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General and local cold responses in humans after 2 weeks at high altitude.

To investigate the effects of a short-term high altitude residence (2 weeks between 4150 m and 6885 m in the Andes) on the general and local cold responses after descent, 11 subjects were submitted both to a whole body standard cold air test (SCAT, dry bulb temperature = 1 degree C, 2 h, nude, at rest) and to a local cold water test of the right upper limb (CWT, 5 degrees C, 5 min) both before and after the expedition. Compared to before the expedition, a lower systolic blood pressure was observed after the high altitude residence [130.00 (SEM 3.35) mm Hg vs 140.40 (SEM 4.74) mm Hg at the end of CWT, P < 0.05] whereas no significant change either in diastolic blood pressure or in heart rate was found. All skin temperatures of the right upper limb were lowered (P < 0.05). During SCAT, body temperatures were unchanged (rectal and mean skin temperature, Tsk) but metabolic heat production was slightly but significantly diminished [110 (SEM 4) W.m-2 vs 125 (SEM 3) W.m-2, P < 0.05] and heat debt increased [11.37 (SEM 1.11) kJ.kg-1 vs 9.30 (SEM 2.30) kJ.kg-1, P < 0.05]. Moreover, the time of onset of continuous shivering (d) was shortened [8.20 (SEM 1.90) min vs 17.30 (SEM 3.60) min, P < 0.05] and the level of Tsk observed at (d) was higher [25.70 (SEM 0.80) degrees C vs 23.57 (SEM 0.78) degrees C, P < 0.05] suggesting an increase in the sensitivity of the thermoregulatory system despite the slight decreased shivering activity observed. It was concluded that general and local cold tolerance were modified by a short-term residence at altitude and that the changes observed were not in accordance with general or (and) local cold adaptation. In contrast, high altitude sojourn could be a risk factor for frostbite of the extremities.

Altitude↗

Fatty acid synthesis in mouse brown adipose tissue. The influence of environmental temperature on the proportion of whole-body fatty acid synthesis in brown adipose tissue and the liver.

Fatty acid synthesis has been measured in vivo with 3H2O in mice acclimated at different environmental temperatures (33, 22, 4 degrees C), and the importance of brown adipose tissue and the liver to whole-body fatty acid synthesis at each temperature assessed. At 33 degrees C, when non-shivering thermogenesis is minimal, the rate of fatty acid synthesis in interscapular brown adipose tissue was lower than in the liver, but higher than in white adipose tissue and the carcass. At 4 degrees C, when non-shivering thermogenesis is maximal, the fatty acid synthesis rate in interscapular brown adipose tissue was many times greater than in any other tissue. High fatty acid synthesis rates were also found in other brown adipose tissue depots--subscapular, dorsocervical and axillary--of cold-acclimated mice. In mice maintained at 22 degrees C the rate of fatty acid synthesis was also higher in brown adipose tissue than in other tissues. Overall, the relative importance of brown adipose tissue as a site of fatty acid synthesis increased with lower environmental temperatures, while that of the liver decreased. It was calculated that brown adipose tissue in total accounted for approx. 5% of whole-body fatty acid synthesis at 33 degrees C, 10% at 22 degrees C and 30% at 4 degrees C. In contrast, hepatic synthesis amounted to 32% of whole-body fatty acid synthesis at 33 degrees C, 16% at 22 degrees C and only 11% at 4 degrees C. An estimate of the contribution that de novo synthesis makes to total fatty acid utilization by interscapular brown adipose tissue suggests that fatty acid synthesis and breakdown constitutes a significant heat-dissipating 'cycle' in brown adipose tissue of cold-acclimated mice. Such a cycle is not evident in suckling animals since fatty acid synthesis in brown adipose tissue is very low during early development.

Adaptation, Physiological↗

Impaired activation of thermogenesis in the corpulent rat.

