Separation of circadian and wake duration-dependent modulation of EEG activation during wakefulness.

The separate contribution of circadian rhythmicity and elapsed time awake on electroencephalographic (EEG) activity during wakefulness was assessed. Seven men lived in an environmental scheduling facility for 4 weeks and completed fourteen 42.85-h 'days', each consisting of an extended (28.57-h) wake episode and a 14.28-h sleep opportunity. The circadian rhythm of plasma melatonin desynchronized from the 42.85-h day. This allowed quantification of the separate contribution of circadian phase and elapsed time awake to variation in EEG power spectra (1-32 Hz). EEG activity during standardized behavioral conditions was markedly affected by both circadian phase and elapsed time awake in an EEG frequency- and derivation-specific manner. The nadir of the circadian rhythm in alpha (8-12 Hz) activity in both fronto-central and occipito-parietal derivations occurred during the biological night, close to the crest of the melatonin rhythm. The nadir of the circadian rhythm of theta (4.5-8 Hz) and beta (20-32 Hz) activity in the fronto-central derivation was located close to the onset of melatonin secretion, i.e. during the wake maintenance zone. As time awake progressed, delta frequency (1-4.5 Hz) and beta (20-32 Hz) activity rose monotonically in frontal derivations. The interaction between the circadian and wake-dependent increase in frontal delta was such that the intrusion of delta was minimal when sustained wakefulness coincided with the biological day, but pronounced during the biological night. Our data imply that the circadian pacemaker facilitates frontal EEG activation during the wake maintenance zone, by generating an arousal signal that prevents the intrusion of low-frequency EEG components, the propensity for which increases progressively during wakefulness.

Sleep, performance, circadian rhythms, and light-dark cycles during two space shuttle flights.

Sleep, circadian rhythm, and neurobehavioral performance measures were obtained in five astronauts before, during, and after 16-day or 10-day space missions. In space, scheduled rest-activity cycles were 20-35 min shorter than 24 h. Light-dark cycles were highly variable on the flight deck, and daytime illuminances in other compartments of the spacecraft were very low (5.0-79.4 lx). In space, the amplitude of the body temperature rhythm was reduced and the circadian rhythm of urinary cortisol appeared misaligned relative to the imposed non-24-h sleep-wake schedule. Neurobehavioral performance decrements were observed. Sleep duration, assessed by questionnaires and actigraphy, was only approximately 6.5 h/day. Subjective sleep quality diminished. Polysomnography revealed more wakefulness and less slow-wave sleep during the final third of sleep episodes. Administration of melatonin (0.3 mg) on alternate nights did not improve sleep. After return to earth, rapid eye movement (REM) sleep was markedly increased. Crewmembers on these flights experienced circadian rhythm disturbances, sleep loss, decrements in neurobehavioral performance, and postflight changes in REM sleep.

Microgravity reduces sleep-disordered breathing in humans.

To understand the factors that alter sleep quality in space, we studied the effect of spaceflight on sleep-disordered breathing. We analyzed 77 8-h, full polysomnographic recordings (PSGs) from five healthy subjects before spaceflight, on four occasions per subject during either a 16- or 9-d space shuttle mission and shortly after return to earth. Microgravity was associated with a 55% reduction in the apnea-hypopnea index (AHI), which decreased from a preflight value of 8.3 +/- 1.6 to 3.4 +/- 0.8 events/h inflight. This reduction in AHI was accompanied by a virtual elimination of snoring, which fell from 16.5 +/- 3.0% of total sleep time preflight to 0.7 +/- 0.5% inflight. Electroencephalogram (EEG) arousals also decreased in microgravity (by 19%), and this decrease was almost entirely a consequence of the reduction in respiratory-related arousals, which fell from 5.5 +/- 1.2 arousals/h preflight to 1.8 +/- 0.6 inflight. Postflight there was a return to near or slightly above preflight levels in these variables. We conclude that sleep quality during spaceflight is not degraded by sleep-disordered breathing. This is the first direct demonstration that gravity plays a dominant role in the generation of apneas, hypopneas, and snoring in healthy subjects.

Dual-mode EPR study of Mn(III) salen and the Mn(III) salen-catalyzed epoxidation of cis-beta-methylstyrene.

