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Biomedical subjects

Yvan Touitou

Publications and source records attributed to Yvan Touitou.

At least 19 recordsLinked to original sources
PubMed2006

Promoting adjustment of the sleep-wake cycle by chronobiotics.

Chronobiotics are substances that adjust the timing of internal biological rhythms. Many classes of drugs have been claimed to possess such properties and arouse growing interest as the circumstances for their use in sleep disturbances caused by circadian rhythms alterations (delayed or advanced sleep-phase syndromes, non-24-h sleep-wake disorders, jet lag, shift work sleep disorders and so on) have become progressively more frequent. Amongst the substances potentially presenting chronobiotic properties, a consensus seems to be reached on the possible use of melatonin or its agonists to shift the phase of the human circadian clock, but optimizing the dose, formulation and especially the time of administration require further studies.

Chronobiology Phenomena↗
PubMed2006

Alcohol consumption does not affect melatonin circadian synchronization in healthy men.

Alcohol intake alters melatonin secretion both in healthy volunteers and in alcoholics in a variety of different situations (while drinking, during or after withdrawal, and with neurological complications). This alteration may reduce secretion or affect its circadian rhythm, thus causing daytime secretion in some alcoholics. We sought to determine if daytime melatonin secretion is caused directly by acute alcohol consumption or if it instead indicates a change in circadian synchronization. Because alcohol consumption as it occurs in alcoholics (continuous consumption of large amounts) has never been examined in healthy volunteers, we exposed 11 healthy volunteers to 256 g of alcohol over 24 h to study the circadian profiles of melatonin secretion. Our results demonstrate a lack of daytime secretion in our subjects. This suggests that the disordered circadian melatonin secretion seen in alcoholics indicates a shift in melatonin secretion rather than an acute effect of alcohol on this secretion, or alternatively, that it is a direct effect of chronic rather than acute exposure to high blood alcohol levels.

Adolescent↗
PubMed2006

Simulation of long-haul flights in humans: prolonged mild hypoxia does not alter the circadian time structure of plasma testosterone and gonadotrophins.

Mild hypobaric hypoxia caused by pressurisation may contribute to alter rhythmicity after long-haul flights, independently of the number of time zones crossed. In this controlled crossover study, we assessed the effects of two levels of hypoxia, equivalent to 8000 ft and 12,000 ft above sea level, on the rhythm of plasma concentrations of three hormones: testosterone, LH, and FSH. A hypoxia-induced decrease in LH and FSH has often been reported during mountaineering while testosterone is considered a marker of fatigue. Sixteen healthy male volunteers, aged 23-39 years, spent 8 h in a hypobaric chamber (08:00-16:30), simulating conditions at 8000 ft. This was followed by an additional 8 h four weeks later, simulating conditions at 12,000 ft. Plasma hormones were assayed every 2 h over two 24-h cycles (control and hypoxic-exposure cycles). We found no significant effects of hypoxia on the circadian profile of the gonadal axis hormones and, therefore, conclude that these hormones do not serve as valuable markers of post-flight alterations of the circadian system in human.

Adult↗
PubMed2006

Responses of the steroid circadian system to alcohol in humans: Importance of the time and duration of intake.

Reports provide conflicting data about the effects of alcohol consumption on the hormonal system. Any study of these effects must control for a number of variables, including sex, alcohol status (alcoholic addiction vs. non-addiction), medical status (malnutrition, liver disease), and conditions of alcohol exposure, including an acute or continuous pattern of intake. The latter appears to be an especially critical factor in interpreting these effects. The authors therefore conducted a trial with a circadian design in which alcohol was administered repeatedly and regularly over a 26 h period for a total dose of 256 g. Because this protocol involves continuous alcohol administration, it is similar to administration among alcoholics and thus sheds new light on alcohol's effect on hormone secretion. Using healthy volunteers rather than alcoholics, however, prevents any confounding due to liver disorders and nutritional deficiencies, and thus makes it possible to focus on the direct role of alcohol in hormonal modifications. In these conditions, the continuous administration of alcohol did not affect cortisol secretion, but serum testosterone levels were significantly higher at all time points during the alcohol session than at the corresponding time points during the control session. These data are not consistent with previously reported findings for the relation between alcohol and both cortisol and testosterone, because in the current experiment the action of ethanol on steroid secretion should involve the circadian clock more than the hormonal system itself.

