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Yvan Touitou

Publications and source records attributed to Yvan Touitou.

36 records · Page 2Linked to original sources

Ethical principles and standards for the conduct of human and animal biological rhythm research.

Most research papers published in Chronobiology International report the findings of investigations conducted on laboratory animals and human beings. The Journal, its editors and the publication committee endorse the compliance of investigators to the principles of the Declaration of Helsinki of the World Medical Association relating to the conduct of ethical research on human beings and the Guide for the Care and Use of Laboratory Animals of the Institute for Laboratory Animal Research of the National Research Council relating to the conduct of ethical research on laboratory and other animals. Chronobiology International requires that submitted manuscripts reporting the findings of human and animal research conform to the respective policy and mandates of the Declaration of Helsinki and the Guide for the Care and Use of Laboratory Animals. The peer review of manuscripts will thus include judgment of whether or not the involved research methods conform to the standards of good research practice. This article outlines the basic expectations for the methods of human and animal biological rhythm research, both from the perspective of the fundamental criteria necessary for quality chronobiology investigation and from the perspective of humane and ethical research on human beings and animals.

Animals↗

Prolonged mild hypoxia modifies human circadian core body temperature and may be associated with sleep disturbances.

Fatigue is often reported after long-haul airplane flights. Hypobaric hypoxia, observed in pressurized cabins, may play a role in this phenomenon by altering circadian rhythms. In a controlled cross-over study, we assessed the effects of two levels of hypoxia, corresponding to cabin altitudes of 8000 and 12,000 ft, on the rhythm of core body temperature (CBT), a marker of circadian rhythmicity, and on subjective sleep. Twenty healthy young male volunteers were exposed for 8 h (08:00-16:00 h) in a hypobaric chamber to a cabin altitude of 8000 ft and, 4 weeks later, 12,000 ft. Each subject served as his own control. For each exposure, CBT was recorded by telemetry for two 24h cycles (control and hypoxic exposure). After filtering out nonphysiological values, the individual CBT data were fitted with a five-order moving average before statistical group analysis. Sleep latency, sleep time, and sleep efficiency were studied by sleep logs completed every day in the morning. Our results show that the CBT rhythm expression was altered, mainly at 12,000 ft, with a significant increase of amplitude and a delay in the evening decline in CBT, associated with alterations of sleep latency. Mild hypoxia may therefore alter circadian structure and result in sleep disturbances. These results may explain in part the frequent complaints of prolonged post-flight fatigue after long flights, even when no time zones are crossed.

Adult↗

Chronobiology of alcohol: from chronokinetics to alcohol-related alterations of the circadian system.

The development of concepts in chronobiology is intimately linked to studies on alcohol, as a number of these are based on chronobiological variations observed in the metabolism of ethanol. This concerns circadian differences in its metabolism (chronokinetics) and effects (chronoefficacy and chronotoxicity) and also inherent circadian rhythmicity in the sensitivity of target organs to its effects (chronesthesy). Chronobiologic discoveries are also fertile grounds for understanding the biological and psychotropic effects of alcohol. Confusing effects, which are difficult to explain by conventional homeostatic theory, are easy to understand when considered in the context of the concepts of chronopharmacology, and thereby uncovering new pathways of investigation. Beyond the studies that have elucidated the rhythm-dependent variation in ethanol, chronobiology is opening new explanatory pathways concerning the attributes of the alcohol withdrawal syndrome and effects of alcohol on the development of the central nervous system, particularly the development of the internal clock, and on the alcohol-dependency syndrome. The concepts of chronopharmacology and chronotoxicology are of equal importance to the fields of occupational medicine and industry medicine.

Alcohol Drinking↗

Hypoxic depression of melatonin secretion after simulated long duration flights in man.

