Jackson DN, Kenny GP. Upright LBPP application attenuates elevated postexercise resting thresholds for cutaneous vasodilation and sweating. J Appl Physiol 95: 121‐128, 2003.
 183. Jacobs I. The effects of thermal dehydration on performance of the Wingate Anaerobic Test. Int J Sports Med 1: 21‐4, 1980.
 184. Janata A, Holzer M. Hypothermia after cardiac arrest. Prog Cardiovasc Dis 52: 168‐179, 2009.
 185. Janeway CA, Medzhitov R. Innate immune recognition. Annu Rev Immunol 20: 197‐216, 2002.
 186. Jay O, Gariepy LM, Reardon FD, Webb P, Ducharme MB, Ramsay T, Kenny GP. A three‐compartment thermometry model for the improved estimation of changes in body heat content. Am J Physiol 292: R167‐R175, 2007.
 187. Jay O, Kenny GP. The determination of changes in body heat content during exercise using calorimetry and thermometry. J Human Environ Syst 10: 19‐29, 2007.
 188. Jay O, Reardon FD, Webb P, Ducharme MB, Ramsay T, Nettlefold L, Kenny GP. Estimating changes in mean body temperature for humans during exercise using core and skin temperatures is inaccurate even with a correction factor. J Appl Physiol 103: 443‐451, 2007.
 189. Jessen C. Interaction of body temperatures in control of thermoregulatory effector mechanisms. In: Blatteis CM, Fregley MJ, editors. Handbook of Physiology. Environmental Physiology. Bethesda, MD: American Physiological Society, 1996, sect. 4, vol. I, chapt. 7, p. 127‐138.
 190. Johnson JM. Exercise and the cutaneous circulation. Exerc Sport Sci Rev 20: 59‐97, 1992.
 191. Johnson JM, Kellogg DL. Local thermal control of the human cutaneous circulation. J Appl Physiol 109: 1229‐1238, 2010.
 192. Johnson JM, Proppe DW. Cardiovascular adjustments to heat stress. In: Blatteis CM, Fregley MJ, editors. Handbook of Physiology. Environmental Physiology. Bethesda, MD: American Physiological Society, 1996, sect. 4, vol. I, chapt. 11, p. 215‐243.
 193. Joyner MJ, Ruiz JR, Lucia A. The two‐hour marathon: Who and when? J Appl Physiol 110: 275‐277, 2011.
 194. Judelson DA, Maresh CM, Farrell MJ, Yamamoto LM, Armstrong LE, Kraemer WJ, Volek JS, Spiering BA, Casa DJ, Anderson JM. Effect of hydration state on strength, power, and resistance exercise performance. Med Sci Sports Exerc 39: 1817‐1824, 2007.
 195. Kark JA, Burr PQ, Wenger CB, Gastaldo E, Gardner JW. Exertional heat illness in Marine Corps recruit training. Aviat Space Environ Med 67: 354‐360, 1996.
 196. Kelker HC, Oppenheim JD, Stone‐Wolff D, Henriksen‐DeStefano D, Aggarwal BB, Stevenson HC, Vilcek J. Characterization of human tumor necrosis factor produced by peripheral blood monocytes and its separation from lymphotoxin. Int J Cancer 36: 69‐73, 1985.
 197. Kellogg DL Jr, Johnson JM, Kenney WL, Pergola PE, Kosiba WA. Mechanisms of control of skin blood flow during prolonged exercise in humans. Am J Physiol 265: H562‐H568, 1993.
 198. Kenefick RW, Cheuvront SN, Palombo LJ, Ely BR, Sawka MN. Skin temperature modifies the impact of hypohydration on aerobic performance. J Appl Physiol 109: 79‐86, 2010.
 199. Kenefick RW, Cheuvront SN, Sawka MN. Thermoregulatory function during the marathon. Sports Med 37: 312‐315, 2007.
 200. Kenefick RW, Mahood NV, Hazzard MP, Quinn TJ, Castellani JW. Hypohydration effects on thermoregulation during moderate exercise in the cold. Eur J Appl Physiol 92: 565‐570, 2004.
 201. Kenefick RW, Sawka MN. Heat exhaustion and dehydration as causes of marathon collapse. Sports Med 37: 378‐381, 2007.
 202. Kenney WL, Johnson JM. Control of skin blood flow during exercise. Med Sci Sports Exerc 24: 303‐312, 1992.
 203. Kenny GP, Reardon FD, Zaleski W, Reardon ML, Haman F, Ducharme MB. Muscle temperature transients before, during, and after exercise measured using an intramuscular multisensor probe. J Appl Physiol 94: 2350‐2357, 2003.
 204. Kew M, Bersohn I, Seftel H, Kent G. Liver damage in heatstroke. Am J Med 49: 192‐202, 1970.
 205. Klausen K, Dill DB, Phillips EE Jr, McGregor D. Metabolic reactions to work in the desert. J Appl Physiol 22: 292‐296, 1967.
 206. Kluger MJ, Ringler DH, Anver MR. Fever and survival. Science 188: 166‐168, 1975.
 207. Knupfer H, Preiss R. sIL‐6R: More than an agonist? Immunol Cell Biol 86: 87‐91, 2008.
 208. Kodesh E, Horowitz M. Soleus adaptation to combined exercise and heat acclimation: Physiogenomic aspects. Med Sci Sports Exerc 42: 943‐952, 2010.
 209. Kolka MA, Quigley MD, Blanchard LA, Toyota DA, Stephenson LA. Validation of a temperature telemetry system during moderate and strenuous exercise. J Therm Biol 18: 203‐210, 1993.
 210. Kolka MA, Stephenson LA, Rock PB, Gonzalez RR. Local sweating and cutaneous blood flow during exercise in hypobaric environments. J Appl Physiol 62: 2224‐2229, 1987.
 211. Kottke FJ, Phalen JS. Effect of hypoxia upon temperature regulation of mice, dogs, and man. Am J Physiol 153: 10‐15, 1948.
 212. Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Laboratory reference values. N Engl J Med 351: 1548‐1563, 2004.
 213. Kregel KC. Heat shock proteins: Modifying factors in physiological stress responses and acquired thermotolerance. J Appl Physiol 92: 2177‐2186, 2002.
 214. Kubica R, Nielsen B, Bonnesen A, Rasmussen IB, Stoklosa J, Wilk B. Relationship between plasma volume reduction and plasma electrolyte changes after prolonged bicycle exercise, passive heating and diuretic dehydration. Acta Physiol Pol 34: 569‐579, 1983.
 215. Ladell WSS. The effects of water and salt intake upon the performance of men working in hot and humid environments. J Physiol 127: 11‐46, 1955.
