Heat-related changes in the velocity and kinetic energy of flowing blood influence the human heart's output during hyperthermia.

Passive whole-body hyperthermia increases limb blood flow and cardiac output ( Q ̇ $\dot Q$ ), but the interplay between peripheral and central thermo-haemodynamic mechanisms remains unclear. Here we tested the hypothesis that local hyperthermia-induced alterations in peripheral blood flow and blood kinetic energy modulate flow to the heart and Q ̇ $\dot Q$ . Body temperatures, regional (leg, arm, head) and systemic haemodynamics, and left ventricular (LV) volumes and functions were assessed in eight healthy males during: (1) 3 h control (normothermic condition); (2) 3 h of single-leg heating; (3) 3 h of two-leg heating; and (4) 2.5 h of whole-body heating. Leg, forearm, and extracranial blood flow increased in close association with local rises in temperature while brain perfusion remained unchanged. Increases in blood velocity with small to no changes in the conduit artery diameter underpinned the augmented limb and extracranial perfusion. In all heating conditions, Q ̇ $\dot Q$ increased in association with proportional elevations in systemic vascular conductance, related to enhanced blood flow, blood velocity, vascular conductance and kinetic energy in the limbs and head (all R2 ≥ 0.803; P < 0.001), but not in the brain. LV systolic (end-systolic elastance and twist) and diastolic functional profiles (untwisting rate), pulmonary ventilation and systemic aerobic metabolism were only altered in whole-body heating. These findings substantiate the idea that local hyperthermia-induced selective alterations in peripheral blood flow modulate the magnitude of flow to the heart and Q ̇ $\dot Q$ through changes in blood velocity and kinetic energy. Localised heat-activated events in the peripheral circulation therefore affect the human heart's output. KEY POINTS: Local and whole-body hyperthermia increases limb and systemic perfusion, but the underlying peripheral and central heat-sensitive mechanisms are not fully established. Here we investigated the regional (leg, arm and head) and systemic haemodynamics (cardiac output: Q ̇ $\dot Q$ ) during passive single-leg, two-leg and whole-body hyperthermia to determine the contribution of peripheral and central thermosensitive factors in the control of human circulation. Single-leg, two-leg, and whole-body hyperthermia induced graded increases in leg blood flow and Q ̇ $\dot Q$ . Brain blood flow, however, remained unchanged in all conditions. Ventilation, extracranial blood flow and cardiac systolic and diastolic functions only increased during whole-body hyperthermia. The augmented Q ̇ $\dot Q$ with hyperthermia was tightly related to increased limb and head blood velocity, flow and kinetic energy. The findings indicate that local thermosensitive mechanisms modulate regional blood velocity, flow and kinetic energy, thereby controlling the magnitude of flow to the heart and thus the coupling of peripheral and central circulation during hyperthermia.

Effect of hyperthermia on simulated muscle activation in female when crossing obstacle.

It is well known that hyperthermia greatly impairs neuromuscular function and dynamic balance. However, whether a greater level of hyperthermia could potentially alter the lower limb simulated muscle activation when crossing an obstacle in female participants remains unknown. Therefore we examined the effect of a systematic increase in oral temperature on lower limb simulated muscle activation when crossing an obstacle in female participants. Eighteen female participants were recruited where they underwent a control trial (Con) and two progressive passive heating trials with Δ 1°C and Δ 2°C increase of oral temperature (Toral) using a 45°C water bath. In each trial, we assessed lower limb simulated muscle activation when crossing an obstacle height of 10%, 20%, and 30% of the participant's leg length and toe-off, toe-above-obstacle and heel-strike events were identified and analyzed. In all events, the lower limb simulated muscle activation were greater in Δ2°C than Δ1°C and Con when both leading and trailing limbs crossed the obstacle height of 20% and 30% leg length (all p < 0.001). However, the lower limb simulated muscle activation were not different between Δ1°C and Con across all obstacle heights (p > 0.05). This study concluded that a greater level of hyperthermia resulted in a greater lower limb simulated muscle activation to ensure safety and stability when females cross an obstacle height of 20% leg length or higher.

