Insulin sensitivity, leptin, adiponectin, resistin, and testosterone in adult male and female rats after maternal-neonatal separation and environmental stress.

Care of premature infants often requires parental and caregiver separation, particularly during hypoxic and hypothermic episodes. We have established a neonatal rat model of human prematurity involving maternal-neonatal separation and hypoxia with spontaneous hypothermia prevented by external heat. Adults previously exposed to these neonatal stressors show a sex difference in the insulin and glucose response to arginine stimulation suggesting a state of insulin resistance. The current study used this cohort of adult rats to evaluate insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)], plasma adipokines (reflecting insulin resistance states), and testosterone. The major findings were that daily maternal-neonatal separation led to an increase in body weight and HOMA-IR in adult male and female rats and increased plasma leptin in adult male rats only; neither prior neonatal hypoxia (without or with body temperature control) nor neonatal hypothermia altered subsequent adult HOMA-IR or plasma adiponectin. Adult male-female differences in plasma leptin were lost with prior exposure to neonatal hypoxia or hypothermia; male-female differences in resistin were lost in the adults that were exposed to hypoxia and spontaneous hypothermia as neonates. Exposure of neonates to daily hypoxia without spontaneous hypothermia led to a decrease in plasma testosterone in adult male rats. We conclude that neonatal stressors result in subsequent adult sex-dependent increases in insulin resistance and adipokines and that our rat model of prematurity with hypoxia without hypothermia alters adult testosterone dynamics.

Acute Administration of the Nonpathogenic, Saprophytic Bacterium, Mycobacterium vaccae, Induces Activation of Serotonergic Neurons in the Dorsal Raphe Nucleus and Antidepressant-Like Behavior in Association with Mild Hypothermia.

Peripheral immune activation can have profound physiologic and behavioral effects. One mechanism through which immune activation may affect physiology and behavior is through actions on brainstem neuromodulatory systems, such as serotonergic systems. To test this hypothesis, in Experiment 1, adult male BALB/c mice were implanted with telemetric recording devices and then immunized with Mycobacterium vaccae NCTC 11659 (0.1 mg, s.c.; Days - 28, - 14; N = 36). On Day 1, mice received an acute challenge with M. vaccae (0.1 mg, s.c.) or borate-buffered saline vehicle. Core body temperature and locomotor activity recordings were conducted during a 36 h period beginning 24 h prior to challenge; 12 h following acute challenge, mice were either tested in a 6-min forced swim test, or served as home cage controls (n = 9 per group). In Experiment 2, the protocol was repeated, but with the aim of assessing c-Fos expression in brainstem serotonergic neurons, assessed 90 min following exposure to forced swim (N = 32; n = 8 per group). In Experiment 1, acute M. vaccae challenge in M. vaccae-immunized mice, relative to vehicle-challenged controls, decreased locomotor activity and core body temperature measured 3 h following challenge, as measured by continuous telemetric recordings, and decreased immobility in the forced swim test measured 12 h following challenge. In Experiment 2, acute M. vaccae challenge in M. vaccae-immunized mice decreased home cage locomotion, in alignment with findings in Experiment 1, as measured by video-based behavioral analysis, and, among mice exposed to the forced swim test, increased c-Fos expression in subsets of serotonergic neurons within the dorsal raphe nucleus (DR) measured 13.5 h following challenge. Together, these data are consistent with the hypothesis that acute peripheral immune activation with a heat-killed preparation of M. vaccae transiently induces mild hypothermia in association with suppression of locomotor activity, activates subsets of serotonergic neurons in the DR, and induces antidepressant-like behavioral responses.

Behavioural traits propagate across generations via segregated iterative-somatic and gametic epigenetic mechanisms.