 216. Ladell WSS. Terrestrial animals in humid heat: Man. In: Dill DB, Adolph EF, Wilber CG, editors. Handbook of Physiology. Adaptation to the Environment. Bethesda, MD: American Physiological Society, 1964, sect. 4, chapt. 39, p. 625‐660.
 217. Lambert GP. Stress‐induced gastrointestinal barrier dysfunction and its inflammatory effects. J Anim Sci 87: E101‐E108, 2009.
 218. Lambert GP, Gisolfi CV, Berg DJ, Moseley PL, Oberley LW, Kregel KC. Selected contribution: Hyperthermia‐induced intestinal permeability and the role of oxidative and nitrosative stress. J Appl Physiol 92: 1750‐1761, 2002.
 219. Lambert GP, Lang J, Bull A, Pfeifer PC, Eckerson J, Moore G, Lanspa S, O'Brien J. Fluid restriction during running increases GI permeability. Int J Sports Med 29: 194‐198, 2008.
 220. Lee DH. Terrestrial animals in dry heat: Man in desert. In: Dill DB, Adolph EF, Wilber CG, editors. Handbook of Physiology. Adaptation to the Environment. Bethesda, MD: American Physiological Society, 1964, sect. 4, chapt. 35, p. 551‐582.
 221. Lee JK, Nio AQ, Lim CL, Teo EY, Byrne C. Thermoregulation, pacing and fluid balance during mass participation distance running in a warm and humid environment. Eur J Appl Physiol 109: 887‐898, 2010.
 222. Leon LR. Invited review: Cytokine regulation of fever: Studies using gene knockout mice. J Appl Physiol 92: 2648‐2655, 2002.
 223. Leon LR. Hypothermia in systemic inflammation: Role of cytokines. Front Biosci 9: 1877‐1888, 2004.
 224. Leon LR. The thermoregulatory consequences of heat stroke. Are cytokines involved? J Therm Biol 39: 67‐81, 2006.
 225. Leon LR. Heat stroke and cytokines. Prog Brain Res 162: 481‐524, 2007.
 226. Leon LR, Blaha MD, DuBose DA. Time course of cytokine, corticosterone, and tissue injury responses in mice during heat strain recovery. J Appl Physiol 100: 1400‐1409, 2006.
 227. Leon LR, DuBose DA, Mason CW. Heat stress induces a biphasic thermoregulatory response in mice. Am J Physiol 288: R197‐R204, 2005.
 228. Leon LR, Gordon CJ, Helwig BG, Rufolo DM, Blaha MD. Thermoregulatory, behavioral, and metabolic responses to heatstroke in a conscious mouse model. Am J Physiol 299: R241‐R248, 2010.
 229. Leon LR, Helwig BG. Heat stroke: Role of the systemic inflammatory response. J Appl Physiol 109: 1980‐1988, 2010.
 230. Leon LR, Kenefick RW. Pathology of heat illness. In: Auerback PS, editor. Wilderness Medicine. London: Elsevier Science, 2011. (In press)
 231. Lepers R, Bigard AX, Diard JP, Gouteyron JF, Guezennec CY. Posture control after prolonged exercise. Eur J Appl Physiol 76: 55‐61, 1997.
 232. Levi M, Ten CH. Disseminated intravascular coagulation. N Engl J Med 341: 586‐592, 1999.
 233. Levy E, Hasin Y, Navon G, Horowitz M. Chronic heat improves mechanical and metabolic response of trained rat heart on ischemia and reperfusion. Am J Physiol 272: H2085‐H2094, 1997.
 234. Libert JP, Candas V, Sagot JC, Meyer JP, Vogt JJ, Ogawa T. Contribution of skin thermal sensitivities of large body areas to sweating response. Jpn J Physiol 34: 75‐88, 1984.
 235. Liebermeister C. Vorlesungen Uber Specielle Pathologie Und Therapie. Leipzig, Germany: Verlag von FCW Vogel, 1887.
 236. Lin MT, Kao TY, Su CF, Hsu SS. Interleukin‐1 beta production during the onset of heat stroke in rabbits. Neurosci Lett 174: 17‐20, 1994.
 237. Lindquist S. The heat‐shock response. Annu Rev Biochem 55: 1151‐1191, 1986.
 238. Line RL, Rust GS. Acute exertional rhabdomyolysis. Am Fam Physician 52: 502‐506, 1995.
 239. Lord PF, Kapp DS, Hayes T, Weshler Z. Production of systemic hyperthermia in the rat. Eur J Cancer Clin Oncol 20: 1079‐1085, 1984.
 240. Lorenzo S, Halliwill JR, Sawka MN, Minson CT. Heat acclimation improves exercise performance. J Appl Physiol 109: 1140‐1147, 2010.
 241. Low DA, Vu A, Brown M, Davis SL, Keller DM, Levine BD, Crandall CG. Temporal thermometry fails to track body core temperature during heat stress. Med Sci Sports Exerc 39: 1029‐1035, 2007.
 242. Lu KC, Wang JY, Lin SH, Chu P, Lin YF. Role of circulating cytokines and chemokines in exertional heatstroke. Crit Care Med 32: 399‐403, 2004.
 243. MacDougall JD, Reddan WG, Layton CR, Dempsey JA. Effects of metabolic hyperthermia on performance during heavy prolonged exercise. J Appl Physiol 36: 538‐544, 1974.
 244. Maes M, Christophe A, Bosmans E, Lin A, Neels H. In humans, serum polyunsaturated fatty acid levels predict the response of proinflammatory cytokines to psychologic stress. Biol Psychiatry 47: 910‐920, 2000.
 245. Malamud N, Haymaker W, Custer RP. Heat stroke. Mil Surg 99: 397‐449, 1946.
 246. Maloyan A, Palmon A, Horowitz M. Heat acclimation increases the basal HSP72 level and alters its production dynamics during heat stress. Am J Physiol 276: R1506‐R1515, 1999.
 247. Mange K, Matsuura D, Cizman B, Soto H, Ziyadeh FN, Goldfarb S, Neilson EG. Language guiding therapy: The case of dehydration versus volume depletion. Ann Intern Med 127: 848‐853, 1997.
 248. Marion DW, Penrod LE, Kelsey SF, Obrist WD, Kochanek PM, Palmer AM, Wisniewski SR, DeKosky ST. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med 336: 540‐546, 1997.
 249. Maron MB, Wagner JA, Horvath SM. Thermoregulatory responses during competitive marathon running. J Appl Physiol 42: 909‐914, 1977.
