Mohamed Mechkouri

Oral contraceptives alter circadian rhythm parameters of cortisol, melatonin, blood pressure, heart rate, skin blood flow, transepidermal water loss, and skin amino acids of healthy young women.

Sixteen healthy women users and nonusers of oral contraceptives (OC) volunteered to document a set of circadian rhythms. Nine were taking OC providing ethynyl estradiol (0.03-0.05 mg/24h, 21 days/month) combined with DL- or L-norgestrel or norethisterone. There was no group difference (p > 0.05) in median age (22 years), weight (57 kg), and height (162) cm). Data were obtained at fixed hours, 5 times/24h, during a 48-h span, in November. (Day activity from approximately 08:00 to approximately 23:00 h and night rest). Environmental conditions were controlled, using air-conditioned rooms of constant temperature (26 degrees +/- 0.5) and relative humidity 45% +/- 1. Both cosinor and ANOVA were used for statistical analyses. All circadian rhythms were validated with one exception: that of salivary melatonin was not detected in OC users. The 24h mean (M) exhibited group differences for certain variables: M was greater in OC than non-OC users for systolic blood pressure (p < 0.0001), heart rate (p < 0.01), skin blood flow (p < 0.04), and transepidermal water loss (p < 0.02). M was lower in OC than non-OC users in salivary cortisol (p < 0.04) and skin amino acids (p < 0.003). No group difference was detected in any other documented rhythms: diastolic blood pressure, grip strength of both hands, oral temperature, self-rated fatigue, and the skin variables of urea, lactate, triglycerides, and acid phosphatase activity.

Circadian rhythm period in reaction time to light signals: difference between right- and left-hand side.

The study was designed to test the hypothesis that the prominent rhythm period tau of simple reaction time (SRT) and three-choice reaction time (CRT) to light signals may vary between the dominant (DH) and non-dominant (NDH) hand. Eleven healthy subjects, 8 males (16-74 years, including two left-handed) and 3 females (18-43 years), synchronized with a diurnal activity (approximately 07.00 h to approximately 23.00 h) and a nocturnal rest, volunteered for the study. A battery-powered ambulatory device was used to self-record SRT to a yellow light signal and CRT to yellow, green and red signals. Tests were performed 4-7 times/24 h during a 12- to 15-day span. Power spectra, ANOVA, cosinor, chi2 and correlation tests were used to individually analyze time series. Tau = 24 h in SRT rhythms of DH (8/11 cases) and NDH (6/11 cases) with chi2 = 3.5 and p > 0.05. In CRT rhythms, tau = 24 h for DH (8/11 cases) while tau = 8 h for NDH (7/11 cases), a difference which was statistically significant (chi2 = 9.4 with p < 0.02). Concordant results were obtained with other statistical tests leading to the conclusion that the rather complex cognitive task (CRT) and, to a certain extent, SRT of certain individuals, were associated with tau = 24 h for DH and tau = 8 h for NDH. These findings are in favor of the hypothesis that functional clocks are present in the human brain cortex, associated with the possible expression of rhythms with a prominent period differing from the right- and left-hand side.

Role of school schedule, age, and parental socioeconomic status on sleep duration and sleepiness of Parisian children.

The aim of the study was to assess the duration and quality of sleep of prepubertal (Tanner Scale level 1) physically and mentally healthy children as a function of school schedule (4 versus 4.5 days per week), age and grade (median age of 9.5 years for 4th grade versus median age of 10.5 years for 5th grade), school district (wealthy versus nonwealthy) in Paris, France, and parental socioeconomic status (high, medium, or low). We studied 51 girl and 44 boy volunteer pupils with written parental consent. The study lasted 2 weeks during the month of March. During the first study week, the children attended school 4.5 days, and during the second week, they attended school only 4 days without difference in the length of the school day. A sleep log was used to ascertain time of lights off for sleep and lights on at awakening, nighttime sleep duration, and self-rated sleep quality. A visual analog scale (VAS) was also used by pupils to self-rate the level of perceived sleepiness at four specific times of the school day. Conventional statistical methods (e.g., t and χ2tests) were used to examine differences in mean values. Sleep duration, self-rated sleepiness, and subjective sleep quality were comparable (P >. 05) by gender, school schedule, school district, and parental socioeconomic status. Overall, the sleep of this sample of Parisian children around 10 years of age was rather stable in its duration and timing, suggesting flexibility to adjust to the different school schedules. (Chronobiology International, 18 (6), 1005–1017, 2001)

Right- and left-brain hemisphere. rhythm in reaction time to light signals is task-load-dependent: Age, gender, and handgrip strength rhythm comparisons