Parental behavioural traits can be transmitted by non-genetic mechanisms to the offspring. Although trait transmission via sperm has been extensively researched, epidemiological studies indicate the exclusive/prominent maternal transmission of many non-genetic traits. Since maternal conditions impact the offspring during gametogenesis and through fetal/early-postnatal life, the resultant phenotype is likely the aggregate of consecutive germline and somatic effects; a concept that has not been previously studied. Here, we dissected a complex maternally transmitted phenotype, reminiscent of comorbid generalized anxiety/depression, to elementary behaviours/domains and their transmission mechanisms in mice. We show that four anxiety/stress-reactive traits are transmitted via independent iterative-somatic and gametic epigenetic mechanisms across multiple generations. Somatic/gametic transmission alters DNA methylation at enhancers within synaptic genes whose functions can be linked to the behavioural traits. Traits have generation-dependent penetrance and sex specificity resulting in pleiotropy. A transmission-pathway-based concept can refine current inheritance models of psychiatric diseases and facilitate the development of better animal models and new therapeutic approaches.

Hypothermia Associated With Thioridazine Use in an Intellectually Disabled Patient.

PURPOSE: To report a case of hypothermia in a patient with intellectual disability treated with thioridazine. SUMMARY: A 59-year-old female presented to the emergency department with altered mental status, generalized weakness, chills, and fatigue and was diagnosed with a urinary tract infection. Upon completion of a history and physical examination, the patient was found to be hypothermic with a temperature of 91 F. A Bair Hugger protocol was initiated to manage hypothermia, and a taper schedule for thioridazine was initiated as it was identified as a possible culprit for the patient's hypothermia. According to the Naranjo probability scale, thioridazine was a possible cause of this adverse effect. Other patient-specific risk factors for hypothermia were evaluated and ruled out. CONCLUSION: This case indicates a possible correlation between hypothermia and the use of phenothiazine antipsychotics such as thioridazine. Appropriate measures, including early detection and identification of possible causative agents, should be taken to prevent and treat this adverse event in patients taking these medications, specifically in patients with the inability to participate in self-care.

Impairment of Rat Spatial Learning and Memory in a New Model of Cold Water-Induced Chronic Hypothermia: Implication for Alzheimer's Disease.

Alzheimer's disease (AD) is a primary neurodegenerative disorder associated with progressive memory impairment. Recent studies suggest that hypothermia may contribute to the development and exacerbation of AD. The aim of this study was to investigate the role of chronic hypothermia on spatial learning and memory performance as well as brain immunohistochemical (IHC) and molecular changes. Four groups of male rats were placed in cold water (3.5 ± 0.5 °C) once a day for 1, 3, 6, and 14 days, four other groups were placed in warm water (32 °C) as the control groups to eliminate the effect of swimming stress, and one more group which comprised intact animals that were kept in a normothermic situation and had no swimming stress. Twenty-four hours after the last intervention, spatial learning and memory were assessed, using the modified Morris water maze. After the behavioral test, the rats' brains were removed for IHC and Western blotting. The results showed that memory retrieval is impaired after 14 days of cold water-induced hypothermia (CWH) (P < 0.05). IHC showed the formation of beta-amyloid plaques after a 14-day CWH. The molecular changes demonstrated that a 14-day CWH induces tau hyperphosphorylation, apoptosis, and reduces COX-II expression. Therefore, chronic CWH, independent of forced swimming stress, impairs learning and memory through molecular mechanisms similar to those of AD. In conclusion, CWH may serve as an important model to assess the role of hypothermia in AD pathogenesis.

The lonely mouse - single housing affects serotonergic signaling integrity measured by 8-OH-DPAT-induced hypothermia in male mice.

Male BALB/c mice single-housed for a period of three weeks were found to respond with a more marked hypothermia to a challenge with a selective serotonergic agonist (8-OH-DPAT) than their group-housed counterparts. This effect of single housing was verified by screening a genetically heterogeneous population of male mice on a C57BL/6 background from a breeding colony. Enhanced activity of the implicated receptor (5-HT1A) leading to an amplified hypothermic effect is strongly associated with depressive states. We therefore suggest that the 8-OH-DPAT challenge can be used to demonstrate a negative emotional state brought on by e.g. long-term single housing in male laboratory mice. The study emphasizes the importance of social housing, and demonstrates that male mice deprived of social contact respond with altered serotonergic signaling activity. Male mice not only choose social contact when given the option, as has previously been shown, but will also, when it is deprived, be negatively affected by its absence. We propose that the 8-OH-DPAT challenge constitutes a simple, but powerful, tool capable of manifesting the effect of social deprivation in laboratory mice. It potentially allows not only for an unbiased, biochemical evaluation of psychological stressors, but may also allow for determining whether the effect of these can be counteracted.

