Impacts of shift work on sleep and circadian rhythms.

Shift work comprises work schedules that extend beyond the typical "nine-to-five" workday, wherein schedules often comprise early work start, compressed work weeks with 12-hour shifts, and night work. According to recent American and European surveys, between 15 and 30% of adult workers are engaged in some type of shift work, with 19% of the European population reportedly working at least 2 hours between 22:00 and 05:00. The 2005 International Classification of Sleep Disorders estimates that a shift work sleep disorder can be found in 2-5% of workers. This disorder is characterized by excessive sleepiness and/or sleep disruption for at least one month in relation with the atypical work schedule. Individual tolerance to shift work remains a complex problem that is affected by the number of consecutive work hours and shifts, the rest periods, and the predictability of work schedules. Sleepiness usually occurs during night shifts and is maximal at the end of the night. Impaired vigilance and performance occur around times of increased sleepiness and can seriously compromise workers' health and safety. Indeed, workers suffering from a shift work sleep-wake disorder can fall asleep involuntarily at work or while driving back home after a night shift. Working on atypical shifts has important socioeconomic impacts as it leads to an increased risk of accidents, workers' impairment and danger to public safety, especially at night. The aim of the present review is to review the circadian and sleep-wake disturbances associated with shift work as well as their medical impacts.

Functional size of C-terminal protein carboxyl methyltransferase from kidney basolateral plasma membranes.

The functional sizes of the C-terminal isoprenylcysteine protein carboxyl methyltransferase (PCMT) from kidney cortex basolateral plasma membranes and yeast membranes have been estimated by the radiation inactivation and fragmentation method. Attempts to solubilize the methyltransferase with detergents were unsuccessful as they resulted in the irreversible denaturation of its enzymatic activity. The radiation inactivation sizes of the methyltransferases were 98 and 24 kDa for kidney and yeast, respectively. Kinetic experiments showed that irradiation affects the Vmax of the reaction but not the apparent Km for either S-adenosyl-L-methionine and N-acetyl farnesylcysteine. The functional size reported here for the kidney membrane is about 4-times larger than the size predicted for the Saccharomyces cerevisiae C-terminal PCMT deduced from the nucleotide sequence of its gene (28 kDa). These results suggest that mammalian methyltransferase has a functional size different from that of the yeast; tetramerization of monomers is one possible hypothesis for this difference.

Tyrosine protein kinase activity in renal brush-border membranes.

Tyrosine protein kinase (TPK) activity was detected in rat renal brush-border membranes (BBM) using poly(Glu80Na,Tyr20) as a substrate. Maximal TPK activity required prior detergent dispersion of the membranes with 0.05% Triton X-100 and the presence of vanadate, a potent inhibitor of phosphotyrosine protein phosphatases, in the phosphorylation medium. Optimal conditions for measurement of TPK activity were 10 mM of MgCl2 and MnCl2, at 30 degrees C and pH 7.0. TPK activity was inhibited by genistein, with a IC50 value of 15 microM, while no inhibition was observed in the presence of 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine dihydrochloride (H7), an inhibitor of serine-threonine kinases. TPK activity was enriched 4-fold in the BBM fraction relative to cortex homogenate. It was co-enriched with BBM enzyme markers, but not with those of the basolateral membrane (BLM). The endogenous substrates of TPK in brush-border and basolateral membranes were determined by Western blot analysis using an antiphosphotyrosine monoclonal antibody (PY20). Various phosphotyrosine-containing proteins were found in the BBM (31, 34, 46, 50, 53, 72, 90, 118 and 170 kDa) and in the BLM (37, 48, 50, 53, 72, 90, 130 and 170 kDa). Addition of exogenous insulin receptor to BBM and BLM increased the phosphorylation of most of the substrates. Solubilization of the TPK activity from BBM with 0.5% CHAPS and subsequent gel filtration on Superdex 75 yielded two peaks of tyrosine protein kinase activity with apparent molecular masses of 49 and 66 kDa. These results provide evidence for a non-receptor TPK activity associated with the renal tubular luminal membrane.

