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Biomedical subjects

W C Dement

Publications and source records attributed to W C Dement.

At least 91 records · Page 5Linked to original sources
PubMed1991

Triazolam fails to induce sleep in suprachiasmatic nucleus-lesioned rats.

Rats with suprachiasmatic nuclei (SCN) lesions did not show increased sleep after triazolam (TRZ) injections at any dose from 0.2 to 1.6 mg/kg, whereas 0.4 mg/kg TRZ given intact rats in the middle of their activity phase significantly increased sleep. Across SCN-lesioned and intact rats, the amount of sleep before and after TRZ 0.4 mg/kg was negatively correlated. SCN-lesioned rats did not have a circadian activity-dominant period and so did not accumulate a biological sleep debt. Their lack of response to TRZ may have resulted from the absence of a sleep debt compared to intact rats injected in the middle of their activity phase. These data support our hypothesis that the homeostatic process controlling sleep gates benzodiazepine hypnotic efficacy.

Animals↗
PubMed1991

Genetic linkage of autosomal recessive canine narcolepsy with a mu immunoglobulin heavy-chain switch-like segment.

Identification of genes determining narcolepsy susceptibility is important not only for understanding that disorder but also for possible clues to general sleep-control mechanisms. Studies in humans reveal at least one such gene related to the major histocompatibility complex and in dog an as-yet-unmapped single, autosomal recessive gene canarc-1. Gene markers for canarc-1 were therefore sought by DNA restriction fragment length polymorphisms in our colony of narcoleptic dogs. A human mu-switch immunoglobulin probe and the enzyme Hae III identified a gene cosegregating with canarc-1 in backcrossed animals (logarithm of odds scores: m = 24, Z max = 7.2 at theta = 0%). canarc-1 was also shown not to be tightly linked with the dog major histocompatibility complex (m = 40, Z less than -2 at theta less than 4.8%). These results represent the mapping of a non-major histocompatibility complex narcolepsy gene and strongly suggest involvement of the immune system in the pathophysiology of that disease.

Animals↗
PubMed1991

Platelet alpha 2 adrenoceptors in human and canine narcolepsy.

We have recently established that canine narcolepsy (an autosomal recessive genetic model of the human disorder) is dramatically improved by treatment with alpha 2 antagonists such as yohimbine (Nishino et al: J Pharmacol Exp Ther 253:1145-1152, 1990). To further investigate the role of alpha 2 adrenoceptors in narcolepsy, receptors labeled with [3H] yohimbine were examined on platelets from human and canine narcoleptic subjects. Twenty-eight Doberman pinschers were studied, 7 controls (C), 7 heterozygous (Hz), and 14 narcoleptics (N) (age and sex matched), including eight animals born in a backcross setting (narcoleptic x heterozygous; 5 narcoleptics and 3 heterozygous). The Kd and Bmax of each group respectively, were as follows: C, Kd = 2.86 +/- 0.76 nmol/L, Bmax = 295.78 +/- 31.89 fmol/mg protein; Hz, Kd = 2.06 +/- 0.23 nmol/L, Bmax = 307.02 +/- 22.21 fmol/mg protein; and N, Kd = 2.72 +/- 0.45 nmol/L, Bmax = 267.52 +/- 19.47 fmol/mg protein. No statistical differences were found between groups using nonparametric (Kruskall-Wallis) statistical procedures, and there were no correlations between any binding parameter and symptom severity within the narcoleptic group. Platelet alpha 2 receptor affinity and density also did not differ between narcoleptic and heterozygous dogs in the backcross litter (N [n = 5], Kd = 1.94 +/- 0.59 nmol/L, Bmax = 290.6 +/- 64.7 fmol/mg protein; Hz [n = 3], Kd = 2.83 +/- 0.47 nmol/L, Bmax = 294.2 +/- 42.9 fmol/mg protein). Fourteen human subjects, seven control and seven narcoleptic patients (age and sex matched), were included in the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Triazolam-induced sleep in the rat: influence of prior sleep, circadian time, and light/dark cycles.

