Extremely low frequency magnetic field exposure modulates the diurnal rhythm of the pain threshold in mice

The aim of this study was to determine whether exposure to extremely low frequency magnetic field (ELF-MF) affects the normal diurnal rhythm of the pain threshold in mice. Pain thresholds were evaluated in mice using the hot plate test. A significant increase of pain threshold during night was observed compared to that during day. This rhythm was attenuated by both constant exposure to light (LL) and constant exposure to darkness (DD) for 5 days. Under DD exposure, the diurnal rhythm in pain threshold was restored when mice were exposed to ELF-MF (60 Hz, 1.5 mT for 12 h daily, from 08:00 to 20:00 h) for 5 days. The diurnal rhythm was not reversed under dark with reversed ELF-MF cycle (exposure to 1.5 mT from 20:00 to 08:00 h, next day) for 5 days, although pain threshold in the ELF-MF exposed period of night was slightly decreased. The diurnal rhythm of melatonin analgesic effect related to pain threshold was also observed under DD by the exposure of ELF-MF for 5 days, but not for 5 nights. The present results suggest that ELF-MF may participate in the diurnal rhythm of pain threshold by acting on the system that is associated with environmental light-dark cycle.     

Urinary 6-sulphatoxymelatonin excretion is increased in rats after 24 hours of exposure to vertical 50 Hz, 100 μT magnetic field

The effect of exposure to a 50 Hz, vertical magnetic field on the excretion of urinary 6-sulphatoxymelatonin (aMT6s) of rats was studied in a self-controlled experiment. Ten male Wistar rats were kept under 9:15 h light:dark conditions in metabolic cages. The rats were exposed to 1.0 or 100 μT flux density for 24 h. The excretion of aMT6s, which is the primary metabolite of melatonin in the urine, did not show a statistically significant decrease, as measured by ¹²⁵I radioimmunoassay, during or after magnetic field exposure of rats to either flux density. At 100 μT flux density, the increase of aMT6s excretion on the day after exposure was statistically significant (P < .02), compared with the value under exposure, but was not significant compared with the baseline values before exposure. Bioelectromagnetics 18:190–192, 1997. © 1997 Wiley-Liss, Inc.     

60 Hz magnetic field exposure and urinary 6-sulphatoxymelatonin levels in the rat

Four separate experiments were carried out to investigate the effect of extremely low frequency magnetic field (MF) exposure (60 Hz, 1 mT rms) on urinary 6-sulphatoxymelatonin (aMT6s) levels in Sprague-Dawley rats. In the first experiment, immature male rats maintained under a regular 12 h daily photoperiod (white fluorescent light) were exposed to a 20 h daily MF exposure for 6 weeks. The second experiment was similar to the first, except that the MF exposure was limited to 10 days. In the third experiment, adult male rats acclimated to a combination of continuous dim red light and regular 12 h daily photoperiod (white fluorescent) were subjected to a single 1 h exposure to intermittent MF (1 min on and 1 min off cycles), 2 h before fluorescent lights went off. The fourth experiment was similar to the third, except that the animals received 2 consecutive days of 20 h daily exposure to intermittent MF, beginning 1 h before the fluorescent lights went off each day. In all four experiments, the circadian profile of urinary aMT6s was examined before, during, and after the MF exposure. No significant effect of 1 mT MF on indoleamine metabolism was observed in any of the above experiments. However, in one of the experiments (no. 4), both the control and the MF groups showed a lower aMT6s level during the exposure days, when compared with that of pre- and post-exposure days, suggesting that the existence of possible effects with lower field strengths at the range of stray field cannot be ruled out. Bioelectromagnetics 19:172–180, 1998. © 1998 Wiley-Liss, Inc.     

Sinusoidal 50 Hz 500 μT magnetic field has no acute effect on urinary 6-sulphatoxymelatonin in wistar rats

The effect of a 50 Hz, vertical magnetic field on the excretion of urinary 6-sulphatoxymelatonin (aMT6s) of male and female Wistar rats was studied in a self-controlled experiment. Twenty rats were kept in metabolic cages under 9:15 h light:dark conditions. The urine of the animals was collected twice per day for 5 consecutive days. The concentration of aMT6s in the rat urine was measured by ¹²⁵I radioimmunoassay. The rats were exposed to 5 and 500 μT flux density for 24 h. The excretion of urinary aMT6s did not show significant changes during or after magnetic field exposure. © 1995 Wiley-Liss, Inc.     