Fatigue is often reported after long duration flights. Mild hypobaric hypoxia caused by pressurization may be involved in this effect through disruption of circadian rhythms, independent of the number of time zones crossed. In this controlled crossover study we assessed the effects of two levels of hypoxia equivalent to 8000 and 12,000 ft on the rhythm of plasma melatonin concentrations, a marker of circadian rhythmicity. Sixteen healthy young male volunteers (23-39 years) were exposed in a hypobaric chamber for 8 hr (08:00-16:00 hours) to 8000 ft, followed 4 wk later by 12,000 ft. Plasma melatonin was assayed over two 24-hr cycles (control and hypoxic exposure) every 2 hr in all subjects. We found a significant decrease in the nocturnal melatonin peak after hypoxic exposure at both altitudes, and we found that this effect was age dependent for the 12,000-ft exposure: the decrease was only seen in the younger subjects (23-28 years). Analysis of heart rate variability allowed us to demonstrate that the older and less trained subjects (29-39 yr) in our study exhibited a far greater increase in sympathetic tone than the younger subjects during the 12,000-ft exposure. These results show that hypoxic depression of melatonin secretion may be influenced by individual factors such as age, physical fitness and sympathetic reactivity to hypoxia. Our findings suggest that hypoxia may by itself contribute at least in part to postflight fatigue after long duration flights, and to the clinical disorders of jet lag in transmeridian flights through its effects on the circadian system.

Adult↗

Isoproterenol-stimulated melatonin production by perifused rat pineal glands: age- and time-related effects.

OBJECTIVES: The purpose of this study was to investigate and compare the effects of the beta-adrenergic agonist, isoproterenol, on induced increase in melatonin production in the pineal gland of young and old rats, at different circadian stages. MATERIALS AND METHODS: We report here the effects of 10(-6) M isoproterenol-stimulated melatonin production by perifused pineal glands obtained from young (55 day old) and old (21 month old) male Wistar rats acclimatised to light:dark cycles regimen of 12:12 for 3 weeks. Pineal glands were collected at different circadian stages: 3, 7, 11, 15, 19 and 23 hours after light onset (HALO), and perifused for 510 min. RESULTS: The basal levels of melatonin production in the young rats were approximately twice greater than those of the old rats. Isoproterenol stimulated melatonin production in both young and old rat pineal glands, whatever the circadian stage. The intensity of the response to 10(-6) M isoproterenol infusion was greater in young than in old rat pineal glands (P<0.001), with a trend towards an increase during the light phase, at 7 HALO, in both young and old rat pineal glands, although this trend towards increased melatonin response did not reach statistical significance (P>0.05). CONCLUSIONS: These results show that isoproterenol is able to stimulate both young and old rat pineal glands whatever the circadian stage. The magnitude of isoproterenol stimulation is greater in young than in old glands. Our results also suggest that the pineal gland response to isoproterenol is not dependent on circadian stage, at least, under our experimental conditions.

Adrenergic beta-Agonists↗

Reproducibility of the circadian rhythms of serum cortisol and melatonin in healthy subjects: a study of three different 24-h cycles over six weeks.

Plasma melatonin and cortisol are characterized by a marked circadian rhythm, but little information is available about the reproducibility and stability of these rhythms over several weeks in the same subjects. This study examined the characteristics of these rhythms in 31 healthy human subjects 20 to 30 years of age. They were synchronized with a diurnal activity from 0800 to 2300 and nocturnal rest. They participated in three 24-hour sessions (S1, S2, and S3): S2 took place two weeks after S1 and S3 4 weeks after S2. Blood samples were taken during each session at 3-hour intervals from 1100 to 2000 and hourly from 2200 to 0800. Comparison of the circadian rhythms between groups used repeated measures 2-way ANOVA, the cosinor method, and Bingham's test. Intraindividual variations were compared by the cosinor method and Bingham's test. The groups did not differ, but a slight difference in the amplitude or acrophase of individual circadian rhythms was observed in 5 of 31 subjects for melatonin and 1 of 31 for cortisol. The circadian means did not differ over the three sessions. These results show that the circadian profile of cortisol and melatonin are highly reproducible over a six-week period, in both individuals and groups. Our study clearly shows that these hormones can be considered to be stable markers of the circadian time structure and therefore useful tools to validate rhythms' synchronisation of human subjects.