 250. Massett MP, Lewis SJ, Bates JN, Kregel KC. Effect of heating on vascular reactivity in rat mesenteric arteries. J Appl Physiol 85: 701‐708, 1998.
 251. Maughan RJ, Shirreffs SM, Merson SJ, Horswill CA. Fluid and electrolyte balance in elite male football (soccer) players training in a cool environment. J Sports Sci 23: 73‐79, 2005.
 252. McCaffrey TV, McCook RD, Wurster RD. Effect of head skin temperature on tympanic and oral temperature in man. J Appl Physiol 39: 114‐118, 1975.
 253. McClung JP, Hasday JD, He JR, Montain SJ, Cheuvront SN, Sawka MN, Singh IS. Exercise‐heat acclimation in humans alters baseline levels and ex vivo heat inducibility of HSP72 and HSP90 in peripheral blood mononuclear cells. Am J Physiol 294: R185‐R191, 2008.
 254. McGregor SJ, Nicholas CW, Lakomy HK, Williams C. The influence of intermittent high‐intensity shuttle running and fluid ingestion on the performance of a soccer skill. J Sports Sci 17: 895‐903, 1999.
 255. McLaughlin CT, Kane AG, Auber AE. MR imaging of heat stroke: External capsule and thalamic T1 shortening and cerebellar injury. Am J Neuroradiol 24: 1372‐1375, 2003.
 256. Mendeloff AI, Smith DE. Extreme physical effort in summer heat followed by collapse, stupor, purpura, jaundice and azotemia. Am J Med 18: 659‐670, 1955.
 257. Meyer F, Bar‐Or O, MacDougall D, Heigenhauser GJ. Sweat electrolyte loss during exercise in the heat: Effects of gender and maturation. Med Sci Sports Exerc 24: 776‐781, 1992.
 258. Minard D. Body heat content. In: Hardy JD, Gagge AP, Stolwijk JA, editors. Physiological and Behavioral Temperature Regulation. Springfield, IL: Charles C. Thomas Publishers, 1970, p. 345‐357.
 259. Mitchell D, Wyndham CH. Comparison of weighting formulas for calculating mean skin temperature. J Appl Physiol 26: 616‐622, 1969.
 260. Mitchell JW, Nadel ER, Stolwijk JA. Respiratory weight losses during exercise. J Appl Physiol 32: 474‐476, 1972.
 261. Mizzen LA, Welch WJ. Characterization of the thermotolerant cell. I. Effects on protein synthesis activity and the regulation of heat‐shock protein 70 expression. J Cell Biol 106: 1105‐1116, 1988.
 262. Modlin RL, Brightbill HD, Godowski PJ. The toll of innate immunity on microbial pathogens. N Engl J Med 340: 1834‐1835, 1999.
 263. Moldoveanu AI, Shephard RJ, Shek PN. The cytokine response to physical activity and training. Sports Med 31: 115‐144, 2001.
 264. Montain SJ, Cheuvront SN, Lukaski HC. Sweat mineral‐element responses during 7 h of exercise‐heat stress. Int J Sport Nutr Exerc Metab 17: 574‐582, 2007.
 265. Montain SJ, Cheuvront SN, Sawka MN. Exercise associated hyponatraemia: Quantitative analysis to understand the aetiology. Br J Sports Med 40: 98‐105, 2006.
 266. Montain SJ, Coyle EF. Influence of graded dehydration on hyperthermia and cardiovascular drift during exercise. J Appl Physiol 73: 1340‐1350, 1992.
 267. Montain SJ, Coyle EF. Influence of the timing of fluid ingestion on temperature regulation during exercise. J Appl Physiol 75: 688‐695, 1993.
 268. Montain SJ, Laird JE, Latzka WA, Sawka MN. Aldosterone and vasopressin responses in the heat: Hydration level and exercise intensity effects. Med Sci Sports Exerc 29: 661‐668, 1997.
 269. Montain SJ, Latzka WA, Sawka MN. Control of thermoregulatory sweating is altered by hydration level and exercise intensity. J Appl Physiol 79: 1434‐1439, 1995.
 270. Montain SJ, Latzka WA, Sawka MN. Impact of muscle injury and accompanying inflammatory response on thermoregulation during exercise in the heat. J Appl Physiol 89: 1123‐1130, 2000.
 271. Montain SJ, Sawka MN, Cadarette BS, Quigley MD, McKay JM. Physiological tolerance to uncompensable heat stress: Effects of exercise intensity, protective clothing, and climate. J Appl Physiol 77: 216‐222, 1994.
 272. Montain SJ, Sawka MN, Latzka WA, Valeri CR. Thermal and cardiovascular strain from hypohydration: Influence of exercise intensity. Int J Sports Med 19: 87‐91, 1998.
 273. Montain SJ, Sawka MN, Wenger CB. Hyponatremia associated with exercise: Risk factors and pathogenesis. Exerc Sport Sci Rev 29: 113‐117, 2001.
 274. Montain SJ, Smith SA, Mattot RP, Zientara GP, Jolesz FA, Sawka MN. Hypohydration effects on skeletal muscle performance and metabolism: A 31P‐MRS study. J Appl Physiol 84: 1889‐1894, 1998.
 275. Morimoto T, Slabochova Z, Naman RK, Sargent F. Sex differences in physiological reactions to thermal stress. J Appl Physiol 22: 526‐532, 1967.
 276. Moseley PL. Exercise, stress, and the immune conversation. Exerc Sport Sci Rev 28: 128‐132, 2000.
 277. Mustafa KY, Omer O, Khogali M, Jamjoom A, Gumaa KA, Abu el‐Nasr N, Gader MA. Blood coagulation and fibrinolysis in heat stroke. Br J Haematol 61: 517‐523, 1985.
 278. Nadel ER, Bullard RW, Stolwijk JA. Importance of skin temperature in the regulation of sweating. J Appl Physiol 31: 80‐87, 1971.
 279. Nadel ER, Cafarelli E, Roberts MF, Wenger CB. Circulatory regulation during exercise in different ambient temperatures. J Appl Physiol 46: 430‐437, 1979.
 280. Nadel ER, Fortney SM, Wenger CB. Effect of hydration state of circulatory and thermal regulations. J Appl Physiol 49: 715‐721, 1980.
 281. Nadel ER, Mitchell JW, Saltin B, Stolwijk JA. Peripheral modifications to the central drive for sweating. J Appl Physiol 31: 828‐833, 1971.
 282. Nadel ER, Mitchell JW, Stolwijk JA. Differential thermal sensitivity in the human skin. Pflugers Arch 340: 71‐76, 1973.
