Gentamicin-Induced Chronotoxicity: Use of Body Temperature as a Orcadian Marker Rhythm

Aminoglycoside antibiotics produce varying degrees of ototoxicity, dependent on dosage time, in animals synchronized for rhythm study. Herein, we illustrate the use of an economical and reliable system to telemeter body temperature of laboratory animals as an endogenous marker rhythm for gentamicin-induxed ototoxicity. Two groups of 3 male Sprague-Dawley rats (250-400 gm) were housed in separate cages in a temperature-controlled room programmed with a 12:12 LD schedule and monitored for hearing thresholds at the frequencies of 8kHz, 16kHz, 24kHz and 32kHz at 2-week intervals. Each rat was dosed with 100 mg/kg/day gentamicin subcutaneously for a duration of 28 days. The animals from one group were dosed at their daily temperature maximum, while the animals of the other group were dosed at their daily temperature minimum. Both after 14 and 28 days of gentamicin treatment there was no important changes in auditory thresholds from baseline values when treatment was timed daily to the circadian peak of body temperature. Animals dosed daily at the trough of the circadian temperature rhythm evidenced an auditory threshold shift of between 5 and 25 dB after 14 days of treatment and a total hearing loss (80-90 dB) after 28 days of such treatment. These results document a dramatically greater level of hearing loss induced in those animals dosed with gentamicin at the body temperature trough (diurnal rest span) as compared to those dosed at the acrophase (nocturnal activity span). The findings indicate that the peak and trough of the circadian pattern of body temperature serve as meaningful markers of the resistance and susceptibility, respectively, of gentamicin-induced ototoxicity in rodent models.     

Disorders of Orcadian Body Temperature Rhythm in Severely Brain-Damaged Patients

Twenty-four hour patterns of body temperature (BT) were recorded during consecutive 3-10 day spans from 14 severely brain-damaged patients. Seven patients exhibited a normal circadian BT rhythm with an amplitude of more than 1°C and a normal phase position of the minimum BT being observed during the latter half of the nocturnal sleep. One patient with a dispersed type of sleep exhibited an extremely low amplitude of the BT rhythm with mean average 0.69°C. In this patient, an 24-hr observation span was insufficient to detect the existence of a BT rhythm. Two patients manifested disturbance of period. As acrophase of the BT rhythm varied from day to day, the standard deviation (S.D.) of mean acrophase wasextremely large. For these patients the light-dark cycle did not act as an entrainer because both had visual disturbance. A phase advance of the minimum BT was observed in four patients. The minimum BT appeared in the first half of nocturnal sleep. These three disturbances (amplitude, period and phase), were revealed only by longitudinal observation of the BT rhythm, indicating the importance of long-term observations over a sufficient period to make the nature of the rhythm disturbances clear. These disturbances were not related to that of the sleep-wake cycle, as two patients showed normal circadian BT rhythm in spite of their dispersed-type sleep.     

Effects of Work and Orcadian Rhythm on Bus Drivers' Oral Temperature

The results described in this paper originate from a research project aiming at the development of a useful measuring instrument which can demonstrate the effect of work and work circumstances on the task performer. Among other physiological (and psychometric) variables, oral temperature data were obtained from eight younger and eight older bus drivers working in various shifts. Measurements were performed in an experimental design under standardized conditions in a mobile laboratory before starting, during some rest intervals, and after finishing work. The same measurements were performed on the bus drivers in a control condition at corresponding times on a day off. The results indicated that only during the working days a temperature pattern could be detected resembling the data found in the literature (low in the morning, a maximum in the late afternoon, then a decline). No clear pattern was discernible on work-free days. On working days the mean oral temperature values were significantly higher at corresponding hours of the day. Upward deviations of the temperature pattern were found before starting work (but also at the beginning of the day off), while lower values were obtained after finishing work (especially in the shifts starting in the morning). These results might be interpreted in terms of interaction between circadian rhythm and activating and de-activating tendencies connected with (structured) daily activities.     