Relatedness of hypoxia and hyperthermia tolerances in the Nile tilapia (Oreochromis niloticus) and their relationships with cardiac and gill traits.

In fish, thermal and hypoxia tolerances may be functionally related, as suggested by the oxygen- and capacity-limited thermal tolerance (OCLTT) concept, which explains performance failure at high temperatures due to limitations in oxygen delivery. In this study the interrelatedness of hyperthermia and hypoxia tolerances in the Nile tilapia (Oreochromis niloticus), and their links to cardiorespiratory traits were examined. Different groups of O. niloticus (n = 51) were subjected to hypoxia and hyperthermia challenges and the O2 tension for aquatic surface respiration (ASR pO2) and critical thermal maximum (CTmax) were assessed as measurement endpoints. Gill filament length, total filament number, ventricle mass, length and width were also measured. Tolerance to hypoxia, as evidenced by ASR pO2 thresholds of the individual fish, was highly variable and varied between 0.26 and 3.39 kPa. ASR events increased more profoundly as O2 tensions decreased below 2 kPa. The CTmax values recorded for the O. niloticus individuals ranged from 43.1 to 44.8 °C (Mean: 44.2 ± 0.4 °C). Remarkably, there was a highly significant correlation between ASR pO2 and CTmax in O. niloticus (r = -0.76, p < 0.0001) with ASR pO2 increasing linearly with decreasing CTmax. There were, however, no discernible relationships between the measured cardiorespiratory properties and hypoxia or hyperthermia tolerances. The strong relationship between hypoxia and hyperthermia tolerances in this study may be related to the ability of the cardiorespiratory system to provide oxygen to respiring tissues under thermal stress, and thus provides some support for the OCLTT concept in this species, at least at the level of the entire organism.

Post-exercise management of exertional hyperthermia in dogs participating in dog sport (canicross) events in the UK.

Exercise is a common trigger of heat-related illness (HRI) events in dogs, accounting for 74% of canine HRI cases treated under primary veterinary care in the United Kingdom. However, few empirical studies have evaluated the effectiveness of differing cooling methods for dogs with exertional hyperthermia or HRI. This study aimed to prospectively evaluate effects of ambient conditions and post-exercise management practices (cooling methods and vehicular confinement) on the post-exercise temperature change of dogs participating in UK canicross events. Canine temperature was recorded at three intervals post-exercise: as close as possible to 0- (immediately post-exercise), 5-, and 15-min post-exercise. Ambient conditions and post-exercise management were recorded for 115 cooling profiles from 52 dogs. In 28/115 (24.4%) profiles, the dog's temperature increased during the first 5-min post-exercise. Overall, 68/115 (59.1%) profiles included passive cooling (stood or walked outside), 35 (30.4%) active cooling (cold-water immersion or application of a cooling coat), and 12 (10.4%) involved no cooling and were immediately housed in vehicles. No dogs developed hypothermia during the study and no adverse effects were observed from any cooling method. In hyperthermic dogs, overall post-exercise body temperature change was significantly negatively associated (i.e. the dogs cooled more) with 0-min post-exercise body temperature (ß = -0.93, p < 0.001), and not being housed in a vehicle (ß = -0.43, p = 0.013). This study provides evidence cold-water immersion (in water at 0.1-15.0 °C) can be used to effectively and safely cool dogs with exertional hyperthermia. Progressive temperature increases in many dogs - even after exercise has terminated - supports the message to "cool first, transport second" when managing dogs with HRI. When transporting dogs post-exercise or with HRI even after active cooling, care should be taken to cool the vehicle before entry and promote air movement around the dog during transport to facilitate ongoing cooling and prevent worsening of hyperthermia during travel.

Establishment and characterization of immortalized sweat gland myoepithelial cells.