Adult↗

Alcohol decreases the nocturnal peak of TSH in healthy volunteers.

RATIONALE: Studies of ethanol's effects on TSH carried out during the daytime, when its secretion is at its nadir, do not reflect the true action of alcohol on TSH secretion since TSH peak occurs at night. OBJECTIVE: The present study investigated the effects of alcohol on the serum concentrations of TSH in healthy volunteers during a 26-h session. METHODS: The trial included a 26-h session during which alcohol was administered at a rate similar to that found in heavy drinkers, i.e. 256 g per day and a 26-h placebo session. Volunteers functioned as their own controls, and we controlled for masking effects in both sessions. RESULTS: The usual TSH circadian rhythm flattened during the alcohol session, and the usual peak in the middle of the night completely disappeared. CONCLUSION: Alcohol dramatically decreased nocturnal TSH secretion in healthy volunteers.

Adolescent↗

Circadian rhythm characteristics of serum cortisol and dehydroepiandrosterone sulfate in healthy Chinese men aged 30 to 60 years. A cross-sectional study.

The relation of adrenal function and aging has been the subject of intense interest in recent years. The circadian variations of plasma cortisol have been described in Caucasians, but little information is available on such hormone variations among the Chinese population, especially its changes with age. This study was, therefore, designed to examine the effects of age on the circadian variations of serum cortisol, dehydroepiandrosterone sulfate (DHEAS) and the molar ratio of cortisol/DHEAS in Chinese men, stratified by 10-year age-groups (i.e. men in their 30-60s, aged from 31 to 63 years old). Circadian variations of serum cortisol and DHEAS were documented at 2-h intervals from 8:00 to 22:00 and hourly from 22:00 to 8:00 in 26 healthy Chinese men. We found that the serum levels of both hormones showed a statistically significant circadian rhythmicity in all age-groups. The circadian pattern of serum cortisol was characterized by peaks (04:00-06:00) and troughs (18:00-24:00) occurring approximately 2h earlier than those usually reported in Caucasians. Aging did not significantly influence serum cortisol concentrations, but serum DHEAS levels declined significantly with age: subjects in their 60s had significantly lower levels, and their cortisol/DHEAS molar ratios were significantly higher than those in the younger age-groups.

Adult↗

Cortisol secretion in the elderly. Influence of age, sex and cardiovascular disease in a Chinese population.

Adrenal function and aging have been the object of intense interest in recent years. In this study we analyzed morning (08:00 h) serum cortisol concentrations from a sample of Chinese subjects aged from 31 to 110 years. These levels differed according to age, health status and sex, although the sex difference was confirmed only among the healthy elderly. These results suggest that age (older than 60 years), disease and male sex are associated with increased morning serum cortisol levels in a Chinese population.

Adrenal Cortex↗

Effects of diazepam and its metabolites on nocturnal melatonin secretion in the rat pineal and Harderian glands. A comparative in vivo and in vitro study.

We investigated the effects of diazepam (DZP) and its three metabolites: nordiazepam (NZP), oxazepam (OZP), and temazepam (TZP) on pineal gland nocturnal melatonin secretion. We looked at the effects of benzodiazepines on pineal gland melatonin secretion both in vitro (using organ perifusion) and in vivo in male Wistar rats sacrificed in the middle of the dark phase. We also examined the effects of these benzodiazepines on in vivo melatonin secretion in the Harderian glands. Neither DZP (10(-5)-10(-6)M) nor its metabolites (10(-4)-10(-5)M) affected melatonin secretion by perifused rat pineal glands in vitro. In contrast, a 10(-4)M suprapharmacological concentration of DZP increased melatonin secretion of perifused pineal glands by 70%. In vivo, a single acute subcutaneous administration of DZP (3 mg/kg body weight) significantly affected pineal melatonin synthesis and plasma melatonin levels, while administration of the metabolites under the same conditions did not. DZP reduced pineal melatonin content (-40%), N-acetyltransferase activity (-70%), and plasma melatonin levels (-40%), but had no affects on pineal hydroxyindole-O-methyltransferase activity. Neither DZP nor its metabolites affected Harderian gland melatonin content. Our results indicate that the in vivo inhibitory effect of DZP on melatonin synthesis is not due to the metabolism of DZP. The results also show that the control of melatonin production in the Harderian glands differ from that observed in the pineal gland.