 283. Nadel ER, Pandolf KB, Roberts MF, Stolwijk JA. Mechanisms of thermal acclimation to exercise and heat. J Appl Physiol 37: 515‐520, 1974.
 284. Nelson MD, Haykowsky MJ, Petersen SR, DeLorey DS, Stickland MK, Cheng‐Baron J, Thompson RB. Aerobic fitness does not influence the biventricular response to whole body passive heat stress. J Appl Physiol 109: 1545‐1551, 2010.
 285. Nelson NG, Collins CL, Comstock RD, McKenzie LB. Exertional heat‐related injuries treated in emergency departments in the U.S.,1997‐2006. Am J Prev Med 40: 54‐60, 2011.
 286. Neumann FJ, Ott I, Marx N, Luther T, Kenngott S, Gawaz M, Kotzsch M, Schomig A. Effect of human recombinant interleukin‐6 and interleukin‐8 on monocyte procoagulant activity. Arterioscler Thromb Vasc Biol 17: 3399‐3405, 1997.
 287. Neville AJ, Sauder DN. Whole body hyperthermia (41‐42 degrees C) induces interleukin‐1 in vivo. Lymphokine Res 7: 201‐206, 1988.
 288. Nguyen MK, Kurtz I. A new quantitative approach to the treatment of the dysnatremias. Clin Exp Nephrol 7: 125‐137, 2003.
 289. Nielsen B. Effect of changes in plasma Na+ and Ca++ ion concentration on body temperature during exercise. Acta Physiol Scand 91: 123‐129, 1974.
 290. Nielsen B, Hales JR, Strange S, Christensen NJ, Warberg J, Saltin B. Human circulatory and thermoregulatory adaptations with heat acclimation and exercise in a hot, dry environment. J Physiol 460: 467‐485, 1993.
 291. Nielsen B, Hyldig T, Bidstrup F, Gonzalez‐Alonso J, Christoffersen GR. Brain activity and fatigue during prolonged exercise in the heat. Pflugers Arch 442: 41‐48, 2001.
 292. Nielsen B, Nybo L. Cerebral changes during exercise in the heat. Sports Med 33: 1‐11, 2003.
 293. Noakes TD, Sharwood K, Speedy D, Hew T, Reid S, Dugas J, Almond C, Wharam P, Weschler L. Three independent biological mechanisms cause exercise‐associated hyponatremia: Evidence from 2,135 weighed competitive athletic performances. Proc Natl Acad Sci U S A 102: 18550‐18555, 2005.
 294. Nybo L. Exercise and heat stress: Cerebral challenges and consequences. Prog Brain Res 162: 29‐43, 2007.
 295. Nybo L. Hyperthermia and fatigue. J Appl Physiol 104: 871‐878, 2008.
 296. Nybo L, Jensen T, Nielsen B, Gonzalez‐Alonso J. Effects of marked hyperthermia with and without dehydration on V·o2max kinetics during intense exercise. J Appl Physiol 90: 1057‐1064, 2001.
 297. Nybo L, Nielsen B. Hyperthermia and central fatigue during prolonged exercise in humans. J Appl Physiol 91: 1055‐1060, 2001a.
 298. Nybo L, Nielsen B. Middle cerebral artery blood velocity is reduced with hyperthermia during prolonged exercise in humans. J Physiol 534: 279‐286, 2001b.
 299. Nybo L, Nielsen B. Perceived exertion is associated with an altered brain activity during exercise with progressive hyperthermia. J Appl Physiol 91: 2017‐2023, 2001c.
 300. Nybo L, Rasmussen P. Inadequate cerebral oxygen delivery and central fatigue during strenuous exercise. Exerc Sport Sci Rev 35: 110‐118, 2007.
 301. Nybo L, Secher NH, Nielsen B. Inadequate heat release from the human brain during prolonged exercise with hyperthermia. J Physiol 545: 697‐704, 2002.
 302. O'Brien C, Freund BJ, Sawka MN, McKay J, Hesslink RL, Jones TE. Hydration assessment during cold‐weather military field training exercises. Arctic Med Res 55: 20‐26, 1996.
 303. O'Brien KK, McPherson MK, Alsip B, Sawka MN. Exertional heat illnesses. In: Lenhart MK, Lounsbury DE, North RB, editors. Textbooks of Military Medicine. Borden, Institute Washington, DC, 2006, p. 493‐516.
 304. O'Brien KK, Montain SJ, Corr WP, Sawka MN, Knapik JJ, Craig SC. Hyponatremia associated with overhydration in U.S. Army trainees. Mil Med 166: 405‐410, 2001.
 305. O'Toole ML, Douglas PS, Laird RH, Hiller DB. Fluid and electrolyte status in athletes receiving medical care at an ultradistance triathlon. Clin J Sport Med 5: 116‐122, 1995.
 306. Ogura Y, Naito H, Akin S, Ichinoseki‐Sekine N, Kurosaka M, Kakigi R, Sugiura T, Powers SK, Katamoto S, Demirel HA. Elevation of body temperature is an essential factor for exercise‐increased extracellular heat shock protein 72 level in rat plasma. Am J Physiol 294: R1600‐R1607, 2008.
 307. Oka T, Oka K, Hori T. Mechanisms and mediators of psychological stress‐induced rise in core temperature. Psychosom Med 63: 476‐486, 2001.
 308. Okusawa S, Gelfand JA, Ikejima T, Connolly RJ, Dinarello CA. Interleukin 1 induces a shock‐like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. J Clin Invest 81: 1162‐1172, 1988.
 309. Oppliger RA, Bartok C. Hydration testing of athletes. Sports Med 32: 959‐971, 2002.
 310. Oshima T, Laroux FS, Coe LL, Morise Z, Kawachi S, Bauer P, Grisham MB, Specian RD, Carter P, Jennings S, Granger DN, Joh T, Alexander JS. Interferon‐gamma and interleukin‐10 reciprocally regulate endothelial junction integrity and barrier function. Microvasc Res 61: 130‐143, 2001.
 311. Pahnke MD, Trinity JD, Zachwieja JJ, Stofan JR, Hiller WD, Coyle EF. Serum sodium concentration changes are related to fluid balance and sweat sodium loss. Med Sci Sports Exerc 42: 1669‐1674, 2010.
 312. Paidas CN, Mooney ML, Theodorakis NG, De MA. Accelerated recovery after endotoxic challenge in heat shock‐pretreated mice. Am J Physiol 282: R1374‐R1381, 2002.
 313. Pandolf KB. Influence of local and central factors in dominating rated perceived exertion during physical work. Percept Mot Skills 46: 683‐698, 1978.
 314. Pandolf KB, Cafarelli E, Noble BJ, Metz KF. Perceptual responses during prolonged work. Percept Mot Skills 35: 975‐985, 1972.