Complex interaction of the sleep-wake cycle and circadian phase modulates mood in healthy subjects.

BACKGROUND: Several studies of healthy volunteers have revealed that subjective mood may vary with the duration of prior wakefulness and with the time of day. However, in these studies, the effects of extended wakefulness and circadian phase remained confounded, and the interaction of these 2 processes could not be assessed quantitatively. METHODS: In the present study, a total of 24 healthy young subjects (16 men, 8 women) lived on a 30-hour sleep-wake schedule for 19 to 23 days or on a 28-hour sleep-wake schedule for 33 to 36 days; both schedules induced desynchrony between the subjects' sleep-wake cycle and their endogenous circadian pacemaker. Subjective mood was assessed by 2 types of visual analog scales, which were administered twice every 2 hours and every 20 minutes, respectively, during all scheduled wakefulness episodes. A circadian phase and an interval elapsed since awakening were attributed to each data point, and circadian and wake-dependent fluctuations of mood were assessed. RESULTS: A significant variation of mood with circadian phase was observed, but no reliable main effect of the duration of prior wakefulness was found. A statistically significant interaction of circadian and wake-dependent fluctuations was evident; when the analysis was restricted to specific circadian phases, mood improved, deteriorated, or remained stable with the duration of prior wakefulness. CONCLUSIONS: These results indicate that, in healthy young subjects, subjective mood is influenced by a complex and nonadditive interaction of circadian phase and duration of prior wakefulness. The nature of this interaction is such that moderate changes in the timing of the sleep-wake cycle may have profound effects on subsequent mood.

Sensitivity of the human circadian pacemaker to moderately bright light.

The aim of the present study was to evaluate the sensitivity of the human circadian pacemaker to the resetting effect of moderately bright light (approximately 1260 lux), and to assess the direct effect of such light exposure by comparison to a control group of subjects undergoing the same behavioral manipulations but with a similarly timed exposure to darkness instead of light. Endogenous circadian phase and amplitude were assessed in dim light (approximately 10-15 lux) before and after two consecutive series of three 5-hr exposures to approximately 1260 lux or to darkness (approximately 0.03 lux) in two different groups of young healthy men, using the constant-routine technique. The light or darkness exposure was centered 1.5 hr after the initial fitted endogenous temperature minimum and 12 hr opposite the newly scheduled midpoint of the sleep episode, in order to induce a phase advance in the light-exposed subjects. The phase of the endogenous circadian pacemaker was assessed by a dual-harmonic regression model from core body temperature recorded every minute during constant routines. Urinary volume was measured at each micturition, subjective alertness every 20 min, and cognitive performance hourly. The endogenous circadian phase shifted to a significantly earlier time after each series of light exposures in the treatment group than it did in the control group (two-way analysis of variance for repeated measures: F = 67.91, p = 0.0001). The analysis of circadian curves of urine production, subjective alertness, and cognitive performance scores revealed that all variables maintained stable temporal relationships with the endogenous circadian temperature minimum--an indication that these rhythms shifted in the same direction and by an equivalent amount. Despite comparable behavioral schedules, including the timing of bedrest/sleep and social contacts, circadian temperature rhythm of control subjects free-ran under dim light conditions, indicating that moderately bright light exerted a direct biological effect on the human circadian pacemaker in the treatment group. The present study also demonstrated that light of approximately 1260 lux (which is of substantially lower intensity that the approximately 7000-12,000 lux used in prior experiments) produces robust phase advances of the endogenous circadian temperature rhythm, which has been shown to be an accurate marker of the output of the circadian pacemaker (Czeisler et al., 1989). These results support the hypothesis that the phase-shifting effect of light on the human circadian pacemaker has a strongly nonlinear relationship to illuminance levels, such that it is preserved despite marked reductions in light intensity.

The effects of L-dopa on excessive daytime sleepiness in narcolepsy.