Sweat glands play an important role in thermoregulation via sweating, and protect human vitals. The reduction in sweating may increase the incidence of hyperthermia. Myoepithelial cells in sweat glands exhibit stemness characteristics and play a major role in sweat gland homeostasis and sweating processes. Previously, we successfully passaged primary myoepithelial cells in spheroid culture systems; however, they could not be maintained for long under in vitro conditions. No myoepithelial cell line has been established to date. In this study, we transduced two immortalizing genes into primary myoepithelial cells and developed a myoepithelial cell line. When compared with primary sweat gland cells, the immortalized myoepithelial cells (designated "iEM") continued to form spheroids after the 4th passage and expressed α-smooth muscle actin and other proteins that characterize myoepithelial cells. Furthermore, treatment with small compounds targeting the Wnt signaling pathways induced differentiation of iEM cells into luminal cells. Thus, we successfully developed an immortalized myoepithelial cell line having differentiation potential. As animal models are not useful for studying human sweat glands, our cell line will be helpful for studying the mechanisms underlying the pathophysiology of sweating disorders.

Effect of extracellular hyperosmolality on sweat rate during metaboreflex activation in passively heated young men.

Metaboreflex activation augments sweating during mild-to-moderate hyperthermia in euhydrated (isosmotic isovolemic) individuals. Recent work indicates that extracellular hyperosmolality may augment metaboreflex-mediated elevations in sympathetic nervous activity. Our primary objective was, therefore, to test the hypothesis that extracellular hyperosmolality would exacerbate metaboreflex-mediated increases in sweat rate. On two separate occasions, 12 young men [means (SD): 25 (5) yr] received a 90-min intravenous infusion of either 0.9% saline (isosmotic condition, ISO) or 3.0% saline (hyperosmotic condition, HYP), resulting in a postinfusion serum osmolality of 290 (3) and 301 (7) mosmol/kgH2O, respectively. A whole body water perfusion suit was then used to increase esophageal temperature by 0.8°C above resting. Participants then performed a metaboreflex activation protocol consisting of 90-s isometric handgrip exercise (40% of their predetermined maximum voluntary contraction), followed by 150 s of brachial occlusion (trapping produced metabolites within the limb). Metaboreflex-induced sweating was quantified as the change in global sweat rate (from preisometric handgrip exercise to brachial occlusion), estimated as the surface area-weighted average of local sweat rate on the abdomen, axilla, chest, bicep, quadriceps, and calf, measured using ventilated capsules (3.8 cm2). We also explored whether this response differed between body regions. The change in global sweat rate due to metaboreflex activation was significantly greater in HYP compared with ISO (0.03 mg/min/cm2 [95% confidence interval: 0.00, 0.06]; P = 0.047), but was not modulated by body region (site × condition interaction: P = 0.679). These findings indicate that extracellular hyperosmolality augments metaboreflex-induced increases in global sweat rate, with no evidence for region-specific differences.

Exercise hyperthermia induces greater changes in gastrointestinal permeability than equivalent passive hyperthermia.

Hyperthermia and exertional heat illness increase gastrointestinal (GI) permeability, although whether the latter is only via hyperthermia is unclear. The aim of this pilot study was to determine whether different changes in GI permeability, characterized by an increased plasma lactulose:rhamnose concentration ratio ([L:R]), occurred in exercise hyperthermia in comparison to equivalent passive hyperthermia. Six healthy adult male participants (age 25 ± 5 years, mass 77.0 ± 6.7 kg, height 181 ± 6 cm, peak oxygen uptake [ V·O2peak ] 48 ± 8 ml.kg-1 .min-1 ) underwent exercise under hot conditions (Ex-Heat) and passive heating during hot water immersion (HWI). Heart rate (HR), rectal temperature (TCORE ), rating of perceived exertion (RPE), and whole-body sweat loss (WBSL) were recorded throughout the trials. The L:R ratio, peak HR, change in HR, and change in RPE were higher in Ex-Heat than HWI, despite no differences in trial duration, peak core temperature or WBSL. L:R was strongly correlated (p < 0.05) with HR peak (r = 0.626) and change in HR (r = 0.615) but no other variable. The greater L:R in Ex-Heat, despite equal TCORE responses to HWI, indicates that increased cardiovascular strain occurred during exercise, and exacerbates hyperthermia-induced GI permeability at the same absolute temperature.