In healthy mature subjects simple reaction time (SRT) to a single light signal (an easy task) is associated with a prominent rhythm with τ=24 h of dominant (DH) as well as nondominant (NDH) hand performance, while three-choice reaction time (CRT), a complex task, is associated with τ=24 h of the DH but τ<24 h of the NDH. The aims of the study were to assess the influence of age and gender on the difference in τ of the NDH and DH, as it relates to the corresponding cortical hemisphere of the brain, in comparison to the rhythm in handgrip strength. Healthy subjects, 9 (5 M and 4 F) adolescents 10–16 yr of age and 15 (8 M and 7 F) adults 18–67 yr of age, active between 08:00±1 h and 23:00±1:30 h and free of alcohol, tobacco, and drug consumption volunteered. Data were gathered longitudinally at home and work 4–7 times daily for 11–20 d. At each test time the following variables were assessed: grip strength of both hands (Dynamometer: Colin–Gentile, Paris, France); single reaction time to a yellow signal (SRT); and CRT to randomized yellow, red, or green signal series with varying instruction from test to test (Psycholog-24: Biophyderm, France). Rhythms in the performance in SRT, CRT, and handgrip strength of both DH and NDH were explored. The sleep–wake rhythm was assessed by sleep-logs, and in a subset of 14 subjects it was also assessed by wrist actigraphy (Mini-Motionlogger: AMI, Ardsley NY). Exploration of the prominent period τ of time series was achieved by a special power spectra analysis for unequally spaced data. Cosinor analysis was used to quantify the rhythm amplitude A and rhythm-adjusted mean M of the power spectral analysis determined trial τ. A 24h sleep–wake rhythm was detected in almost all cases. In adults, a prominent τ of 24 h characterized the performance of the easy task by both the DH and NDH. In adults a prominent τ of 24 h was also detected in the complex CRT task performed by the DH, but for the NDH the τ was <24 h. This phenomenon was not gender-related but was age-related since it was seldom observed in adolescent subjects. Hand-side differences in the grip strength rhythms in the same individuals were detected, the τ being ultradian rather than circadian in adolescent subjects while in mature subjects the τ frequently differed from that of the rhythm in CRT. These findings further support the hypothesis that functional biological clocks exist in both the left and right hemispheres of the human cortex.

24-hour, weekly, and annual patterns in traumatic and non-traumatic surgical pediatric emergencies

24 h patterns with high frequency components in the incidence of pediatric trauma were validated and quantified in one of our earlier studies. Herein, we further explored the temporal—high frequency, 24 h, weekly (7 d), hemi‐weekly (3.5 d), and annual – patterns in traumatic (1990–1997; n=15,110 events) and non‐traumatic pediatric surgical emergencies (PSE) (1992–2001; n=5,593 events) as well as automobile accidents (AA) (1990–1997; n=67,712) in the County of Vaud, Switzerland. The latter served as a reference system of human adult activity and risk. Two‐way ANOVA, χ2, correlation, and cosinor analyses were used as statistical tools. A 24 h pattern, reproducible from year to year, was validated in traumatic and non‐traumatic PSE and AA. The 24 h patterns were not correlated and differed from one another in terms of their acrophase (peak time) and amplitude. A gender‐related difference was found only in the non‐traumatic time series for weekly (7 d) and hemi‐weekly (3.5 d) patterns. The latter were detected in boys but not girls. No statistically significant difference was found in the acrophase and amplitude between boys and girls in the temporal patterns of other periods. An annual pattern was validated in automobile accidents (acrophase: 4th of September ±37 d (SD)) and pediatric trauma (acrophase: 14th of June ±10 d), but not in non‐traumatic PSE. These results suggest that environmental modulations differ between the incidence of traumatic and non‐traumatic PSE. Presumably, the two phenomena involve different aspects of the temporal organization and/or different levels of susceptibility of a set of biological rhythms to environmental factors.

Variability in the period of the blood pressure circadian rhythm in human beings

In studies and assessments of human beings done in natural settings, it is assumed that the period tau of circadian rhythms, including ones of systolic (SBP) and diastolic (DBP) blood pressure, is equal to 24 hours. To test this hypothesis, SBP and DBP rhythms were studied in 112 medication-free, non-hospitalized subjects (62 males, 47.1 + 2.0 years [x +/- SEM], and 50 females, 54.5 +/- 2.1 years) by 48 h ambulatory blood pressure monitoring (ABPM). Of these, 26 were hypertensive (diurnal SBP > 140 mmHg and diurnal DBP > 90 mmHg) and 86 normotensive. All subjects were synchronized by their habitual daytime activities from approximately 08:00 h to approximately 23:00 h +/- 1 h and by sleep at night. The BP was assessed at 15-minute intervals during a continuous 48h span using a Spacelabs model #90207 ABPM. The time series data of each subject were individually evaluated by power spectra analysis for the prominent tau of the SBP and DBP rhythms. The prominent tau differed from 24 hours in 22/112 subjects for SBP and in 16/112 subjects for DBP. Generally, in these individuals the tau was less than 24 hours. The occurrence of non-24 h taus was more frequent in hypertensive than normotensive subjects; the difference between the groups in the distribution of the prominent taus by class (tau = 24 h, tau = 12, 12 h > tau < 24 h, etc.) was statistically significant (chi 2 test = 19.1; p < 0.001). No difference in the distribution of taus of blood pressure was detected according to the subjects age and gender. These findings suggest that ABPM done only for a duration of 24 h may be too short to characterize accurately the features of the day-night variation in human BP, including the precise period of its rhythm.

