Influence of time of day on propofol pharmacokinetics and pharmacodynamics in rabbits

This study evaluates the administration time-of-day effects on propofol pharmacokinetics and sedative response in rabbits. Nine rabbits were sedated with 5?mg/kg propofol at three local clock times: 10:00, 16:00, and 22:00?h. Each rabbit served as its own control by being given a single infusion at the three different times of day on three separate occasions. Ten arterial blood samples were collected during each clock-time experiment for propofol assay. A two-compartment model was used to describe propofol pharmacokinetics, and the pedal withdrawal reflex was used as the sedation pharmacodynamic response. The categorical data comprising the presence or absence of pedal withdrawal reflex was described by a logistic model. The typical volume of the central compartment equaled 7.67?L and depended on rabbit body weight. The elimination rate constant depended on drug administration time; it was lowest at 10:00?h, highest at 16:00?h, and intermediate at 22:00?h. Delay of the anesthetic effect, with respect to plasma concentrations, was described by the effect compartment, with the rate constant for the distribution to the effector compartment equal to 0.335?min(-1). Drug concentration had a large effect on the probability of anesthesia. The degree of anesthesia was largest at 10:00?h, lowest at 16:00?h, and intermediate at 22:00?h. In summary, both the pharmacokinetics and pharmacodynamics of propofol in rabbits depended on administration time. The developed population approach may be used to assess chronopharmacokinetics and chronopharmacodynamics of medications in animals and humans.     

PARADOXICAL POST-EXERCISE RESPONSES OF ACYLATED GHRELIN AND LEPTIN DURING A SIMULATED NIGHT SHIFT

Approximately 10% of employees undertake night work, which is a significant predictor of weight gain, possibly because responses to activity and eating are altered at night. It is known that the appetite-related hormone, acylated ghrelin, is suppressed after an acute bout of exercise during the day, but no researcher has explored whether evening exercise alters acylated ghrelin and other appetite-related outcomes during a subsequent night shift. Six healthy men (mean?±?SD: age 30?±?8 yrs, body mass index 23.1?±?1.1?kg/m²) completed two crossover trials (control and exercise) in random order. Participants fasted from 10:00?h, consumed a test meal at 18:00?h, and then cycled at 50% peak oxygen uptake or rested between 19:00–20:00?h. Participants then completed light activities during a simulated night shift which ended at 05:00?h. Two small isocaloric meals were consumed at 22:00 and 02:00?h. Venous blood samples were drawn via cannulation at 1?h intervals between 19:00–05:00?h for the determination of acylated ghrelin, leptin, insulin, glucose, triglyceride, and non-esterified fatty acids concentrations. Perceived hunger and wrist actimetry were also recorded. During the simulated night shift, mean?±?SD acylated ghrelin concentration was 86.5?±?40.8 pg/ml following exercise compared with 71.7?±?37.7 pg/ml without prior exercise (p?=?0.015). Throughout the night shift, leptin concentration was 263?±?242 pg/ml following exercise compared with 187?±?221 pg/ml without prior exercise (p?=?0.017). Mean levels of insulin, triglyceride, non-esterified fatty acids, and wrist actimetry level were also higher during the night shift that followed exercise (p?<?0.05). These data indicate that prior exercise increases acylated ghrelin and leptin concentrations during a subsequent simulated night shift. These findings differ from the known effects of exercise on acylated ghrelin and leptin during the day, and therefore have implications for energy balance during night work. (Author correspondence: c.j.morris@2006.ljmu.ac.uk).     