Adolescent↗
PubMed2006

Ethics, standards, and procedures of animal and human chronobiology research.

The majority of research papers published in Chronobiology International report the findings of investigations conducted on laboratory animals and human beings. The editors and the readers of the journal expect the authors of submitted manuscripts to have made an important contribution to biological rhythm and related research through the ethical conduct of investigations and unbiased and accurate reporting of findings. Authors of scientific papers are required to disclose any potential conflict of interest. The journal accepts only papers that are original work, no part of which has been submitted for publication elsewhere, except as brief abstracts. The journal and its editors endorse the compliance of investigators to the principles of the Declaration of Helsinki of the World Medical Association, which relate 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, which relate to the conduct of ethical research on laboratory and other animals. The peer review of manuscripts by Chronobiology International thus includes judgment as to whether or not the investigative methods conform to the standards of good research practice. This article updates the ethical policies, standards, and procedures for manuscripts submitted to Chronobiology International that involve human and animal biological rhythm research, both from the perspective of the criteria of quality chronobiology investigation and from the perspective of humane and ethical research on human beings and animals.

Animal Experimentation↗
PubMed2005

Population pharmacokinetics of tacrolimus in full liver transplant patients: modelling of the post-operative clearance.

OBJECTIVE: To investigate the population pharmacokinetics of tacrolimus in an adult liver transplant cohort using routine drug monitoring data and to identify patient characteristics that influence pharmacokinetic parameters. METHODS: Tacrolimus pharmacokinetics was studied in 37 adult patients using a population approach performed with NONMEM. RESULTS: A one-compartment open model with linear absorption and elimination adequately described the data. The apparent clearance (CL) was approximately zero in the immediate post-operative days (PODs) and then rapidly increased as a function of POD to reach a plateau. This was modelled as a sigmoid relationship with the characteristic parameters CL(max) (plateau), TCL(50) (time to obtain 50% of the plateau) and gamma (coefficient of sigmoidicity). This clearance model was thought to describe the hepatic function regeneration after transplantation. Typical population estimates (percentage inter-individual variability) of CL(max), TCL50, and gamma and apparent distribution volumes (V) were 36 l/h (43%), 6.3 days (33%), and 4.9 l and 1870 l (49%), respectively. The CL(max) was negatively related to plasma albumin, and TCL50 was positively related to aspartate amino transferase (ASAT). Bayesian estimations performed at different POD times indicated that acceptable precisions in individual pharmacokinetic predictions could be obtained after the 15th POD. CONCLUSION: Tacrolimus clearance modelling showed that there was a large variation in individual CL estimates up to the 15th day post-surgery. After this period, the mean error resulting from the Bayesian estimation was strongly decreased and this estimation method could be applicable and should limit tacrolimus monitoring.

Bayes Theorem↗
PubMed2005

Old rats are more sensitive to photoperiodic changes. A study on pineal melatonin.