Circadian Rhythms in Toxic Effects of the Serotonin Antagonist Ondansetron in Mice

The aim of the study was to learn whether the lethal and the motor incoordination (ataxia) side effect of ondansetron (Zophren®) administration is dosing‐time dependent. Ondansetron is a serotonin 5‐HT3 receptor antagonist used primarily to control nausea and vomiting arising from cytotoxic chemo‐ and radiotherapy. A total of 210 male Swiss mice 10 to 12 weeks of age were synchronized for 3 weeks by 12h light (rest span)/12h dark (activity span). Different doses of ondansetron were injected intraperitoneally (i.p.) at fixed times during the day to determine both the sublethal (TD50) and lethal (LD50) doses, which were, respectively, 3.7 ± 0.6 mg/kg and 4.6 ± 0.5 mg/kg. In the chronotoxicologic study a single dose of ondansetron (3.5 mg/kg, i.p.) was administered to different and comparable groups of animals at four different circadian stages [1, 7, 13, and 19h after light onset (HALO)]. The lethal toxicity was statistically significantly dosing time‐dependent (χ2 = 21.51, p < 0.0001). Drug dosing at 1 HALO resulted in 100% survival rate whereas drug dosing at 19 HALO was only one‐half that (52%). Similarly, lowest and highest ataxia occurred when ondansetron was injected at 1 and 19 HALO, respectively (χ2 = 22.24, p < 0.0001). Effects on rectal temperature were also dosing‐time related (Cosinor analysis, p < 0.0001). The characteristics of the waveform describing the temporal patterns differed between the studied variables, e.g., lethal toxicity and survival rate showing two peaks and rectal temperature showing one peak in the 24h time series waveform pattern. Cosinor analysis also revealed a statistically significant ultradian (τ ≡ 8h) rhythmic component in the considered variables. Differences in curve patterns in toxicity elicited by ondansetron on a per end point basis are hypothesized to represent the phase relations between the identified 24h and 8h periodicities.

Circadian Time Organization of Professional Firemen: Desynchronization—Tau Differing from 24.0 Hours—Documented by Longitudinal Self-assessment of 16 Variables

*This work is dedicated to the memories of Drs. Israel Ashkenazi and Erhard Haus, outstanding pioneers of medical chronobiology, dear colleagues, and distinguished gentlemen of exceptional human qualities.We investigated the circadian synchronization/desynchronization (by field-study assessment of differences in period, τ, of 16 coexisting and well-documented rhythms) of 30 healthy firemen (FM) exposed to irregular, difficult, and stressful nocturnal work hours who demonstrated excellent clinical tolerance (allochronism). Three groups of FM were studied (A = 12 FM on 24-h duty at the fire station; B = 9 FM on 24-h duty at the emergency call center; C = 9 day-shift administrative FM) of mostly comparable average age, body mass index, career duration, chronotype—morningness/eveningness, and trait of field dependence/independence. The self-assessed 16 circadian rhythms were (i) physiological ones of sleep-wake (sleep log), activity-rest (actography), body temperature (internal transmitter pill probe), right- and left-hand grip strength (hand dynamometer), systolic and diastolic blood pressure (BP) plus heart rate (ambulatory BP monitoring device); (ii) psychological ones (visual analog self-rating scales) of sleepiness, fatigue, fitness for work, and capacity to cope with aggressive social behavior; and (iii) cognitive ones of eye-hand skill and letter cancellation, entailing performance speed (tasks completed/unit time) and accuracy (errors). Data (4–6 time points/24 h; 2 591 480 values in total) were gathered continuously throughout two 8-d spans, one in winter 2010–2011 and one in summer 2011. Each of the resulting 938 unequal-interval time series was analyzed by a special power spectrum analysis to objectively determine the prominent τ. The desynchronization ratio (DR: number of study variables with τ = 24.0 h/number of study variables × 100) served to ascertain the strength/weakness of each rhythm per individual, group, and season. The field study confirmed, independent of group and season, coexistence of rather strong and weak circadian oscillators. Interindividual differences in DR were detected between groups and seasons (χ2, correlation tests, analysis of variance [ANOVA]). Moreover, in each group, both in winter and summer, a normal distribution was observed in the number of FM with rhythms with τ = 24.0 h, e.g., ranging from 5/16 (large desynchronization) to 16/16 (no desynchronization). Such a normal distribution with intraindividual stability over time (i.e., seasons) is consistent with the hypothesis of an inherited origin of a differential propensity to circadian desynchronization and which is supported by the distribution of τs in winter and summer following the Dian-Circadian Genetic Model, i.e., with τ = 24.0 h, τ = 24.0 h + n(0.8 h), and τ = 24.0 h − n(0.8 h).