Effects of Work and Orcadian Rhythm on Bus Drivers' Oral Temperature

The results described in this paper originate from a research project aiming at the development of a useful measuring instrument which can demonstrate the effect of work and work circumstances on the task performer. Among other physiological (and psychometric) variables, oral temperature data were obtained from eight younger and eight older bus drivers working in various shifts. Measurements were performed in an experimental design under standardized conditions in a mobile laboratory before starting, during some rest intervals, and after finishing work. The same measurements were performed on the bus drivers in a control condition at corresponding times on a day off. The results indicated that only during the working days a temperature pattern could be detected resembling the data found in the literature (low in the morning, a maximum in the late afternoon, then a decline). No clear pattern was discernible on work-free days. On working days the mean oral temperature values were significantly higher at corresponding hours of the day. Upward deviations of the temperature pattern were found before starting work (but also at the beginning of the day off), while lower values were obtained after finishing work (especially in the shifts starting in the morning). These results might be interpreted in terms of interaction between circadian rhythm and activating and de-activating tendencies connected with (structured) daily activities.     

荒漠沙蜥活动期间的体温节律

爬行动物的体温依赖于外界热环境的变化,本研究以荒漠沙蜥(Phrynocephalus przewalskii)为对象,收集其冬眠前活动期间的体温与地面和离地10 cm的空气温度,研究爬行动物体温节律性变化与环境温度的关系.研究结果表明,荒漠沙蜥在环境温度高于20℃后开始外出活动,其体温随着地面温度和空气温度的上升而逐步...     

Effect of Ambient Temperature on the Body Temperature Rhythm of Male Gray Mouse Lemurs (Microcebus murinus)

In order to cope with the seasonal variations in ambient temperature and food availability in the natural habitat, gray mouse lemurs (Microcebus murinus) exhibit adaptive energy-saving mechanisms similar to those in hibernating species with seasonal and daily heterothermia. To determine thermoregulatory responses, via telemetry we recorded body temperature and locomotor activity variations during the breeding season in three captive male mouse lemurs kept at ambient temperatures (T_a) ranging from 18° to 34°C. Rhythms in body temperature and locomotor activity were clearly exhibited regardless of ambient temperature. As _a increased, mean body temperature increased from 36.5 ± 0.1°C to 37.6 ± 0.3°C, with significant change in the amplitude of the body temperature rhythm when _a rose above 28°C. Effects of _a were mostly due to changes in the fall in body temperature occurring daily at the beginning of the light phase when the subjects entered diurnal sleep. The daily decrease in body temperature was not modified by exposure to ambient temperatures from 18°C to 28°C whereas it disappeared under warmer condition. Changes in locomotor activity levels only delayed the occurrence of thermoregulatory modulation. These results strongly suggest that, during the breeding season, the thermoneutral zone of mouse lemurs is close to 28°C and that the diurnal fall in body temperature could be considered as an important adaptive energy-saving mechanism adjusted to ecological constraints.     

Heart Rate Orcadian Rhythm as a Biological Marker of Desynchronization in Major Depression: A Methodological and Preliminary Report

Heart rate (HR) was continuously monitored during successive 24-hr periods in 19 healthy subjects and 26 major depressed patients (DSM III-R). Recordings were performed after a 2-week wash-out period and the morningness or eveningness typology of each subject was determined. The chronobiological parameters and rhythm percentage (RP) were calculated by the single cosinor method from the smoothed HR curves of each subject. In normal subjects, HR follows a circadian rhythm (RP > 65%) with the lowest values at night. Morning type subjects have an earlier peak time (13:30) than evening type subjects (17:30). Major depressive patients were split into two groups; in the first one HR circadian rhythm was still present (RP > 63%) with a decrease in amplitude (24%) while in the second group, no circadian rhythm of HR could be detected (RP < 25%, decrease in amplitude > 70%). In the group of patients with a persisting HK circadian rhythm, no veritable phase advance was observed. Our results suggest that circadian HR rhythm, which can be easily studied with non-invasive methods, might represent a chronobiological marker of some depressions. Given the lag that exists between the rhythms of morning type and evening type subjects, our study also stresses the importance of taking into account this behavioural trait in chronobiological studies.     