The capacity for non-shivering thermogenesis was measured in groups of 12 week-old congenic lean and corpulent LA/N-cp rats of both sexes to determine if their obese state might be associated with an impairment in energy expenditure via non-shivering thermogenesis. Body weights of the corpulent phenotypes were 1.6 to 1.8 times greater than those of the lean phenotype. Measurements of resting oxygen consumption were similar in lean and in corpulent rats, and were greater in female than in male rats. Isoproterenol stimulation resulted in a significant increase in oxygen consumption in lean rats, while the rates of oxygen consumption of isoproterenol-stimulated corpulent rats were unchanged. Acute exposure of male rats to a 5 degrees C cold environment resulted in significant decreases in colonic and in rectal temperature in both phenotypes, but body temperatures recovered more rapidly in lean than in corpulent rats. Urinary VMA excretion was greater in lean than in corpulent rats and increased following cafeteria-feeding in lean but not in corpulent rats. These observations are consistent with an impaired mechanism of sympathetically-mediated thermogenesis in the corpulent phenotype of the LA/N-cp rat, and which may be a contributing factor in the development of their obese state via a decreased capacity for energy expenditure.

Animals↗

Improving cold tolerance in elderly rats by aminophylline.

During severe cold exposure, old rats (23-26 months) were less capable in maintaining normal body temperature as compared to young rats (6-9 months) due to lower rate of heat production (HP). Single injection of optimal doses of aminophylline (AMPY; 10 and 18.7 mg/kg, i.p.), a phosphodiesterase inhibitor which enhances the intracellular cyclic AMP concentration, significantly increased the rate of HP in old rats to levels beyond the control values observed in young rats. Consequently, cold tolerance of the old rats was significantly improved. This AMPY-improved cold tolerance is apparently not due to increased non-shivering thermogenesis (NST) since AMPY failed to enhance norepinephrine-stimulated NST in the old rats. It is likely that AMPY increased substrate mobilization and/or conversion, thereby circumventing the limiting role of substrate availability for shivering thermogenesis. Thus, the age-dependent decrease in cold tolerance may be due to a reduced capacity for substrate mobilization when challenged by cold.

Aging↗

Role of the stretch reflex in oxotremorine tremor.

Although the basic mechanism for parkinsonian tremor is known to be central, the case for the oscillator(s) of physiological tremor and shivering is still a matter of dispute. In this case, an important role has been proposed for muscle afferents. Oxotremorine tremor has in common with shivering its frequency range (10-28 Hz) and the co-contraction of flexors and extensors. On the other hand, in contradistinction, it can be blocked by atropine, as is the case with parkinsonian tremor. Thus it was of interest to analyze the role of muscle afferents in the production and maintenance of oxotremorine tremor in the acutely decorticated cat. This was studied with two experimental approaches. In one, either a front or hind limb of a cat was completely deafferented by dorsal rhizotomy and the tremor activity recorded electromyographycally in a pair of antagonistic muscles. In the other, the nerve and muscle electrical activity and force produced by the tremoring muscle (gastrocnemius) were recorded simultaneously. Tremor activity was induced by oxotremorine injection (200-750 micrograms/kg i.p.) given at different postoperative periods. The drug induced a regular tremor in the chronically deafferented animals (3 weeks to 5 months) but not in the acutely deafferented limb (3 hrs after dorsal rhizotomy). The tremor observed in the former group was very regular and had the same frequency range (10-28 Hz) for both normal and deafferentd sides. Section of all the muscle afferents of a given pool (agonist and its main synergist) did not have any effect on the regularity and frequency of the oscillation (tremor) of that pool. The role of other muscle and/or cutaneous afferents, although perhaps of some importance, remains unclear. A pure spinal mechanism to account for the regular oscillations (tremor) is proposed.

Animals↗

The effect of naloxone on some neuroendocrine responses to limb ischaemia.