Animals↗

Temporal pattern in consumption of the first drink of the day in alcohol-dependent persons.

Loss of control over drinking and the craving for alcohol are cardinal signs of alcohol dependence. Our clinical practice indicates that these cravings do not occur randomly during the day, but at the same times each day for the same patient. To validate this hypothesis that alcohol-dependent patients have a circadian rhythmic craving in their desire for their first drink of the day, we asked 217 persons diagnosed as alcohol-dependent according to DSM-IV criteria to complete a questionnaire that surveyed whether this craving occurred at a fixed time each day. Of the respondents, 82% reported it did; 87% of them could state the time of day they consumed their first daily drink; and 80% reported that the time of their first drink of the day did not vary much from one day to the next. The most frequent time of consuming the first drink of alcohol was between 09:00 and 11:00 h, and it was independent of the subjects' sleep-wake routine (the delay between the hours of wake-up and the time of the first urge for alcohol was 3:45 +/- 3:30 h) and lunch or dinner time. This rhythmicity seems to be a pertinent criterion for alcohol dependence syndrome.

Alcohol Drinking↗

Magnetic fields and the melatonin hypothesis: a study of workers chronically exposed to 50-Hz magnetic fields.

Because epidemiological studies report clinical disorders (mainly neurobehavioral alterations and/or cancer) that may be related to diminished melatonin secretion or to changes in its circadian rhythm in subjects living or working in environments exposed to magnetic fields, research on the effects of these fields in humans is particularly important. In this study, we examine the circadian rhythm of melatonin in 15 men exposed chronically and daily for a period of 1-20 yr, in the workplace and at home, to a 50-Hz magnetic field in search of any cumulative effect from those chronic conditions of exposure. The weekly geometric mean of individual exposures ranged from 0.1 to 2.6 microT. The results are compared with those for 15 unexposed men who served as controls (individual exposures ranged from 0.004 to 0.092 microT). Blood samples were taken hourly from 2000 to 0800. Nighttime urine was also collected and analyzed. This work shows that subjects exposed over a long period (up to 20 yr) and on a daily basis to magnetic fields experienced no changes in their plasma melatonin level, their urinary 6-sulfatoxymelatonin level, or the circadian rhythm of melatonin. Our data strongly suggest that magnetic fields do not have cumulative effects on melatonin secretion in humans and thus clearly rebut the "melatonin hypothesis" that a decrease in plasma melatonin concentration (or a disruption in its secretion) explains the occurrence of clinical disorders or cancers possibly related to magnetic fields.

Circadian Rhythm↗

Mid-morning tryptophan depletion delays REM sleep onset in healthy subjects.

Because serotonin is involved in the diachronic regulation of sleep, we tested the effect of a midmorning rapid deficiency in the serotonin precursor tryptophan on the next night's sleep. After a 48-h low-protein diet, 17 healthy volunteers received either a tryptophan-free mixture of amino acids or a placebo at 10:30 A.M., in a randomized double-blind cross-over design, resulting in a 77% decrease and 41% decrease of serum tryptophan at 3:30 P.M. and 9:30 P.M., respectively. Urinary sulfatoxy-melatonin excretion and mood were unaffected by the rapid tryptophan depletion (RTD), but rapid eye movement (REM) sleep latency increased by 21 min (from 91.5 +/- 4.5 min to 112.2 +/- 6.9 min), sleep fragmentation 58%, and REM density of the first REM sleep period doubled. The results show that midmorning RTD delays REM sleep latency during following night-time sleep, whereas evening RTD shortens REM sleep latency in previous studies, and suggest that the serotonin control of REM sleep latency is upregulated.