Use of a novel allele of the Escherichia coli aacC4 aminoglycoside resistance gene as a genetic marker in mycobacteria

The aacC4 gene from Escherichia coli can be expressed in mycobacteria and confers resistance to apramycin. However, the major limitation of the aacC4 gene as a genetic tool is that the gene also confers resistance to kanamycin and gentamicin, two antibiotics commonly used for selection in mycobacterial genetics, thus reducing the utility of the aacC4 gene in the mycobacterial field. To overcome this problem we constructed, by chemical mutagenesis, a mutant allele of the E. coli aacC4 gene that still confers resistance to apramycin but has a reduced ability to confer resistance to kanamycin and gentamicin. We then constructed a variety of E. coli-mycobacteria shuttle plasmids containing this mutant allele.     

Design and Analysis of Temperature Preference Behavior and its Circadian Rhythm in Drosophila

The circadian clock regulates many aspects of life, including sleep, locomotor activity, and body temperature (BTR) rhythms^1,2. We recently identified a novel Drosophila circadian output, called the temperature preference rhythm (TPR), in which the preferred temperature in flies rises during the day and falls during the night ³. Surprisingly, the TPR and locomotor activity are controlled through distinct circadian neurons³. Drosophila locomotor activity is a well known circadian behavioral output and has provided strong contributions to the discovery of many conserved mammalian circadian clock genes and mechanisms⁴. Therefore, understanding TPR will lead to the identification of hitherto unknown molecular and cellular circadian mechanisms. Here, we describe how to perform and analyze the TPR assay. This technique not only allows for dissecting the molecular and neural mechanisms of TPR, but also provides new insights into the fundamental mechanisms of the brain functions that integrate different environmental signals and regulate animal behaviors. Furthermore, our recently published data suggest that the fly TPR shares features with the mammalian BTR³. Drosophila are ectotherms, in which the body temperature is typically behaviorally regulated. Therefore, TPR is a strategy used to generate a rhythmic body temperature in these flies^5-8. We believe that further exploration of Drosophila TPR will facilitate the characterization of the mechanisms underlying body temperature control in animals.     

The Circadian Body Temperature Rhythm in the Elderly: Effect of Single Daily Melatonin Dosing

The present study is part of a more extensive investigation dedicated to the study and treatment of age‐dependent changes/disturbances in the circadian system in humans. It was performed in the Tyumen Elderly Veteran House and included 97 subjects of both genders, ranging from 63 to 91 yrs of age. They lived a self‐chosen sleep‐wake regimen to suit their personal convenience. The experiment lasted 3 wks. After 1 control week, part of the group (n=63) received 1.5 mg melatonin (Melaxen?) daily at 22:30 h for 2 wks. The other 34 subjects were given placebo. Axillary temperature was measured using calibrated mercury thermometers at 03:00, 08:00, 11:00, 14:00, 17:00, and 23:00 h each of the first and third week. Specially trained personnel took the measurements, avoiding disturbing the sleep of the subjects. To evaluate age‐dependent changes, data obtained under similar conditions on 58 young adults (both genders, 17 to 39 yrs of age) were used. Rhythm characteristics were estimated by means of cosinor analyses, and intra‐ and inter‐individual variability by analysis of variance (ANOVA). In both age groups, the body temperature underwent daily changes. The MESOR (36.38±0.19°C vs. 36.17±0.21°C) and circadian amplitude (0.33±0.01°C vs. 0.26±0.01°C) were slightly decreased in the elderly compared to the young adult subjects (p<0.001). The mean circadian acrophase was similar in both age groups (17.19±1.66 vs. 16.93±3.08 h). However, the inter‐individual differences were higher in the older group, with individual values varying between 10:00 and 23:00 h. It was mainly this phase variability that caused a decrease in the inter‐daily rhythm stability and lower group amplitude. With melatonin treatment, the MESOR was lower by 0.1°C and the amplitude increased to 0.34±0.01°C, a similar value to that found in young adults. This was probably due to the increase of the inter‐daily rhythm stability. The mean acrophase did not change (16.93 vs. 16.75 h), although the inter‐individual variability decreased considerably. The corresponding standard deviations (SD) of the group acrophases were 3.08 and 1.51 h (p<0.01). A highly significant correlation between the acrophase before treatment and the phase change under melatonin treatment indicates that this is due to a synchronizing effect of melatonin. Apart from the difference in MESOR, the body temperature rhythm in the elderly subjects undergoing melatonin treatment was not significantly different from that of young adults. The data clearly show that age‐dependent changes mainly concern rhythm stability and synchronization with the 24 h day. A single daily melatonin dose stabilizes/synchronizes the body temperature rhythm, most probably via hypothermic and sleep‐improving effects.     