Rats entrained to 12-h on /12-h off light schedule and injected with triazolam 0.4 mg/kg at the mid-point of their activity phase (6 h after lights out: circadian time = CT-18) had a stronger hypnotic response than animals free-running in constant dark injected at the equivalent circadian time. In contrast, entrained rats injected 5 h after lights on (CT-5) showed increased wake after injection relative to baseline, largely due to REM sleep inhibition. Hypnotic efficacy was found to be inversely related to prior accumulated sleep. During the 6 h before injection, entrained rats injected at CT-18 slept significantly less than the free-running rats, which in turn slept significantly less than entrained rats injected at CT-5. Taken together, the results suggest that the amount of prior sleep was a more important influence on the response to triazolam than either light/dark per se or circadian phase. Methodologically, automated sleep scoring was found to be an efficient method for examining drug effects, particularly when corroborated by concurrent independent physiological variables and spectral analysis.

Animals↗
PubMed1991

Influence of running wheel activity on free-running sleep/wake and drinking circadian rhythms in mice.

Previous studies have indicated that manipulation of activity levels can modify characteristics of sleep/wake and activity rhythms. The generality of these observations was evaluated by simultaneously measuring drinking and sleep/wake rhythms while mice had free or no access to a running wheel in constant conditions (DD). Robust circadian rhythms in all parameters were observed in the "wheel free" (unrestricted) condition. When wheels were locked, the peak amplitude of the sleep/wake circadian rhythm decreased by approximately 50% without affecting the amplitude of the drinking rhythm. Total wake time decreased 11% per circadian day when wheels were locked with increases in both NREM and REM sleep. Whereas the amplitude of the drinking waveform was unaffected, wheel restriction caused an equivalent increase in period length (tau) for both rhythms. These results indicate that, unlike the generalized effects of activity on tau, activity restriction influences on rhythm amplitude do not generalize to all behavioral and/or physiological variables. This work also supports the notion that activity influences on sleep/wake rhythm amplitude reflect behavioral "masking" rather than a fundamental change in the direct coupling mechanisms of the biological clock.

Animals↗
PubMed1991

Real-time automated sleep scoring: validation of a microcomputer-based system for mice.

Long-term circadian studies of sleep and wakefulness in rodents have been hindered by the labor required to analyze long polygraph records. To expedite such studies, we have designed and implemented SCORE, a microcomputer-based real-time sleep scoring system for rodents. The electroencephalograph is digitized in 10-s epochs at 100 Hz. Frequency and amplitude information from the waveform are extracted into a 48-dimension vector that is then compared to previously taught vectors representing the canonical features of four arousal states: wakefulness, theta-dominated wakefulness, rapid eye movement (REM) sleep, and nonREM (NREM) sleep. Match values are assigned for each state to each epoch; after excluding states based on wheel-running or drinking activity data, the nonexcluded state with the best match value for the epoch is scored. Analysis of over 23,000 epochs for four mice yielded an overall agreement of 94.0% between two human scorers and the program, compared with a 94.5% agreement between the two human scorers. The SCORE algorithm matched the human concensus best for wakefulness (97.8%) and NREM sleep (94.7%), but was lower for REM sleep (75.2%) and theta-dominated wakefulness (83.3%). Most errors in scoring of REM sleep were in close temporal proximity to human-scored REM epochs. SCORE is capable of scoring arousal states for eight animals simultaneously in real time on a standard IBM PC equipped with a commercially available analog-to-digital conversion board, and should considerably facilitate the performance of long-term studies of sleep and wakefulness in the rodent.

Algorithms↗
PubMed1991

Regularly scheduled voluntary exercise synchronizes the mouse circadian clock.

Circadian rhythm entrainment has long been thought to depend exclusively on periodic cues in the external environment. However, evidence now suggests that appropriately timed vigorous activity may also phase shift the circadian clock. Previously it was not known whether levels of exercise/activity associated with spontaneous behavior provided sufficient feedback to phase shift or synchronize circadian rhythms. The present study investigated this issue by monitoring the sleep-wake, drinking, and wheel-running circadian rhythms of mice (Mus musculus) during unrestricted access to running wheels and when free wheel rotation was limited to either 12- or 6-h intervals with a fixed period of 24 h. Wheel rotation was controlled remotely. Mice spontaneously ran in wheels during scheduled access, and free-running sleep-wake and drinking circadian rhythms became entrained to scheduled exercise in 11 of 15 animals. However, steady-state entrainment was achieved only when exercise commenced several hours into the subjective night. The temporal placement of running during entrainment was related (r = 0.7003, P less than 0.02) to free-running period before entrainment. Mice with a free-running period less than 23.0 h did not entrain but exhibited relative coordination between free-running variables and the wheel availability schedule. Thus the circadian timekeeping system responds to temporal feedback arising from the timing of volitional exercise/activity, suggesting that the biological clock not only is responsive to periodic geophysical events in the external environment but also derives physiological feedback from the spontaneous activity behaviors of the organism.

