Hypothermia provides neuroprotection after cardiac arrest, hypoxic-ischemic encephalopathy, and in animal models of ischemic stroke. However, as drug development for stroke has been beset by translational failure, we sought additional evidence that hypothermia protects human neurons against ischemic injury.

Systemic inflammation is accompanied by an increased production of reactive oxygen species (ROS) and by either fever or hypothermia (or both). To study aseptic systemic inflammation, it is often induced in rats by the intravenous administration of bacterial lipopolysaccharide (LPS). Knowing that bilirubin is a potent ROS scavenger, we compared responses to LPS between normobilirubinemic Gunn rats (heterozygous, asymptomatic; J/+) and hyperbilirubinemic Gunn rats (homozygous, jaundiced; J/J) to establish whether ROS mediate fever and hypothermia in aseptic systemic inflammation. These two genotypes correspond to undisturbed versus drastically suppressed (by bilirubin) tissue accumulation of ROS, respectively. A low dose of LPS (10 μg/kg) caused a typical triphasic fever in both genotypes, without any intergenotype differences. A high dose of LPS (1,000 μg/kg) caused a complex response consisting of early hypothermia followed by late fever. The hypothermic response was markedly exaggerated, whereas the subsequent fever response was strongly attenuated in J/J rats, as compared to J/+ rats. J/J rats also tended to respond to 1,000 μg/kg with blunted surges in plasma levels of all hepatic enzymes studied (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase), thus suggesting an attenuation of hepatic damage. We propose that the reported exaggeration of LPS-induced hypothermia in J/J rats occurs via direct inhibition of nonshivering thermogenesis by bilirubin and possibly via a direct vasodilatatory action of bilirubin in the skin. This hypothermia-exaggerating effect might be responsible, at least in part, for the observed tendency of J/J rats to be protected from LPS-induced hepatic damage. The attenuation of the fever response to 1,000 μg/kg could be due to either direct actions of bilirubin on thermoeffectors or the ROS-scavenging action of bilirubin. However, the experiments with 10 μg/kg strongly suggest that ROS signaling is not involved in the fever response to low doses of LPS.

Regulatory T cells (Tregs) play crucial role in maintenance of peripheral tolerance. Recent clinical trials confirmed safety and efficacy of Treg treatment of deleterious immune responses. However, Tregs lose their characteristic phenotype and suppressive potential during expansion ex vivo. Therefore, multiple research teams have been studding Treg biology in aim to improve their stability in vitro. In the current paper, we demonstrate that mild hypothermia of 33 °C induces robust proliferation of Tregs, preserves expression of FoxP3, CD25 and Helios, and prevents TSDR methylation during culture in vitro. Tregs expanded at 33 °C have stronger immunosuppressive potential and remarkably anti-inflammatory phenotype demonstrated by the whole transcriptome sequencing. These observations shed new light on impact of temperature on regulation of immune response. We show that just a simple change in temperature can preserve Treg stability, function and accelerate their proliferation, responding to unanswered question- how to preserve Treg stability in vitro.

No abstract available

Introduction: Cochlea implants can cause severe trauma leading to intracochlear apoptosis, fibrosis, and eventually to loss of residual hearing. Mild hypothermia has been shown to reduce toxic or mechanical noxious effects, which can result in inflammation and subsequent hearing loss. This paper evaluates the usability of standard surgical otologic rinsing as cooling medium during cochlea implantation as a potential hearing preservation technique. Material and Methods: Three human temporal bones were prepared following standard mastoidectomy and posterior tympanotomy. Applying a retrocochlear approach leaving the mastoidectomy side intact, temperature probes were placed into the basal turn (n = 4), the middle turn (n = 2), the helicotrema, and the modiolus. Temperature probe positions were visualized by microcomputed tomography (μCT) imaging and manually segmented using Amira® 7.6. Through the posterior tympanotomy, the tympanic cavity was rinsed at 37°C in the control group, at room temperature (in the range between 22 and 24°C), and at iced water conditions. Temperature changes were measured in the preheated temporal bone. In each temperature model, rinsing was done for 20 min at the pre-specified temperatures measured in 0.5-s intervals. At least five repetitions were performed. Data were statistically analyzed using pairwise t-tests with Bonferroni correction. Results: Steady-state conditions achieved in all three different temperature ranges were compared in periods between 150 and 300 s. Temperature in the inner ear started dropping within the initial 150 s. Temperature probes placed at basal turn, the helicotrema, and middle turn detected statistically significant fall in temperature levels following body temperature rinses. Irrigation at iced conditions lead to the most significant temperature drops. The curves during all measurements remained stable with 37°C rinses. Conclusion: Therapeutic hypothermia is achieved with standard surgical irrigation fluid, and temperature gradients are seen along the cochlea. Rinsing of 120 s duration results in a therapeutic local hypothermia throughout the cochlea. This otoprotective procedure can be easily realized in clinical practice.