Mild hypothermia can disrupt extinction learning but not original conditioning.

Using a retrograde amnesia procedure, the susceptibility of the extinction of fear conditioning was assessed in two experiments. Extinction of a passive-avoidance task was impaired by a body-cooling treatment (e.g., hypothermia; [7]) which was too mild to induce amnesia for the avoidance training, suggesting that the memory for extinction is more susceptible to body cooling than the memory for the initial fear conditioning. Decreasing the severity of the treatment decreased its ability to disrupt extinction. Thus, the study demonstrates a difference in the vulnerability to amnesia of fear conditioning vs. extinction of that fear.

Hypothermia after chronic mild stress exposure in rats with a history of postnatal maternal separations.

The circadian system develops and changes in a gradual and programmed process over the lifespan. Early in life, maternal care represents an important zeitgeber and thus contributes to the development of circadian rhythmicity. Exposure to early life stress may affect circadian processes and induce a latent circadian disturbance evident after exposure to later life stress. Disturbance of the normal regulation of circadian rhythmicity is surmised to be an etiological factor in depression. We used postnatal maternal separation in rats to investigate how the early life environment might modify the circadian response to later life unpredictable and chronic stress. During postnatal days 2-14, male Wistar rats (n = 8 per group) were daily separated from their mothers for a period of either 180 min (long maternal separation; LMS) or 10 min (brief maternal separation; BMS). In adulthood, rats were exposed to chronic mild stress (CMS) for 4 weeks. Body temperature, locomotor activity and heart rate were measured and compared before and after CMS exposure. LMS offspring showed a delayed body temperature acrophase compared to BMS offspring. Otherwise, adult LMS and BMS offspring demonstrated similar diurnal rhythms of body temperature, locomotor activity and heart rate. Exposure to CMS provoked a stronger and longer lasting hypothermia in LMS rats than in BMS rats. The thermoregulatory response appears to be moderated by maternal care following reunion, an observation made in the LMS group only. The results show that early life stress (LMS) in an early developmental stage induced a thermoregulatory disturbance evident upon exposure to unpredictable adult life stressors.

Being cold when injured in a cold environment--patients' experiences.

BACKGROUND: Patients in prehospital care, irrespective of diseases or trauma might experience thermal discomfort because of a cold environment and are at risk for decreasing body temperature which can increase both morbidity and mortality. OBJECTIVE: To explore patients' experiences of being cold when injured in a cold environment. METHOD: Twenty persons who had been injured in a cold environment in northern Sweden were interviewed. Active heat supply was given to 13 of them and seven had passive heat supply. The participants were asked to narrate their individual experience of cold and the pre- and post-injury event, until arrival at the emergency department. The interviews were transcribed verbatim, then analyzed with qualitative content analysis. RESULTS: Patients described that they suffered more from the cold than because of the pain from the injury. Patients who received active heat supply experienced it in a positive way. Two categories were formulated: Enduring suffering and Relief of suffering. CONCLUSION: Thermal discomfort became the largest problem independent of the severity of the injuries. We recommend the use of active heat supply to reduce the negative experiences of thermal discomfort when a person is injured in a cold environment.

[Case report: fatal diving-accident. Or: accident while diving?]. / Tödlicher Tauchunfall. Oder: Unfall während des Tauchens mit Todesfolge?

This example of a fatal diving accident shows how challenging such cases can be in pre-hospital and clinical care. There is no common mechanism in diving fatalities and more than one group of disorders coming along with decompression sickness. Diving medicine is not an element of medical education, which results in insecurity and hampers adequate therapy of diving incidents. This is aggravated by an insufficient availability of hyperbaric chambers in Germany.

Lack of effect of dopaminergic denervation on caudate-putamen hyperthermia or hypothermia induced by drugs and mild stressors.