 315. Patel DR, Gyamfi R, Torres A. Exertional rhabdomyolysis and acute kidney injury. Phys Sportsmed 37: 71‐79, 2009.
 316. Patel RT, Deen KI, Youngs D, Warwick J, Keighley MR. Interleukin 6 is a prognostic indicator of outcome in severe intra‐abdominal sepsis. Br J Surg 81: 1306‐1308, 1994.
 317. Patterson MJ, Galloway SD, Nimmo MA. Variations in regional sweat composition in normal human males. Exp Physiol 85: 869‐875, 2000.
 318. Patterson MJ, Stocks JM, Taylor NA. Humid heat acclimation does not elicit a preferential sweat redistribution toward the limbs. Am J Physiol 286: R512‐R518, 2004a.
 319. Patterson MJ, Stocks JM, Taylor NA. Sustained and generalized extracellular fluid expansion following heat acclimation. J Physiol 559: 327‐334, 2004b.
 320. Periard JD, Cramer MN, Chapman PG, Caillaud C, Thompson MW. Cardiovascular strain impairs prolonged self‐paced exercise in the heat. Exp Physiol 96: 134‐144, 2011.
 321. Pierau FK. Peripheral thermosensors. In: Blatteis CM, Fregley MJ, editors. Handbook of Physiology. Environmental Physiology. Bethesda, MD: American Physiological Society, 1996, sect. 4, vol. II, chapt. 5, p. 85‐104.
 322. Pirnay F, Deroanne R, Petit JM. Maximal oxygen consumption in a hot environment. J Appl Physiol 28: 642‐645, 1970.
 323. Pitts GC, Johnson FC, Consolazio FC. Work in the heat as affected intake of water, salt and glucose. Am J Physiol 142: 259, 1944.
 324. Pradier O, Gerard C, Delvaux A, Lybin M, Abramowicz D, Capel P, Velu T, Goldman M. Interleukin‐10 inhibits the induction of monocyte procoagulant activity by bacterial lipopolysaccharide. Eur J Immunol 23: 2700‐2703, 1993.
 325. Raman A, Schoeller DA, Subar AF, Troiano RP, Schatzkin A, Harris T, Bauer D, Bingham SA, Everhart JE, Newman AB, Tylavsky FA. Water turnover in 458 American adults 40‐79 yr of age. Am J Physiol 286: F394‐F401, 2004.
 326. Ramanathan NL. A new weighting system for mean surface temperature of the human body. J Appl Physiol 19: 531‐533, 1964.
 327. Rasmussen P, Nybo L, Volianitis S, Moller K, Secher NH, Gjedde A. Cerebral oxygenation is reduced during hyperthermic exercise in humans. Acta Physiol (Oxf) 199: 63‐70, 2010.
 328. Rasmussen P, Stie H, Nybo L, Nielsen B. Heat induced fatigue and changes of the EEG is not related to reduced perfusion of the brain during prolonged exercise in humans. J Therm Biol 29: 731‐737, 2004.
 329. Regan JM, Macfarlane DJ, Taylor NA. An evaluation of the role of skin temperature during heat adaptation. Acta Physiol Scand 158: 365‐375, 1996.
 330. Roberts MF, Wenger CB, Stolwijk JA, Nadel ER. Skin blood flow and sweating changes following exercise training and heat acclimation. J Appl Physiol 43: 133‐137, 1977.
 331. Roberts WO. Determining a “do not start” temperature for a marathon on the basis of adverse outcomes. Med Sci Sports Exerc 42: 226‐232, 2010.
 332. Robertson GL, Mahr EA, Athar S, Sinha T. Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma. J Clin Invest 52: 2340‐2352, 1973.
 333. Robinson S. Temperature regulation in exercise. Pediatrics 32: 691‐702, 1963.
 334. Romanovsky AA. Thermoregulation: Some concepts have changed. Functional architecture of the thermoregulatory system. Am J Physiol 292: R37‐R46, 2007.
 335. Romanovsky AA, Blatteis CM. Heat stroke: Opioid‐mediated mechanisms. J Appl Physiol 81: 2565‐2570, 1996.
 336. Ronneberg K, Roberts WO, McBean AD, Center BA. Temporal artery temperature measurements do not detect hyperthermic marathon runners. Med Sci Sports Exerc 40: 1373‐1375, 2008.
 337. Rosner MH, Kirven J. Exercise‐associated hyponatremia. Clin J Am Soc Nephrol 2: 151‐161, 2007.
 338. Rowell LB. Human cardiovascular adjustments to exercise and thermal stress. Physiol Rev 54: 75‐159, 1974.
 339. Rowell LB. Cardiovascular adjustments to thermal stress. In: Shephard JT, Abboud FM, editors. Handbook of Physiology. The Cardiovascular System, Peripheral Circulation and Skin Blood Flow. Bethesda, MD: American Physiological Society, 1983, sect. 2, pt. II, vol. 3, p. 967‐1023.
 340. Rowell LB. Human Circulation: Regulation during Physical Stress. New York: Oxford University Press, 1986.
 341. Rowell LB, Brengelmann GL, Blackmon JR, Twiss RD, Kusumi F. Splanchnic blood flow and metabolism in heat‐stressed man. J Appl Physiol 24: 475‐484, 1968.
 342. Rowell LB, Brengelmann GL, Murray JA, Kraning KK, Kusumi F. Human metabolic responses to hyperthermia during mild to maximal exercise. J Appl Physiol 26: 395‐402, 1969.
 343. Rowell LB, Marx HJ, Bruce RA, Conn RD, Kusumi F. Reductions in cardiac output, central blood volume, and stroke volume with thermal stress in normal men during exercise. J Clin Invest 45: 1801‐1816, 1966.
 344. Rowell LB, O'Leary D, Kellogg DL Jr. Integration of cardiovascular control systems in dynamic exercise. In: Rowell LB, Shepherd JT, editors. Handbook of Physiology. Exercise Regulation and Integration of Multiple Systems. Bethesda, MD: American Physiological Society, 1996, sect. 12, chapt. 17, p. 770‐838.
 345. Rubel LR. Hepatic injury associated with heatstroke. Ann Clin Lab Sci 14: 130‐136, 1984.
 346. Saissy JM. Liver transplantation in a case of fulminant liver failure after exertion. Intensive Care Med 22: 831, 1996.
 347. Saltin B. Circulatory response to submaximal and maximal exercise after thermal dehydration. J Appl Physiol 19: 1125‐1132, 1964.