No abstract available

The cytotoxicity of the arsenical vesicant Lewisite was assessed in first passage cultures of proliferating neonatal human skin keratinocytes. Both munitions grade and distilled Lewisite were extremely toxic with LC(50) values in the low ng/ml range, with no significant differences between them. This similarity in toxicity was also mirrored with respect to their toxic effects on hairless guinea pig skin. Two-, 4- and 6-min vapour exposures of these agents resulted in similar and severe skin injury that was obvious by 3-5h post-exposure and almost maximal at 24h. The toxicity of Lewisite in culture was temperature dependent, with a >10-fold reduction in 24h LC(50) values as the incubation temperature was reduced from 37 to 25 degrees C. However, this cooling induced protection was not persistent. In contrast, cooling of Lewisite exposed hairless guinea pig skin at approximately 10 degrees C for as little as 30 min post-exposure resulted in dramatic and permanent protection, with 4h of cooling almost completely eliminating Lewisite induced skin injury. Further, significant protection was also evident even when cooling was delayed for as long as 2h post-Lewisite exposure. In an effort to investigate whether cooling might also increase the window in which chelation therapy against this vesicant agent would be useful, we examined the protective effects of the heavy metal chelator dimercaptosuccinic acid (DMSA). Topical application to Lewisite exposed skin was extremely protective, even when delayed for 2h after Lewisite. Cooling of Lewisite exposed skin for 2h, followed by DMSA topical application resulted in decreased skin injury compared to either treatment in isolation. It appears that the simple and non-invasive application of cooling measures may provide not only significant therapeutic relief to Lewisite exposed skin, but that it may also increase the therapeutic window in which medical countermeasures against this vesicant agent are useful.

Therapeutic hypothermia (TH) is a potent neuroprotectant against multiple forms of brain injury, but in some cases, prolonged cooling is needed. Such cooling protocols raise the risk that TH will directly or indirectly impact neuroplasticity, such as after global and focal cerebral ischemia or traumatic brain injury. TH, depending on the depth and duration, has the potential to broadly affect brain plasticity, especially given the spatial, temporal, and mechanistic overlap with the injury processes that cooling is used to treat. Here, we review the current experimental and clinical evidence to evaluate whether application of TH has any adverse or positive effects on postinjury plasticity. The limited available data suggest that mild TH does not appear to have any deleterious effect on neuroplasticity; however, we emphasize the need for additional high-quality preclinical and clinical work in this area.

Mild hypothermia improves survival and neurological outcome after cardiac arrest, as well as increasing activation of the extracellular-signal-regulated kinase (ERK) in hippocampus. ERK signaling is involved in neuronal growth and survival. We tested the hypothesis that the beneficial effects of hypothermia required ERK activation. ERK activation was measured by immunoblotting with phosphorylation-specific antibodies. Rats (n = 8 per group) underwent 8 min of asphyxial cardiac arrest and were resuscitated with chest compressions, ventilation, epinephrine and bicarbonate. At 30 min after resuscitation, vehicle (50% saline:50% DMSO) or the ERK kinase inhibitor U0126 (100 microg) was infused into the lateral ventricle. Cranial temperature was kept at either 33 degrees C (hypothermia) or 37 degrees C (normothermia) between 1 and 24 h. Neurological function was assessed daily for 14 days. Surviving neurons were counted in the hippocampus. A dose of 100 mug U0126 inhibited ERK bilaterally for 12 to 24 h and decreased phosphorylation of the ERK substrates ATF-2 and CREB. As in previous studies, hypothermia improved survival, neurological and histological outcome after cardiac arrest. However, survival, neurological score and histology did not differ between U0126 and vehicle-treated rats after cardiac arrest. Therefore, a dose of U0126 sufficient to inhibit biochemical markers of ERK signaling in hippocampus does not alter the beneficial effects of hypothermia induced after resuscitation in rats and did not affect recovery of normothermia-treated rats. These results suggest that hypothermia-induced improvement in outcomes does not require ERK activation.