The finding that naloxone reverses the arterial hypotension produced by bacterial endotoxin in the rat was confirmed and the effect of naloxone on the responses to another form of injury, limb ischaemia was studied. Naloxone had no effect on the fall in blood pressure and colon temperature or on behaviour and survival after bilateral hind-limb ischaemia. The ambient temperature threshold for the onset of shivering was depressed by limb ischaemia as in untreated rats. The increases in the plasma concentrations of glucose and corticosterone and the decrease in that of prolactin after limb ischaemia were unaltered by naloxone. In control rats naloxone reduced the ambient temperature threshold for the onset of shivering and the plasma prolactin concentration. It is concluded that the endogenous opioids do not play a very significant part in the responses to ischaemic limb trauma.

Animals↗

Myelin deficient mice: expression of myelin basic protein and generation of mice with varying levels of myelin.

Mice homozygous for the mutation myelin deficient (mld), an allele of shiverer, exhibit decreased CNS myelination, tremors, and convulsions of progressively increasing severity leading to an early death. In this report we demonstrate in mld mice that the gene encoding myelin basic protein (MBP) is expressed at decreased levels and on an abnormal temporal schedule relative to the wild-type gene. Southern blot analyses, field-inversion gel electrophoresis studies, and analyses of mld MBP cosmid clones indicate that there are multiple linked copies of the MBP gene in mld mice. We have introduced an MBP transgene into mld mice and found that myelination increases and tremors and convulsions decrease. Mld and shiverer mice with zero, one, or two copies of the MBP transgene express distinct levels of MBP mRNA and myelin. The availability of a range of mice expressing graded levels of myelin should facilitate quantitative analysis of the roles of MBP in the myelination process and of myelin in nerve function.

Alleles↗

Immunohistochemical, biochemical and electron microscopic analysis of myelin formation in the central nervous system of myelin deficient (mld) mutant mice.

Myelin deficiency (mld) is an autosomal recessive mutation in mice and is considered to be allelic to the shiverer (shi) mutation. Mld mice are characterized by hypomyelination of the central nervous system (CNS). They show typical symptoms such as tremor, tonic convulsion and ataxic movement. Subcellular fractionation of the CNS revealed that the MBP bands were greatly decreased in the P2A (myelin) fraction and the total content of myelin basic protein (MBP) was much lower than that in the control in all parts of the CNS. Sections from mld mice were examined by immunohistochemical tests with MBP antiserum, and a mosaic expression of MBP was found in the myelin of the mld mice. Since the major dense line is considered to be composed mainly of MBP, we investigated the myelin of mld mice by electron microscopy and found that there were 3 types of myelin: (1) a normal type compact myelin with a major dense line, (2) a shiverer-type myelin with no major dense line, and (3) a mixed-type myelin, in which within a myelin lamella the major dense line abruptly changes to cytoplasm of oligodendrocytes.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

Repair of a myelin lesion by Schwann cells transplanted in the adult mouse spinal cord.

In multiple sclerosis and experimental demyelination, oligodendrocytes and Schwann cells are able to repair myelin lesions of the central nervous system. However, spontaneous myelin repair is often insufficient. Several approaches to enhance remyelination have been considered and transplantation of myelin-forming cells has been proposed as one of them. In this paper, we present results which confirm the ability of transplanted Schwann cells to remyelinate an induced demyelinated lesion of the spinal cord. Schwann cells were either purified Schwann cells isolated from 1-2-day-old rat sciatic nerves, or immortalized Schwann cells (MSC80) arising from a purified culture of 7-day-old mouse sciatic nerves. They were transplanted into or at a distance from a lysolecithin-induced lesion of the Shiverer spinal cord. Labelling of the Schwann cells with the fluorochrome Hoechst 33342 enabled us to trace them after transplantation in their host and evaluate their ability to reach and to repair the demyelinated lesion. Using the Hoechst-Shiverer model, we show that when transplanted in the lesion, cultured Schwann cells, even immortalized, are able to remyelinate such a lesion efficiently. In addition, when transplanted at a distance from the lesion, they are able to reach and repair the lesion in time frames which allow them to compete actively with host oligodendrocytes.

Animals↗

The influence of ambient temperature on metabolism and body temperature of newborn and growing reindeer calves (Rangifer tarandus tarandus L.).