 348. Saltin B, Gagge AP, Stolwijk JA. Muscle temperature during submaximal exercise in man. J Appl Physiol 25: 679‐688, 1968.
 349. Sareh H, Tulapurkar ME, Shah NG, Singh IS, Hasday JD. Response of mice to continuous 5‐day passive hyperthermia resembles human heat acclimation. Cell Stress Chaperones 16: 297‐307, 2011.
 350. Sato K. The mechanism of eccrine sweat secretion. In: Gisolfi CV, Lamb DR, Nadel ER, editors. Exercise, Heat, and Thermoregulation. Dubuque, IA: Brown & Benchmark, 1993, p. 85‐117.
 351. Sawka MN. Physiological consequences of hypohydration: Exercise performance and thermoregulation. Med Sci Sports Exerc 24: 657‐670, 1992.
 352. Sawka MN, Burke LM, Eichner ER, Maughan RJ, Montain SJ, Stachenfeld NS. American College of Sports Medicine position stand. Exercise and fluid replacement. Med Sci Sports Exerc 39: 377‐390, 2007.
 353. Sawka MN, Cheuvront SN, Carter R, III. Human water needs. Nutr Rev 63: S30‐S39, 2005.
 354. Sawka MN, Gonzalez RR, Pandolf KB. Effects of sleep deprivation on thermoregulation during exercise. Am J Physiol 246: R72‐R77, 1984.
 355. Sawka MN, Latzka WA, Montain SJ, Cadarette BS, Kolka MA, Kraning KK, Gonzalez RR. Physiologic tolerance to uncompensable heat: Intermittent exercise, field vs laboratory. Med Sci Sports Exerc 33: 422‐430, 2001.
 356. Sawka MN, Pandolf KB, Avellini BA, Shapiro Y. Does heat acclimation lower the rate of metabolism elicited by muscular exercise? Aviat Space Environ Med 54: 27‐31, 1983.
 357. Sawka MN, Toner MM, Francesconi RP, Pandolf KB. Hypohydration and exercise: Effects of heat acclimation, gender, and environment. J Appl Physiol 55: 1147‐1153, 1983.
 358. Sawka MN, Wenger CB. Physiological responses to acute exercise‐heat stress. In: Pandolf KB, Sawka MN, Gonzalez RR, editors. Human Performance Physiology and Environmental Medicine at Terrestrial Extremes. Indianapolis, IL: Benchmark, 1988, chapt. 3, p. 97‐151.
 359. Sawka MN, Wenger CB, Pandolf KB. Thermoregulatory responses to acute exercise – heat stress and heat acclimation. In: Blatteis CM, Fregley MJ, editors. Handbook of Physiology. Environmental Physiology. Bethesda, MD: American Physiological Society, 1996, sect. 4, vol. I, chapt. 9, p. 157‐186.
 360. Sawka MN, Young AJ. Physiological systems and their responses to conditions of heat and cold. In: Tipton CM, Sawka MN, Tate CA, Terjung RL, editors. ACSM's Advanced Exercise Physiology. Baltimore: Lippincott, Williams & Wilkins, 2006, 26, p. 535‐563.
 361. Sawka MN, Young AJ, Cadarette BS, Levine L, Pandolf KB. Influence of heat stress and acclimation on maximal aerobic power. Eur J Appl Physiol 53: 294‐298, 1985.
 362. Sawka MN, Young AJ, Francesconi RP, Muza SR, Pandolf KB. Thermoregulatory and blood responses during exercise at graded hypohydration levels. J Appl Physiol 59: 1394‐1401, 1985.
 363. Sawka MN, Young AJ, Latzka WA, Neufer PD, Quigley MD, Pandolf KB. Human tolerance to heat strain during exercise: Influence of hydration. J Appl Physiol 73: 368‐375, 1992.
 364. Schobitz B, Pezeshki G, Pohl T, Hemmann U, Heinrich PC, Holsboer F, Reul JM. Soluble interleukin‐6 (IL‐6) receptor augments central effects of IL‐6 in vivo. FASEB J 9: 659‐664, 1995.
 365. Schucany WG. Exercise‐associated hyponatremia. Proc (Bayl Univ Med Cent) 20: 398‐401, 2007.
 366. Schwager I, Jungi TW. Effect of human recombinant cytokines on the induction of macrophage procoagulant activity. Blood 83: 152‐160, 1994.
 367. Sculier JP, Bron D, Verboven N, Klastersky J. Multiple organ failure during interleukin‐2 administration and LAK cells infusion. Intensive Care Med 14: 666‐667, 1988.
 368. Selkirk GA, McLellan TM, Wright HE, Rhind SG. Mild endotoxemia, NF‐kappaB translocation, and cytokine increase during exertional heat stress in trained and untrained individuals. Am J Physiol 295: R611‐R623, 2008.
 369. Selkirk GA, McLellan TM, Wright HE, Rhind SG. Expression of intracellular cytokines, HSP72, and apoptosis in monocyte subsets during exertional heat stress in trained and untrained individuals. Am J Physiol 296: R575‐R586, 2009.
 370. Senay LC Jr. Relationship of evaporative rates to serum [Na+], [K+], and osmolarity in acute heat stress. J Appl Physiol 25: 149‐152, 1968.
 371. Shapiro Y, Moran D, Epstein Y, Stroschein L, Pandolf KB. Validation and adjustment of the mathematical prediction model for human sweat rate responses to outdoor environmental conditions. Ergonomics 38: 981‐986, 1995.
 372. Shapiro Y, Pandolf KB, Goldman RF. Predicting sweat loss response to exercise, environment and clothing. Eur J Appl Physiol 48: 83‐96, 1982.
 373. Sherman KE. Alanine aminotransferase in clinical practice. A review. Arch Intern Med 151: 260‐265, 1991.
 374. Shibasaki M, Wilson TE, Crandall CG. Neural control and mechanisms of eccrine sweating during heat stress and exercise. J Appl Physiol 100: 1692‐1701, 2006.
 375. Shibolet S, Coll R, Gilat T, Sohar E. Heatstroke: Its clinical picture and mechanism in 36 cases. Q J Med 36: 525‐548, 1967.
 376. Shirreffs SM, Aragon‐Vargas LF, Chamorro M, Maughan RJ, Serratosa L, Zachwieja JJ. The sweating response of elite professional soccer players to training in the heat. Int J Sports Med 26: 90‐95, 2005.
 377. Shirreffs SM, Maughan RJ. Whole body sweat collection in humans: An improved method with preliminary data on electrolyte content. J Appl Physiol 82: 336‐341, 1997.
 378. Shirreffs SM, Maughan RJ. Volume repletion after exercise‐induced volume depletion in humans: Replacement of water and sodium losses. Am J Physiol 274: F868‐F875, 1998.