We examined the effects of L-dopa on the excessive daytime sleepiness of six narcoleptic patients while using a double-blind design and objective measurements of vigilance. The two treatment periods, L-dopa or placebo, lasted for 2 weeks each, separated by a 1-week washout period. In addition to the standard Multiple Sleep Latency Test (MSLT), two different tests assessed the daytime vigilance: the Analogue Vigilance Scale (AVS) and the Four Choice Reaction Time Test (FCRTT). L-dopa improved vigilance and performance as evaluated by the AVS and the FCRTT, while the capacity to fall asleep rapidly remained unchanged as evaluated by the MSLT. Results of the present study suggest that L-dopa is effective in improving the vigilance level of narcoleptic patients and raises the hypothesis that dopamine may play a role in the physiopathology of excessive daytime sleepiness of this condition.

Effects of bromocriptine on periodic limb movements in human narcolepsy.

We studied the effects of bromocriptine on periodic limb movements in sleep (PLMS) of narcoleptic patients. Bromocriptine significantly reduced the number and index of PLMS without improving the nocturnal sleep disruption in that disorder. These results support the hypothesis that dopaminergic mechanisms are involved in the physiopathology of PLMS, and suggest that PLMS do not play a major role in the nocturnal sleep disruption of narcoleptic patients.

Spontaneous alternation and habituation in a t-maze in nervous mutant mice.

Nervous mutant mice have a selective degeneration of Purkinje cells and deep cerebellar nuclei. In comparison with littermate controls, nervous mutant mice did not alternate spontaneously in a successive trial procedure (six consecutive trials per day) and did not habituate in a restricted part of a t-maze in a 4-min session. These data indicate that the cerebellum may have a role in spatial learning.

Resetting of circadian melatonin and cortisol rhythms in humans by ordinary room light.

The present study was designed to investigate whether a weak photic stimulus can reset the endogenous circadian rhythms of plasma melatonin and plasma cortisol in human subjects. A stimulus consisting of three cycles of 5 h exposures to ordinary room light (approximately 180 lux), centered 1.5 h after the endogenous temperature nadir, significantly phase-advanced the plasma melatonin rhythm in eight healthy young men compared with the phase delays observed in eight control subjects who underwent the same protocol but were exposed to darkness (p < or = 0.003). After light-induced phase advances, the circadian rhythms of plasma melatonin and plasma cortisol maintained stable temporal relationships with the endogenous core body temperature cycle, consistent with the conclusion that exposure to ordinary indoor room light had shifted a master circadian pacemaker.

Nosology and diagnosis of alcoholism. Issues and perspectives in subtyping (DSM III) simple alcoholism and alcoholism associated with other psychopathologies.

The presence of psychopathological syndromes in alcoholic in-patients was assessed using the NIMH-Diagnosis. The most stricking finding of this study was the high percentage of additional psychopathological syndromes associated to alcoholism. Based on this finding, a tentative classification of alcoholism is proposed. The urgent need for a comprehensive diagnostic scheme for alcoholism is underlined.

Object exploration in staggerer mutant mice.

Staggerer mutant mice, which lose Purkinje and granule cells in the cerebellum, were found to explore for a longer period of time than normal mice a novel object placed in a familiar environment. There was no difference between the two groups in terms of general motor activity. These results are discussed in regard to a role for the cerebellum in behavioral inhibition and emotion.

Effects of bromocriptine in human narcolepsy.

Bromocriptine, a preferential D2 receptor agonist, was administered to six human narcoleptic patients during a double-blind, cross-over study. Laboratory sessions consisted of two all-night polysomnographic recordings and three daytime tests of vigilance: the Analogue Vigilance Scale (AVS), the Maintenance of Wakefulness Test (MWT), and the Four-Choice Reaction Time Test (FCRTT). No change in nocturnal sleep organization, daytime somnolence, or psychomotor performance was observed during bromocriptine administration. Periodic limb movements in sleep (PLMS) were significantly reduced during bromocriptine condition. These results suggest that D2 receptors are unlikely to play a major role in the physiopathology of human narcolepsy, and support the hypothesis that dopaminergic mechanisms are involved in PLMS.