ACCIDENTS IN CHILDREN DO NOT HAPPEN AT RANDOM: PREDICTABLE TIME-OF-DAY INCIDENCE OF CHILDHOOD TRAUMA

In a prospective study, 15,110 childhood traumas were recorded by the Pediatric Surgery Service (CHUV, Lausanne) between January 1, 1990 and December 31, 1997. The exact clock hour when the injury occurred and other germane data were obtained. Time series thus obtained were analyzed by several statistical (ANOVA, cosinor, χ2, Table Curve, etc.) methods. High statistically significant circadian patterns were detected with a trough at night—almost no traumas/hour (t/h), and a peak in the afternoon (∼16:00h)—9.3±0.4 (SD) t/h. Such 24h variation was validated for the whole sample for the entire 8yr study span as well as the data of each year. Neither gender- nor age-related differences in the 24h pattern were detected between children under 5 yr of age, who have not yet attended school and children from 5 to 16 yr of age, who attend school. Small but statistically significant differences in the 24h patterns were observed when categorized by the type of activity associated with the trauma and the place of trauma occurrence. The great stability of the 24h pattern in childhood trauma over the 8yr study span suggests an endogenous origin in addition to the role presumably played by environmental factors. Periods of 12 and 8 h were also detected in the time series. The afternoon peak time of childhood traumas differs from that of adults, which is located ∼04:00h in rotating shift workers and automobile drivers and 06:00–08:00h in adult day-workers. The validation of a circadian pattern in childhood traumas with an afternoon peak should be taken into account in the design of childrens preventative injury programs.

24-hour pattern in lag time of response by firemen to calls for urgent medical aid.

The aim of the study was to assess the group 24-h pattern of lag time (LT) in response by regular and volunteer firemen (RFM and VFM) to calls for medical help (CFMH), specifically calls for out-of-hospital cardiac arrest (OHCA). LT, duration in min between a CFMH and departure of service vehicle equipped with a semiautomated defibrillator and generally staffed with four well-trained and ready-to-go FM, represents the integrated duration of several processes, each with separate reaction and decision-making times. The exact time of each CFHM (in min, h, day, month, yr) was recorded electronically, and the exact departure time from the station of the responding FM vehicle was recorded by an on-duty FM. Overall, CFMH made up 53 ± 9% (SEM) of all emergencies calls for aid. To standardize the study methods, the reported findings are based on 568 CFMH specifically regarding OHCA that occurred during the 4-yr study span (January 2005 to December 2008). CFMH exhibited a 24-h pattern with a major peak at 10:00 h (mean ± SEM: n = 9.5 ± 1.6) and major trough at 01:00 h (n = 1.3 ± 0.3; t test, p < .001). From year to year and season to season, a 24-h pattern was detected in the total of CFMH/h with two peaks (∼10:00 and ∼17:00h) and two troughs (∼01:00 and ∼15:00 h) (analysis of variance [ANOVA], p < .01; Cosinor, p < .05 to < .003), with neither season- nor year-related differences (χ2, p > .05). In CFMH/h pooled time series, ANOVA-detected differences between the hourly means (p < .01), and Cosinor analysis validated a 24-h rhythm (p < .002). In raw data, the longest LT, indicative of poorest performance, occurred at 05:00 h (8.8 ± 0.7 min) and the trough of LT, indicative of best performance, at 16:00 h (4.3 ± 0.8 min (t test, p < .02). 24-h patterning in LT was validated both by ANOVA of hourly means (p < .0006) and Cosinor analysis (p < .05), with longest LT ∼05:00 h and shortest LT ∼16.00 h for data of the individual yearly time-series data. The 24-h LT rhythm was also validated in the pooled time series by Cosinor (p < .0001), with the 24-h mean ± SEM = 6 ± 0.17 min and acrophase (peak) of 03:00 h ± 88 min (SD). Curve patterns of CFMH/h and LT/h differed widely. As a group phenomenon, the LT 24-h rhythm mimics the 24-h pattern of performance, as demonstrated by many laboratory and field investigations. The stability of the LT rhythm between years and seasons and its weak relationship with the CFMH 24-h pattern favors the hypothesis of an endogenous component or origin. The nighttime trough of performance is presumably linked to the elevated risk of work accidents in the same population of FM.