Protocol for fever-range whole-body hyperthermia (WBH) in mice to study febrile effect on T-cell adhesion and migration.

Fever is a complex physiological response enhancing immune surveillance during infection and inflammation. Fever-range whole-body hyperthermia (WBH) treatment can experimentally mimic the febrile condition in mice. Here, we describe a protocol for the treatment of mice with WBH and normothermia. We describe the isolation of T cells from mouse spleen followed by the evaluation of T-cell adhesion and transmigration. This animal model can be applied to studying the dysfunction of the immune system induced by fever. For complete details on the use and execution of this protocol, please refer to Lin et al. (2019).

Proteomic signature of the Dravet syndrome in the genetic Scn1a-A1783V mouse model.

BACKGROUND: Dravet syndrome is a rare, severe pediatric epileptic encephalopathy associated with intellectual and motor disabilities. Proteomic profiling in a mouse model of Dravet syndrome can provide information about the molecular consequences of the genetic deficiency and about pathophysiological mechanisms developing during the disease course. METHODS: A knock-in mouse model of Dravet syndrome with Scn1a haploinsufficiency was used for whole proteome, seizure, and behavioral analysis. Hippocampal tissue was dissected from two- (prior to epilepsy manifestation) and four- (following epilepsy manifestation) week-old male mice and analyzed using LC-MS/MS with label-free quantification. Proteomic data sets were subjected to bioinformatic analysis including pathway enrichment analysis. The differential expression of selected proteins was confirmed by immunohistochemical staining. RESULTS: The findings confirmed an increased susceptibility to hyperthermia-associated seizures, the development of spontaneous seizures, and behavioral alterations in the novel Scn1a-A1873V mouse model of Dravet syndrome. As expected, proteomic analysis demonstrated more pronounced alterations following epilepsy manifestation. In particular, proteins involved in neurotransmitter dynamics, receptor and ion channel function, synaptic plasticity, astrogliosis, neoangiogenesis, and nitric oxide signaling showed a pronounced regulation in Dravet mice. Pathway enrichment analysis identified several significantly regulated pathways at the later time point, with pathways linked to synaptic transmission and glutamatergic signaling dominating the list. CONCLUSION: In conclusion, the whole proteome analysis in a mouse model of Dravet syndrome demonstrated complex molecular alterations in the hippocampus. Some of these alterations may have an impact on excitability or may serve a compensatory function, which, however, needs to be further confirmed by future investigations. The proteomic data indicate that, due to the molecular consequences of the genetic deficiency, the pathophysiological mechanisms may become more complex during the course of the disease. As a result, the management of Dravet syndrome may need to consider further molecular and cellular alterations. Ensuing functional follow-up studies, this data set may provide valuable guidance for the future development of novel therapeutic approaches.

TMEM16C is involved in thermoregulation and protects rodent pups from febrile seizures.

Febrile seizures (FSs) are the most common convulsion in infancy and childhood. Considering the limitations of current treatments, it is important to examine the mechanistic cause of FSs. Prompted by a genome-wide association study identifying TMEM16C (also known as ANO3) as a risk factor of FSs, we showed previously that loss of TMEM16C function causes hippocampal neuronal hyperexcitability [Feenstra et al., Nat. Genet. 46, 1274-1282 (2014)]. Our previous study further revealed a reduction in the number of warm-sensitive neurons that increase their action potential firing rate with rising temperature of the brain region harboring these hypothalamic neurons. Whereas central neuronal hyperexcitability has been implicated in FSs, it is unclear whether the maximal temperature reached during fever or the rate of body temperature rise affects FSs. Here we report that mutant rodent pups with TMEM16C eliminated from all or a subset of their central neurons serve as FS models with deficient thermoregulation. Tmem16c knockout (KO) rat pups at postnatal day 10 (P10) are more susceptible to hyperthermia-induced seizures. Moreover, they display a more rapid rise of body temperature upon heat exposure. In addition, conditional knockout (cKO) mouse pups (P11) with TMEM16C deletion from the brain display greater susceptibility of hyperthermia-induced seizures as well as deficiency in thermoregulation. We also found similar phenotypes in P11 cKO mouse pups with TMEM16C deletion from Ptgds-expressing cells, including temperature-sensitive neurons in the preoptic area (POA) of the anterior hypothalamus, the brain region that controls body temperature. These findings suggest that homeostatic thermoregulation plays an important role in FSs.