Temperature Dependency of Circadian Period in a Single Cell (Acetabularia)

The circadian rhythm in the oxygen production of 30 individual Acetabularia cells has been studied at different temperatures. The temperature induced period variation was continuously evaluated over the whole data record of each individual cell with an advanced spectral analysis technique. The observed circadian periods of O₂ production displayed a well established region of temperature compensation between 25 °C and 30 °C with a Q₁₀, value of 0.9, whereas between 15°C and 22°C a positive temperature coefficient was measured (Q₁₀ at 22 °C 0.9, Q₁₀ at 20°C 0.8, Q₁₀at 17°C 0.7).     

The Circadian Rhythm of Core Temperature: Origin and some Implications for Exercise Performance

This review first examines reliable and convenient ways of measuring core temperature for studying the circadian rhythm, concluding that measurements of rectal and gut temperature fulfil these requirements, but that insulated axilla temperature does not. The origin of the circadian rhythm of core temperature is mainly due to circadian changes in the rate of loss of heat through the extremities, mediated by vasodilatation of the cutaneous vasculature. Difficulties arise when the rhythm of core temperature is used as a marker of the body clock, since it is also affected by the sleep‐wake cycle. This masking effect can be overcome directly by constant routines and indirectly by “purification” methods, several of which are described. Evidence supports the value of purification methods to act as a substitute when constant routines cannot be performed. Since many of the mechanisms that rise to the circadian rhythm of core temperature are the same as those that occur during thermoregulation in exercise, there is an interaction between the two. This interaction is manifest in the initial response to spontaneous activity and to mild exercise, body temperature rising more quickly and thermoregulatory reflexes being recruited less quickly around the trough and rising phase of the resting temperature rhythm, in comparison with the peak and falling phase. There are also implications for athletes, who need to exercise maximally and with minimal risk of muscle injury or heat exhaustion in a variety of ambient temperatures and at different times of the day. Understanding the circadian rhythm of core temperature may reduce potential hazards due to the time of day when exercise is performed.     

The Validity of Temperature-Sensitive Ingestible Capsules for Measuring Core Body Temperature in Laboratory Protocols

The human core body temperature (CBT) rhythm is tightly coupled to an endogenous circadian pacemaker located in the suprachiasmatic nucleus of the anterior hypothalamus. The standard method for assessing the status of this pacemaker is by continuous sampling of CBT using rectal thermometry. This research sought to validate the use of ingestible, temperature-sensitive capsules to measure CBT as an alternative to rectal thermometry. Participants were 11 young adult males who had volunteered to complete a laboratory protocol that extended across 12 consecutive days. A total of 87 functional capsules were ingested and eliminated by participants during the laboratory internment. Core body temperature samples were collected in 1-min epochs and compared to paired samples collected concurrently via rectal thermistors. Agreement between samples that were collected using ingestible sensors and rectal thermistors was assessed using the gold-standard limits of agreement method. Across all valid paired samples collected during the study (n?=?120,126), the mean difference was 0.06°C, whereas the 95% CI (confidence interval) for differences was less than ±0.35°C. Despite the overall acceptable limits of agreement, systematic measurement bias was noted across the initial 5?h of sensor-transit periods and attributed to temperature gradations across the alimentary canal. (Author correspondence: david.darwent@unisa.edu.au)     

Older Poor-Sleeping Women Display a Smaller Evening Increase in Melatonin Secretion and Lower Values of Melatonin and Core Body Temperature Than Good Sleepers

