Onset Of Hyperthermia Research Articles

Suppressive effects of a transient receptor potential melastatin 8 (TRPM8) agonist on hyperthermia-induced febrile seizures in infant mice.

Background: Febrile seizures (FSs) are the most frequent type of seizures in infancy and childhood. Epileptiform discharges (EDs) on electroencephalogram at the time of first FS recurrence can increase the risk of epilepsy development. Therefore, inhibition of EDs is important. Recently, WS-3, a transient receptor potential melastatin 8 (TRPM8) agonist, reportedly suppressed penicillin G-induced cortical-focal EDs. However, the effects of TRPM8 agonists on FSs remain unknown. In this study, we aimed to clarify the effects of the TRPM8 agonist, and the absence of TRPM8 channels, on hyperthermia-induced FS by analyzing the fast ripple band. Methods: Hyperthermia (43°C for 30min) induced by a heating pad caused FSs in postnatal day 7 wild-type (WT) and TRPM8 knockout (TRPM8KO) mice. FSs were defined as EDs occurring during behavioral seizures involving hindlimb clonus and loss of the righting reflex. Mice were injected with 1% dimethyl sulfoxide or 1mM WS-3 20min before the onset of hyperthermia, and electroencephalograms; movies; and rectal, brain and heating pad temperatures were recorded. Results: In wild-type mice, WS-3 reduced the fast ripple amplitude in the first FS without changing rectal and brain temperature thresholds. In contrast, the anti-FS effect induced by the TRPM8 agonist was not observed in TRPM8KO mice and, compared with wild-type mice, TRPM8 deficiency lowered the rectal and brain temperature thresholds for FSs, exacerbated the fast ripple amplitude, and prolonged the duration of the initial FS induced by hyperthermia. Conclusion: Our findings suggest that TRPM8 agonists can be used to treat hyperthermia-induced FSs.

Experimental infection of sheep at mid-pregnancy with archetypal type II and type III Toxoplasma gondii isolates exhibited different phenotypic traits

Toxoplasma gondii is a major cause of reproductive failure in small ruminants. Genotypic diversity of T. gondii strains has been associated with variations in phenotypic traits in in vitro and murine models. However, whether such diversity could influence the outcome of infection in small ruminants remains mostly unexplored. Here, we investigate the outcome of oral challenge in sheep at mid-pregnancy with 10 sporulated oocysts from three different T. gondii isolates belonging to archetypal II and III and selected according to their genetic and phenotypic variations shown in previous studies. Seventy-three pregnant sheep were divided in four groups: G1 infected with TgShSp1 isolate (type II, ToxoDB#3), G2 with TgShSp16 isolate (type II, ToxoDB#3), G3 with TgShSp24 isolate (type III, ToxoDB#2) and G4 of uninfected control sheep. Two different approaches were carried out within this study: (i) the outcome for the pregnancy after infection (n = 33) and (ii) the lesions and parasite tropism and burden at 14 and 28 days post infection (dpi) (n = 40). The onset of hyperthermia and seroconversion occurred one and two days later, respectively in G1 when compared to G2 and G3. However, sheep that suffered from reproductive failure, either by abortion, foetal dead at the time of euthanasia or stillbirth were similar among infected groups (50%, 40% and 47%, respectively). Histological lesions in placentomes and foetal tissues from euthanized animals from the second approach were only detected at 28 dpi and mainly in G1. At 14 dpi, T. gondii-DNA was only detected in G1 in the 11% of the placentomes. However, at 28 dpi the frequency of detection in placentomes was higher in G1 (96%) than in G2 and G3 (7% and 47%, respectively) besides in foetuses was lower in G2 (20%) than in G1 and G3 (100% and 87%, respectively). Regarding late abortions, stillbirths, and lambs of G1, G2 and G3, the frequency of microscopic lesions was similar between groups (79%, 78% and 67%, respectively) whereas T. gondii-DNA was evidenced in 100%, 55% and 100%, respectively. These recently obtained T. gondii isolates led to similar reproductive losses but intra- and inter-genotype variations in the rise of hyperthermia, dynamics of antibodies, frequency of lesions and parasite detection and distribution. Thus, the different phenotypic traits of the isolates could influence the outcome of the infection and mechanisms responsible for it, and further investigations are warranted.