No abstract available

Although hypothermia has received substantial attention as an indicator of severity in anaphylaxis, it has been neglected from the perspective of whether it could act as a disease-modifying factor in this condition. Here, the impact of naturally occurring (spontaneous) hypothermia on anaphylaxis was evaluated in a murine model of ovalbumin (OVA)-induced allergy. Nonextreme changes in the ambient temperature (Ta) were used to modulate the magnitude of spontaneous hypothermia. At a Ta of 24°C, challenge with OVA intraperitoneally or intravenously resulted in a rapid, transient fall in body core temperature, which reached its nadir 4-6°C below baseline in 30 min. This hypothermic response was largely attenuated when the mice were kept at a Ta of 34°C. The Ta-dependent attenuation of hypothermia resulted in a survival rate of only 30%, as opposed to survival of 100% in the condition that favored the development of hypothermia. The protective effect of hypothermia did not involve changes in the rate of mast cell degranulation, as assessed by the concentration of mast cell protease-1 in bodily fluids. On the other hand, hypothermia improved oxygenation of the brain and kidneys, as indicated by higher NAD+/NADH ratios. Therefore, it is plausible to propose that naturally occurring hypothermia makes organs more resistant to the anaphylactic insult.

Rewarming from accidental hypothermia is often complicated by hypothermia-induced cardiac dysfunction, calling for immediate pharmacologic intervention. Studies show that although cardiac pharmacologic support is applied when rewarming these patients, a lack of updated treatment recommendations exist. Mainly due to lack of clinical and experimental data, neither of the international guidelines includes information about pharmacologic cardiac support at temperatures below 30 °C. However, core temperature of accidental hypothermia patients is often reduced below 30 °C. Few human studies exploring effects of adrenergic drugs during hypothermia have been published, and therefore prevailing information is collected from pre-clinical studies. The most prominent finding in these studies is an apparent depressive effect of adrenaline on cardiac function when used in doses which elevate cardiac output during normothermia. Also noradrenaline and isoprenaline largely lacked positive cardiac effects during hypothermia, while dopamine is a more promising drug for supporting cardiac function during rewarming. Data and information from these studies are in support of the prevailing notion; not to use adrenergic drugs at core temperatures below 30 °C.

The urocortin1 (Ucn1) neurons of the mid-brain-localized Edinger-Westphal nucleus (EW) are robustly responsive to ethanol (EtOH) administration, and send projections to the dorsal raphe nucleus (DRN), which contains corticotropin-releasing factor type 2 receptors (CRF2) that are responsive to Ucn1. In addition, the DRN has been shown to be involved in regulation of body temperature, a function greatly affected by EtOH administration. The goal of the present study was to identify the role that the urocortinergic projections from the EW to the DRN have in mediating EtOH-induced and lipopolysaccharide (LPS)-induced hypothermia. Male C57BL6/J mice were used. Groups of mice underwent cannulation of the DRN, and then received i.p. injections of EtOH (2g/kg) or LPS (600 microg/kg or 400 microg/kg), followed by intra-DRN injections of artificial cerebrospinal fluid (aCSF) or anti-sauvagine (aSVG) (55 pmol), a CRF2 antagonist. Separate groups of mice received single intra-DRN injections of Ucn1 (20 pmol), CRF (20 pmol) or aCSF. For all experiments, core temperatures were monitored rectally every 30 min for several hours post-injection. Both EtOH and LPS induced hypothermia, and aSVG significantly attenuated this effect after EtOH; however, there was no significant attenuation of hypothermia after either dose of LPS. Ucn1 injection also caused hypothermia, while CRF injection did not. These data demonstrate that EtOH-induced hypothermia, but not LPS-induced hypothermia, may involve Ucn1 from EW acting at CRF2 receptors in the DRN.

Therapeutic hypothermia (TH) is considered to improve survival with favorable neurological outcome in the case of global cerebral ischemia after cardiac arrest and perinatal asphyxia. The efficacy of hypothermia in acute ischemic stroke (AIS) and traumatic brain injury (TBI), however, is not well studied. Induction of TH typically requires a multimodal approach, including the use of both pharmacological agents and physical techniques. To date, clinical outcomes for patients with either AIS or TBI who received TH have yielded conflicting results; thus, no adequate therapeutic consensus has been reached. Nevertheless, it seems that by determining optimal TH parameters and also appropriate applications, cooling therapy still has the potential to become a valuable neuroprotective intervention. Among the various methods for hypothermia induction, intravascular cooling (IVC) may have the most promise in the awake patient in terms of clinical outcomes. Currently, the IVC method has the capability of more rapid target temperature attainment and more precise control of temperature. However, this technique requires expertise in endovascular surgery that can preclude its application in the field and/or in most emergency settings. It is very likely that combining neuroprotective strategies will yield better outcomes than utilizing a single approach.