After having previously demonstrated that beta-adrenergic stimulation of melatonin under a standard light:dark (LD) cycle regimen of 12:12 is more effective in young than in old pineal glands, we have now studied how the daylength change LD 18:6 affects pineal melatonin secretion and its regulation by the beta-adrenergic system. Young (10 weeks) and old (22 months) male Wistar rats were synchronized with either a standard LD 12:12 for 4 weeks, or acclimatized under the same LD conditions for 4 weeks, then subjected to a long LD 18:6 photoperiod for 1 week. The rats were sacrificed at three time samplings: 0, 4, and 7h after dark onset (HADO) for LD 12:12 or 0, 2, and 3.5 HADO for LD 18:6. Pineal glands were collected and perifused for 480 min. Isoproterenol (10(-4)M) was infused for 20 min, 4h 10 min after the beginning of the perifusion. Basal levels of melatonin production in the young rats displayed a 1.5-2.5-fold increase compared to those in the old rats. Interestingly, mean basal melatonin levels in old rats under standard LD 12:12 conditions were significantly higher (P<0.05) than mean levels at the same relative dark phase intervals under LD 18:6 conditions. Isoproterenol stimulated melatonin production in both young and old rat pineal glands, regardless of time sampling or photoperiodic conditions. The magnitude of the response to 10(-4)M isoproterenol infusion in old pineals was approximately half that found in young glands (P<0.001), and tended to be higher under LD 12:12, in both young and old rat pineal glands, although no significant difference was found in melatonin response between the two photoperiods (P>0.05). This study shows that basal pineal melatonin levels in old rats are more sensitive to photoperiod changes than in young rats. These results also demonstrate that isoproterenol can stimulate both young and old rat pineal glands irrespective of time or photoperiod and confirm previous findings, showing that the melatonin response to isoproterenol is age-dependent and that pineal gland response to isoproterenol is not photoperiod-dependent, at least under our experimental conditions.

Adrenergic beta-Agonists↗
PubMed2005

The phasing of circadian rhythms in mice kept under normal or short photoperiods.

Mammals represent a multi-oscillatory system. Not only different rhythmic function but also a certain rhythmic function may be controlled by several oscillators. Also, the LD cycle, though being the main zeitgeber, may have different effects on different rhythmic functions. The aim of the present study was to investigate putative changes of internal phase relationships between different rhythms and their phase relationship with respect to the light-dark cycle following a gradual lengthening of the dark time. The investigations were carried out on adult female mice (HaZ:ICR). Animals were initially kept in a 12:12 h LD cycle. The dark time was then lengthened once a week by delaying the time of lights-on by 1 h until an L/D=6:18 h was reached. The motor activity was recorded continuously. The daily profiles of food intake, liver glycogen and melatonin in the serum and the pineal gland were estimated as transverse studies under L/D=12:12 h and L/D=6:18 h. Under short-day conditions (L/D=6:18 h), the evening onset of the main maximum of motor activity and food intake was delayed in relation to lights-off and the onset of the secondary maximum in the morning was advanced in relation to lights-on. Similar phase changes were found with respect to the onset of glycogen synthesis and its breakdown. In the case of melatonin, the rise and the fall occurred earlier or later, respectively, and the phase differences with respect to lights-off and lights-on became smaller. If the mid-point between the evening and morning onsets of activity and food intake and between the rises and falls of glycogen and melatonin concentrations are considered, then the changes in all rhythmic functions were similar. Consequently, the phase relationships between different rhythmic functions and with respect to the light-dark cycle, and thus the internal and the external temporal order, were preserved under different light-dark ratios. Also, the results are in good accordance with a modified two-oscillator model where lights-off triggers advances of an evening oscillator and lights-on delays a morning oscillator.

Animals↗
PubMed2005

Lack of effect of ghrelin treatment on melatonin production in rat pineal and Harderian glands.

The effects of ghrelin, a peptide hormone secreted from the stomach, on melatonin remain unknown. The aim of the study was to investigate possible ghrelin-melatonin interactions by studying the effect of ghrelin treatment on melatonin production in rat pineal and Harderian glands. Young (9 weeks) and old (20 months) male Wistar rats, maintained under a light:dark cycle regimen of 12:12, were assigned randomly to either a single subcutaneous (s.c.) injection of saline or ghrelin (1 microg/rat or 15 microg/rat) 1 h before sacrifice in the middle of the dark phase, or repeated s.c. saline or ghrelin injections (15 microg/rat), 3, 2 and 1 h before sacrificed in the middle of the dark phase. Neither ghrelin doses (1 microg/rat or 15 microg/rat) nor type of treatment (acute or repeated) influenced melatonin levels or the melatonin synthesizing enzymes N-acetyltransferase and hydroxyindole-O-methyltransferase activities, either in pineal gland or in Harderian glands. At the concentrations used, ghrelin does not influence melatonin production in rat pineal and Harderian glands, and therefore is not involved in the regulation of melatonin secretion, at least under our experimental conditions.