A number of drugs and psychological stressors induce brain hyperthermia and increase extracellular dopamine in the caudate-putamen. The present study tested whether caudate-putamen hyperthermia produced by such stimuli is dependent on dopaminergic transmission. Rats were infused with 6-hydroxydopamine unilaterally into the medial forebrain bundle, and after a two-week recovery period, removable thermocouples were used to monitor temperature in the depleted and intact caudate-putamen in freely-moving animals. The indirect dopamine agonist d-amphetamine (1 and 2mg/kg s.c.) increased caudate-putamen temperature, whereas a low dose of the direct agonist apomorphine (0.1mg/kg s.c.) reduced it. Gamma-butyrolactone, which strongly inhibits dopamine release at the dose administered (700mg/kg i.p.), initially reduced and then increased caudate-putamen temperature. Brief (5-10min) presentation of mild stressors, including tail pinch, produced a rapid and transient caudate-putamen hyperthermia. Quantitative (125)I-RTI-55 autoradiography in post-mortem tissue revealed a 97-100% loss of binding to dopamine transporters in the lesioned caudate-putamen. Despite this near-total dopamine denervation, neither basal caudate-putamen temperature, nor any of the observed temperature responses to drugs or mild stressors, was altered. We conclude that in the caudate-putamen, endogenous dopamine is unlikely to modulate temperature significantly at a local level.

Conversion of elderly to Alzheimer's dementia: role of confluence of hypothermia and senescent stigmata--the plausible pathway.

Aging is a consequence of progressive decline in special and somatosensory functions and specific brain stem nuclei. Many senescent stigmata, including hypoxia, hypoxemia, depressed cerebral blood flow and glucose metabolism, diseases of senescence, and their medications all enhance hypothermia as do alcohol, cold environment, and malnutrition. Hypothermia is a critical factor having deleterious impact on brain stem and neocortical functions. Additionally, anesthesia in elderly also promotes hypothermia; anesthetics not only cause consciousness (sensory and motor) changes, but memory impairment as well. Anesthesia inhibits cholinergic pathways, reticular and thalamocortical systems, cortico-cortical connectivity, and causes post-operative delirium and cognitive dysfunction. Increasing evidence indicates that anesthetic exposures may contribute to dementia onset and Alzheimer's disease (AD) in hypothermic elderly. Inhaled anesthetics potentiate caspases, BACE, tau hyperphosphorylation, and apoptosis. This paper addresses the important question: "Why do only some elderly fall victim to AD"? Based on information on the pathogenesis of early stages of cognitive dysfunction in elderly (i.e., due to senescent stigmata), and the effects of anesthesia superimposed, a detailed plausible neuropathological substrate (mechanism/pathway) is delineated here that reveals the possible cause(s) of AD. Basically, it encompasses several risk factors for cognitive dysfunction during senescence plus several hypothermia-enhancing routes; they all converge and tip the balance towards dementia onset. This knowledge of the confluence of heterogeneous risk factors in perpetuating dementia relentlessly is of importance in order to: (a) avoid their convergence; (b) take measures to stop/reverse cognitive dysfunction; and (c) to develop therapeutic strategies to enhance cognitive function and attenuate AD.

A single bout of torpor in mice protects memory processes.

Memory consolidation is the process by which new and labile information is stabilized as long-term memory. Consolidation of spatial memories is thought to involve the transfer of information from the hippocampus to cortical regions. While the hypometabolic and hypothermic state of torpor dramatically changes hippocampal connectivity, little work has considered the functional consequences of these changes. The present study examines the role of a single bout of shallow torpor in the process of memory consolidation in mice. Adult female C57Bl/6NHSD mice were trained on the Morris Water Maze (MWM) task. Immediately following acquisition, the mice were exposed to one of four experimental manipulations for 24 h: fasted at an ambient temperature of 19 degrees C, fasted at 29 degrees C, allowed free access to food at 19 degrees C, or allowed free access to food at 29 degrees C. Mice fasted at 19 degrees C entered a bout of torpor as assessed by core body temperature while none of the mice in the other conditions did so. Spatial biases were then assessed with a probe trial in the MWM. During the probe trial, mice that had entered torpor and mice that were fed at 29 degrees C spent twice as much time in the prior target platform location than mice that were fed at 19 degrees C and those that were fasted at 29 degrees C. These findings demonstrate that, while food restriction or cool ambient temperature independently disrupt memory processes, together they cause physiological changes including the induction of a state of torpor that result in functional preservation of the memory process.

