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Biomedical subjects

P C Zee

Publications and source records attributed to P C Zee.

At least 19 recordsLinked to original sources
PubMed2001

Current understanding of the circadian clock and the clinical implications for neurological disorders.

The changes in behavior that occur on a 24-hour basis to match the 24-hour changes in the physical environment due to the rotation of the earth on its axis are a hallmark of life on the planet Earth. The nervous system of both lower and higher organisms has evolved over millions of years to meet the demands of the dramatic changes in the physical environment that occur in relation to the changes in the light-dark cycle, optimizing the survival and reproductive success of the organism. During the past 50 years, it has been clearly established that the 24-hour nature of life was not simply a response to the 24-hour changes in the physical environment imposed by celestial mechanics, but instead was due to an internal time-keeping system in the brain. Many neurological disorders are associated with abnormal 24-hour rhythms, including the sleep-wake cycle. The recent discovery of the molecular basis of the neural clock in animals offers neurologists new avenues for studying the pathophysiology of neurological disorders.

Animals↗
PubMed2001

Familial advanced sleep phase syndrome.

BACKGROUND: The circadian rhythms of sleep propensity and melatonin secretion are regulated by a central circadian clock, the suprachiasmatic nucleus of the hypothalamus. The most common types of sleep disorders attributed to an alteration of the circadian clock system are the sleep/wake cycle phase disorders, such as delayed sleep phase syndrome and advanced sleep phase syndrome (ASPS). Advanced sleep phase syndrome is characterized by the complaint of persistent early evening sleep onset and early morning awakening. Although the complaint of awakening earlier than desired is relatively common, particularly in older adults, extreme advance of sleep phase is rare. OBJECTIVE: To phenotypically characterize a familial case of ASPS. METHODS: We identified a large family with ASPS; 32 members of this family gave informed consent to participate in this study. Measures of sleep onset and offset, dim light melatonin onset, the Horne-Ostberg morningness-eveningness questionnaire, and clinical interviews were used to characterize family members as affected or unaffected with ASPS. RESULTS: Affected members rated themselves as "morning types" and had a significant advance in the phase of sleep onset (P<.001) and offset (P =.006) times. The mean sleep onset was 2121 hours for the affected family members and 0025 hours for the unaffected family members. The mean sleep offset was 0507 hours for the affected members and 0828 hours for the unaffected members. (Times are given in military form.) In addition, the phase of the circadian rhythm of melatonin onset for the affected family members was on average 3-1/2 hours earlier than for the unaffected members. CONCLUSIONS: The ASPS trait segregates with an autosomal dominant mode of inheritance. The occurrence of familial ASPS indicates that human circadian rhythms, similar to those in animals, are under genetic regulation. Genetic analysis of familial sleep and circadian rhythm disorders is important for identifying a specific gene(s) responsible for the regulation of sleep and circadian rhythms in humans.

Adult↗
PubMed2000

The circadian clock mutation alters sleep homeostasis in the mouse.

The onset and duration of sleep are thought to be primarily under the control of a homeostatic mechanism affected by previous periods of wake and sleep and a circadian timing mechanism that partitions wake and sleep into different portions of the day and night. The mouse Clock mutation induces pronounced changes in overall circadian organization. We sought to determine whether this genetic disruption of circadian timing would affect sleep homeostasis. The Clock mutation affected a number of sleep parameters during entrainment to a 12 hr light/dark (LD 12:12) cycle, when animals were free-running in constant darkness (DD), and during recovery from 6 hr of sleep deprivation in LD 12:12. In particular, in LD 12:12, heterozygous and homozygous Clock mutants slept, respectively, approximately 1 and approximately 2 hr less than wild-type mice, and they had 25 and 51% smaller increases in rapid eye movement (REM) sleep during 24 hr recovery, respectively, than wild-type mice. The effects of the mutation on sleep are not readily attributable to differential entrainment to LD 12:12 because the baseline sleep differences between genotypes were also present when animals were free-running in DD. These results indicate that genetic alterations of the circadian clock system and/or its regulatory genes are likely to have widespread effects on a variety of sleep and wake parameters, including the homeostatic regulation of sleep.