Thermoregulatory capacities of 51 reindeer calves (Rangifer tarandus tarandus L.) aged 1-35 days were studied at -26.5 to +35.0 degrees C ambient temperatures at Kaamanen reindeer research station, Finland (69 degrees 10' N) during calving periods in May 1981 and May-July 1982. The newborn calves aged 1-4 days maintained a high body temperature (Tre) (mean +40.2 degrees C) even at the lowest experimental temperature of -22.5 degrees C by increasing their metabolic rate five-fold above the level at +11.0 degrees C. Heat production of the new-born calves was largely based on the metabolism of brown adipose tissue, stimulated by cold-induced discharge of the sympathetic nervous transmitter, noradrenaline (NA). Sensitivity of the calves to exogenous NA disappeared during the first 3-4 weeks of life. Thermal conductance of the calves was low at low ambient temperatures, but rose strongly as Ta increased above +10 degrees C. The extensive peripheral cooling, especially in the feet, was demonstrated in the calves aged 1-10 days. The lowest foot temperature (+10.5 degrees C) was measured in a 4-day-old calf at -14.5 degrees C. Slight shivering thermogenesis was recorded in the calves aged 1-4 days and occasionally in the older calves at low values of Ta. Shivering appears to be a reserve mechanism against severe cold. At about +20 degrees C and above the calves increased their Tre (approximately 1 degree C), oxygen consumption and heart rate. In the newborn calves oxygen consumption rose four- to five-fold and in 1-month-old calves about two-fold. Fast growing calves (maximum 400 g/day) appear to be more stressed by heat than by cold exposure.

Aging↗

Repeated exposures to cold and the relationship between skin and core temperatures in control of metabolic rate in the goat (Capra hircus).

1. After 10-12 experiments in each of three goats, in which skin or core temperatures were lowered while the other temperatures remained sufficiently high to prevent metabolic rate from increasing, the core temperature threshold of shivering was lowered by 0.35 degrees C. 2. After 10-15 experiments, in which skin and core temperatures were simultaneously lowered to induce major increases of metabolic rate, no further change of threshold was observed, while the slope of metabolic rate over core temperature was reduced. 3. It is concluded that repeated cold exposures without manifest shivering can induce tolerance adaptation to cold.

Adaptation, Physiological↗

Hoechst 33342 a suitable fluorescent marker for Schwann cells after transplantation in the mouse spinal cord.

Purified rat Schwann cells labeled with Hoechst 33342 were transplanted into a lysophosphatidyl choline induced myelin lesion of the adult shiverer mouse spinal cord. Remyelination by grafted Schwann cells within the lesion was evidenced by codetection of Hoechst labeled Schwann cells and P0 (peripheral myelin protein) immunolabeled myelin on serial cryostat sections and confirmed on adjacent sec ions by electron microscopy. These data show that the Hoechst-shiverer model is an excellent model which can be used in intraspinal transplantation of myelin forming cells to demonstrate the origin of the newly formed myelin. Using this model, we bring the unquestionable evidence that cultured Schwann cells are capable after transplantation to participate with host oligodendrocytes in repair of a myelin lesion of the central nervous system.

Animals↗

Effect of lipid peroxidation on Na+,K(+)-ATPase, 5'-nucleotidase and CNPase in mouse brain myelin.

In the presence of H2O2, solutions of Fe2+ were applied to brain homogenate and isolated myelin from adult SWV control mice and the shiverer dysmyelinating mutant mouse as a source of a reactive oxygen species (Fenton reaction). Under these conditions, lipid peroxidation was initiated and measured as thiobarbituric acid-reactive oxidation products (TBAR). This was accompanied by 85% inhibition of myelin-associated Na+,K(+)-ATPase and 25% inhibition of 5'-nucleotidase. In contrast, CNPase activity was not altered. Studies on the shiverer mutant brain revealed that in spite of hypomyelination and prevalence of premature, myelin-like membranes in the homogenate, the myelin-related enzymes reacted as normal enzymes to peroxidation. Differences in the resistance of Na+,K(+)-ATPase to peroxidation in the brain homogenate and myelin suggest that the myelin enzyme is extremely sensitive to reactive oxygen toxicity.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

Hypothermia in hypoxic animals: mechanisms, mediators, and functional significance.