The effects of L-dopa on periodic leg movements and sleep organization in narcolepsy.

A large proportion of narcoleptic patients have periodic leg movements (PMS) in sleep. The contribution of these movements to the nocturnal sleep disturbance observed in narcoleptics remains a controversial issue. The aim of the present study was to look at the sleep organization of narcoleptic patients before and after suppression of periodic leg movements with L-dopa. L-dopa and a placebo were administered in a double-blind fashion to six narcoleptic patients. Each treatment period lasted 2 weeks and the treatment order was reversed for one-half of the subjects. The effects of L-dopa and placebo were evaluated by polysomnography. A significant reduction of PMS was seen after treatment with L-dopa, but this treatment did not improve sleep organization. On the contrary, L-dopa increased wake time after sleep onset. This result supports the hypothesis that PMS does not play a major role in the nocturnal sleep disruption observed in narcolepsy. It also supports the hypothesis that dopaminergic mechanisms play a role in the physiopathology of PMS.

Effects of modafinil on symptomatology of human narcolepsy.

We studied the effects of modafinil, a putative central alpha-1 agonist, on the excessive daytime sleepiness (EDS) of 10 narcoleptic patients while using a double-blind design and objective measurements of vigilance. There were two treatment periods, in which either modafinil or placebo was used; each lasted four weeks and was preceded by a 2-week "run-in" period and separated by a 2-week "wash-out" period. The effects of treatment on EDS were evaluated by daily home questionnaires and a psychomotor performance test, the Four Choice Reaction Time Test (FCRTT). Modafinil reduced the daily number of sleep attacks significantly, and markedly improved performances during the FCRTT. Results of this study suggest that modafinil is effective in treating EDS in narcolepsy, and that noradrenergic mechanisms could be involved in the physiopathology of EDS in that disorder.

Clinical sub-groups of multiple sclerosis in relation to HLA: DR alleles as possible markers of disease progression.

We have examined the distribution of HLA antigens in 70 multiple sclerosis (MS) patients divided in three groups defined according to clinical criteria: benign MS, severe MS, cerebellar MS. We have found a significant association between severe MS and HLA-DR2, and between benign MS of more than 15 years of evolution and HLA-DR3. We review previous work along the same line and conclude that the association of HLA antigens with "clinical subgroups of MS" could indicate a genetically based heterogeneity of the disease and offer help in establishing a prognosis.

Interhemispheric EEG coherence before and after partial callosotomy.

Measures of interhemispheric EEG coherence during REM and NREM sleep reflect the functional connectivity of the right and left hemispheres mediated by the corpus callosum. Surface recordings of interhemispheric coherence in two patients reflected fairly accurately the degree of anatomical section produced by partial callosotomy. With further development, EEG coherence may prove useful as a noninvasive method for assessing interhemispheric integration under different physiological and experimental conditions.

The epidemiology of cocaine and opiate abuse in urban Canada.

This study describes the epidemiology of cocaine and heroin abuse in urban Canada as part of an initial report on a national substance abuse surveillance system, the Canadian Community Epidemiology Network on Drug Use. Data pertaining to prevalence of use, law enforcement, treatment, morbidity and mortality of cocaine and heroin were obtained from the appropriate health and law enforcement institutions in six sentinel cities: Vancouver, Calgary, Winnipeg, Toronto, Montreal and Halifax. Cocaine and heroin appear to be more available in Vancouver than in the remaining cities. In all CCENDU cities, large proportions of persons in treatment programs for substance abuse identified cocaine as their major addiction; however, there is considerable variation in treatment utilization regarding heroin. Vancouver ranks first in terms of the per capita number of cocaine- and heroin-related hospital separations and mortality rate. Cocaine abuse appears to be an emerging problem in Calgary, Winnipeg and Halifax, and opiate abuse appears to be an emerging problem in Calgary.