Animals↗
PubMed2000

Daily social and physical activity increases slow-wave sleep and daytime neuropsychological performance in the elderly.

Decreased levels of physical and social activity associated with aging can be particularly pronounced in residents of assisted living facilities. Reduced exposure to important behavioral and time-giving cues may contribute to the age-related changes in circadian rhythmicity and sleep. The present study was conducted to test the hypothesis that an enforced schedule of structured social and physical activity (0:900 to 10:30 and 19:00 to 20:30 daily for two weeks) can have beneficial effects on circadian rhythmicity, nocturnal sleep, daytime functioning, mood, and vigor. The subjects were 14 elderly residents of continued-care retirement facilities while a similar group of 9 elderly residents served as controls. The group exposed to structured activities had increased amounts of slow-wave sleep and demonstrated improvement in memory-oriented tasks following the intervention. Conversely, no significant changes were noted in the amplitude and phase of the body temperature rhythm or in subjective measures of vigor and mood. These results indicate that short-term exposure to structured social intervention and light physical activity can significantly improve memory performance and enhance slow-wave sleep in older adults without alterations to the circadian phase or amplitude of body temperature. This is the first report to demonstrate that low intensity activity in an elderly population can increase deep sleep and improve memory functioning. The high degree of interest in these activities paired with the simple nature of the tasks makes this a potentially practical intervention which can be adapted for both community dwelling and assisted-living elders.

Adult↗
PubMed1999

Nimodipine potentiates the light-induced suppression of melatonin.

In mammals the phase shifting response of the circadian clock to light can be enhanced by administration of the calcium channel antagonist nimodipine. In the present study we assessed the potential for nimodipine to affect the responsiveness of the human circadian clock to light by measuring the light-induced suppression of melatonin levels in plasma. Seven healthy young subjects (3M, 4F, 27.3 +/- 1.8 years old) were admitted on four occasions to the Clinical Research Center at Northwestern University Medical School. Blood was collected during the night to assess the effect of nimodipine (30 mg, orally, 01:30 h) on plasma melatonin levels in the presence or absence of light (500 lux, 2-3 am). Melatonin levels in plasma were measured by radioimmunoassay. Exposure to light for 1 h suppressed melatonin levels in plasma by nearly 38% relative to samples obtained at the same time in the absence of light (P = 0.013). Nimodipine administration did not modify plasma melatonin levels. However, combined treatment with nimodipine and light suppressed melatonin levels in plasma by 59%. Levels of plasma melatonin were significantly lower following treatment with nimodipine and light than following treatment with placebo/light (P = 0.014). Thus, the calcium channel antagonist nimodipine potentiated the suppressive effect of light on melatonin levels in plasma. These results suggest that the calcium channel antagonist nimodipine may also potentiate the response of the human circadian clock to light, and might thus be useful in combination with phototherapy for the treatment of sleep and circadian rhythm disorders.

Adult↗
PubMed1998

Effects of aging on lens transmittance and retinal input to the suprachiasmatic nucleus in golden hamsters.

Old animals are less sensitive by almost an order of magnitude to the phase-shifting effects of a low intensity light pulse on the locomotor activity rhythm and the associated induction of immediate early genes in the circadian clock. The transmittance of energy from 200 to 700 nm through the excised lens of the eyes of young and old golden hamsters was measured to determine if an age-related difference exists in the transmittance of light. There is only a small decrease (8-50%) in transmittance, with the magnitude being dependent upon wavelength. No significant differences were detected between young and old animals in the retinal innervation of the suprachiasmatic nucleus (SCN). These results support the hypothesis that the observed decrease in sensitivity to light in the aged circadian system occurs within the SCN itself and/or retino-hypothalamic tract photoreceptors.

Aging↗
PubMed1998

Effects of aging on sleep in the golden hamster.