Acetylserotonin O-Methyltransferase↗
PubMed2005

Nocturnal excretion of 6-sulphatoxymelatonin in children and adolescents with autistic disorder.

BACKGROUND: Many studies in autistic disorder report sleep problems and altered circadian rhythms, suggesting abnormalities in melatonin physiology. Additionally, melatonin, a pineal gland hormone produced from serotonin, is of special interest in autistic disorder given reported alterations in central and peripheral serotonin neurobiology. METHODS: Nocturnal urinary excretion of 6-sulphatoxymelatonin was measured by radioimmunoassay in groups of children and adolescents with autistic disorder (n = 49) and normal control individuals (n = 88) matched on age, sex, and Tanner stage of puberty. RESULTS: Nocturnal 6-sulphatoxymelatonin excretion rate was significantly and substantially lower in patients with autism than in normal controls (mean +/- SEM, .75 +/- .11 vs. 1.80 +/- .17 microg/hr, p =.0001), and was significantly negatively correlated with severity of autistic impairments in verbal communication and play (p < .05). CONCLUSIONS: These findings indicate clearly that nocturnal production of melatonin is reduced in autism. Further research is warranted in order to understand the mechanisms underlying the lower melatonin production, to assess the impact of altered melatonin on the pathophysiology and behavioral expression of autistic disorder, and to determine the utility of melatonin administration in individuals with autism.

Adolescent↗
PubMed2005

Hypoxic alterations of cortisol circadian rhythm in man after simulation of a long duration flight.

Fatigue is often reported after long duration flights. Mild hypobaric hypoxia caused by pressurisation may be involved in this effect through disruption of circadian rhythms, independently 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 circadian rhythm of plasma cortisol, a marker of the circadian time structure. Sixteen healthy young male volunteers (23-39 years) were exposed in a hypobaric chamber for 8 h (08:00-16:00 h) to 8000 ft, followed 4 weeks later to 12,000 ft. Plasma cortisol was assayed during two 24-h cycles (control and hypoxic exposure) every 2h in all subjects. We found a significant change in the pattern of cortisol secretion during both hypoxic exposures, with an initial fall in cortisol followed by a transient rebound, whereas the phase and the 24-h mean level remained unchanged. The change in cortisol pattern followed the alterations in autonomic balance assessed by heart rate variability (HRV) spectral analysis. The normalised high frequencies and the low-to-high frequencies ratio showed a significant shift toward sympathetic dominance with some differences in time course for both altitudes studied. HRV analysis improved the interpretation of cortisol 24-h profiles. Our data, which strongly suggest that prolonged mild hypoxia alters the expression of cortisol circadian rhythm, should be taken into account to interpret secretory rhythm changes after transmeridian flights.

Adult↗
PubMed2005

Response of circulating leptin to Ramadan daytime fasting: a circadian study.

Although the effects of short-term fasting on serum leptin concentrations are known, those resulting from long-lasting modifications of food intake schedule, as during the month of Ramadan, have not yet been extensively studied. Therefore, serum concentrations of leptin were measured around the clock at 4-hourly intervals before the beginning of Ramadan and on the twenty-third day of Ramadan daytime fasting in ten male subjects keeping the same usual activity pattern and general synchronisation in both situations. Time series were analysed with repeated measures ANOVA and Cosinor. No significant changes in amplitude or 24 h mean concentration were seen, but significant shifts of 5 h 30 min in peak and trough serum leptin levels were found on the twenty-third day of Ramadan.