Identification of Human Plasma Metabolites Exhibiting Time-of-Day Variation Using an Untargeted Liquid Chromatography–Mass Spectrometry Metabolomic Approach

Although daily rhythms regulate multiple aspects of human physiology, rhythmic control of the metabolome remains poorly understood. The primary objective of this proof-of-concept study was identification of metabolites in human plasma that exhibit significant 24-h variation. This was assessed via an untargeted metabolomic approach using liquid chromatography–mass spectrometry (LC-MS). Eight lean, healthy, and unmedicated men, mean age 53.6 (SD?±?6.0) yrs, maintained a fixed sleep/wake schedule and dietary regime for 1 wk at home prior to an adaptation night and followed by a 25-h experimental session in the laboratory where the light/dark cycle, sleep/wake, posture, and calorific intake were strictly controlled. Plasma samples from each individual at selected time points were prepared using liquid-phase extraction followed by reverse-phase LC coupled to quadrupole time-of-flight MS analysis in positive ionization mode. Time-of-day variation in the metabolites was screened for using orthogonal partial least square discrimination between selected time points of 10:00 vs. 22:00?h, 16:00 vs. 04:00?h, and 07:00 (d 1) vs. 16:00?h, as well as repeated-measures analysis of variance with time as an independent variable. Subsequently, cosinor analysis was performed on all the sampled time points across the 24-h day to assess for significant daily variation. In this study, analytical variability, assessed using known internal standards, was low with coefficients of variation <10%. A total of 1069 metabolite features were detected and 203 (19%) showed significant time-of-day variation. Of these, 34 metabolites were identified using a combination of accurate mass, tandem MS, and online database searches. These metabolites include corticosteroids, bilirubin, amino acids, acylcarnitines, and phospholipids; of note, the magnitude of the 24-h variation of these identified metabolites was large, with the mean ratio of oscillation range over MESOR (24-h time series mean) of 65% (95% confidence interval [CI]: 49–81%). Importantly, several of these human plasma metabolites, including specific acylcarnitines and phospholipids, were hitherto not known to be 24-h variant. These findings represent an important baseline and will be useful in guiding the design and interpretation of future metabolite-based studies. (Author correspondence: Jooern.Ang@icr.ac.uk or Florence.Raynaud@icr.ac.uk)     

Chronopharmacological Study of an Antimicrobial Agent,Norfloxacin, in the Rat

Circadian rhythms in physiological processes may affect pharmacological actions of drugs. The purpose of this study was to determine whether pharmacokinetics or acute lethality (LD 50) of norfloxacin, exhibited circadian rhythmicity. Female Sprague- Dawley prepuberal rats (weight 115.8 ± 10.2 g) synchronized with a 12-h-light/ 12-h-dark cycle (lights on 7:00h) were used throughout the study. Norfloxacin pharmacokinetics after intraperitoneal administration at 4:00, 10:00, 16:00 and 22:00h was characterized. Intraperitoneal norfloxacin LD 50 was administered at 2:00, 6:00, 10:00, 14:00, 18:00 and 22:00 h. Pharmacokinetic parameters and lethality percentages were analyzed by the cosinor method for the presence of circadian rhythmicity. The results showed evidence of circadian rhythmicity for norfloxacin k abs, t ½abs, t max, MRT abs, Cl t /f and AUC. Absorption was higher when the drug was administered during the rest (16:00 h) period, meanwhile elimination was higher when administered during the activity (22:00 h) period. No rhythmicity was determined for norfloxacin lethality. It is concluded that, in this study, time of administration modifies the pharmacokinetics of norfloxacin.     

Ring the Bell for Matins: Circadian Adaptation to Split Sleep by Cloistered Monks and Nuns