The regulation of central and peripheral circadian clocks in humans.

Many circadian rhythms are controlled by the central clock of the suprachiasmatic nucleus of the hypothalamus, as well as clocks located in other brain regions and most peripheral tissues. These central and peripheral clocks are based on clock genes and their protein products. In recent years, the expression of clock genes has started to be investigated in human samples, primarily white blood cells, but also skin, oral mucosa, colon cells, adipose tissue as well as post-mortem brain tissue. The expression of clock genes in those peripheral tissues offers a way to monitor human peripheral clocks and to compare their function and regulation with those of the central clock, which is followed by markers such as melatonin, cortisol and core body temperature. We have recently used such an approach to compare central and peripheral rhythms in subjects under different lighting conditions. In particular, we have monitored the entrainment of the clock of blood cells in subjects undergoing a simulated night shift protocol with bright light treatment, known to efficiently reset the central clock. This line of research will be helpful for learning more about the human circadian system and to find ways to alleviate health problems of shift workers, and other populations experiencing altered circadian rhythms.

A non invasive wearable sensor for the measurement of brain temperature.

As the thermoregulation centres are deep in the brain, the cerebral temperature is one of the most important markers of fever, circadian rhythms physical and mental activities. However due to a lack of accessibility, the brain temperature is not easily measured. The axillary, buccal, tympanic and rectal temperatures do not reflect exactly the cerebral temperature. Nevertheless the rectal temperature is used as probably the most reliable indicator of the core body temperature. The brain temperature can be measured using NMR spectroscopy, microwave radiometry, near infrared spectroscopy, ultra-sound thermometry. However none of those methods are amenable to long term ambulatory use outside of the laboratory or of the hospital during normal daily activities, sport, etc. The brain core temperature "BCT" sensor, developed by the Biomedical Microsensors dpt of LPM at INSA-Lyon is a flexible active sensor using "zero-heat-flow" principle. The sensor has been used for experimental measurement: brain temperature during mental activity, and in hospital for the study of circadian rhythms. The results are in agreement with the measurement by the rectal probe. There are 2 versions of this sensor: a non ambulatory for the use in hospitals, and an ambulatory version using teletransmission. We are working for improving the autonomy of the ambulatory version up to several days. This wearable biomedical sensor (WBS) can be used for circadian assessment for chronobiology studies and in medical therapies.

Influence of sleep-wake and circadian rhythm disturbances in psychiatric disorders.

Recent evidence shows that the temporal alignment between the sleep-wake cycle and the circadian pacemaker affects self-assessment of mood in healthy subjects. Despite the differences in affective state between healthy subjects and patients with psychiatric disorders, these results have implications for analyzing diurnal variation of mood in unipolar and bipolar affective disorders and sleep disturbances in other major psychiatric conditions such as chronic schizophrenia. In a good proportion of patients with depression, mood often improves over the course of the day; an extension of waking often has an antidepressant effect. Sleep deprivation has been described as a treatment for depression for more than 30 years, and approximately 50% to 60% of patients with depression respond to this approach, especially those patients who report that their mood improves over the course of the day. The mechanisms by which sleep deprivation exerts its antidepressant effects are still controversial, but a reduction in rapid eye movement sleep (REM sleep), sleep pressure and slow-wave sleep (SWS), or a circadian phase disturbance, have been proposed. Although several studies support each of these hypotheses, none is sufficient to explain all observations reported to date. Unfortunately, the disturbed sleep-wake cycle or behavioural activities of depressed patients often explain several of the abnormalities reported in the diurnal rhythms of these patients. Thus, protocols that specifically manipulate the sleep-wake cycle to unmask the expression of the endogenous circadian pacemaker are greatly needed. In chronic schizophrenia, significant disturbances in sleep continuity, REM sleep, and SWS have been consistently reported. These disturbances are different from those observed in depression, especially with regard to REM sleep. Circadian phase abnormalities in schizophrenic patients have also been reported. Future research is expected to clarify the nature of these abnormalities.