Melatonin excretion of man and rats: Effect of time of day,sleep, pinealectomy and food consumption

Pineal function was assessed in human subjects by measuring the excretion of melatonin. The hormone was extracted from the urine by adsorption on a nonionic polymeric resin and then elution with organic solvents; its concentration was determined with a bioassay based ontthe dermal melanophore response of larval anurans to melatonin in their bathing medium. Melatonin excretion among healthy, adult volunteers was 5- to 7-fold greater during the hours of sleep, darkness, and recumbancy (23:00–07:00 h) than during the active, waking hours (07:00–15:00 h or 15:00–23:00 h). When 2 subjects slept only during the daylight at odd, 8-hour intervals, their melatonin excretion was also greatest during their time of sleep. Three bedfast fracture patients (for whom sleep data were not available) failed to display melatonin rhythms. A new radioimmunoassay for melatonin was investigated in preliminary studies with experimental animals and was found to be expedient and sensitive; it was not as specific as the bioassay, however. Both analytical methods were used in studies on intact and pinealectomized rats, and the findings suggest that rhythmic melatonin excretion persists (although at a reduced amplitude) in the absence of the pineal. Fasting in the pinealectomized animal abolished the day/night variation in urinary melatonin, but did not have this effect in intact rats.     

Nocturnal urinary melatonin levels and urine biochemistry in microwave-irradiated rats

The aim of this study was to explore whether, during the course of a 15 days-lasting experiment, a two hours per day and five days per week, 2.45 GHz microwave whole-body irradiation may substantially and therefore provably affect rats’ nocturnal urinary 6-hydroxy-melatonin sulphate (aMT6s) excretion and urinalysis parameters. The average whole-body specific absorption rate (SAR) equalled to 1.25 (± 0.36 SE) W/kg. To collect nocturnal urine samples, animals were held in individual metabolic cages every experimental night from 7:00 PM till 7:00 AM next day. The concentration of aMT6s in rat urine samples was determined by a direct radioimmunoassay. Bilirubin, ketones, and urine protein content have been determined via multiple-use reagent strips. In comparison to the sham-exposed group, no significant changes in body temperature and food or water intake were observed in the exposed group. A decline in aMT6s, determined in the exposed rats, was observed from day 8 to day 11 of the experiment (P < 0.05). The aMT6s level remained consistently low until the end of the experiment, but not significantly lower than the control values. The results of the urine samples biochemical workup failed to reveal any significant differences between the exposed and the control animal groups. The results of this study suggest that, under the above described experimental conditions, repeated 2.45 GHz irradiation could act as a stressor and therefore influence the melatonine balance in rat.     

Increase in Parasympathetic Nerve Activity During the Nighttime Following Bright Light Exposure During the Daytime

A spectral analysis of heart rate was carried out on 11 young female adults in order to evaluate the effects of bright light exposure on autonomic nervous activity. Bright light (5,000 lx) was provided by fluorescent lamps during the daytime (07:00-15:00) on day 1. Dim light (200 lx) was given on day 2. High frequency components (HF: 0.15-0.4Hz) were used as a marker of parasympathetic activity and the ratio of low frequency (LF: 0.04-0.15 HZ) to high frequency (LF/HF) as an indicator of sympathetic activity. The average value during the sleep period (23:30-06:30) was compared following diurnal exposure to bright or dim light. HF component was significantly greater from 23:30 to 02:00 after diurnal exposure of bright light, being accompanied by lower heart rate during these periods. There existed negative correlation between heart rate and HF component from 23:30 to 02:00 under diurnal exposure to bright and dim lights. The results indicate that bright light exposure during the daytime (07:00-15:00) could enhance parasympathetic activity around midnight.     