Progressive hyperthermia elicits distinct responses in maximum and rapid torque production.

OBJECTIVES: To investigate the effect of progressive whole-body hyperthermia on maximal, and rapid voluntary torque production, and their neuromuscular determinants. DESIGN: Repeated measures, randomised. METHODS: Nine participants performed sets of neuromuscular assessments in HOT conditions (∼50°C, ∼35% relative humidity) at rectal temperatures (Tre) of 37, 38.5 and 39.5°C and in CON conditions (∼22°C, ∼35% relative humidity) at a Tre of ∼37°C and pre-determined comparative time-points. Electrically evoked twitch (single impulse) and octet (8 impulses at 300Hz) responses were measured at rest. Maximum voluntary torque (MVT), surface electromyography (EMG) normalised to maximal M-wave, and voluntary activation (VA) were measured during 3-5s isometric maximal voluntary contractions. Rate of torque development (RTD) and normalised EMG were measured during rapid voluntary isometric contractions from rest. RESULTS: All neuromuscular variables were unaffected by time in CON. In HOT, MVT, normalised EMG at MVT and VA were lower at 39.5°C compared to 37°C (p<0.05). Early- (0-50ms) and middle- (50-100ms) phase voluntary RTD were unaffected by increased Tre (p>0.05), despite lower normalised EMG at Tre 39.5°C (p<0.05) in rapid contractions. In contrast, late-phase (100-150ms) voluntary RTD was lower at 38.5°C and 39.5°C compared to 37°C (p<0.05) in HOT. Evoked twitch and octet RTD increased with increased Tre (p<0.05). CONCLUSIONS: Hyperthermia reduced late-phase voluntary RTD, likely due to reduced neural drive and the reduction in MVT. In contrast, early- and middle-phase voluntary RTD were unaffected by hyperthermia, likely due to the conflicting effects of reduced neural drive but faster intrinsic contractile properties.

The Role of Skeletal Muscles in Exertional Heat Stroke Pathophysiology.

The active participation of skeletal muscles is a unique characteristic of exertional heat stroke. Nevertheless, the only well-documented link between skeletal muscle activities and exertional heat stroke pathophysiology is the extensive muscle damage (e. g., rhabdomyolysis) and subsequent leakage of intramuscular content into the circulation of exertional heat stroke victims. Here, we will present and discuss rarely explored roles of skeletal muscles in the context of exertional heat stroke pathophysiology and recovery. This includes an overview of heat production that contributes to severe hyperthermia and the synthesis and secretion of bioactive molecules, such as cytokines, chemokines and acute phase proteins. These molecules can alter the overall inflammatory status from pro- to anti-inflammatory, affecting other organ systems and influencing recovery. The activation of innate immunity can determine whether a victim is ready to return to physical activity or experiences a prolonged convalescence. We also provide a brief discussion on whether heat acclimation can shift skeletal muscle secretory phenotype to prevent or aid recovery from exertional heat stroke. We conclude that skeletal muscles should be considered as a key organ system in exertional heat stroke pathophysiology.

Impact of elevated core temperature on cognition in hot environments within a military context.