Cloistered monks and nuns adhere to a 10-century-old strict schedule with a common zeitgeber of a night split by a 2- to 3-h-long Office (Matins). The authors evaluated how the circadian core body temperature rhythm and sleep adapt in cloistered monks and nuns in two monasteries. Five monks and five nuns following the split-sleep night schedule for 5 to 46 yrs without interruption and 10 controls underwent interviews, sleep scales, and physical examination and produced a week-long sleep diary and actigraphy, plus 48-h recordings of core body temperature. The circadian rhythm of temperature was described by partial Fourier time-series analysis (with 12- and 24-h harmonics). The temperature peak and trough values and clock times did not differ between groups. However, the temperature rhythm was biphasic in monks and nuns, with an early decrease at 19:39?±?4:30?h (median?±?95% interval), plateau or rise of temperature at 22:35?±?00:23?h (while asleep) lasting 296?±?39?min, followed by a second decrease after the Matins Office, and a classical morning rise. Although they required alarm clocks to wake-up for Matins at midnight, the body temperature rise anticipated the nocturnal awakening by 85?±?15?min. Compared to the controls, the monks and nuns had an earlier sleep onset (20:05?±?00:59?h vs. 00:00?±?00:54?h, median?±?95% confidence interval, p?=?.0001) and offset (06:27?±?0:22?h, vs. 07:37?±?0:33?h, p?=?.0001), as well as a shorter sleep time (6.5?±?0.6 vs. 7.6?±?0.7?h, p?=?.05). They reported difficulties with sleep latency, sleep duration, and daytime function, and more frequent hypnagogic hallucinations. In contrast to their daytime silence, they experienced conversations (and occasionally prayers) in dreams. The biphasic temperature profile in monks and nuns suggests the human clock adapts to and even anticipates nocturnal awakenings. It resembles the biphasic sleep and rhythm of healthy volunteers transferred to a short (10-h) photoperiod and provides a living glance into the sleep pattern of medieval time. (Author correspondence: isabelle.arnulf@psl.aphp.fr)     

Comparison of dipyrone/propofol versus fentanyl/propofol anaesthesia during surgery in rabbits

In this study, the investigation of the intraoperative effects of dipyrone (metamizol) on heart rate (HR), mean arterial pressure (MAP) and analgesic efficacy in rabbits is described for the first time. This was carried out to evaluate the cardiovascular stability achieved using dipyrone compared with fentanyl. In this prospective study, 17 female New Zealand White rabbits were randomly allocated to either one of two groups: dipyrone/propofol (DP) or fentanyl/propofol (FP). Anaesthesia was induced in both groups using propofol to effect (4.0-8.0 mg/kg intravenously) until the swallowing reflex was lost for intubation. After induction, anaesthesia was maintained with continuous infusion of propofol 1.5-1.7 mg/kg/min intravenously. Analgesics were then injected in defined boluses of either dipyrone 65 mg/kg or fentanyl 0.0053 mg/kg. After surgical tolerance, defined as loss of the ear pinch reflex and loss of the anterior and posterior pedal withdrawal reflex, was achieved, two surgical procedures were performed. The surgical procedures (implantation of either a pacemaker or an electrocardiogram transmitter), both require a comparable level of analgesic depth. During and after surgery, clinical variables, such as MAP, HR, peripheral arterial oxygen saturation (SpO?) and end-tidal CO? (P(E')CO?) were recorded simultaneously every 2 min. Eight time points were chosen for comparison: baseline, surgical tolerance (ST), values at 10, 20 and 30 min after reaching ST, values at the end of propofol infusion (EI) and data at 10 and 20 min after EI. Both FP and DP combinations provided effective anaesthesia and analgesia in rabbits. In both groups a significant decrease of HR and MAP was measured. The results of this study indicate that the non-opioid drug dipyrone produces similar analgesic and even better cardiovascular effects by trend in rabbits. Therefore we conclude that dipyrone in combination with propofol can be used as an alternative to FP for intraoperative analgesia.     

Light Exposure Among Adolescents With Delayed Sleep Phase Disorder: A Prospective Cohort Study