The Effect on Body Temperature and Melatonin of A 39-H Constant Routine with Two Different Light Levels at Nighttime

Eight healthy subjects were studied during 39-h spans (from 07:00 on one day until 22:00 the second) in which they remained awake. During one experiment, subjects were exposed to 100 lux of light between 18:00 and 8:00, and during a second experiment, they were exposed to 1000 lux during the same time span. Throughout the daytime period, they were exposed to normal daylight (1500 lux or more). The nighttime 1000-lux light treatment suppressed the melatonin metabolite aMT6s, while the 100 lux treatment did not. On the treatment day, the 1000 lux, in comparison to the 100 lux, light treatment resulted in both an elevated temperature minimum and a delay in its clock-time occurrence overnight. No real circadian phase shift in the temperature, urinary melatonin, or Cortisol rhythms was detected after light treatment. This study confirmed that nocturnal exposure to lower light intensities is capable of modifying circadian variables more than previously estimated. The immediate effects of all-night light treatment are essentially not different from those of evening light. This may be important if bright light is used to improve alertness of night workers. Whether subsequent daytime alertness and sleep recovery are affected by the protocol used in our study remains to be determined.     

Melatonin production and light exposure of rotating night workers

Decreased melatonin production, due to acute suppression of pineal melatonin secretion by light exposure during night work, has been suggested to underlie higher cancer risks associated with prolonged experience of night work. However, the association between light exposure and melatonin production has never been measured in the field. In this study, 24-h melatonin production and ambulatory light exposure were assessed during both night-shift and day/evening-shift periods in 13 full-time rotating shiftworkers. Melatonin production was estimated with the excretion of urinary 6-sulfatoxymelatonin (aMT6s), and light exposure was measured with an ambulatory photometer. There was no difference in total 24-h aMT6s excretion between the two work periods. The night-shift period was characterized by a desynchrony between melatonin and sleep-wake rhythms, as shown by higher melatonin production during work and lower melatonin production during sleep when working night shifts than when working day/evening shifts. Light exposure during night work showed no correlation with aMT6s excreted during the night of work (p?>?.5), or with the difference in 24-h aMT6s excretion between the two work periods (p >?.1). However, light exposure during night work was negatively correlated with total 24-h aMT6s excretion over the entire night-shift period (p?相似文献   

BIOLOGICAL RHYTHM RESEARCH,Circadian rhythms,monoamines and behaviorTitlepage and Contents

A spectral analysis of heart rate was carried out on 11 young female adults in order to evaluate the effects of bright light exposure on autonomic nervous activity. Bright light (5,000 lx) was provided by fluorescent lamps during the daytime (07:00–15:00) on day 1. Dim light (200 lx) was given on day 2. High frequency components (HF: 0.15–0.4Hz) were used as a marker of parasympathetic activity and the ratio of low frequency (LF: 0.04–0.15 HZ) to high frequency (LF/HF) as an indicator of sympathetic activity. The average value during the sleep period (23:30–06:30) was compared following diurnal exposure to bright or dim light. HF component was significantly greater from 23:30 to 02:00 after diurnal exposure of bright light, being accompanied by lower heart rate during these periods. There existed negative correlation between heart rate and HF component from 23:30 to 02:00 under diurnal exposure to bright and dim lights. The results indicate that bright light exposure during the daytime (07:00–15:00) could enhance parasympathetic activity around midnight.     

Emergence and evolution of the circadian rhythm of melatonin in children

OBJECTIVE: To assess the age at which the circadian rhythm of melatonin begins. METHODS: 55 children, divided into groups from the neonatal period to 24 months of life, were studied. Urine samples were taken from 28 newborn babies to measure 6-sulfatoxymelatonin (aMT6s). Salivary samples were collected from infants (27 cases), to measure melatonin (aMT). aMT was measured by RIA and aMT6s by ELISA using commercial kits. Changes in the levels of aMT6s and aMT were evaluated using the Friedman test and Wilcoxon matched pair test. RESULTS: The group aged 27-41 days showed statistically significant differences in daily aMT6s and aMT concentrations. The highest values were always found between 24.00 and 8.00 h. This day/night difference persisted from 2-3 to 13-24 months of age. CONCLUSION: The data indicate that the circadian melatonin rhythm appears at the end of the neonatal period and persists thereafter.     

东北鼢鼠活动强度及其与土壤温度和湿度的关系

动物的活动节律是对环境条件的综合适应,营地下生活的啮齿动物常年栖息于相对低氧和黑暗的土壤环境,其活动节律及强度如何受栖息地土壤温度和湿度影响,是否具有性别差异特征,一直受到广泛关注.这种影响的结果能够较为客观地反映出地下生活啮齿动物对其栖息地长期适应的生活史策略.东北鼢鼠(Myospalax psilurus)是我国北...     