PURPOSE: Cognition can be impaired during exercise in the heat, potentially contributing to military casualties. To our knowledge, the independent role of elevated core temperature during exercise has not been determined. The aim of the current study was to evaluate effects of elevated core temperature on cognition during physically encumbering, heated exercise, and to determine whether the perceptual cooling effects of menthol preserves cognition. METHODS: Eight participants complete three trials in randomised order: one normothermic (CON) and two with elevated (38.5°C) core temperature, induced by prior immersion in neutral versus hot water The CON trial and one hot trial (HOT) used a water mouth-rinse following each cognitive task of the trial, (HOT) while the other used a menthol mouth-rinse (MENT). Participants walked in humid heat (33°C, 75% relative humidity) in military clothing, completing a cognitive battery of reaction time, perceptual processing, working memory, executive function, cognitive flexibility, vigilance, and declarative memory. RESULTS: No differences in cognitive performance were observed between any conditions. Near-infrared spectroscopy showed greater oxygenated haemoglobin tissue content in HOT and MENT compared to CON (ΔO2Hb-deO2Hb: 2.3 ± 4.5 µM, p < .024), and lower deoxygenated haemoglobin in MENT than in CON or HOT (p = .017), suggesting higher brain metabolism during the more stressful conditions. CONCLUSION: Moderately elevated core (38.5°C) and skin temperature does not appear to impair cognitive performance during exercise despite mildly elevated cerebral metabolism. The effects of menthol remain undetermined due to the lack of heat-mediated cognitive impairment.

Changes in gastrointestinal cell integrity after marathon running and exercise-associated collapse.

PURPOSE: Endurance exercise and hyperthermia are associated with compromised intestinal permeability and endotoxaemia. The presence of intestinal fatty acid-binding protein (I-FABP) in the systemic circulation suggests intestinal wall damage, but this marker has not previously been used to investigate intestinal integrity after marathon running. METHODS: Twenty-four runners were recruited as controls prior to completing a standard marathon and had sequential I-FABP measurements before and on completion of the marathon, then at four and 24 h later. Eight runners incapacitated with exercise-associated collapse (EAC) with hyperthermia had I-FABP measured at the time of collapse and 1 hour later. RESULTS: I-FABP was increased immediately on completing the marathon (T0; 2593 ± 1373 ng·l-1) compared with baseline (1129 ± 493 ng·l-1; p < 0.01) in the controls, but there was no significant difference between baseline and the levels at four hours (1419 ± 1124 ng·l-1; p = 0.7), or at 24 h (1086 ± 302 ng·l-1; p = 0.5). At T0, EAC cases had a significantly higher I-FABP concentration (15,389 ± 8547 ng.l-1) compared with controls at T0 (p < 0.01), and remained higher at 1 hour after collapse (13,951 ± 10,476 ng.l-1) than the pre-race control baseline (p < 0.05). CONCLUSION: I-FABP is a recently described biomarker whose presence in the circulation is associated with intestinal wall damage. I-FABP levels increase after marathon running and increase further if the endurance exercise is associated with EAC and hyperthermia. After EAC, I-FABP remains high in the circulation for an extended period, suggesting ongoing intestinal wall stress.

TRPV4 channel blockade does not modulate skin vasodilation and sweating during hyperthermia or cutaneous postocclusive reactive and thermal hyperemia.

Transient receptor potential vanilloid 4 (TRPV4) channels exist on vascular endothelial cells and eccrine sweat gland secretory cells in human skin. Here, we assessed whether TRPV4 channels contribute to cutaneous vasodilation and sweating during whole body passive heat stress (protocol 1) and to cutaneous vasodilation during postocclusive reactive hyperemia and local thermal hyperemia (protocol 2). Intradermal microdialysis was employed to locally deliver pharmacological agents to forearm skin sites, where cutaneous vascular conductance (CVC) and sweat rate were assessed. In protocol 1 (12 young adults), CVC and sweat rate were increased by passive whole body heating, resulting in a body core temperature elevation of 1.2 ± 0.1°C. The elevated CVC and sweat rate assessed at sites treated with TRPV4 channel antagonist (either 200 µM HC-067047 or 125 µM GSK2193874) were not different from the vehicle control site (5% dimethyl sulfoxide). After whole body heating, the TRPV4 channel agonist (100 µM GSK1016790A) was administered to each skin site, eliciting elevations in CVC. Relative to control, this response was partly attenuated by both TRPV4 channel antagonists, confirming drug efficacy. In protocol 2 (10 young adults), CVC was increased following a 5-min arterial occlusion and during local heating from 33 to 42°C. These responses did not differ between the control and the TRPV4 channel antagonist sites (200 µM HC-067047). We show that TRPV4 channels are not required for regulating cutaneous vasodilation or sweating during a whole body passive heat stress. Furthermore, they are not required for regulating cutaneous vasodilation during postocclusive reactive hyperemia and local thermal hyperemia.