The objective of this study was to compare light exposure and sleep parameters between adolescents with delayed sleep phase disorder (DSPD; n?=?16, 15.3?±?1.8 yrs) and unaffected controls (n?=?22, 13.7?±?2.4 yrs) using a prospective cohort design. Participants wore wrist actigraphs with photosensors for 14 days. Mean hourly lux levels from 20:00 to 05:00?h and 05:00 to 14:00?h were examined, in addition to the 9-h intervals prior to sleep onset and after sleep offset. Sleep parameters were compared separately, and were also included as covariates within models that analyzed associations with specified light intervals. Additional covariates included group and school night status. Adolescent delayed sleep phase subjects received more evening (p?<?.02, 22:00–02:00?h) and less morning (p?<?.05, 08:00–09:00?h and 10:00–12:00?h) light than controls, but had less pre-sleep exposure with adjustments for the time of sleep onset (p?<?.03, 5–7?h prior to onset hour). No differences were identified with respect to the sleep offset interval. Increased total sleep time and later sleep offset times were associated with decreased evening (p?<?.001 and p?=?.02, respectively) and morning (p?=?.01 and p?<?.001, respectively) light exposure, and later sleep onset times were associated with increased evening exposure (p?<?.001). Increased total sleep time also correlated with increased exposure during the 9?h before sleep onset (p?=?.01), and a later sleep onset time corresponded with decreased light exposure during the same interval (p?<?.001). Outcomes persisted regardless of school night status. In conclusion, light exposure interpretation requires adjustments for sleep timing among adolescents with DSPD. Pre- and post-sleep light exposures do not appear to contribute directly to phase delays. Sensitivity to morning light may be reduced among adolescents with DSPD. (Author correspondence: auger.raymond1@mayo.edu)     

Time-of-Day Effect on Cardiac Responses to Progressive Exercise

This study was designed to examine time-of-day effects on markers of cardiac functional capacity during a standard progressive cycle exercise test. Fourteen healthy, untrained young males (mean?±?SD: 17.9?±?0.7 yrs of age) performed identical maximal cycle tests in the morning (08:00–11:00?h) and late afternoon (16:00–19:00?h) in random order. Cardiac variables were measured at rest, submaximal exercise, and maximal exercise by standard echocardiographic techniques. No differences in morning and afternoon testing values at rest or during exercise were observed for oxygen uptake, heart rate, cardiac output, or markers of systolic and diastolic myocardial function. Values at peak exercise for Vo₂ at morning and afternoon testing were 3.20?±?0.49 and 3.24?±?0.55?L min^?1, respectively, for heart rate 190?±?11 and 188?±?15?bpm, and for cardiac output 19.5?±?2.8 and 19.8?±?3.5?L min^?1. Coefficients of variation for morning and afternoon values for these variables were similar to those previously published for test-retest reproducibility. This study failed to demonstrate evidence for significant time-of-day variation in Vo₂max or cardiac function during standard progressive exercise testing in adolescent males. (Author correspondence: thomas.rowland@bhs.org)     

CHRONOKINETICS OF CEFTAZIDIME AFTER INTRAMUSCULAR ADMINISTRATION TO DOGS

Ceftazidime, a third-generation cephalosporin, is widely used for the treatment of Pseudomonas aeruginosa infections. The aims of the present study were to characterize the pharmacokinetics of ceftazidime and to estimate the T?>?MIC against P. aeruginosa, after its intramuscular (im) administration at two different dosing times (08:30?h and 20:30?h) to dogs, in order to determine whether time-of-day administration modifies ceftazidime pharmacokinetics and/or predicted clinical antipseudomonal efficacy. Six female healthy beagle dogs were administered ceftazidime pentahydrate by the intramuscular route in a single dose of 25?mg/kg at both 08:30 and 20:30?h, two weeks apart. Plasma ceftazidime concentrations were determined by microbiological assay. Pharmacokinetic parameters and time above the minimum inhibitory concentration (T?>?MIC) and 4xMIC for Pseudomonas aeruginosa were calculated from the disposition curve of each dog. No differences between the daytime and nighttime administrations were found for the main pharmacokinetic parameters, including C_max, t_max, t_{½ λ}, AUC, and MRT; however, the high interindividual variability shown by these values and the small number of individuals may account for this lack of difference. Rate of absorption (k_a) was significantly higher after the 20:30?h than 08:30?h administration. No significant differences between T?>?MIC were found when comparing the 08:30?h and 20:30?h administrations. Mean T?>?MIC values predicted a favorable bacteriostatic effect for all susceptible strains of P. aeruginosa for the 12?h dosing interval at both dosing times. Our results suggest that similar antipseudomonal activity may be expected when ceftazidime is administered at 8:30 and 20:30?h; however, as only two timepoints of drug administration were explored, we are unable to draw any conclusions for other treatment times during the 24?h. (Author correspondence: rebuelto@fvet.uba.ar).     