Age-associated changes and sex differences in urinary 6-sulphatoxymelatonin circadian rhythm in the rat.

The circadian rhythm of 6-sulphatoxymelatonin (aMT6s) excretion has been determined in male and female rats at 3 weeks and at 2, 8, 14 and 20 months of age. All animals have a pronounced circadian pattern of aMT6s excretion under a 12 hour dark: 12 hour light cycle. A significant increase in aMT6s excretion is observed from 3 weeks to 14 months followed by a decrease at 20 months. There is a highly significant correlation between aMT6s excretion and body weight (r = 0.73 for female rats and r = 0.74 for male rats; p values are all less than 0.001). Thus, a decrease in aMT6s excretion associated with increasing age occurs when body weight is taken into consideration. aMT6s excretion is higher in males at 3 weeks and at 2 and 8 months of ages. Urinary testosterone in male rats and estradiol in female rats increase from 3 weeks to 8 months and decrease at older ages. These data suggest that increase of body weight from 3 weeks to 14 months is an important factor responsible for the age-related alteration. The sex differences in aMT6s excretion in younger rats may be associated with their sex hormonal milieu.     

Differences in sleep, light, and circadian phase in offshore 18:00-06:00 h and 19:00-07:00 h shift workers

Complaints concerning sleep are high among those who work night shifts; this is in part due to the disturbed relationship between circadian phase and the timing of the sleep-wake cycle. Shift schedule, light exposure, and age are all known to affect adaptation to the night shift. This study investigated circadian phase, sleep, and light exposure in subjects working 18:00-06:00 h and 19:00-07:00 h schedules during summer (May-August). Ten men, aged 46+/-10 yrs (mean+/-SD), worked the 19:00-07:00 h shift schedule for two or three weeks offshore (58 degrees N). Seven men, mean age 41+/-12 yrs, worked the 18:00-06:00 h shift schedule for two weeks offshore (61 degrees N). Circadian phase was assessed by calculating the peak (acrophase) of the 6-sulphatoxymelatonin rhythm measured by radioimmunoassay of sequential urine samples collected for 72 h at the end of the night shift. Objective sleep and light exposure were assessed by actigraphy and subjective sleep diaries. Subjects working 18:00-06:00 h had a 6-sulphatoxymelatonin acrophase of 11.7+/-0.77 h (mean+/-SEM, decimal hours), whereas it was significantly later, 14.6+/-0.55 h (p=0.01), for adapted subjects working 19:00-07:00 h. Two subjects did not adapt to the 19:00-07:00 h night shift (6-sulphatoxymelatonin acrophases being 4.3+/-0.22 and 5.3+/-0.29 h). Actigraphy analysis of sleep duration showed significant differences (p=0.03), with a mean sleep duration for those working 19:00-07:00 h of 5.71+/-0.31 h compared to those working 18:00-06:00 h whose mean sleep duration was 6.64+/-0.33 h. There was a trend to higher morning light exposure (p=0.07) in the 19:00-07:00 h group. Circadian phase was later (delayed on average by 3 h) and objective sleep was shorter with the 19:00-07:00 h than the 18:00-06:00 h shift schedule. In these offshore conditions in summer, the earlier shift start and end time appears to favor daytime sleep.     

Twelve-hour night shifts of healthcare workers: a risk to the patients?

We assessed the impact of 12h fixed night shift (19:00-07:00h) work, followed by 36h of off-time, on the sleep-wake cycle, sleep duration, self-perceived sleep quality, and work-time alertness on a group composed of 5 registered and 15 practical nurses. Wrist actigraphy (Ambulatory Monitoring, Inc.), with data analysis by the Cole-Kripke algorithm, was applied to determine sleep/wake episodes and their duration. The sleep episodes were divided into six categories: sleep during the night shift (x = 208.6; SD +/- 90.6 mins), sleep after the night shift (x = 138.7; SD +/- 79.6 min), sleep during the first night after the night work (x = 318.5; SD +/- 134.6 min), sleep before the night work (x = 104.3; SD +/- 44.1 min), diurnal sleep during the rest day (x = 70.5; SD +/- 43.0 min), and nocturnal sleep during the rest day (x = 310.4; SD +/- 188.9mins). A significant difference (p < .0001; T-test for dependent samples) was detected between the perceived quality of sleep of the three diurnal sleep categories compared to the three nocturnal sleep categories. Even thought the nurses slept (napped) during the night shift, their self-perceived alertness systematically decreased during it. Statistically significant differences were documented by one-way ANOVA (F = 40.534 p < .0001) among the alertness measurements done during the night shift. In particular, there was significant difference in the level of perceived alertness (p < .0001) between the 7th and 10th of the 12h night shift. These findings of decreased alertness during the terminal hours of the night shift are of concern, since they suggest risk of comprised patient care.     