The golden hamster (Mesocricetus auratus) has been a model organism for the study of circadian rhythmicity and, in particular, the effects of age on the circadian system. Surprisingly, nothing is known about the effects of advanced age on sleep in this species. As a first step in determining the effects of aging on sleep in the golden hamster, we recorded sleep for 24 hours in 12 young (3 months) and 18 old (17-18 months) golden hamsters entrained to a 14:10 light:dark (LD) cycle. Aged hamsters exhibited small but significant increases in overall NREM sleep time, primarily due to an increase in time the old animals spent in the NREM sleep state during the dark period relative to the young hamsters. There were no significant differences in REM sleep, median sleep episode length, or the number of arousals. The most striking differences between the sleep of young and old hamsters was in NREM delta (0.5-4 Hz) power per epoch. Old hamsters showed approximately 27% less (p=0.0004) delta power per NREM epoch than young hamsters. It is possible that increased NREM sleep time in the old hamsters may be a failed attempt to maintain cumulative delta power; ie, old hamsters may have more NREM sleep in order to make up for the lower intensity of their sleep. This decline in delta power with age parallels earlier findings in cats and humans, although has it not been previously reported in rodents.

Age Factors↗
PubMed1998

Chronic circadian desynchronization decreases the survival of animals with cardiomyopathic heart disease.

Shift work is associated with increased cardiovascular morbidity and mortality. Whereas it has been suggested that continuous shifting of the circadian clock/sleep-wake cycle may have negative effects on health, there is very little experimental evidence to support such a hypothesis. Cardiomyopathic Syrian hamsters were either maintained on a fixed light-dark (LD) cycle (n = 31) or were subjected to a 12-h phase shift in the LD cycle on a weekly basis (n = 32). The duration of the life span was recorded for each animal. Chronic reversal of the external LD cycle at weekly intervals resulted in a significant decrease in the survival time in cardiomyopathic hamsters with the median life span being reduced by 11%. Disrupting normal circadian rhythmicity in an animal susceptible to early mortality due to cardiac disease results in a further decrease in longevity. The deleterious effects of the chronic phase shifts in the LD cycle in cardiomyopathic hamsters may be related to reports of increased cardiovascular morbidity and mortality in humans engaged in shift work.

Animals↗
PubMed1998

Effects of bright light on age-related changes in the locomotor activity of Syrian hamsters.

Syrian hamsters display age-related changes in the expression of circadian rhythms and in responsiveness of the circadian system to photic and non-photic stimuli. This study characterized the effects of age on the locomotor activity rhythm of middle-aged and old hamsters and evaluated the effects of strengthening the entraining light signal. Compared with young (4.5 mo) animals, middle-aged (11.25 mo) and old (16 mo) animals displayed increased daily bouts of activity (P < 0.001) and reduced total daily activity and activity rhythm amplitude (P < 0.05) in 14:10-h light-dark cycles. After the light intensity was increased from 300 to 1,500 lx during the light cycle, middle-aged hamsters demonstrated decreased daily activity bouts (P < 0.05) and increased total daily activity (P < or = 0.01) and activity rhythm amplitude (P < or = 0.001) compared with controls maintained in 300 lx. The pattern of changes in the activity rhythm of old experimental animals was similar to trends observed in middle-aged experimental hamsters, although not as robust. Thus age-related changes in the activity rhythm are occurring by middle age in hamsters, and the provision of stronger entraining signals may lead to more stable circadian organization.

Aging↗
PubMed1997

[Changes in the 24-hour rhythm of plasma melatonin in patients with liver cirrhosis--relation to sleep architecture].