Early stage leucocytosis in Nigerian pigs experimentally infected with <i>Trypanosoma brucei</i>

Sequential leukocyte changes associated with early phase of Trypanosoma brucei infection were investigated in indigenous Nigerian pigs. This was with the view to providing further hematological basis for effective chemotherapy of natural porcine trypanosomosis and to assessing the possible roles of leukocytes in determining tolerance to infecting trypanosomes in this early phase of infection, earlier believed to be a crisis period for most infected animals. The parameters measured included, daily body temperatures and weekly body weights as indicators of onset of clinical aspect of the disease as well as total and differential white blood cell (WBC) counts. After infection, parasitemia was first detected in the pigs on day 3 post-infection (PI) which was accompanied by onset of hyperthermia, manifested as rise in rectal temperatures on the same day and afterwards by undulating increase throughout the 40 day observation period. The weekly body weights however showed fluctuating increase throughout this period. The total WBC counts of infected pigs increasedprogressively from the pre-infection value of 13.2±1.4 x 109 /L to the peak value of 38.5±12.6 x 109 /L (which corresponded to 191.7% increase above pre-infection values) on day 40 post infection (PI) while that of the control group only fluctuated within normal range. This was accompanied by an overwhelming, fluctuating surge in lymphocyte counts from the pre-infection value of 8.2±0.4 x 109 /L from day 1 to the peak value of 33.5±11.2 x 109 /L (corresponding to 308.5% increase above pre-infection values) on day 40 PI (P<0.05). The neutrophil counts also increased, though with a lesser intensity from the pre-infection value of 4.8±1.1 x 109 /Lto the peak value of 6.6±3.3 x 109/L (corresponding to 37.5% increase above pre-infection values) on day 17 PI (P<0.05) which is at variance to the known hematological derangement patterns in most trypanosome infections. These were also accompanied by persistent eosinopenia but fluctuating monocytosis in the infected group. It was concluded that leukocyte derangement in the early phase of T. brucei infection of pigs was characterized by overwhelming lymphocytosis and was attributed to strain specific trypanosome antigenic challenge leading to an increased proliferation of immunocompetent cells into antibody and or lymphokineproducing cells. This is believed to be beneficial to the host as it could serve as determinant of host tolerance to infecting trypanosome and ability to survive this crisis phase of T. brucei infections.Keywords: Pigs, leukocytosis, lymphocytosis, Trypanosoma brucei, early phase.

Dual responsive magnetic composite nanogels for thermo-chemotherapy

With the onset of hyperthermia and their advantage in increasing vascular perfusion and permeability in the cancer milieu, thermo-responsive polymers have become an attractive candidate for designing therapeutic nano-vehicles for targeted on-demand delivery of bioactive agents. For this purpose, we developed a dual (thermo- and pH-) responsive nanotherapeutic composite system rendering a combinational therapy of hyperthermia mediated drug delivery. This composite system comprises of magnetic chitosan-g-PNVCL (MCP) polymeric nanogels loaded with anticancer drug, Doxorubicin (DOX). The size distribution and the stability of the MCP nanogels have been characterized using DLS and Zeta-potential studies. XRD and TG-DTA confirms the presence of magnetic nanoparticles loaded onto MCP nanogel. ICP-AES analysis was done to determine the amount of iron content in the MCP nanogels. The magnetic property of the MCP nanogels was estimated to be ∼37 emu/g using Vibrating Sample Magnetometer (VSM). The heating ability of MCP nanogels was calculated to be ∼204W/g for the concentration of 2mg/mL using time-dependent Specific Absorption Rate (SAR) method. Magnetic field induced thermo-responsive and pH responsive drug release studies were carried out and it was found that MCP nanogels have a good on-demand drug release properties. The DOX-MCP nanogels were evaluated for its in vitro killing efficacy of breast cancer cells MCF 7 and MDAMB 231 cells with synergistic effects of both hyperthermia and chemotherapy in presence of magnetic field at the concentration of 2mg/mL. Thus, MCP nanogels can be a potential dual modal on-demand hyperthermia mediated drug delivery platform for the breast cancer treatment.