Epidural analgesia, intrapartum hyperthermia, and neonatal brain injury: a systematic review and meta-analysis.

BACKGROUND: Epidural analgesia is associated with intrapartum hyperthermia, and chorioamnionitis is associated with neonatal brain injury. However, it is not known if epidural hyperthermia is associated with neonatal brain injury. This systematic review and meta-analysis investigated three questions: (1) does epidural analgesia cause intrapartum hyperthermia, (2) is intrapartum hyperthermia associated with neonatal brain injury, and (3) is epidural-induced hyperthermia associated with neonatal brain injury? METHODS: PubMed, ISI Web of Knowledge, The Cochrane Library, and Embase were searched from inception to January 2020 using Medical Subject Headings (MeSH) terms relating to epidural analgesia, hyperthermia, labour, and neonatal brain injury. Studies were reviewed independently for inclusion and quality by two authors (Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach). Two meta-analyses were performed using the Mantel-Haenszel fixed effect method to generate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Forty-one studies were included for Question 1 (646 296 participants), 36 for Question 2 (11 866 021 participants), and two studies for Question 3 (297 113 participants). When the mode of analgesia was randomised, epidural analgesia was associated with intrapartum hyperthermia (OR: 4.21; 95% CI: 3.48-5.09). There was an association between intrapartum hyperthermia and neonatal brain injury (OR: 2.79; 95% CI: 2.54-2.3.06). It was not possible to quantify the association between epidural-induced hyperthermia and neonatal brain injury. CONCLUSIONS: Epidural analgesia is a cause of intrapartum hyperthermia, and intrapartum hyperthermia of any cause is associated with neonatal brain injury. Further work is required to establish if epidural-induced hyperthermia is a cause of neonatal brain injury.

The effects of acute dopamine reuptake inhibition on cognitive function during passive hyperthermia.

Dopamine activity can modulate physical performance in the heat, but less is known about its effects on cognition during thermal stress. Twelves males completed a randomized, double-blinded protocol consisting of oral ingestion of 20 mg of methylphenidate (MPH) or placebo (lactose pill) during passive heating using a water-perfused suit (water temperature ∼49 °C). To identify the impact of peripheral versus central thermal strain, a cognitive test battery was completed at 4 different thermal states: baseline (BASE; 37.2 ± 0.6 °C core, 32.9 ± 0.7 °C skin), neutral core-hot skin (NC-HS; 37.2 ± 0.3 °C, 37.4 ± 0.3 °C), hyperthermic core-hot skin (HC-HS; 38.7 ± 0.4 °C, 38.7 ± 0.2 °C), and hyperthermic core-cooled skin (HC-CS; 38.5 ± 0.4 °C, 35.1 ± 0.8 °C). The cognitive test battery consisted of the 2-back task (i.e., working memory), set-shifting (i.e., executive function), Groton Maze Learning Task (i.e., executive function) and detection task (i.e., psychomotor processing). MPH led to significantly higher heart rates (∼5-15 b·min-1) at BASE, NC-HS, and HC-HS (all p < 0.05). There were no significant differences in the number of errors made on each task (all p < 0.05). Participants were significantly faster (p < 0.05) on the set-shifting task in the HC-HS timepoint, irrespective of drug condition (p > 0.05). In summary, we demonstrated that 20 mg of MPH did not significantly alter cognitive function during either normothermia or moderate hyperthermia. Novelty: Twenty milligrams of MPH did not significantly alter cognitive function during passive heat stress. MPH led to significant higher heart rates (∼5-15 b·min-1) in thermoneutral and during passive heat stress. Future studies are needed to determine the mechanisms of why MPH improves physical but not cognitive performance during heat stress.

Sex difference in cerebral blood flow velocity during exercise hyperthermia.