CHRONIC SLEEP DEFICIT AND PERFORMANCE OF A SUSTAINED ATTENTION TASK—AN ELECTROOCULOGRAPHY STUDY

Electrooculography (EOG) was used to explore performance differences in a sustained attention task during rested wakefulness (RW) and after 7 days of partial sleep deprivation (SD). The RW condition was based on obtaining regular sleep, and the SD condition involved sleep restriction of 3?h/night for a week resulting in a total sleep debt of 21?h. The study used a counterbalanced design with a 2-wk gap between the conditions. Participants performed a sustained attention task for 45?min on four occasions: 10:00–11:00, 14:00–15:00, 18:00–19:00, and 22:00–23:00?h. The task required moving gaze and attention as fast as possible from a fixation point to a target. In each session, 120 congruent and 34 incongruent stimuli were presented, totaling 1232 observations/participant. Correct responses plus errors of omission (lapses) and commission (false responses) were recorded, and the effect of time-of-day on sustained attention following SD was investigated. The analysis of variance (ANOVA) model showed that SD affected performance on a sustained attention task and manifested itself in a higher number of omission errors: congruent stimuli (F_(1,64)?=?13.3, p?<?.001) and incongruent stimuli (F_(1,64)?=?14.0, p?<?.001). Reaction times for saccadic eye movements did not differ significantly between experimental conditions or by time-of-day. Commission errors, however, exhibited a decreasing trend during the day. The visible prevalence of omissions in SD versus RW was observed during the mid-afternoon hours (the so-called post-lunch dip) for both congruent and incongruent stimuli (F_(1,16)?=?5.3, p?=?.04 and F_(1,16)?=?5.6, p?=?.03, respectively), and at 18:00?h for incongruent stimuli (F_(1,13)?=?5.7, p?=?.03). (Author correspondence: magda.fafrowicz@uj.edu.pl)     

Chronopharmacokinetic Study of Gentamicin in Dogs

The purpose of this experiment was to determine whether the time of day of single intravenous doses of gentamicin affects the drug's pharmacokinetics in dogs maintained under a 12 h light (08:00 to 20:00 h), 12 h dark (20:00 to 08:00 h) cycle. Using a crossover design, 6 mixed‐breed male dogs received a single dose of 2 mg/kg of gentamicin at 8:00 or 20:00 h. Serial blood samples were collected and pharmacokinetic parameters were calculated following each timed dose. The concentration of the antibiotic was lower following the 08:00 h compared to the 20:00 h administration. When gentamicin was administered at 20:00 h, the initial concentration, mean residence time, and area under the disposition curve were significantly higher (p<0.05) and the apparent volume of distribution of the central compartment, apparent volume of distribution, apparent volume of distribution at steady‐state, and total body clearance (1.73±0.55 at 20:00 h versus 3.31±0.67 L/min/kg at 08:00 h) were significantly lower than for the 08:00 h administration (p<0.05). Our results show that the pharmacokinetics of gentamicin exhibits significant temporal variation when administered to dogs at different times of day.     

Chronopharmacokinetic study of gentamicin in dogs

The purpose of this experiment was to determine whether the time of day of single intravenous doses of gentamicin affects the drug's pharmacokinetics in dogs maintained under a 12 h light (08:00 to 20:00 h), 12 h dark (20:00 to 08:00 h) cycle. Using a crossover design, 6 mixed-breed male dogs received a single dose of 2 mg/kg of gentamicin at 8:00 or 20:00 h. Serial blood samples were collected and pharmacokinetic parameters were calculated following each timed dose. The concentration of the antibiotic was lower following the 08:00 h compared to the 20:00 h administration. When gentamicin was administered at 20:00 h, the initial concentration, mean residence time, and area under the disposition curve were significantly higher (p < 0.05) and the apparent volume of distribution of the central compartment, apparent volume of distribution, apparent volume of distribution at steady-state, and total body clearance (1.73+/-0.55 at 20:00 h versus 3.31+/-0.67 L/min/kg at 08:00 h) were significantly lower than for the 08:00 h administration (p < 0.05). Our results show that the pharmacokinetics of gentamicin exhibits significant temporal variation when administered to dogs at different times of day.     