Evaluation of Myocardial Damage in Dogs with Heat Stroke

Twenty cases of heat stroke in dogs, observed during hot/hot humid months, were investigated for myocardial damage, if any, employing electrocardiography and estimation of cardiac troponin-I. Heat stroke in dogs was clinically characterized by sudden onset of hyperthermia (temperature > 107.0 °F) during hot/hot humid months, impaired consciousness, severe panting and associated symptoms. Their haemogram reflected thrombocytopenia and increased levels of haemoglobin, packed cell volume, total erythrocytes and total leucocytes. Electrocardiographic abnormalities such as sinus tachycardia (heart rate 240 to 320 beats per minutes), ventricular premature complexes (8–10 per minute), ventricular tachycardia (ventricular rate 180–220), ventricular fibrillations, and 3rd degree heart block associated with increased level of cardiac troponin-I (mean 3.34±1.11 ng/ml) suggested myocardial damage in the dogs with heat stroke.

Role of hydrogen peroxide in generation of a signal inducing heat tolerance of wheat seedlings

The effects of 1-min-long exposure to 42°C (hardening heating) on heat tolerance and dynamics of ROS (superoxide anion radical and hydrogen peroxide) generation were investigated in the wheat (Triticum aestivum L., cv. Elegiya) seedlings. During the initial 5–30 min after the onset of hyperthermia, ROS generation by roots and shoots was intensified, and superoxide dismutase (SOD) was activated. During the first hour after hardening heating, the seedling tolerance to injurious 10-min-long treatment with high temperature (46°C) decreased but subsequently it gradually rose, reaching maximum in 24 h. Transient accumulation of hydrogen peroxide induced by hardening was suppressed by seedling treatment with H2O2 scavenger dimethylthiourea, by inhibitors of NADPH-oxidase (imidazole) and DDC (sodium diethyldithiocarbamate). These compounds considerably reduced favorable effect of hardening on seedling heat tolerance. It was concluded that generation of a signal inducing the development of heat tolerance depended on NADPH-oxidase producing superoxide anion radical and SOD that transforms it into hydrogen peroxide (more stable ROS performing signaling functions).

Mitochondrial dysfunction induced by heat stress in cultured rat CNS neurons

Previous work demonstrated that hyperthermia (43°C for 2 h) results in delayed, apoptotic-like death in striatal neuronal cultures. We investigated early changes in mitochondrial function induced by this heat stress. Partial depolarization of the mitochondrial membrane potential (ΔΨ(m)) began about 1 h after the onset of hyperthermia and increased as the stress continued. When the heat stress ended, there was a partial recovery of ΔΨ(m), followed hours later by a progressive, irreversible depolarization of ΔΨ(m). During the heat stress, O(2) consumption initially increased but after 20-30 min began a progressive, irreversible decline to about one-half the initial rate by the end of the stress. The percentage of oligomycin-insensitive respiration increased during the heat stress, suggesting an increased mitochondrial leak conductance. Analysis using inhibitors and substrates for specific respiratory chain complexes indicated hyperthermia-induced dysfunction at or upstream of complex I. ATP levels remained near normal for ∼4 h after the heat stress. Mitochondrial movement along neurites was markedly slowed during and just after the heat stress. The early, persisting mitochondrial dysfunction described here likely contributes to the later (>10 h) caspase activation and neuronal death produced by this heat stress. Consistent with this idea, proton carrier-induced ΔΨ(m) depolarizations comparable in duration to those produced by the heat stress also reduced neuronal viability. Post-stress ΔΨ(m) depolarization and/or delayed neuronal death were modestly reduced/postponed by nicotinamide adenine dinucleotide, a calpain inhibitor, and increased expression of Bcl-xL.