Analysis of Variance↗
PubMed2005

Diazepam affects both level and amplitude of rat locomotor activity rhythm but has no effect on core body temperature.

The present study investigates the effects of a chronic administration of diazepam, a benzodiazepine widely used as an anxiolytic, on locomotor activity and body core temperature rhythms in male Wistar rats housed under 12 : 12 light : dark (LD) cycle conditions. Diazepam was administered subcutaneously for 3 wks in a dosage of 3 mg/kg body weight/day, 1 h before the onset of darkness. Diazepam increased the level of locomotor activity from the first day until the end of treatment, and also increased the amplitude of the activity circadian rhythm, but only on the third wk of treatment. Diazepam exerted no effects on the length of the period and did not affect the phase of the locomotor activity rhythm. The body temperature rhythm of rats was affected neither by short-term (a single injection) nor by long-term (every day for 3 wks) diazepam treatment. Diazepam lacked effect on body core temperature even on the first day of administration, thereby ruling out the possibility of drug tolerance development. The fact that diazepam affects locomotor activity, but not core body temperature, suggests that different mechanisms mediate the actions of diazepam on locomotor activity and on core body temperature.

Animals↗
PubMed2005

Tumor antigen markers for the detection of solid cancers in inflammatory myopathies.

Dermatomyositis and polymyositis patients have an increased risk of developing cancers. We have assessed the diagnostic values of serum tumor markers for the detection of solid cancer in dermatomyositis/polymyositis patients. Serum carcinoembryonic antigen, CA15-3, CA19-9, and CA125 were assayed by immunoradiometric methods in 102 dermatomyositis/polymyositis patients. All the patients had complete physical examination, chest X-ray, echocardiogram, gastrointestinal tract endoscopic explorations, thoracoabdomino-pelvic computed tomography scan, and all women had gynecologic examination and mammogram. Exclusion criteria for study were childhood dermatomyositis, inclusion body myositis, myositis associated with a connective tissue disease, prior history of cancer, and the presence of benign conditions known to elevate serum tumor markers. After a median follow-up of 59 months, 10 (9.8%) patients had a solid cancer. Initial elevation of CA125 was associated with an increased risk of developing solid cancer [P = 0.0001 by Fisher's exact test; odds ratio (OR), 29.7; 95% confidence interval (95% CI), 8.2-106.6]. For CA19-9, there was a trend towards a significant association (P = 00.7; OR, 4.5; 95% CI, 1-18.7, respectively). Diagnostic values of elevated CA125 and CA19-9 at screening increased when the study analysis was restricted to patients who developed a cancer within 1 year (P < 0.0001 and P = 0.018, respectively) or to patients without interstitial lung disease (P = 0.00001; OR, 133; 95% CI, 6.5-2733 and P = 0.027; OR, 9; 95% CI, 1.5-53, respectively). Individual comparisons of the baseline and the second CA125 value showed that three of the eight patients with cancers versus 3 of the 76 patients without, displayed an increase of their CA125 level (P = 0.01 by Fisher's exact test). We conclude that CA125 and CA19-9 assessment could be useful markers of the risk of developing tumors for patients with dermatomyositis and polymyositis and should therefore be included in the search for cancer in dermatomyositis/polymyositis patients, especially for patients without interstitial lung disease.

Adult↗
PubMed2005

[Melatonin: what for?].