Melatonin concentration and core body temperature (CBT) follow endogenous circadian biological rhythms. In the evening, melatonin level increases and CBT decreases. These changes are involved in the regulation of the sleep-wake cycle. Therefore, the authors hypothesized that age-related changes in these rhythms affect sleep quality in older people. In a cross-sectional study design, 11 older poor-sleeping women (aged 62–72 yrs) and 9 older good-sleeping women (60–82 yrs) were compared with 10 younger good-sleeping women (23–28 yrs). The older groups were matched by age and body mass index. Sleep quality was assessed by the Pittsburgh Sleep Quality Index questionnaire. As an indicator of CBT, oral temperature was measured at 1-h intervals from 17:00 to 24:00?h. At the same time points, saliva samples were collected for determining melatonin levels by enzyme-linked immunosorbent assay (ELISA). The dim light melatonin onset (DLMO), characterizing the onset of melatonin production, was calculated. Evening changes in melatonin and CBT levels were tested by the Friedman test. Group comparisons were performed with independent samples tests. Predictors of sleep-onset latency (SOL) were assessed by regression analysis. Results show that the mean CBT decreased in the evening from 17:00 to 24:00?h in both young women (from 36.57°C to 36.25°C, p < .001) and older women (from 36.58°C to 35.88°C, p < .001), being lowest in the older poor sleepers (p < .05). During the same time period, mean melatonin levels increased in young women (from 16.2 to 54.1 pg/mL, p < .001) and older women (from 10.0 to 23.5 pg/mL, p < .001), being lowest among the older poor sleepers (from 20:00 to 24:00?h, p < .05 vs. young women). Older poor sleepers also showed a smaller increase in melatonin level from 17:00 to 24:00?h than older good sleepers (mean?±?SD: 7.0?±?9.63 pg/mL vs. 15.6?±?24.1 pg/mL, p = .013). Accordingly, the DLMO occurred at similar times in young (20:10?h) and older (19:57?h) good-sleeping women, but was delayed ～50?min in older poor-sleeping women (20:47?h). Older poor sleepers showed a shorter phase angle between DLMO and sleep onset, but a longer phase angle between CBT peak and sleep onset than young good sleepers, whereas older good sleepers had intermediate phase angles (insignificant). Regression analysis showed that the DLMO was a significant predictor of SOL in the older women (R²?=?0.64, p < .001), but not in the younger women. This indicates that melatonin production started later in those older women who needed more time to fall asleep. In conclusion, changes in melatonin level and CBT were intact in older poor sleepers in that evening melatonin increased and CBT decreased. However, poor sleepers showed a weaker evening increase in melatonin level, and their DLMO was delayed compared with good sleepers, suggesting that it is not primarily the absolute level of endogenous melatonin, but rather the timing of the circadian rhythm in evening melatonin secretion that might be related to disturbances in the sleep-wake cycle in older people. (Author correspondence: mdittmar@zoologie.uni-kiel.de)     

Changes of Body Temperature and Thermoregulation in the Course of the Ovarian Cycle in Laboratory Mice

In the course of the ovarian cycle, numerous physiological functions, particularly body temperature, undergo pronounced changes. The role played in cycle-dependent changes by activity is still a matter of debate. In female laboratory mice, body temperature and motor activity have been measured telemetrically, every 10 min for one month, while the stage of the estrous cycle was determined by means of vaginal smears. The circadian rhythm of body temperature underwent regular infradian changes corresponding to the sexual cycle, with body temperature higher on the days of estrous. Also, the level of motor activity was slightly elevated on days of estrous, though less consistently so. As shown by the method of purification, the temperature increase on the days of estrous was not caused by the higher activity but, presumably, rather by hormonal changes around the time of ovulation. After removing the direct effect of motor activity on the body temperature, the difference between estrous and non-estrous days was even more marked. The purification method also enabled the gradient of temperature change per unit activity, a measure of thermoregulatory efficiency, to be estimated. This gradient was lower on the days of estrous, mainly because of the higher temperatures then, but also partly due to changed thermoregulatory mechanisms. Thus, it would seem that hormones not only increase the body temperature in estrous but also promote-heat loss mechanisms. Despite the quite marked cycle-dependent changes in body temperature, it was not possible to use the temperature profile on a particular day to classify that day as an estrous or a non-estrous day; only a consideration of data from several consecutive days allowed this determination to be made.     