TIME-OF-DAY EFFECTS ON THE INTERNAL SIMULATION OF MOTOR ACTIONS: PSYCHOPHYSICAL EVIDENCE FROM POINTING MOVEMENTS WITH THE DOMINANT AND NON-DOMINANT ARM

It is well known that circadian rhythms modulate human physiology and behavior at various levels. However, chronobiological data concerning mental and sensorimotor states of motor actions are still lacking in the literature. In the present study, we examined the effects of time-of-day on two important aspects of the human motor behavior: prediction and laterality. Motor prediction was experimentally investigated by means of imagined movements and laterality by comparing the difference in temporal performance between right and left arm movements. Ten healthy participants had to actually perform or to imagine performing arm-pointing movements between two targets at different hours of the day (i.e., 08:00, 11:00, 14:00, 17:00, 20:00, and 23:00?h). Executed and imagined movements were accomplished with both the right and left arm. We found that both imagined and executed arm pointing movements significantly fluctuated through the day. Furthermore, the accuracy of motor prediction, investigated by the temporal discrepancy between executed and imagined movements, was significantly better in the afternoon (i.e., 14:00, 17:00, and 20:00?h) than morning (08:00 and 11:00?h) and evening (23:00?h). Our results also revealed that laterality was not stable throughout the day. Indeed, the smallest temporal differences between the two arms appeared at 08:00 and 23:00?h, whereas the largest ones occurred at the end of the morning (11:00?h). The daily variation of motor imagery may suggest that internal predictive models are flexible entities that are continuously updated throughout the day. Likewise, the variations in temporal performance between the right and the left arm during the day may indicate a relative independence of the two body sides in terms of circadian rhythms. In general, our findings suggest that cognitive (i.e., mental imagery) and motor (i.e., laterality) states of human behavior are modulated by circadian rhythms. (Author correspondence: charalambos.papaxanthis@u-bourgogne.fr)     

Effect of Pedal Rate on Diurnal Variations in Cardiorespiratory Variables

Recently, it was observed that the freely chosen pedal rate of elite cyclists was significantly lower at 06:00 than at 18:00 h, and that ankle kinematics during cycling exhibits diurnal variation. The modification of the pedaling technique and pedal rate observed throughout the day could be brought about to limit the effect of diurnal variation on physiological variables. Imposing a pedal rate should limit the subject's possibility of adaptation and clarify the influence of time of day on physiological variables. The purpose of this study was to determine whether diurnal variation in cardiorespiratory variables depends on pedal rate. Ten male cyclists performed a submaximal 15 min exercise on a cycle ergometer (50% W_max). Five test sessions were performed at 06:00, 10:00, 14:00, 18:00, and 22:00 h. The exercise bout was divided into three equivalent 5 min periods during which different pedal rates were imposed (70 rev · min^?1, 90 rev · min^?1 and 120 rev · min^?1). No significant diurnal variation was observed in heart rate and oxygen consumption, whatever the pedal rate. A significant diurnal variation was observed in minute ventilation (p=0.01). In addition, the amplitude of the diurnal variation in minute ventilation depended on pedal rate: the higher the pedal rate, the greater the amplitude of its diurnal variation (p=0.03). The increase of minute ventilation throughout the day is mainly due to variation in breath frequency (p=0.01)—the diurnal variation of tidal volume (all pedal rate conditions taken together) being non‐significant—but the effect of pedal rate×time of day interaction on minute ventilation specific to the higher pedal rate conditions (p=0.03) can only be explained by the increase of tidal volume throughout the day. Even though an influence of pedal rate on diurnal rhythms in overall physiological variables was not also evidenced, high pedal rate should have been imposed when diurnal variations of physiological variables in cycling were studied.     