A retrospective analysis of American football hyperthermia deaths in the United States

Over the period 1980-2009, there were 58 documented hyperthermia deaths of American-style football players in the United States. This study examines the geography, timing, and meteorological conditions present during the onset of hyperthermia, using the most complete dataset available. Deaths are concentrated in the eastern quadrant of the United States and are most common during August. Over half the deaths occurred during morning practices when high humidity levels were common. The athletes were typically large (79% with a body mass index >30) and mostly (86%) played linemen positions. Meteorological conditions were atypically hot and humid by local standards on most days with fatalities. Further, all deaths occurred under conditions defined as high or extreme by the American College of Sports Medicine using the wet bulb globe temperature (WBGT), but under lower threat levels using the heat index (HI). Football-specific thresholds based on clothing (full football uniform, practice uniform, or shorts) were also examined. The thresholds matched well with data from athletes wearing practice uniforms but poorly for those in shorts only. Too few cases of athletes in full pads were available to draw any broad conclusions. We recommend that coaches carefully monitor players, particularly large linemen, early in the pre-season on days with wet bulb globe temperatures that are categorized as high or extreme. Also, as most of the deaths were among young athletes, longer acclimatization periods may be needed.

Quality of Life (QOL) Studies in Patients with Various Malignancies Treated with Local Hyperthermia Combined with Chemo- and/or Radiotherapy

Improvement in the quality of life (QOL) is considered to be one of the main goals in the treatment of patients with advanced cancer. The purpose of this study was to assess the QOL for patients during the course of combined treatments which included local hyperthermia (HT) plus chemotherapy and/or radiotherapy. Eighty nine patients (M/F ratio was 44/45) with various malignancies were questioned using the Japanese version of the ‘European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire Core 30'. Assessment was performed before the beginning of HT therapy, and after 8 weekly sessions. In addition, a longitudinal study was performed with 14 patients after 16, 24 and 30 sessions. It was seen that gender may influence various aspects of the QOL during the treatments. For instance, female patients performed better with regards to the social aspects whereas they displayed worse somatic parameters. Regarding age, although younger patients claimed more financial problems before HT, onset of HT did not cause any additional difficulties in this respect. Surprisingly, HT led to a better recovery from a loss of appetite in elderly patients. In considering the relationship between the QOL and treatment response, better responses were associated with both superior pretreatment emotional functioning and improvement in the QOL during the therapy. The best QOL performance was observed for patients with breast and lung cancer. In addition, patients who underwent long-term HT which lasted for 36 weeks, had stable QOL parameters throughout the entire period of observation. This leads us to suggest that somatic, social and psychological QOL parameters for cancer patients may be improved by combined treatment modalities which include HT. In addition, both pretreatment emotional status and improvement in the QOL during the course of treatment may influence the objective treatment outcome.

Effect of a standardized rewarming protocol and acetaminophen on core temperature after coronary artery bypass

Cardiac surgical patients who require hypothermic cardiopulmonary bypass experience hypothermia, normothermia, and hyperthermia during the early postoperative period. Research-based rewarming protocols are needed to manage temperature variations. To describe the effect of a standardized rewarming protocol and acetaminophen on the following outcome variables: core temperature, peak core temperature, rewarming time, and hyperthermia. Patients (N = 60) were rewarmed using a standardized rewarming protocol. Electric heating blankets were used for subjects with core temperatures less than 36 degrees C on admission to the intensive care unit; other subjects were covered with cotton bath blankets. Subjects were also assigned to one of three acetaminophen groups (650 mg at 38.1 degrees C, 650 mg at 37 degrees C, 1300 mg at 37 degrees C). Using the protocol, subjects warmed to normothermia in 3.6 to 6 hours. The 16-hour core temperature thermal curves of heating blanket versus cotton bath blanket subjects differed significantly; thermal curves of the acetaminophen groups were similar. Peak core temperature was significantly lower in heating blanket subjects and unaffected by acetaminophen group. The onset of hyperthermia was not significantly affected by the method of rewarming (electric heating blanket versus cotton blankets) or acetaminophen group. Rewarming time was significantly longer for electric heating blanket subjects. Our results indicate that mildly hypothermic subjects rewarmed with electric heating blankets during the early postoperative period have lower peak core temperatures and longer rewarming times than those rewarmed with cotton bath blankets. Acetaminophen administration at normothermia does not significantly affect peak core temperature or the onset of hyperthermia.