A basic tenet of biology is that body temperature (Tb) has a marked effect on oxygen uptake of resting animals. For most animals, the temperature coefficient (Q10) is >> 2.5; e.g., resting oxygen uptake changes about 11% per degree C change in Tb. An important consequence of this dependence is that hyperthermia could be deleterious for hypoxic animals, particularly for oxygen sensitive organs, e.g., heart and brain. Conversely, a moderate degree of hypothermia could be beneficial during hypoxia. This concept is not new. Forced hypothermia is sometimes used in surgical procedures, particularly for heart and brain surgery. However, in many situations where hypothermia might have benefits, e.g., pediatric intensive care, it is not permitted. This is due in part to dogma and in part to the real and potential disadvantages of hypothermia, even in severely hypoxic animals. Among these in ventricular fibrillation. This is apparently preventable if blood pH is allowed to rise following the "Buffalo Curve." Another important disadvantage, were it to occur, is elevation of oxygen demand due to a thermogenic responses. However, at least in some species, the thermogenic response is blunted during hypoxia; e.g., in young rats. Furthermore, even if a thermogenic response occurs, this takes place primarily in muscles (shivering) and brown fat (non-shivering) and not in the O2-sensitive organs, heart and brain. A third disadvantage, for prolonged hypothermia, might be impairment of the immune response, a serious problem if hypoxia is combined with infection. This paper will review four aspects of behavioral fever and hypothermia: the occurrence among animals, the mechanisms and mediators that might trigger behavioral responses, and the functional significance.

Adaptation, Physiological↗

Convergence of thermal signals on the reticulospinal neurons in the midbrain, pons and medulla oblongata.

A total of 670 reticulospinal (RfS) and non-RfS neurons in the mesencephalic, pontile and medullary reticular formation (mRf, pRf and mdRf) were studied for the responsiveness to changes in temperatures of local brain sites, preoptic and anterior hypothalamus (PO/AH) and skin in the urethane anesthetized rat. Local thermoresponsiveness was found in 49.6% of 139 mRf neurons, 61.9% of 160 pRf neurons and 75.4% of 126 mdRf neurons. While the ventromedial region of pRf and mdRf contained predominantly warm-responsive neurons (54.8% and 62.5%), cold-responsive neurons were much more frequently found in the mRf (33.8%) and the dorsolateral region of pRf (41.9%) and mdRf (50.0%). Responsiveness to hypothalamic temperature and/or skin temperature was observed in about 40-74% of Rf neurons. Higher incidence of responsiveness to remote temperatures was found among locally thermoresponsive neurons than among locally thermounresponsive neurons in all three areas. Particularly, there was a high degree of convergence of 'cold' signals from local and remote sites on the RfS neurons in the mRf and the dorsolateral pRf and mdRf. Microinjections of procaine and glutamate into these regions decreased and increased the cold-induced increase in EMG activity and shivering without any correlated changes in cardiovascular and respiratory parameters and pilomotor activity. The results suggest that RfS and non-RfS neurons in the mRf and the dorsolateral pRf and mdRf are involved in the control of thermoregulatory muscle tone and shivering.

Action Potentials↗

Age-related changes in thermoregulation in male albino rats.

Male Sprague Dawley rats were followed longitudinally from 3 to 24 months of age. Resting oxygen consumption (VO2), measured in the thermal neutral zone (29 +/- 1.0 degrees C) decreased 47% between 3 and 24 months of age with a stable period from 6 to 9 months. Changes in rectal temperature in general followed changes in VO2. On the average the decline in rectal temperature from 3 to 24 months was 0.8 degrees C. Thermal conductance dropped initially from 3 to 6 months and remained stable during further age periods. Thermal circulation index rose slightly from 3 to 13 months, and dropped thereafter from 13 to 24 months. When animals were exposed to a mild cold challenge (18-19 degrees C for 90 min.), the increase in VO2 was the same from 3 to 13 months of age. At 24 months this increase was significantly higher. The capacity for non-shivering thermogenesis (NST) measured after norepinephrine stimulation declined from 3 to 6 months, remained stable from 6 to 9 months and declined to 13 months. The capacity for NST after a mild cold challenge was significantly decreased at 24 months of age. These results suggest that shivering thermogenesis (ST) may be the main source of heat production in the old organism when faced with a mild cold challenge. Since ST is more energy consuming than NST it may explain the accidental hypothermia which occurs often in the elderly.