Differences in Daily Rhythms of Wrist Temperature Between Obese and Normal-Weight Women: Associations With Metabolic Syndrome Features

The circadian rhythm of core body temperature is associated with widespread physiological effects. However, studies with other more practical temperature measures, such as wrist (WT) and proximal temperatures, are still scarce. The aim of this study was to investigate whether obesity is associated with differences in mean WT values or in its daily rhythmicity patterns. Daily patterns of cortisol, melatonin, and different metabolic syndrome (MetS) features were also analyzed in an attempt to clarify the potential association between chronodisruption and MetS. The study was conducted on 20 normal-weight women (age: 38?±?11 yrs and BMI: 22?±?2.6?kg/m²) and 50 obese women (age: 42?±?10 yrs and BMI: 33.5?±?3.2?kg/m²) (mean?±?SEM). Skin temperature was measured over a 3-day period every 10?min with the “Thermochron iButton.” Rhythmic parameters were obtained using an integrated package for time-series analysis, “Circadianware.” Obese women displayed significantly lower mean WT (34.1°C?±?0.3°C) with a more flattened 24-h pattern, a lower-quality rhythm, and a higher intraday variability (IV). Particularly interesting were the marked differences between obese and normal-weight women in the secondary WT peak in the postprandial period (second-harmonic power [P2]), considered as a marker of chronodisruption and of metabolic alterations. WT rhythmicity characteristics were related to MetS features, obesity-related proteins, and circadian markers, such as melatonin. In summary, obese women displayed a lower-quality WT daily rhythm with a more flattened pattern (particularly in the postprandial period) and increased IV, which suggests a greater fragmentation of the rest/activity rhythm compared to normal-weight women. These 24-h changes were associated with higher MetS risk. (Author correspondence: garaulet@um.es)     

Simultaneous Collection of Body Temperature and Activity Data in Burrowing Mammals: a New Technique

Abstract: Integrating physiological and behavioral observations into ecological field studies of animals can provide novel insights into relationships among animal behavior, physiology, and ecology. We describe and evaluate a new technique for simultaneously collecting body temperature (T_b) and burrow use data for semi-fossorial mammals by combining light-sensitive radiotransmitters and implanted temperature-sensitive dataloggers. We used this approach to collect core T_b and activity data for 9 free-ranging arctic ground squirrels (Spermophilus parryii) in northern Alaska, USA, at approximately 5-minute intervals for 30–90 days each to address questions related to thermoregulation, energetics, foraging, sociality, and timing of activity in natural environments.     

Wrist Skin Temperature,Motor Activity,and Body Position as Determinants of the Circadian Pattern of Blood Pressure

Although the circadian blood pressure (BP) pattern has been extensively studied, the determinants of this rhythm are not fully understood. Peripheral vasodilatation is a regulatory mechanism for BP maintenance. However, it remains to be established whether the increase of nocturnal distal skin temperature associated with heat loss could also reflect the dipping status. For the first time, this paper investigates the relationship between BP and skin wrist temperature (WT), to evaluate whether the WT circadian rhythm can serve as screening procedure to detect dipping/non-dipping BP patterns. In addition, the authors compare the relationship between WT and other variables previously described as determinants of the BP pattern, such as physical activity and body position. Measurements of WT, motor activity, and body position for 5 d, plus ambulatory BP for 24-h during that span, were obtained from 28 diurnally active normotensive volunteers. WT was negatively correlated, whereas activity and body position were positively correlated, with systolic and diastolic BPs. However, these relationships were stronger during the rest than activity phase. In addition, a 78.6% concordance was detected between the observed dips in BP and the predicted BP pattern calculated based on the WT rhythm. Thus, these results suggest that the increase in WT produced by heat loss during the rest phase through peripheral skin blood vessels is the result of blood vessel vasodilatation reflexes in response to a shift from a standing to a supine position, together with shift in the circadian sympathetic/parasympathetic balance (nocturnal parasympathetic activation). In conclusion, WT could be considered as a potential new screening procedure to implement the diagnosis of non-dipping BP pattern. (Author correspondence: angerol@um.es)