Diurnal Variation in Vascular Function: Role of Sleep

Although vascular function is lower in the morning than afternoon, previous studies have not assessed the influence of prior sleep on this diurnal variation. The authors employed a semiconstant routine protocol to study the contribution of prior nocturnal sleep to the previously observed impairment in vascular function in the morning. Brachial artery vascular function was assessed using the flow-mediated dilation technique (FMD) in 9 healthy, physically active males (mean?±?SD: 27?±?9 yrs of age), at 08:00 and 16:00?h following, respectively, 3.29?±?.37 and 3.24?±?.57?h prior sleep estimated using actimetry. Heart rate and systolic and diastolic blood pressures were also measured. The data of the experimental sleep condition were compared with the data of the “normal” diurnal sleep condition, in which FMD measurements were obtained from 21 healthy individuals who slept only during the night, as usual, before the morning test session. The morning-afternoon difference in FMD was 1?±?4% in the experimental sleep condition compared with 3?±?4% in the normal sleep condition (p?=?.04). This difference was explained by FMD being 3?±?3% lower in afternoon following the prior experimental sleep (p?=?.01). These data suggest that FMD is more dependent on the influence of supine sleep than the endogenous circadian timekeeper, in agreement with our previous finding that diurnal variation in FMD is influenced by exercise. These findings also raise the possibility of a lower homeostatic “set point” for vascular function following a period of sleep and in the absence of perturbing hemodynamic fluctuation. (Author correspondence: h.jones1@ljmu.ac.uk)     

INCREASED SENSITIVITY TO LIGHT-INDUCED MELATONIN SUPPRESSION IN PREMENSTRUAL DYSPHORIC DISORDER

Increased sensitivity to light-induced melatonin suppression characterizes some, but not all, patients with bipolar illness or seasonal affective disorder. The aim of this study was to test the hypothesis that patients with premenstrual dysphoric disorder (PMDD), categorized as a depressive disorder in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), have altered sensitivity to 200 lux light during mid-follicular (MF) and late-luteal (LL) menstrual cycle phases compared with normal control (NC) women. As an extension of a pilot study in which the authors administered 500 lux to 8 PMDD and 5 NC subjects, in the present study the authors administered 200 lux to 10 PMDD and 13 NC subjects during MF and LL menstrual cycle phases. Subjects were admitted to the General Clinical Research Center (GCRC) in dim light (<50 lux) to dark (during sleep) conditions at 16:00?h where nurses inserted an intravenous catheter at 17:00?h and collected plasma samples for melatonin at 30-min intervals from 18:00 to 10:00?h, including between 00:00 and 01:00?h for baseline values, between 01:30 and 03:00?h during the 200 lux light exposure administered from 01:00 to 03:00?h, and at 03:30 and 04:00?h after the light exposure. Median % melatonin suppression was significantly greater in PMDD (30.8%) versus NC (?0.2%) women (p?=?.040), and was significantly greater in PMDD in the MF (30.8%) than in the LL (?0.15%) phase (p?=?.047). Additionally, in the LL (but not the MF) phase, % suppression after 200 lux light was significantly positively correlated with serum estradiol level (p ?=? .007) in PMDD patients, but not in NC subjects (p?>?.05). (Author correspondence: bparry@ucsd.edu)     