OBJECTIVE: To assess the 24 hr plasma melatonin profile as a marker of the output rhythm from the circadian clock and to study sleep diaries as reflection of subjective sleep quality in patients with liver cirrhosis. DESIGN: Prospective cohort study. PATIENTS: A total of 14 subjects, 7 non-alcoholic cirrhotics and 7 age-, sex-, and educationally-matched controls. Exclusion criteria were factors that could affect melatonin levels (intercontinental travel, shift work, therapy with betablockers or corticosteroids). MEASUREMENTS: Plasma melatonin was measured every 30 min for 24 hr by radioimmuno assay and sleep recordings by polysomnography. Neuropsychological testing included visual reaction time. Trailmaking test A and B and the Digit Symbol Test. Sleep diaries were kept for the week prior to admission. RESULTS: Time of onset of melatonin rise was displaced from 19:50 +/- 26 min in the controls to 21:30 +/- 13 min (p = 0.013) in patients with liver cirrhosis. The time of peak melatonin levels was consistently and significantly delayed from 00:36 +/- 33 min in controls to 5:36 +/- 29 min (p < 0.001) in patients. Cirrhotic subjects showed markedly elevated melatonin levels during daytime, when melatonin is normally absent. Polysomnographic tracings showed no differences in patients and controls, but sleep diaries indicated more frequent nocturnal awakenings (p = 0.05) and daytime naps. CONCLUSIONS: A marked alteration of plasma melatonin rhythm is found in cirrhotic patients with subclinical hepatic encephalopathy. This disruption may reflect changes in the output of the circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. It is possible that some of the metabolic disturbances that lead to hepatic encephalopathy may also alter the function of the biological "clock".

Adult↗
PubMed1997

Comparative effects of a melatonin agonist on the circadian system in mice and Syrian hamsters.

S-20098 has potent and specific agonist properties on melatonin receptors both in vitro and in vivo. Behavioral studies on rodents already showed that repeated intraperitoneal administration of S-20098 could dose-dependently alter the functioning of the circadian clock. To determine whether single administration of S-20098 could alter the circadian rhythms of rodents, we first used the phase-response curve (PRC) approach in two different species: Syrian hamsters and mice (C3H/HeJ). Our results show that the shape, circadian times and extent of the PRC to S-20098 look very similar in mice and hamsters. In both species, the phase advance portion of the PRC to S-20098 is limited to a 3 h window preceding the onset of locomotor activity, but the magnitude of phase shifts is larger in mice. We also tested the phase shifting effects of increasing doses of S-20098 during the interval of maximal sensitivity to this compound. Treatment with S-20098 induces dose-dependent phase shifts, with maximal shifts observed after injections of 20 and 25 mg/kg S-20098 i.p., respectively, in mice and hamsters. Those results are in agreement with the limited distribution of melatonin-binding sites within the circadian clock of adult Syrian hamsters, as compared to other rodents.

Acetamides↗
PubMed1997

Melatonin: a clinical perspective.

Over the last several decades the pineal gland has emerged as an active neuroendocrine transducer of important environmental information. However, the current understanding of the function of its major hormone, melatonin, in humans remains ill defined and based exclusively on correlative observations. In a similar manner, the multitude of phenomenological descriptions of the effects of exogenous melatonin is contrasted by the limited understanding of the underlying mechanisms and the lack of firmly established clinical applications for the hormone. Future randomized, double-blind, placebo-controlled clinical studies will be necessary to determine the precise indications, treatment regimens, and safety of melatonin in clinical practice. The recent rapid progress in the area of melatonin research should lead to a better understanding of its role in human health and disease.

Humans↗
PubMed1997

Aging alters the serotonergic modulation of light-induced phase advances in golden hamsters.

Recent findings have raised the possibility that some of the age-related changes in the circadian system and the response of the circadian pacemaker to environmental stimuli may involve central serotonergic mechanisms. The present study compared the effects ofpretreatment with the serotonin agonist 8-hydroxy-2(di-n-propylamino)tetralin (5 mg/kg ip) on the magnitude of light-induced phase advances in young (2-4 mo) and old (18-20 mo) golden hamsters. The ability of this serotonin agonist to attenuate the photic phase resetting of circadian locomotor rhythmicity in young animals was decreased by 46% in old hamsters (P < 0.05). These results suggest that deficits in the mechanisms for serotonergic control of circadian function may interfere with the optimal adaptation of the senescent organism to its temporal environment.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1997

Quantitative analysis of the age-related fragmentation of hamster 24-h activity rhythms.