Survey of public knowledge and responses to educational slogans regarding cold-water immersion.

OBJECTIVES: Cold water temperature is a significant factor in North American drownings. These deaths are usually attributed to hypothermia. Survey questions were administered to 661 attendees of cold-stress seminars-including medical, rescue, law enforcement and lay attendees-to determine general knowledge of the effects of ice water immersion and responses to 2 public service educational slogans. METHODS: Five questions were posed at the beginning of seminars to 8 groups (ranging in size from 46 to 195) during a 2-year period. Pi(2) analyses were used to determine if responses within any occupational category differed from the group responses. RESULTS: A high portion of respondents greatly underestimated the time to become hypothermic in ice water (correct answer >30 minutes; 84% stated 15 minutes or less) and the time until cooling was life threatening (correct answer >60 minutes; 85% stated 30 minutes or less). There were no occupational differences in these responses. Most of the respondents identified a correct cause of death during cold stress (81% stated cardiac arrest, hypothermia, or drowning). Although both educational slogans had some advantages, between 40% (Slogan #1) to 50% (Slogan #2) of respondents did not respond correctly. CONCLUSIONS: The majority of respondents underestimated the time available for survival during ice water immersion. It is important to educate the public accurately to decrease the probability of panic under these circumstances. More work is required to develop effective educational slogans that provide proper information and actions for victims of cold-water immersion.

Time-window for sensitivity to cooling distinguishes the effects of hypothermia and protein synthesis inhibition on the consolidation of long-term memory.

The effects of hypothermia on memory formation have been examined extensively, and while it is clear that post-training cooling interferes with the process of consolidation, the nature of the temperature sensitive processes disrupted in this way remain poorly defined. Post-training manipulations that disrupt consolidation tend to be effective during specific time-windows of sensitivity, the timing and duration of which are directly related to the mechanism through which the treatment induces amnesia. As such, different treatments that target the same basic processes should be associated with similar time-windows of sensitivity. Using this rationale we have investigated the possibility that cooling induced blockade of long-term memory (LTM) stems from the disruption of protein synthesis. By varying the timing of post-training hypothermia we have determined the critical period during which cooling disrupts the consolidation of appetitive long-term memory in the pond snail Lymnaea. Post-training hypothermia was found to disrupt LTM only when applied immediately after conditioning, while delaying the treatment by 10 min left the 24 h memory trace intact. This brief (<10 min) window of sensitivity differs from the time-window we have previously described for the protein synthesis inhibitor anisomycin, which was effective during at least the first 30 min after conditioning [Fulton, D., Kemenes, I., Andrew, R. J., & Benjamin, P. R. (2005). A single time-window for protein synthesis-dependent long-term memory formation after one-trial appetitive conditioning. European Journal of Neuroscience, 21, 1347-1358]. We conclude that hypothermia and protein synthesis inhibition exhibit distinct time-windows of effectiveness in Lymnaea, a fact that is inconsistent with the hypothesis that cooling induced amnesia occurs through the direct disruption of macromolecular synthesis.

Neuropsychological outcome following near-drowning in ice water: two adult case studies.

Two men, 56 and 33 years old, (case 1 and case 2) were examined neuropsychologically after successful resuscitation from circulatory arrest following extreme accidental hypothermia and near drowning. After submersion in ice water for at least 20 minutes they received CPR for 45 to 60 minutes. Body-core temperature at start of CPB was 24 degrees C and 22 degrees C, respectively. A neuropsychological examination was performed within two months after the accident and 1 year later. An additional follow-up interview was made 3 years after the accidents. Both had severe problems with memory, visuospatial performance, executive function, and verbal fluency. The follow-up demonstrated improvement in the visuospatial test in both and in the verbal learning, recall, and logical reasoning tests in case 2. Both still had problems with executive function, and case 2 also in verbal fluency. Case 1 also had problems with flexibility, planning and abstract ability. Despite the protective effects of hypothermia and gradual improvement of symptoms over time, some of the deficits were permanent. A thorough neuropsychological examination of patients suffered from anoxia is advisable, because gross neurological examination and MRI scans may not always reveal underlying brain dysfunction.