Effects of hyperthermia and/or hyperglycemia on pH and p0 2 in well oxygenated xenotransplanted human sarcoma

The heat-induced interdependent changes of tumor blood flow, p0 2, and pH decisively influence the therapeutic effect of hyperthermia (HT). This fact has induced us to determine simultaneously the frequency distribution of local pO 2 values and the intratumoral pH in a xenotransplanted human sarcoma cell line at a normal blood glucose level and under hyperglycemic conditions before, during, and after HT. Two groups, one of 10 and one of 9 congenitally athymic nude rats with a subcutaneously implanted S117 human sarcoma into the right hind paw (mean tumor volume 5.3 cm 3) were treated with local waterbath HT (tumor temperature 43°C, 1 hr) alone or in combination with i.p. glucose injections (6 g/kg, 2 hr before the onset of HT). Tumor oxygenation remained improved throughout HT. Tumor pH did not decrease during HT. Hyperglycemia alone elicited a decrease of intratumoral pH and pO 2, probably mainly due to hemoconcentration. The additional warming of the tumors (43°C) during hyperglycaemia did not further decrease pO 2 and pH. Silver stained sections of the tumors showed only a few very small necrotic areas, even in tumors of volumes up to 8 cm 3. Our results indicate a well oxygenated tumor. In contrast to most tumors studied so far, hyperthermia in this tumor induces not only an initial increase of oxygenation but a lasting elevation of mean tumor pO 2 for the duration of HT (up to 60 min).

Oxygen uptake and mean blood pressure as indicators of induced hyperthermia

This dog study was designed to identify which of two measurements (oxygen consumption, mean blood pressure) tracked the onset of hyperthermia as reflected by rectal temperature. The animals were anesthetized, paralyzed, and mechanically ventilated. Hyperthermia was induced with 2,4-dinitrophenol (5 mg/kg) injected intravenously in 5 dogs. It was found that the best and earliest predictor of approaching hyperthermia was the increase in oxygen consumption, which increased 10% in 1.72 min. Mean blood pressure was an insensitive indicator of approaching hyperthermia. Rectal temperature, not surprisingly, was found to be a late and undependable early indicator of developing hyperthermia, requiring about 15 minutes to exhibit a definite increase. It is concluded that among these indicators, monitoring oxygen consumption (ml/min) is the most reliable way to identify a metabolic change such as incipient hyperthermia.

An Evaluation of the Weinbaum-Jiji Bioheat Equation for Normal and Hyperthermic Conditions

The predictions of the simplified Weinbaum-Jiji (WJ) bioheat transfer equation in one dimension are compared to those of the complete one-dimensional three-equation model that represented the starting point for the derivation of the WJ equation, as well as results obtained using the traditional bioheat transfer equation of Pennes [6]. The WJ equation provides very good agreement with the three-equation model for vascular generations 2 to 9, which are located in the outer half of the muscle layer, where the paired vessel diameters are less than 500 microns, under basal blood flow conditions. At the same time, the Pennes equation yields a better description of heat transfer in the first generation, where the vessels' diameters are greater than 500 microns and epsilon, the vessels' normalized thermal equilibration length, is greater than 0.3. These results were obtained under both normothermic and hyperthermic conditions. A new conceptual view of the blood source term in the Pennes equation has emerged from these results. This source term, which was originally intended to represent an isotropic heat source in the capillaries, is shown to describe instead the heat transfer from the largest countercurrent microvessels to the tissue due to small vessel bleed-off. The WJ equation includes this effect, but significantly overestimates the second type of tissue heat transfer, countercurrent convective heat transfer, when epsilon greater than 0.3. Indications are that a "hybrid" model that applies the Pennes equation in the first generation (normothermic) and first two to three generations (after onset of hyperthermia) and the Weinbaum-Jiji equation in the subsequent generations would be most appropriate for simulations of bioheat transfer in perfused tissue.