Animals↗
PubMed1991

Activity feedback to the mammalian circadian pacemaker: influence on observed measures of rhythm period length.

In the mouse, activity is precisely timed by the circadian clock and is normally most intense in the early subjective night. Since vigorous activity (e.g., wheel running) is thought to induce phase shifts in rodents, the temporal placement of daily exercise/activity could be a determinant of observed circadian rhythm period. The relationship between spontaneous running-wheel activity and the circadian period of free-running rhythms was studied to assess this possibility. With ad libitum access to a running wheel, mice exhibited a free-running period (tau) of 23.43 +/- 0.08 hr (mean +/- SEM). When running wheels were locked, tau increased (23.88 +/- 0.04 hr, p less than 0.03), and restoration of ad libitum wheel running again produced a shorter period (tau = 23.56 +/- 0.06 hr, p less than 0.05). A survey of free-running activity patterns in a population of 100 mice revealed a significant correlation between the observed circadian period and the time of day in which spontaneous wheel running occurred (r = 0.7314, p less than 0.0001). Significantly shorter periods were observed when running was concentrated at the beginning of the subjective night (tau = 23.23 +/- 0.04), and longer periods were observed if mice ran late in the subjective night (tau = 23.89 +/- 0.04), F (1, 99) = 34.96, p less than 0.0001. It was previously believed that the period of the circadian clock was primarily responsive to externally imposed tonic or phasic events. Systematic influences of spontaneous exercise on tau demonstrate that physiological and/or behavioral determinants of circadian timekeeping exist as well.

Animals↗
PubMed1991

Relative validity of self-reported snoring as a symptom of sleep apnea in a sleep clinic population.

The purpose of this study was to evaluate the relative validity of responses to three different questions about snoring as indicators for sleep apnea in a population referred to a sleep clinic. Secondary goals were to evaluate the meaning of a "don't know" response to these questions and to examine how the associations between snoring and sleep apnea are influenced by demographics. Results from 1,409 patients in a sleep clinic indicated that nearly all levels of estimated snoring frequency were associated with a greater likelihood of sleep apnea. In addition, a "don't know" response indicated a likelihood of sleep apnea. In the sample from this clinic, sensitivities approximating 90 percent were obtained in men, and specificities approximating 90 percent were obtained in women, but high diagnostic accuracy (high specificity in men; high sensitivity in women) could not be achieved with the three snoring questions used here. Generally, associations between snoring and sleep apnea were independent of age and sex. Single persons, persons living alone, and persons customarily sleeping alone of both sexes all showed associations between self-reported snoring and the presence of sleep apnea.

Confidence Intervals↗
PubMed1991

Objective measurements of daytime sleepiness and performance comparing quazepam with flurazepam in two adult populations using the Multiple Sleep Latency Test.

Daytime residual drowsiness and psychomotor performance were assessed for two long half-life benzodiazepines, quazepam and flurazepam, in two randomized, parallel, and double-blind studies in insomniacs. Seventeen middle-aged patients took quazepam 15 mg or 30 mg, or flurazepam 30 mg; the 47-night study included 4 placebo baseline nights, 28 consecutive treatment nights, and 15 posttreatment nights. Forty-eight geriatric patients took either flurazepam 15 mg, quazepam 15 mg, or placebo; the 15-night study included 1 placebo baseline night, 7 treatment nights, and 7 posttreatment nights. The Multiple Sleep Latency Test (MSLT), an objective test for measuring daytime sleepiness, and performance tests were administered. In the first study, flurazepam patients were significantly (p less than .05) sleepier after the 7th and 14th treatment nights when compared to baseline, whereas quazepam patients were not. In the second study, flurazepam patients were sleepier at midday (p less than .10) and late afternoon (p less than .05) after 1 treatment week than were quazepam and placebo patients. Performance test results suggested quazepam has a relatively low potential for daytime impairment. Thus, quazepam 15 mg produces less daytime somnolence and fewer psychomotor performance decrements than does flurazepam.