Control of hormonal stress reactivity by the endogenous opioid system.

Regulations of hormonal stress responses entail the initiation, amplitude and termination of the reaction, as well as its integration with other stress response systems. This study investigates the role of endogenous opioids in the regulation and integration of behavioral, thermal and hormonal stress responses, as these neuromodulators and their receptors are expressed in limbic structures responsible for stress responses. For this purpose, we subjected mice with selective deletion of beta-endorphin, enkephalin or dynorphin to the zero-maze test, a mildly stressful situation, and registered behaviors and stress hormone levels. Behavioral stress reactivity was assessed using zero-maze, light-dark and startle-reactivity paradigms. Animals lacking enkephalin displayed increased anxiety-related behavioral responses in each three, dynorphin knockouts in two models, whereas the responses of beta-endorphin knockouts indicated lower anxiety level in the zero-maze test. All knockout strains showed marked changes in hormonal stress reactivity. Increase in ACTH level after zero-maze test situation, unlike in wild type animals, failed to reach the level of significance in Penk1(-/-) and Pdyn(-/-) mice. Corticosterone plasma levels rapidly increased in all strains, with a lower peak response in knockouts. In wild-type and beta-endorphin-deficient mice, corticosterone levels returned to baseline within 60min after stress exposure. In contrast, mice lacking dynorphin and enkephalin showed longer-lasting elevated corticosterone levels, indicating a delayed termination of the stress reaction. Importantly, the behavioral and hormonal responses correlated in wild-type but not in knockout mice. Hyperthermia elicited by stress was reduced in animals lacking dynorphin and absent in Penk1(-/-) mice, despite of the heightened behavioral anxiety level of these strains. These results demonstrate an important role on the endogenous opioid system in the integration of behavioral and hormonal stress responses.

Central hypothermia as a cause of acute pancreatitis in children with neurodevelopmental impairment.

Children with severe neurodevelopmental impairment are at risk for recurrent hypothermia, defined as a temperature of less than 35 degrees C, as a result of hypothalamic dysfunction. Acute pancreatitis following hypothermia from environmental exposure or induced as medical therapy has been reported in adults. In this case series of 10 children (six males, four females) with severe neurodevelopmental impairment and associated hypothermia, five had an episode of acute pancreatitis. These five patients had documented hypothermia, an elevated lipase of greater than 1000U/L, and presenting symptoms of irritability or lethargy along with gastrointestinal symptoms such as feeding intolerance. Four of these five children had no other explanation for pancreatitis; the fifth had multiple gallstones. This case series identifies the risk of acute pancreatitis in children with central hypothermia. Monitoring for resolution upon establishment of euthermia can minimize unnecessary testing and cost.

Cognitive, psychomotor, and physical performance in cold air after cooling by exercise in cold water.

INTRODUCTION: This study evaluated performance after lowering core temperature at different rates while local tissues were either cooled (lower body) or not cooled (upper body). METHODS: There were 10 men who volunteered to perform up to 8 cold water immersions (CWI) at combinations of 2 water temperatures (10 degrees C and 15 degrees C), 2 depths [waist (W), chest (C)], and 2 walking speeds (0.44 or 0.88 m x s(-1)) until their core temperature fell to 35.5 degrees C, stabilized above that temperature, or they requested to stop. They also completed a control trial (120 min rest in 19 degrees C air). Immediately following each CWI and control, cognitive and physical performance tests were performed in cold air (10 degrees C; CAE). RESULTS: Overall, the CWI protocol lowered rectal temperature by 0.3-1.0 degrees C. Mean skin temperature was approximately 26 degrees C and finger temperature was approximately 15 degrees C during CAE. No statistical differences were observed across trials for any cognitive test. On the physical performance tests, step test performance was degraded approximately 12% on CWI trials compared with control, but there were no differences in manual dexterity, hand grip strength, marksmanship, or pull-ups. CONCLUSIONS: These results indicate that cognitive performance can be maintained despite mild hypothermia, and that physical performance is related to local tissue temperature, not a moderately reduced core temperature.