The continuous monitoring of spontaneous locomotor activity has emerged as one of the most widely used metrics in rodent circadian research. This behavioral measure is also extremely useful for the description of the effects of aging on circadian rhythms. The present study describes the successful use of a log-survivorship approach to identify discrete bouts of hamster wheel-running activity and provides a detailed description of the age-related fragmentation in the 24-h profile of this behavioral variable. In addition, stepwise discriminant analysis identified the most important quantitative measures for distinguishing between the individual patterns of wheel-running activity of young (3 mo) and old (17-18 mo) golden hamsters. The results suggest that this method of bout analysis can be a valuable tool for the study of genetic, developmental, neurochemical, physiological, and environmental factors involved in the temporal control of rodent locomotor behavior.

Aging↗
PubMed1996

Phase-shifting effects of a serotonin agonist in tau mutant hamsters.

Previous studies indicate that the advance region of the tau mutant hamster's phase-response curve (PRC) to non-photic stimuli, such as NPY and wheel pulses, is characterized by earlier timing and increased amplitude in comparison with that of wild-type animals. Since, recent evidence suggests that serotonergic pathways may play an important role for the non-photic phase resetting of the rodent circadian pacemaker, PRCs to the serotonin (5-HT) agonist, 8-OH-DPAT (5 mg/kg i.p), were generated in both wild-type and tau mutant hamsters kept in constant darkness. The results indicate that the tau mutation is associated with changes in the timing, but not the amplitude of the advance region of the PRC to 8-OH-DPAT and suggest that serotonergic agents and other non-photic or activity-inducing stimuli may share some common mechanisms for resetting the phase of the rodent circadian pacemaker.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Effects of aging on light-induced phase-shifting of circadian behavioral rhythms, fos expression and CREB phosphorylation in the hamster suprachiasmatic nucleus.

Aging is associated with a variety of alterations in circadian rhythms, including changes in the response to environmental stimuli. The underlying causes for these age-related changes in the circadian system remain unknown. Recent studies have demonstrated that light induces the expression of Fos and phosphorylation of the cyclic-AMP response element-binding protein in the rodent suprachiasmatic nuclei, the location of a master circadian pacemaker in mammals, suggesting that these transcription factors may mediate the effects of light on the circadian clock. The purpose of this study was to determine the effects of aging upon light-induced phase-shifting of circadian locomotor activity rhythms, Fos protein expression and cyclic-AMP response element-binding protein phosphorylation in the suprachiasmatic nuclei. Young (three to four months) and old (18-22 months) male golden hamsters free-running in constant darkness were exposed to 5-min monochromatic light pulses of different irradiance levels, at circadian time 19, after which either steady-state phase shifts of locomotor activity rhythms were measured, or else immunocytochemistry for Fos or for phospho-cyclic-AMP response element-binding protein was performed. Old hamsters were approximately 20 times less sensitive to the phase-shifting effects of light on the activity rhythm, and the photic irradiance threshold for Fos-like immunoreactivity induction in the suprachiasmatic nuclei was elevated when compared to young animals. Aging was also associated with a deficit in cyclic-AMP response element-binding protein phosphorylation by light. These data indicate that there are dramatic changes in light-activated molecular responses in the suprachiasmatic nuclei of old hamsters, and suggest that these molecular changes may underlie age-related changes in the effects of light on the circadian clock system.

Age Factors↗
PubMed1996

A low-protein diet ameliorates disrupted diurnal locomotor activity in rats after portacaval anastomosis.

In previous studies we noted a disruption of the circadian locomotor activity rhythm in rats after portacaval anastomosis (PCA). To examine whether this abnormality is related to factors that aggravate hepatic encephalopathy in humans, we studied the effect of dietary formulation and protein content on body weight, locomotor activity, and entrainment to the light-dark cycle in rats after PCA or sham operation. Postoperative weight loss was prevented by pair-feeding with a purified liquid diet. However, the behavioral abnormalities persisted in PCA rats fed a high-protein diet, with a reduction in total activity and entrainment to the light-dark cycle. These were ameliorated by a low dietary protein content. Since this treatment reduces the load of gut-derived nitrogenous substances that might alter brain metabolism, our data strengthen the hypothesis that the abnormal circadian activity patterns in PCA rats may be part of the spectrum of hepatic encephalopathy.

Animals↗