Adolescent↗
PubMed1991

Dopamine D2 mechanisms in canine narcolepsy.

Narcolepsy is a sleep disorder characterized by abnormal manifestations of rapid-eye-movement (REM) sleep and excessive daytime sleepiness. Using a canine model of the disease, we found that central D2 antagonists suppressed cataplexy, a form of REM-sleep atonia occurring in narcolepsy, whereas this symptom was aggravated by D2 agonists. The effect on cataplexy was stereospecific for the S(-) enantiomer of sulpiride (a D2 antagonist) and the R(+) enantiomer of 3-PPP (a D2 agonist). There was also a significant correlation between the in vivo pharmacological potency and in vitro drug affinity for D2 receptors (but not for D1 and alpha 2 receptors) among the seven central D2 antagonists tested. Selective D1 compounds were also tested; however, the results were inconsistent because both antagonists and agonists generally suppressed cataplexy. Our current results demonstrate that central D2-type receptors are critically involved in the control of cataplexy and REM sleep. Furthermore, the finding that small doses of D2 antagonists suppressed cataplexy and induced behavioral excitation, while small doses of D2 agonists aggravated cataplexy and induced sedation, suggests that this effect is mediated presynaptically. However, considering the fact that selective dopamine reuptake inhibitors did not modify cataplexy and that our previous pharmacological results demonstrated a preferential involvement of the noradrenergic system in the control of cataplexy, we believe that the effect of D2 compounds on cataplexy is mediated secondarily via the noradrenergic systems.

Animals↗
PubMed1990

Prostaglandin E2 levels in cerebrospinal fluid of normal and narcoleptic dogs.

It has been shown that endogenous prostaglandin D2 and prostaglandin E2 (PGE2) are involved in sleep-wake regulation. Our recent experimental result that exogenously administered PGE2 significantly reduces canine cataplexy (a pathological equivalent of rapid-eye-movement sleep atonia and a symptom of narcolepsy) suggests that PGE2 is involved in the pathophysiology of canine narcolepsy. In order to further investigate the role of prostaglandins (PGs) in this disorder, PG levels in cerebrospinal fluid (CSF) of genetically homozygous narcoleptic, heterozygous (unaffected), and control Doberman pinschers were studied. PGE2 levels were measured by direct radioimmunoassay (RIA) and after high-grade purification using PG affinity columns and high-performance liquid chromatography. PGD2 and PGF2 alpha levels were measured by RIA after high-grade purification. There was no significant difference in PGE2 levels between homozygous narcoleptic and heterozygous or controls dogs, and PGD2 and PGF2 alpha levels were undetectable in most cases. Our results do not favor the hypothesis that central PGE2 levels are modified in canine narcolepsy, assuming that PGE2 levels in cisternal CSF properly reflect PGE2 production in the brain.

Animals↗
PubMed1990

CNS monoamines and their metabolites in canine narcolepsy: a replication study.

In two separate studies a significantly greater concentration of DA (dopamine) and its metabolite, DOPAC (3,4-dihydroxyphenylacetic acid), was observed in the amygdala of narcoleptic canines. DOPAC was also significantly elevated in the reticularis parvicellularis, whereas NE (norepinephrine) was significantly elevated in the reticularis oralis, but depressed in the preoptic hypothalamus. No changes were observed in concentrations of serotonin or its metabolite, 5-HIAA (5-hydroxyindoleauric acid) in any region in the narcoleptic canine brain. Results of the two studies were similar, except that previously observed differences between narcoleptic and control canines in DOPAC levels in the caudate and reticularis oralis failed to replicate. Thus, steady state measures of neurotransmitter/metabolite tissue concentrations suggest region-specific alterations in DA and NE metabolism, rather than a global deficit in catecholamine neurotransmission in canine narcolepsy.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Direct measurement of daytime sleepiness after administration of cetirizine and hydroxyzine with a standardized electroencephalographic assessment.