Effect of short-wave (6-22 MHz) magnetic fields on sleep quality and melatonin cycle in humans: the Schwarzenburg shut-down study

This paper describes the results of a unique "natural experiment" of the operation and cessation of a broadcast transmitter with its short-wave electromagnetic fields (6-22 MHz) on sleep quality and melatonin cycle in a general human population sample. In 1998, 54 volunteers (21 men, 33 women) were followed for 1 week each before and after shut-down of the short-wave radio transmitter at Schwarzenburg (Switzerland). Salivary melatonin was sampled five times a day and total daily excretion and acrophase were estimated using complex cosinor analysis. Sleep quality was recorded daily using a visual analogue scale. Before shut down, self-rated sleep quality was reduced by 3.9 units (95% CI: 1.7-6.0) per mA/m increase in magnetic field exposure. The corresponding decrease in melatonin excretion was 10% (95% CI: -32 to 20%). After shutdown, sleep quality improved by 1.7 units (95% CI: 0.1-3.4) per mA/m decrease in magnetic field exposure. Melatonin excretion increased by 15% (95% CI: -3 to 36%) compared to baseline values suggesting a rebound effect. Stratified analyses showed an exposure effect on melatonin excretion in poor sleepers (26% increase; 95% CI: 8-47%) but not in good sleepers. Change in sleep quality and melatonin excretion was related to the extent of magnetic field reduction after the transmitter's shut down in poor but not good sleepers. However, blinding of exposure was not possible in this observational study and this may have affected the outcome measurements in a direct or indirect (psychological) way.     

Decrease in the Time-Dependent Difference in Urinary Excretion of Furosemide with Age

The influence of age on the time-dependent difference in urinary excretion of furosemide, a loop diuretic agent, was examined in this longitudinal study. Male Wistar rats were maintained under conditions of light from 07:00 to 19:00 h and dark from 19:00 to 07:00 h. Furosemide (30 mg/kg) was given orally at 12:00 h (day trial) or 00:00 h (night trial) to rats at 3 months of age, and urine was collected for 8 h after dosage. Thereafter, the identical protocol was repeated using the same animals at 6, 9, 12, 15, 18, and 21 months of age. The urinary excretion of furosemide was significantly greater in the day than in the night trial at 3 months of age. Such a time-dependent difference was observed for up to 15 months, but disappeared at 18 and 21 months of age. The time-dependent difference in urinary excretion of furosemide (day trial — night trial) decreased gradually throughout the observation period of the study. These results suggest that the time-dependent difference in the urinary excretion of furosemide diminishes during the aging process and disappears by 18 months of age in male Wistar rats.     

Diurnal Variation in Scent Marking Behavior in Captive Male and Female Common Marmosets, Callithrix jacchus

Chemical communication by scent-marking behavior in New World primates is used to prevent the access of potential competitors to a territory, to identify food resources and the reproductive condition of mates, among others. In common marmosets, primates of the Callitrichidae family, this behavior also occurs as olfactory identification of an individual or of the reproductive status of females. Despite this information, the diurnal variation and gender differences in the profile of this behavior remain to be investigated. The aims of this study were to establish the diurnal profile of the distribution of this behavior and the influence of the sex of markers. We used 18 adult common marmosets, Callithrix jacchus, 10 males and 8 females from 6 family groups (6 fathers and 4 sons; 4 mothers and 4 daughters). The frequency of scent-marking behavior was recorded for each animal over a period of 8 days, twice a week, for 4 weeks, starting when the animals left the nest box (approximately at 05:00 a.m.) until the end of the photophase, at about 05:00 p.m. A MANOVA test was performed to compare the frequency of scent-marking behavior at 2 hour intervals using pooled data for males and females. The results showed that significantly higher levels of scent-marking behavior occurred during the 03:00-05:00 p.m. interval compared to all other intervals. Lower values were recorded during the 11:00-13:00 interval and an effect of the sex factor was also found, with the values being higher for females than for males, although a significant difference was recorded only for the 07:00-09:00 interval. Minimal values for males were recorded during the 07:00-09:00 interval, whereas minimum values for females were recorded during the 11:00-13:00 interval. However, the highest values for both sexes continued to occur during the 15:00-17:00 interval. These results suggest that scent marking behavior in common marmosets has a preferential incidence at the end of the day and this might be occurring in association with feeding behavior. At this time these animals usually forage more to prepare for the night's fast. Since these animals can discriminate chemical clues as long as 24 hours after they have been left, the higher incidence of this behavior at this time probably will assure that the animals will localize feeding resources used on the preceding day. Significant elevation of scent marking behavior in females in relation to males was found only at 07:00-09:00 interval and seems to be associated with signalizing of reproductive status, preferential access to foraging or both.     