Melatonin (N-acetyl-5 methoxy-tryptamine) is a hormone secreted mainly by the pineal gland or epiphysis; it is also produced, but in much smaller quantities, by the retina. The key enzyme in melatonin synthesis is N-acetyl-transferase (NAT) whose activity increases during darkness. This explains why melatonin is mainly secreted at night. The circadian rhythm of melatonin synthesis is controlled by the suprachiasmatic nuclei--the "biologic clock". This clock itself functions rhythmically, being entrained by environmental synchronizers. According to the time of exposure, light has two effects on melatonin secretion, either suppressing or shifting its secretion (phase-response curve). Exposure to light in the morning advances the phase of the rhythm, while exposure in the evening delays it. Melatonin works in the opposite way, acting as a light signal transducer, and relaying information on the duration of day and night. Exogenous melatonin can synchronize some circadian rhythms, such as body core temperature. Current research is focusing on the properties of melatonin (and of light) as a resynchronizing agent in situations such as aging, blindness, shift work, night work, phase-advanced or phase-delayed sleep syndrome, and jet lag. Melatonin also has strong antioxidant properties (stronger than those of vitamin E), and an oncostatic action. Interestingly, three recent epidemiological studies show that women who work exclusively at night for long periods have a significantly elevated relative risk of breast cancer (RR 1.1-1.6). Other studies are required to confirm these results.

Aging↗
PubMed2004

Daily variation in the concentration of neuropeptide Y in the rat atrium: effects of age and photoperiodic conditions.

This study investigates the release characteristics of neuropeptide Y (NPY) from young (10 weeks) and old (22 months) rat atrium. Levels of NPY release from samples of atrium were studied by organ perifusion. Rats were exposed to light:dark (LD) cycles of 12:12 or 18:6 and sacrificed at different circadian stages: 0, 4, 7, 12, 18, and 20 h after dark onset (HADO) for LD 12:12 or 0, 2, 3.5, 6, 15, and 22 HADO for LD 18:6. The heart was collected, and the right atrium was removed, weighed, and perifused with Krebs-bicarbonate buffer for 100 min, including a period of 50 min for stabilization of secretion rate. NPY concentrations released by atrium did not differ between the two age groups. NPY exhibited daily variations in concentrations in LD 12:12, with a peak during the end of scotophase, at 12 HADO, in both the young and old rats. These variations were strongly modified in LD 18:6, where the pattern of the release exhibited two peaks occurring during the two thirds of dark (3.5 HADO) and light (22 HADO) periods. This strongly suggests that the NPY rhythm is dependent on the environmental light:dark cycle. In this paper we show that NPY concentrations in the rat atrium exhibit daily variations, which are maintained with ageing. Moreover, photoperiod greatly influences NPY levels in the atrium.

Aging↗
PubMed2004

Ex vivo studies on the acute and chronic effects of DHEA and DHEA-sulfate on melatonin synthesis in young- and old-rat pineal glands.

This study investigates the effects of acute and chronic injections of the neurosteroid dehydroepiandrosterone (DHEA) and its sulfate DHEA-S on pineal gland melatonin synthesis. Pineal melatonin production and plasma melatonin levels were investigated in young (9-week-old) and old (27-month-old) male Wistar rats. DHEA or DHEA-S have been administered acutely in a single intraperitoneal injection at a dosage of 50, 250, or 500 microg per animal, or on a long-term basis, i.e., for 8 days at a dosage of 100 microg per animal, 1 h before the onset of darkness. DHEA, at a dose of 50, 250, or 500 microg per animal, administered acutely to rats had no significant effects on pineal melatonin production whatever the age of the animals. In contrast, 500 microg DHEA-S induced a significant increase in the pineal melatonin content (15% in young animals and 35% in old animals) and the activity of N-acetyltransferase, the rate-limiting enzyme for melatonin synthesis in the pineal gland, (40% in young animals and 20% in old animals), without altering the activity of hydroxyindole-O-methyltransferase whatever the age of the animals. At lower concentrations (50 or 250 microg) DHEA-S had no effect on pineal melatonin production regardless of the age of the rats. Chronic injection of DHEA or DHEA-S at a dose of 100 microg had no effect on pineal melatonin or NAT and HIOMT activities in the two age groups. This work shows that DHEA-S (and not DHEA) is able, at pharmacological concentrations, to stimulate melatonin production by rat pineal glands regardless of the age of the animals.

Acetylserotonin O-Methyltransferase↗