 379. Shvartz E, Bhattacharya A, Sperinde SJ, Brock PJ, Sciaraffa D, Van BW. Sweating responses during heat acclimation and moderate conditioning. J Appl Physiol 46: 675‐680, 1979.
 380. Skidmore R, Gutierrez JA, Guerriero V Jr, Kregel KC. HSP70 induction during exercise and heat stress in rats: Role of internal temperature. Am J Physiol 268: R92‐R97, 1995.
 381. Smiles KA, Robinson S. Sodium ion conservation during acclimatization of men to work in the heat. J Appl Physiol 31: 63‐69, 1971.
 382. Smith AD, Crabtree DR, Bilzon JL, Walsh NP. The validity of wireless iButtons and thermistors for human skin temperature measurement. Physiol Meas 31: 95‐114, 2010.
 383. Snellen JW. An improved estimation of mean body temperature using combined direct calorimetry and thermometry. Eur J Appl Physiol 82: 188‐196, 2000.
 384. Sonna LA, Fujita J, Gaffin SL, Lilly CM. Invited review: Effects of heat and cold stress on mammalian gene expression. J Appl Physiol 92: 1725‐1742, 2002.
 385. Sonna LA, Gaffin SL, Pratt RE, Cullivan ML, Angel KC, Lilly CM. Effect of acute heat shock on gene expression by human peripheral blood mononuclear cells. J Appl Physiol 92: 2208‐2220, 2002.
 386. Sonna LA, Hawkins L, Lissauer ME, Maldeis P, Towns M, Johnson SB, Moore R, Singh IS, Cowan MJ, Hasday JD. Core temperature correlates with expression of selected stress and immunomodulatory genes in febrile patients with sepsis and noninfectious SIRS. Cell Stress Chaperones 15: 55‐66, 2010.
 387. Sonna LA, Kuhlmeier MM, Khatri P, Chen D, Lilly CM. A microarray analysis of the effects of moderate hypothermia and rewarming on gene expression by human hepatocytes (HepG2). Cell Stress Chaperones 15: 687‐702, 2010.
 388. Sonna LA, Sawka MN, Lilly CM. Exertional heat illness and human gene expression. Prog Brain Res 162: 321‐346, 2007.
 389. Sonna LA, Wenger CB, Flinn S, Sheldon HK, Sawka MN, Lilly CM. Exertional heat injury and gene expression changes: A DNA microarray analysis study. J Appl Physiol 96: 1943‐1953, 2004.
 390. Speedy DB, Noakes TD, Kimber NE, Rogers IR, Thompson JM, Boswell DR, Ross JJ, Campbell RG, Gallagher PG, Kuttner JA. Fluid balance during and after an ironman triathlon. Clin J Sport Med 11: 44‐50, 2001.
 391. Speedy DB, Noakes TD, Rogers IR, Thompson JM, Campbell RG, Kuttner JA, Boswell DR, Wright S, Hamlin M. Hyponatremia in ultradistance triathletes. Med Sci Sports Exerc 31: 809‐815, 1999.
 392. Stachenfeld NS, Silva C, Keefe DL. Estrogen modifies the temperature effects of progesterone. J Appl Physiol 88: 1643‐1649, 2000.
 393. Stephenson LA, Wenger CB, O'Donovan BH, Nadel ER. Circadian rhythm in sweating and cutaneous blood flow. Am J Physiol 246: R321‐R324, 1984.
 394. Stitt JT. Fever versus hyperthermia. Fed Proc 38: 39‐43, 1979.
 395. Stohr EJ, Gonzalez‐Alonso J, Pearson J, Low DA, Ali L, Barker H, Shave R. Effects of graded heat stress on global left ventricular function and twist mechanics at rest and during exercise in healthy humans. Exp Physiol 96: 114‐124, 2010.
 396. Strother SV, Bull JM, Branham SA. Activation of coagulation during therapeutic whole body hyperthermia. Thromb Res 43: 353‐360, 1986.
 397. Suzuki K, Nakaji S, Yamada M, Liu Q, Kurakake S, Okamura N, Kumae T, Umeda T, Sugawara K. Impact of a competitive marathon race on systemic cytokine and neutrophil responses. Med Sci Sports Exerc 35: 348‐355, 2003.
 398. Suzuki K, Nakaji S, Yamada M, Totsuka M, Sato K, Sugawara K. Systemic inflammatory response to exhaustive exercise. Cytokine kinetics. Exerc Immunol Rev 8: 6‐48, 2002.
 399. Suzuki K, Yamada M, Kurakake S, Okamura N, Yamaya K, Liu Q, Kudoh S, Kowatari K, Nakaji S, Sugawara K. Circulating cytokines and hormones with immunosuppressive but neutrophil‐priming potentials rise after endurance exercise in humans. Eur J Appl Physiol 81: 281‐287, 2000.
 400. Szold O, Reider‐Groswasser II, Ben AR, Aviram G, Segev Y, Biderman P, Sorkine P. Gray‐white matter discrimination—a possible marker for brain damage in heat stroke? Eur J Radiol 43: 1‐5, 2002.
 401. Takamata A, Nagashima K, Nose H, Morimoto T. Osmoregulatory inhibition of thermally induced cutaneous vasodilation in passively heated humans. Am J Physiol 273: R197‐R204, 1997.
 402. Takamata A, Nagashima K, Nose H, Morimoto T. The role of plasma osmolality in exercise‐induced inhibition of cutaneous vasodilation. In: The 1997 Nagano Symposium on Sports Sciences. Carmel, IN: Cooper Publishing Group, LLC, 1998, p. 344‐348.
 403. Tatterson AJ, Hahn AG, Martin DT, Febbraio MA. Effects of heat stress on physiological responses and exercise performance in elite cyclists. J Sci Med Sport 3: 186‐193, 2000.
 404. Taylor WF, Johnson JM, Kosiba WA, Kwan CM. Graded cutaneous vascular responses to dynamic leg exercise. J Appl Physiol 64: 1803‐1809, 1988.
 405. Taylor WF, Johnson JM, O'Leary DS, Park MK. Effect of high local temperature on reflex cutaneous vasodilation. J Appl Physiol 57: 191‐196, 1984a.
 406. Taylor WF, Johnson JM, O'Leary DS, Park MK. Modification of the cutaneous vascular response to exercise by local skin temperature. J Appl Physiol 57: 1878‐1884, 1984b.
 407. Tetievsky A, Horowitz M. Post‐translational modifications in Histones underlie heat acclimation‐mediated cytoprotective memory. J Appl Physiol 109: 1552‐1561, 2010.