The effect of strength training at the same time of the day on the diurnal fluctuations of muscular anaerobic performances

The aim of this study was to examine the effects of training at the same time of the day on the diurnal variations of anaerobic performances to provide some recommendations to adjust training hours with the time of the day of competitive events. Thirty participants underwent 8 weeks of lower-extremity progressive resistance training performed 3 times per week designed to promote muscular strength and power. These subjects were randomly assigned to a morning training group (MTG, 07:00-08:00 hours, n = 10), an evening training group (ETG, 17:00-18:00 hours, n = 10), and a control group (CG, completed all tests but did not train, n = 10). Performance in the squat jump, the countermovement jump, the Wingate and 1 repetition maximum (1RM) during leg extension, leg curl, and squat tests was recorded just before and 2 weeks after an 8-week course of regular training. For all the subjects, the morning and evening tests were scheduled at the same time of the day as for the morning and evening training sessions. Before training, the results indicated a significant increase in performance from morning to evening tests (ca. 2.84-17.55% for all tests) for all groups. After training, the diurnal variations in anaerobic performances were blunted in the MTG. In fact, there was no significant difference in muscular power or strength between morning and evening tests. However, these intradaily variations in anaerobic performances persisted in the ETG and CG. From a practical point of view, adaptation to strength training is greater at the time of the day at which training was scheduled than at other times.     

Chronopharmacokinetics of Imipramine and Desipramine in Rat Forebrain and Plasma After Single and Chronic Treatment with Imipramine

Daily variations in the pharmacokinetics of imipramine (IMI) could contribute to circadian phase-dependent effects of the drug. Therefore, the chronopharmacokinetics of IMI and its metabolite, desipramine (DMI), were studied after single and chronic application. Male rats were synchronized to a 12:12 hour lightdark (L:D) regimen with lights on from 07:00 to 19:00 (dark, 19:00-07:00). In single-dose experiments rats were injected with IMI (10 mg/kg) i.p. or i.v. at 07:30 or 19:30 and groups of rats were killed 0-22 hours thereafter. After chronic application of IMI in drinking water (≈ 15 mg/kg/d) groups of rats were killed during the 14th day of treatment at 02:00, 08:00, 14:00, and 20:00, respectively. Brain and plasma concentrations of IMI and DMI were determined by reversed-phase high-performance liquid chromatography with ultraviolet detection. After single i.p. application of IMI, maximal brain concentrations (C_max) of IMI and DMI were nearly twofold higher in darkness (IMI, 4.8 μg/g; DMI, 1.8 μg/g) than in light (IMI, 2.85 Mg/g; DMI, 0.85 Mg/g). Also, the area under the curve (AUC) (0-22 hours) was about 1.6-fold greater in darkness than in light for IMI and DMI; half-lives were not circadian phase dependent. After i.v. injection of IMI, the AUC in brain was also about 30% greater in darkness than in light. After chronic application of IMI in drinking water, brain concentrations of IMI and DMI varied more than threefold within 24 hours. The data demonstrate that the pharmacokinetics of IMI and DMI are circadian phase dependent. It is assumed that circadian variations in drug distribution are more likely to contribute to the drug's chronopharmacokinetics than variations in the drug's metabolism. The 24-hour variations in the drug's concentrations after chronic IMI application in drinking water can be explained by the drinking behavior of the rats, which by itself is altered by IMI.