INTRODUCTION: Cerebral blood flow and thermal perception during physical exercise under hyperthermia conditions in females are poorly understood. Because sex differences exist for blood pressure control, resting middle cerebral artery velocity (MCAVmean), and pain, we tested the hypothesis that females would have greater reductions in MCAvmean and increased thermal perceptual strain during exercise hyperthermia compared to males. METHODS: Twenty-two healthy active males and females completed 60 min of matched exercise metabolic heat production in a 1) control cool (24.0 ± 0.0 °C; 14.4 ± 3.4% Rh) and 2) hot (42.3 ± 0.3 °C; 28.4 ± 5.2% Rh) conditions in random order, separated by at least 3 days while MCAvmean, thermal comfort, and preference was obtained during the exercise. RESULTS: Compared to 36 °C mean body temperature (Mbt), as hyperthermia increased to 39 °C Mbt, females had a greater reduction in absolute (MCAvmean), and relative change (%Δ MCAvmean) and conductance (%Δ MCAvmean conductance) in MCAVmean compared to males (Interaction: Temperature x Sex, P ≤ 0.002). During exercise in cool conditions, absolute and conductance MCAvmean was maintained from rest through exercise; however, females had greater MCAVmean compared to males (Main effect: Sex, P < 0.0008). We also found disparities in females' perceptual thermal comfort and thermal preference. These differences may be associated with a greater reduction in partial pressure of end-tidal CO2, and different cardiovascular and blood pressure control to exercise under hyperthermia. CONCLUSIONS: In summary, females exercise cerebral blood flow velocity is reduced to a greater extent (25% vs 15%) and the initial reduction occurs at lower hyperthermia mean body temperatures (~38 °C vs ~39 °C) and are under greater thermal perceptual strain compared to males.

Pharmacological evaluation of Acacia modesta bark for antipyretic, anti-inflammatory, analgesic, antidepressant and anticoagulant activities in Sprague Dawley rats.

In this study the bark of Acacia modesta was evaluated for anti-inflammatory, antipyretic, analgesic, antidepressant and anticoagulant activity by carrageenan, hot plat, forced swim and capillary tube method respectively in rats. Highest anti-inflammatory activity was exhibited by chloroform (AMC) extract (74.96% inhibition) while other two active fractions being n-hexane (AMH) and ethyl acetate (AME) exhibited 71.26% and 52.87% inhibition of edema respectively. On the other hand, the aqueous (AMA) fraction showed most effective response with 67.06% analgesic activity. Additionally, the significant (p<0.05) post-treatment antipyretic effect was found by all fractions in time dependent manner. The current findings showed that AMC, AME and AMA had significant reduction in immobility time in the antidepressant test, while AMH showed mild antidepressant activity. In anticoagulant assay, the coagulation time of crude extract A. modesta and its all fractions were comparable to that of positive control aspirin (208s). Moreover, neither mortality nor lethality was observed in the tested animals. Overall, the plant extracts showed potent anti-inflammatory, antipyretic, analgesic, antidepressant and anticoagulant activities which concludes that the bark of A. modesta have significant therapeutic potential.

Evaluation of human brain hyperthermia using exergy balance equation.

Hyperthermia is caused by disturbance in the thermoregulatory system of the human body and requires emergency treatment to prevent disability or possible mortality. To design any therapeutic device for hyperthermia, an exhaustive effort is required to establish the extremities of such thermal traumas. In this context, the authors have incorporated the human-body exergy-balance equation to compute the hyperthermia thresholds. This is a pioneer attempt to model hyperthermia states. An induced-hyperthermia technique is used to evaluate the extremities of metabolic heat generation and other dependent parameters. Moreover, a case study is also presented to calculate the parameters of prime importance i.e. exergy consumption (EC) and entropy generation rate (δSg) to provide the body's accumulative and exhaustive thermal energy maxima, respectively. Furthermore, the thresholds have been evaluated and simulated by the varying body and/or environmental conditions. The resulting states have been analysed to setup critical ranges to provide the guidelines for rehabilitation therapy. A thermal manikin has also been developed, mimicking the blood circulation in humans, to further substantiate the use of an exergy-based approach. The results indicate that the exergy-based approach is well suited to model hyperthermia at pathophysiological boundaries, contrary to existing approaches which predominantly are limited to the physiological domain.