Adolescent↗

Marker rhythms of circadian system function: a study of patients with metastatic colorectal cancer and good performance status.

Cancer patients may exhibit normal or altered circadian rhythms in tumor and healthy tissues. Four rhythms known to reflect circadian clock function were studied in 18 patients with metastatic colorectal cancer and good performance status. Rest-activity was monitored by wrist actigraphy for 72 h before treatment, and its circadian rhythm was estimated by an autocorrelation coefficient at 24h and a dichotomy index that compared the activity level when in and out of bed. Blood samples (9-11 time points, 3-6 h apart) were drawn on day 1 and day 4 of the first course of chronochemotherapy (5-fluorouracil: 800 mg/m2/day; folinic acid: 300 mg/m2/day; oxaliplatin: 25 mg/m2/day). Group 24h rhythms were validated statistically for plasma concentrations of melatonin, 6-alpha-sulfatoxymelatonin, and cortisol and for lymphocyte counts. Significant individual 24h rhythms were displayed in melatonin by 15 patients, cortisol by seven patients, lymphocytes by five patients, and prominent circadian rhythms in activity were displayed by 10 patients; only one patient exhibited significant rhythms in all the variables. The results suggest the rhythms of melatonin, cortisol, lymphocytes, and rest/activity reflect different components of the circadian system, which may be altered differently during cancer processes. Such 24h rhythm alterations appeared to be independent of conventional clinical factors.

Adult↗

Aging and the circadian rhythm of melatonin: a cross-sectional study of Chinese subjects 30-110 yr of age.

Although previous reports indicate that nocturnal plasma melatonin secretion declines with age, some recent findings do not support this point. In the present cross-sectional study, we documented serum melatonin concentrations at two time points, 02:00 and 08:00 h, in 144 persons aged 30-110 yr and found a significant age-related decline. It began around the age of 60 and reached a very significantly lower level in subjects in their 70s and over 80 yr of age (P < 0.01, when compared with age <60 yr). Nocturnal melatonin levels were higher among (post-menopausal only) women than men overall (P < 0.05). In the older age-groups, nocturnal melatonin levels did not differ between healthy controls and subjects with high blood pressure or ischemic heart disease. To further check these results, we also assessed the circadian pattern of serum melatonin in four subgroups of healthy men, aged 30-39, 40-49, 50-59, and 60-69 yr: blood samples were taken at 2 h intervals from 08:00 to 22:00 h and hourly from 22:00 to 08:00 h. Our results showed generally similar circadian melatonin patterns that peaked at night with very low levels during the daytime. No significant difference was found among the three younger groups, but nocturnal melatonin levels were significantly lower in the men in their 60s.

Adult↗

[Evaluation of the effect of magnetic fields on the secretion of melatonin in humans and rats. Circadian study].