Alertness is a vital function, and medications that do not impair this vital function are clinically desirable in terms of safety. In a comparative study to measure daytime alertness objectively, 60 men and women in good health were assigned to receive either cetirizine, 5 mg, 10 mg, or 20 mg, hydroxyzine, 25 mg, or placebo in a randomized, double-blind, parallel-group design. Subjects slept in the laboratory for 2 consecutive nights to facilitate adaptation. During the second night, the subjects' sleep patterns were recorded by electroencephalogram (EEG), electrooculogram, and chin electromyogram. After the second night, subjects were awakened at 7:30 AM and given a single dose of the assigned treatment. Multiple Sleep Latency Tests (standardized 20-minute opportunities to fall asleep in bed while EEG and eye movements are recorded) were given every 2 hours. Subjects who received cetirizine did not differ from control subjects given placebo in any measure of daytime alertness. Subjects who received hydroxyzine were significantly more sedated than were control subjects given placebo for about 4 hours after treatment. The data from this study provide evidence that cetirizine does not differ from placebo with respect to alertness. The usefulness of the specific and sensitive standardized electroencephalogram, compared with alternative assessments of daytime alertness, is discussed.

Adult↗
PubMed1990

Systematic 24-hr behavioral observations of sleep and wakefulness in a skilled-care nursing facility.

Sleep patterns of aged, infirm, demented, chronically institutionalized residents of a skilled-care nursing facility were studied. The purpose of this naturalistic study was to describe sleep and wakefulness (S/W) within the limits afforded by brief behavioral observations and to examine homeostasis and diurnal rhythmicity of S/W as a function of psychoactive drug intake. Observers noted S/W every 15 min, 24 hr a day for 10 days in 24 Ss. Results indicated substantial individual variation in daytime hours. Daily and weekly variation within Ss was minimal. Sleep was least likely near sunset. Ss on psychoactive drugs showed dampened diurnal variation in S/W rhythms. In Ss not on such drugs, there was a suggestion of homeostasis of S/W between sleep during the morning and evening hours. Results are discussed methodologically (viability of approach), theoretically (age-related change in sleep), and practically (potential treatments).

Aged↗
PubMed1990

Amplified RNA synthesized from limited quantities of heterogeneous cDNA.

The heterogeneity of neural gene expression and the spatially limited expression of many low-abundance messenger RNAs in the brain has made cloning and analysis of such messages difficult. To generate amounts of nucleic acids sufficient for use in standard cloning strategies, we have devised a method for producing amplified heterogeneous populations of RNA from limited quantities of cDNA. Whole cerebellar RNA was primed with a synthetic oligonucleotide containing the T7 RNA polymerase promoter sequence 5' to a polythymidylate region. After second-strand cDNA synthesis, T7 RNA polymerase was used to generate amplified antisense RNA (aRNA). Up to 80-fold molar amplification has been achieved from nanogram quantities of cDNA. The amplified material is similar in size distribution to the parent cDNA and shows sequence heterogeneity as assessed by Southern and Northern blot analysis. Specific messages for moderate-abundance mRNAs for actin and guanine nucleotide-binding protein (G-protein) alpha subunits have been detected in the amplified material. By using in situ transcription to generate cDNA, sequences for cyclophilin have been detected in aRNA derived from single cerebellar tissue sections. cDNA derived from a single cerebellar Purkinje cell also has been amplified and yields material that hybridizes to cognate whole RNA and mRNA but not to Escherichia coli RNA.

Actins↗
PubMed1990

Predictors of observed sleep/wakefulness in residents in long-term care.

This cross-sectional study investigated predictors of sleep/wakefulness in residents in a skilled care nursing facility. Sleep/wakefulness was defined behaviorally by observations made four times an hour over four 12-hour observation periods. Predictors studied were mental status, functional capacity, relative likelihood of cardiovascular/respiratory, musculoskeletal, and endocrine disease, psychotropic medication intake, and presence of sleep apnea. Results based on 39 residents indicated that sleep apnea was a positive consistent predictor of observed sleep in the nursing home. Apnea generally was unrelated to other predictors. We discuss these findings in terms of the viability of this technique to study sleep as well as other potential predictors of sleep/wakefulness in elderly institutionalized patients.

Aged↗