 408. Thomas MM, Cheung SS, Elder GC, Sleivert GG. Voluntary muscle activation is impaired by core temperature rather than local muscle temperature. J Appl Physiol 100: 1361‐1369, 2006.
 409. Todd G, Butler JE, Taylor JL, Gandevia SC. Hyperthermia: A failure of the motor cortex and the muscle. J Physiol 563: 621‐631, 2005.
 410. Toner MM, McArdle WD. Human thermoregulatory responses to acute cold stress with special reference to water immersion. In: Blatteis CM, Fregley MJ, editors. Handbook of Physiology. Environmental Physiology. Bethesda, MD: American Physiological Society, 1996, sect. 4, vol. I, chapt. 17, p. 379‐418.
 411. Tracey KJ, Lowry SF, Cerami A. Physiological responses to cachectin. Ciba Found Symp 131: 88‐108, 1987.
 412. Trinity JD, Pahnke MD, Lee JF, Coyle EF. Interaction of hyperthermia and heart rate on stroke volume during prolonged exercise. J Appl Physiol 109: 745‐751, 2010.
 413. Tulapurkar ME, Asiegbu BE, Singh IS, Hasday JD. Hyperthermia in the febrile range induces HSP72 expression proportional to exposure temperature but not to HSF‐1 DNA‐binding activity in human lung epithelial A549 cells. Cell Stress Chaperones 14: 499‐508, 2009.
 414. Vasselon T, Detmers PA. Toll receptors: A central element in innate immune responses. Infect Immun 70: 1033‐1041, 2002.
 415. Verbalis JG. Renal function and vasopressin during marathon running. Sports Med 37: 455‐458, 2007.
 416. Verde T, Shephard RJ, Corey P, Moore R. Sweat composition in exercise and in heat. J Appl Physiol 53: 1540‐1545, 1982.
 417. Wagner M, Kaufmann P, Fickert P, Trauner M, Lackner C, Stauber RE. Successful conservative management of acute hepatic failure following exertional heatstroke. Eur J Gastroenterol Hepatol 15: 1135‐1139, 2003.
 418. Wallace RF, Kriebel D, Punnett L, Wegman DH, Amoroso PJ. Prior heat illness hospitalization and risk of early death. Environ Res 104: 290‐295, 2007.
 419. Walsh RM, Noakes TD, Hawley JA, Dennis SC. Impaired high‐intensity cycling performance time at low levels of dehydration. Int J Sports Med 15: 392‐398, 1994.
 420. Wang AY, Li PK, Lui SF, Lai KN. Renal failure and heatstroke. Ren Fail 17: 171‐179, 1995.
 421. Welch G, Foote KM, Hansen C, Mack GW. Nonselective NOS inhibition blunts the sweat response to exercise in a warm environment. J Appl Physiol 106: 796‐803, 2009.
 422. Welch WJ. Mammalian stress response: Cell physiology, structure/function of stress proteins, and implications for medicine and disease. Physiol Rev 72: 1063‐1081, 1992.
 423. Welch WJ, Mizzen LA. Characterization of the thermotolerant cell. II. Effects on the intracellular distribution of heat‐shock protein 70, intermediate filaments, and small nuclear ribonucleoprotein complexes. J Cell Biol 106: 1117‐1130, 1988.
 424. Wenger CB. Human heat acclimatization. In: Pandolf KB, Sawka MN, Gonzalez RR, editors. Human Performance Physiology and Environmental Medicine at Terrestrial Extremes. Indianapolis, IL: Benchmark, 1988, chapt. 4, p. 153‐197.
 425. White JG. Effects of heat on platelet structure and function. Blood 32: 324‐335, 1968.
 426. Wilkinson DA, Burholt DR, Shrivastava PN. Hypothermia following whole‐body heating of mice: Effect of heating time and temperature. Int J Hyperthermia 4: 171‐182, 1988.
 427. Wilson TE, Brothers RM, Tollund C, Dawson EA, Nissen P, Yoshiga CC, Jons C, Secher NH, Crandall CG. Effect of thermal stress on Frank‐Starling relations in humans. J Physiol 587: 3383‐3392, 2009.
 428. Wilson TE, Cui J, Zhang R, Crandall CG. Heat stress reduces cerebral blood velocity and markedly impairs orthostatic tolerance in humans. Am J Physiol 291: R1443‐R1448, 2006.
 429. Wingo JE, Cureton KJ. Maximal oxygen uptake after attenuation of cardiovascular drift during heat stress. Aviat Space Environ Med 77: 687‐694, 2006.
 430. Wingo JE, Low DA, Keller DM, Brothers RM, Shibasaki M, Crandall CG. Skin Blood Flow and Local Temperature Independently Modify Sweat Rate During Passive Heat Stress in Humans. J Appl Physiol 109: 1301‐1306, 2010.
 431. Winkenwerder W, Sawka MN. Disorders due to heat and cold. In: Goldman L, Ausiello DA, Arend W, editors. Cecil Textbook of Medicine. Philadelphia: Saunders, 2007, p. 763‐767.
 432. Winslow CEA, Herrington LP, Gagge AP. A new method of partitional calorimetry. Am J Physiol 116: 641‐655, 1936.
 433. Wright GL. Critical thermal maximum in mice. J Appl Physiol 40: 683‐687, 1976.
 434. Yamada PM, Amorim FT, Moseley P, Robergs R, Schneider SM. Effect of heat acclimation on heat shock protein 72 and interleukin‐10 in humans. J Appl Physiol 103: 1196‐1204, 2007.
 435. Young AJ, Sawka MN, Levine L, Cadarette BS, Pandolf KB. Skeletal muscle metabolism during exercise is influenced by heat acclimation. J Appl Physiol 59: 1929‐1935, 1985.
 436. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464: 104‐107, 2010.
 437. Zieker D, Fehrenbach E, Dietzsch J, Fliegner J, Waidmann M, Nieselt K, Gebicke‐Haerter P, Spanagel R, Simon P, Niess AM, Northoff H. cDNA microarray analysis reveals novel candidate genes expressed in human peripheral blood following exhaustive exercise. Physiol Genomics 23: 287‐294, 2005.

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Article Title: Integrated Physiological Mechanisms of Exercise Performance, Adaptation, and Maladaptation to Heat Stress
 

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Michael N. Sawka, Lisa R. Leon, Scott J. Montain, Larry A. Sonna. Integrated Physiological Mechanisms of Exercise Performance, Adaptation, and Maladaptation to Heat Stress. Compr Physiol 2011, 1: 1883-1928. doi: 10.1002/cphy.c100082