Chronic critical illness (CCI) is a phenotype that occurs frequently in patients with severe injury. Previous work has suggested that inflammatory changes leading to CCI occur early following injury. However, the modifiable factors associated with CCI are unknown. We hypothesized that hypothermia, an early modifiable factor, is associated with CCI.

Many mechanisms have been proposed to explain acute antidepressant drug-induced activation of TrkB neurotrophin receptors, but several questions remain. In a series of pharmacological experiments, we observed that TrkB activation induced by antidepressants and several other drugs correlated with sedation, and most importantly, coinciding hypothermia. Untargeted metabolomics of pharmacologically dissimilar TrkB activating treatments revealed effects on shared bioenergetic targets involved in adenosine triphosphate (ATP) breakdown and synthesis, demonstrating a common perturbation in metabolic activity. Both activation of TrkB signaling and hypothermia were recapitulated by administration of inhibitors of glucose and lipid metabolism, supporting a close relationship between metabolic inhibition and neurotrophic signaling. Drug-induced TrkB phosphorylation was independent of electroencephalography slow-wave activity and remained unaltered in knock-in mice with the brain-derived neurotrophic factor (BDNF) Val66Met allele, which have impaired activity-dependent BDNF release, alluding to an activation mechanism independent from BDNF and neuronal activity. Instead, we demonstrated that the active maintenance of body temperature prevents activation of TrkB and other targets associated with antidepressants, including p70S6 kinase downstream of the mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3β (GSK3β). Increased TrkB, GSK3β, and p70S6K phosphorylation was also observed during recovery sleep following sleep deprivation, when a physiological temperature drop is known to occur. Our results suggest that the changes in bioenergetics and thermoregulation are causally connected to TrkB activation and may act as physiological regulators of signaling processes involved in neuronal plasticity.

Macro-modeling of cerebral blood flow can help determine the impact of thermal intervention during instances of head trauma to mitigate tissue damage. This work presents a bioheat model using a 3D fluid-porous domain coupled with intersecting 1D arterial and venous vessel trees. This combined vascular porous (VaPor) model resolves both cerebral blood flow and energy equations, including heat generated by metabolism, using vasculature extracted from MRI data and is extended using a tree generation algorithm. Counter-current flows are expected to increase thermal transfer within the brain and are enforced using either the vascular structure or flow reversal, represented by a flow reversal constant, C R . These methods exhibit larger average brain cooling (from 0.56 °C ± <0.01 °C to 0.58 °C ± <0.01 °C) compared with previous models (0.39 °C) when scalp temperature is reduced. An greater reduction in core brain temperature is observed (from 0.29 °C ± <0.01 °C to 0.45 °C ± <0.01 °C) compared to previous models (0.11 °C) due to the inclusion of counter-current cooling effects. The VaPor model also predicts that a hypothermic average temperature (<36 °C) can be reached in core regions of neonatal models using scalp cooling alone.

Anaesthesia is commonly employed prior to surgical investigations and to permit icv injections in rodents. Indeed it is standard practise in many studies examining the subsequent actions of hormones and growth factors on the brain. Recent evidence that the basal activity of specific intracellular signalling proteins can be affected by anaesthesia prompted us to examine the effect of anaesthesia not only on the basal activity but also the insulin sensitivity of the major insulin signalling pathways.

A six-year-old boy fell into an ice-cold mountain stream and was immediately washed away. He was rescued 65 min later, 6 1/2 km downstream, seemingly lifeless with a rectal temperature of 16.4 degrees C. He was flown by helicopter to the surgical clinic of Innsbruck University, while resuscitation measures were undertaken by an accompanying doctor. After cannulation of the femoral artery and vein, extracorporeal circulation (ECC) with a child-size oxygenator was started and the blood rewarmed over 96 min in steps of 3 degrees C. Once circulatory stability and adequate cardiac output had been achieved ECC was gradually discontinued while the patient was still slightly hypothermic. Ten months after the accident the boy is restored to health, except for minimal residual neurological signs. There is a high chance for full neurological recovery.

Hypothermia is a rare, but potentially fatal adverse effect of antipsychotic drug (APD) use. Although the opposite condition, hyperthermia, has been researched extensively in the context of the malignant antipsychotic syndrome, little is known about hypothermia due to APDs.