The effects of the protein synthesis inhibitor anisomycin on the febrile responses to intracerebroventricular injections of bacterial pyrogen, arachidonic acid and prostaglandin E2

1. Anisomycin (15 mg/kg) was administered s.c. to cats at ambient temperatures of 5 degrees C, 20 degrees C and 38 degrees C. It produced biphasic effects on body temperature at 5 degrees C and 20 degrees C, an initial fall in temperature followed by a rise in body temperature, and a rise in body temperature of long latency at 38 degrees C. 2. Anisomycin (15 mg/kg) attenuated the hyperthermic responses to centrally injected PGE2 (1 microgram) at all ambient temperatures studied and also completely abolished the hyperthermic response to arachidonic acid (100 ng i.c.v.) at 20 degrees C. 3. Shigella dysenteriae (100 ng i.c.v.) raised the body temperature of cats by increasing heat production and reducing heat loss at 5 degrees C and 20 degrees C, and by increasing heat conservation at 38 degrees C. Anisomycin (15 mg/kg s.c.) pretreatment did not affect the temperature responses to the pyrogen at 20 degrees C and 38 degrees C, but did reduce the responses to Shigella dysenteriae (100 ng and 1 microgram i.c.v.) at 5 degrees C. 4. Anisomycin (15 mg/kg s.c.) was administered to cats, 90 min after the injection of Shigella dysenteriae (100 ng i.c.v.), at 20 degrees C at the onset of hyperthermia in control experiments. Under these conditions, no hyperthermia was observed over a 2 h period following anisomycin injection. 5. It is concluded that anisomycin interferes with pyrogen induced fever by acting at a site after PGE2 in the pathway to fever.

Serum thyroid hormone changes during whole body hyperthermia.

In order to elucidate changes in thyroid hormone metabolism during acute heat stress, we measured sequentially serum thyroxine (T4), triiothyronine (T3), and reverse T3 (rT3) levels in 5 patients with neoplasia during treatment with whole body hyperthermia. The core temperature was raised from 37.0 degrees C to 42.0 degrees C over a 2-hour period, maintained at 42.0 degrees C for 2 hours, and then cooled to 37.0 degrees C over 2 hours. This short period of severe hyperthermia produced a fivefold rise in rT3 and a fall in T3 levels to one half of baseline levels. T4 and free T4 levels increased slightly, but thyrotropin (measured in two patients) did not change. These changes in T3 and rT3 levels were detectable at the fourth hour after onset of hyperthermia, were maximal at 24 and 48 hours, and in one patient were uncorrected after 4 days. We conclude that this reciprocal change in T3 and rT3 levels is a response to stress and may represent in part adaptation to a high environmental temperature by the suppression of theromengic T3. Whole body hyperthermia of short duration for cancer therapy produces profound changes in the peripheral degradation of thyroxine, which last for several days. This must be considered in the management of patients receiving hyperthermia, and the technique itself may prove to be a useful model for the study of adaptation to heat stress.

Physiological effects of cocaine in the squirrel monkey

Doses of cocaine that have previously been shown to have behavioral effects produced dose-related increases in arterial blood pressure, heart rate and core temperature in unanesthetized squirrel monkeys ( Saimiri sciureus ). The pressor effect was immediate, but heart rate increased more gradually after cocaine injection. The onset of hyperthermia was substantially delayed. The squirrel monkey may be a good animal model of the physiological concomitants of cocaine abuse in humans.