Aging↗

Effects of arginine vasotocin on cardiorespiratory and thermoregulatory responses in the pigeon.

1. The effects of intramuscular injections (10 ng, 100 ng, 1 mu or 10 mu/pigeon) of two preparations of synthetic arginine vasotocin (AVT), deamino-dicarba-arginine vasotocin (ddAVT) and arginine vasotocin diacetate tetrahydrate (AVTdt) on heart rate (HR), breathing frequency (BF), oxygen consumption (VO2), cloacal and foot temperatures (Tc and Tf) and shivering (S) were studied in the pigeon housed in a respiratory flow chamber maintained at a temperature of 22.5 degrees, during a 4 hr post-injection period. 2. In general, with the exception of the lowest dose, AVT-treatment produced hypothermic responses, as was indicated by Tc and Tf. 3. Both ddAVT and AVTdt produced increases in HR and BF when administered in high concentrations (10 micrograms/pigeon), the effect being more potent with AVTdt than ddAVT; with lower doses, the effects were considerably less pronounced. This increase in HR and BF is attributed to a probable compensatory response to the hypothermic effect. 4. With a 10 micrograms dose, ddAVT produced a greater decline in VO2 than AVTdt. Although other doses too evoked a drop in VO2 at certain post-injection time points, the effect was of lesser magnitude. 5. No significant shivering response was elicited, in spite of the drop in Tc. 6. It is suggested that, besides the antidiuretic function of AVT, its hypothermic effect would be of considerable importance in thermal homeostasis during flight in birds.

Animals↗

The clinical effectiveness of epidural bupivacaine, bupivacaine with lidocaine, and bupivacaine with fentanyl for labor analgesia.

STUDY OBJECTIVE: To examine the efficacy of bupivacaine alone and in combination with lidocaine or fentanyl for epidural analgesia during labor. DESIGN: Randomized, single-blind study. SETTING: Labor and delivery unit at a university medical center. PATIENTS: Forty-five primiparas requesting epidural analgesia. INTERVENTIONS: Following epidural placement at L3-4 interspace, patients received either bupivacaine 0.5% (Group 1, n = 15), bupivacaine 0.25% with lidocaine 1% (Group 2, n = 15), or bupivacaine 0.5% with fentanyl 50 micrograms in 10 ml of saline (Group 3, n = 15). Patients in Groups 1 and 2 received 6 to 10 ml of local anesthetic depending on patient height, while patients in Group 3 received 5 ml of local anesthetic plus 50 micrograms of fentanyl in 10 ml of saline. All solutions contained epinephrine 1:200,000. MEASUREMENTS AND MAIN RESULTS: Patients were assessed at regular intervals following administration of the epidural solution. Visual analog scale (VAS) scores were used to measure onset of analgesia, time to complete pain relief, duration of analgesia, and patient satisfaction with therapy. The frequency of shivering and pruritus and the extent of sensory/motor block also were evaluated. There were no intragroup differences in time to complete pain relief or patient satisfaction. However, patients in Group 3 noted the most rapid onset and longest duration of pain relief. Patients in Group 3 also experienced significantly less shivering and had the lowest degree of motor block. Two patients in Group 3 experienced mild pruritus. CONCLUSIONS: Epidurally administered fentanyl safely extended the duration of labor analgesia while reducing bupivacaine dose requirements and magnitude of motor block. In this setting, the combination of bupivacaine and lidocaine offered no clinical advantage over bupivacaine alone.

Adult↗