THERMOCYCLIC AND PHOTOCYCLIC ENTRAINMENT OF CIRCADIAN LOCOMOTOR ACTIVITY RHYTHMS IN SLEEPY LIZARDS,TILIQUA RUGOSA

Australian sleepy lizards (Tiliqua rugosa) exhibit marked locomotor activity rhythms in the field and laboratory. Light-dark (LD) and temperature cycles (TCs) are considered important for the entrainment of circadian locomotor activity rhythms and for mediating seasonal adjustments in aspects of these rhythms, such as phase, amplitude, and activity pattern. The relative importance of 24 h LD and TCs in entraining the circadian locomotor activity rhythm in T. rugosa was examined in three experiments. In the first experiment, lizards were held under LD 12:12 and subjected to either a TC of 33:15?°?C in phase with the LD cycle or a reversed TC positioned in antiphase to the LD cycle. Following LD 12:12, lizards were maintained under the same TCs but were subjected to DD. Activity was restricted to the thermophase in LD, irrespective of the lighting regime and during the period of DD that followed, suggesting entrainment by the TC. The amplitude of the TC was lowered by 8?°?C to reduce the intensity and possible masking effect of the TC zeitgeber in subsequent experiments. In the second experiment, lizards were held under LD 12.5:11.5 and subjected to one of three treatments: constant 30?°?C, normal TC (30:20?°?C) in phase with the LD cycle, or reversed TC. Following LD, all lizards were subjected to DD and constant 30?°?C. Post-entrainment free-run records revealed that LD cycles and TCs could both entrain the locomotor rhythms of T. rugosa. In LD, mean activity duration (α) of lizards in the normal TC group was considerably less than that in the constant 30?°?C group. Mean α also increased between LD and DD in lizards in the normal TC group. Although there was large variation in the phasing of the rhythm in relation to the LD cycle in reversed TC lizards, TCs presented in phase with the LD cycle most accurately synchronized the rhythm to the photocycle. In the third experiment, lizards were held in DD at constant 30?°?C before being subjected to a further period of DD and one of four treatments: normal TC (06:00 to 18:00 h thermophase), delayed TC (12:00 to 00:00 h thermophase), advanced TC (00:00 to 12:00 h thermophase), or control (no TC, constant 30?°?C). While control lizards continued to free-run in DD at constant temperature, the locomotor activity rhythms of lizards subjected to TCs rapidly entrained to TCs, whether or not the TC was phase advanced or delayed by 6 h. There was no difference in the phase relationships of lizard activity rhythms to the onset of the thermophase among the normal, delayed, and advanced TC groups, suggesting equally strong entrainment to the TC in each group. The results of this experiment excluded the possibility that masking effects were responsible for the locomotor activity responses of lizards to TCs. The three experiments demonstrated that TCs are important for entraining circadian locomotor activity rhythms of T. rugosa, even when photic cues are conflicting or absent, and that an interaction between LD cycles and TCs most accurately synchronizes this rhythm. (Author correspondence: david.j.ellis@adelaide.edu.au)     

Effect of pedal rate on diurnal variations in cardiorespiratory variables

Recently, it was observed that the freely chosen pedal rate of elite cyclists was significantly lower at 06:00 than at 18:00 h, and that ankle kinematics during cycling exhibits diurnal variation. The modification of the pedaling technique and pedal rate observed throughout the day could be brought about to limit the effect of diurnal variation on physiological variables. Imposing a pedal rate should limit the subject's possibility of adaptation and clarify the influence of time of day on physiological variables. The purpose of this study was to determine whether diurnal variation in cardiorespiratory variables depends on pedal rate. Ten male cyclists performed a submaximal 15 min exercise on a cycle ergometer (50% W_max). Five test sessions were performed at 06:00, 10:00, 14:00, 18:00, and 22:00 h. The exercise bout was divided into three equivalent 5 min periods during which different pedal rates were imposed (70 rev · min^-1, 90 rev · min^-1 and 120 rev · min^-1). No significant diurnal variation was observed in heart rate and oxygen consumption, whatever the pedal rate. A significant diurnal variation was observed in minute ventilation (p=0.01). In addition, the amplitude of the diurnal variation in minute ventilation depended on pedal rate: the higher the pedal rate, the greater the amplitude of its diurnal variation (p=0.03). The increase of minute ventilation throughout the day is mainly due to variation in breath frequency (p=0.01)—the diurnal variation of tidal volume (all pedal rate conditions taken together) being non-significant—but the effect of pedal rate×time of day interaction on minute ventilation specific to the higher pedal rate conditions (p=0.03) can only be explained by the increase of tidal volume throughout the day. Even though an influence of pedal rate on diurnal rhythms in overall physiological variables was not also evidenced, high pedal rate should have been imposed when diurnal variations of physiological variables in cycling were studied.