The consequences of electromagnetic exposure on human health are receiving increasing scientific attention and have become the subject of a vigorous public debate. In the present study we evaluated the effects of magnetic field on pineal function in man and rat. Two groups of Wistar male rats were exposed to 50-Hz magnetic fields of either 1, 10 or 100 microT. The first group was exposed for 12 hours and the second for 30 days (18 hours per day). Short-term exposure depressed both pineal NAT activity and nocturnal serum melatonin concentration but only with the highest intensity used (100 microT). Long-term exposure to a magnetic field significantly depressed the nighttime peak of serum melatonin concentration and pineal NAT activity with 10 and 100 microT. Our results show that sinusoidal magnetic fields altered the production of melatonin through an inhibition of pineal NAT activity. Both duration and intensity of exposure played an important role in this effect. In the second step of this study, thirty-two young men (20-30 years old) were divided into two groups (control group, i.e., sham-exposed: 16 subjects; exposed group: 16 subjects). The subjects were exposed to the magnetic field from 23 h to 08 h (i.e. for 9 h) while lying down. In one experiment the exposure was continuous, in the second one, the magnetic field was intermittent. No significant differences were observed between sham-exposed (control) and exposed men for serum melatonin and 6-sulfatoxymelatonin. In our last and more recent study, we looked for the circadian rhythm of melatonin in 15 men exposed chronically and daily for a period of 1-20 years, in the workplace and at home, to a 50 Hz (exposure 0.1 to > 0.3 microT) magnetic field. The results are compared to those for 15 unexposed men who served as controls. Blood samples were taken hourly from 2000 to 0800. Nighttime urine was also collected and analyzed. This work shows that subjects exposed over a long period (up to 20 years) and on a daily basis to magnetic fields experienced no changes in their plasma melatonin level, their urinary 6-sulfatoxymelatonin level, or the circadian rhythm of melatonin. It thus clearly rebuts the "melatonin hypothesis" that a decrease in plasma melatonin concentration--or a disruption in its secretion--explains the occurrence of, clinical disorders or cancers possibly related to magnetic fields.

Adult↗

Age-related modifications of circadian rhythm of serum leptin in healthy men.

BACKGROUND: Leptin, the product of the ob gene, is secreted by the adipocyte and is involved in the regulation of body weight, energy homeostasis and a wide spectrum of biological activities. OBJECTIVE: We studied how variations in circadian serum leptin levels change as people age. METHODS: Serum leptin levels were studied on a circadian basis in 26 men, 6 overweight (BMI >27.8) and 20 with normal weight. The normal-weight men were divided into four age groups: (A) in their 30s, (B) in their 40s, (C) in their 50s, and (D) in their 60s. Serum samples were drawn at 2-hour intervals from 8:00 to 22:00 and hourly from 22:00 to 8:00 for a total of 24 h. RESULTS: A significant circadian variation of leptin levels was found whatever the age with a peak at night and a trough around noon. The circadian leptin levels were higher in the older normal-weight groups (50s and 60s) and in the groups with a BMI >27.8. CONCLUSION: Our study demonstrates that changes in the characteristics of the circadian rhythm of serum leptin in healthy men are associated with both advancing age and increased BMI.

Adult↗

Cortisol diurnal variation in blood and saliva of patients with metastatic colorectal cancer: relevance for clinical outcome.

BACKGROUND: In healthy humans, cortisol displays marked 24-hour rhythms in serum and saliva, with a strong correlation between both fluids; the circadian variation of salivary cortisol is prognostic of longer survival in patients with metastatic breast cancer. In order to confirm these results in a non-hormone-dependent cancer, cortisol concentrations in serum and saliva were compared at different circadian stages, in patients with metastatic colorectal cancer. PATIENTS AND METHODS: A first study consisted of round-the-clock sampling for two 24-hour periods, in 18 patients. A second study consisted of blood and salivary sampling at 8:00h and 16:00h, on 2 consecutive days, in 192 patients. RESULTS: Group circadian variations were validated in both body fluids. Cortisol concentrations in the serum and in saliva were significantly correlated in only 62% of the 18 patients in the first study. In the second study, the average cortisol concentrations were higher at 8:00h than at 16:00h, in serum as well as in saliva. Measures from both body fluids were correlated in patients with a marked 24-hour rhythm, but plasma and salivary cortisol did not correlate in patients with a damped diurnal variation. The patient's performance status and extent of liver involvement, as well as the patient's rest activity cycle were influential on cortisol average concentration, but not on its circadian variation. The circadian variation in cortisol was prognostic of neither response, nor survival. CONCLUSION: These results indicate that the assessment of salivary cortisol cannot substitute for that of serum cortisol in metastatic colorectal cancer. This study suggests that the clinical relevance of cortisol circadian rhythm for patient outcome may differ according to the hormonal dependency of the tumor.

Adult↗