Dual-mode electron paramagnetic resonance (EPR), in which an oscillating magnetic field is alternately applied parallel or perpendicular to the static magnetic field, is a valuable technique for studying both half-integer and integer electron spin systems and is particularly useful for studying transition metals involved in redox chemistry. We have applied this technique to the characterization of the Mn(III) salen (salen = N,N'-ethylene bis(salicylideneaminato)) complex [(R,R)-(-)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III)], with an S = 2 integer electron spin system. Furthermore, we have used dual-mode EPR to study the Mn salen complex during the Mn(III) salen-catalyzed epoxidation of cis-beta-methylstyrene. Our study shows that the additives N-methylmorpholine N-oxide (NMO) and 4-phenylpyridine-N-oxide (4-PPNO), which are used to improve epoxidation yields and enantioselection, bind to the Mn(III) center prior to the epoxidation reaction, as evidenced by the alteration of the Mn(III) parallel mode EPR signal. With these additives as ligands, the axial zero-field splitting values and (55)Mn hyperfine splitting of the parallel mode signal are indicative of an axially elongated octahedral geometry about the Mn(III) center. Since the dual-mode EPR technique allows the observation of both integer and half-integer electron spin systems, Mn oxidation states of II, III, IV, and potentially V can be observed in the same sample as well as any radical intermediates or Mn(III,IV) dinuclear clusters formed during the Mn(III) salen-catalyzed epoxidation reaction. Indeed, our study revealed the formation of a Mn(III,IV) dinuclear cluster in direct correlation with expoxide formation. In addition to showing the possible reaction intermediates, dual-mode EPR offers insight into the mechanism of catalyst degradation and formation of unwanted byproducts. The dual-mode technique may therefore prove valuable for elucidating the mechanism of Mn(III) salen catalyzed reactions and ultimately for designing optimum catalytic conditions (solvents, oxidants, and additives such as NMO or 4-PPNO).

Protein-degrading enediynes: library screening of Bergman cycloaromatization products.

[structure: see text] A screening method based on Bergman cycloaromatization products was applied to a compact library of estrogenic-enediyne hybrids. An enediyne candidate identified from the screen was subsequently synthesized, and it induced temperature- and concentration-dependent degradation of human estrogen receptor alpha upon cycloaromatization.

Endogenous circadian control of the human autonomic nervous system.

To determine if an endogenous circadian rhythmicity, independent from sleep/wake cycles, exists in autonomic nervous system (ANS) function, heart rate variability analysis of electrocardiogram R-R intervals was applied to data collected during a 27-day forced desynchrony protocol. Results during wakefulness indicate that the circadian pacemaker may control both the sympathetic and vagal limbs of the ANS. Vagal tone was maximal during the circadian phase corresponding to the usual sleep episode (although these measurements were made in the absence of sleep) with an acrophase at 4 AM to 5 AM. Sympathovagal balance was minimal between 9 AM and 1 PM. These endogenous circadian rhythms in ANS function may contribute to mortality from cardiovascular disease and nocturnal asthma.

Circadian temperature and melatonin rhythms, sleep, and neurobehavioral function in humans living on a 20-h day.

The interaction of homeostatic and circadian processes in the regulation of waking neurobehavioral functions and sleep was studied in six healthy young subjects. Subjects were scheduled to 15-24 repetitions of a 20-h rest/activity cycle, resulting in desynchrony between the sleep-wake cycle and the circadian rhythms of body temperature and melatonin. The circadian components of cognitive throughput, short-term memory, alertness, psychomotor vigilance, and sleep disruption were at peak levels near the temperature maximum, shortly before melatonin secretion onset. These measures exhibited their circadian nadir at or shortly after the temperature minimum, which in turn was shortly after the melatonin maximum. Neurobehavioral measures showed impairment toward the end of the 13-h 20-min scheduled wake episodes. This wake-dependent deterioration of neurobehavioral functions can be offset by the circadian drive for wakefulness, which peaks in the latter half of the habitual waking day during entrainment. The data demonstrate the exquisite sensitivity of many neurobehavioral functions to circadian phase and the accumulation of homeostatic drive for sleep.

EEG and ocular correlates of circadian melatonin phase and human performance decrements during sleep loss.

The aim of this study was to quantify the associations between slow eye movements (SEMs), eye blink rate, waking electroencephalogram (EEG) power density, neurobehavioral performance, and the circadian rhythm of plasma melatonin in a cohort of 10 healthy men during up to 32 h of sustained wakefulness. The time course of neurobehavioral performance was characterized by fairly stable levels throughout the first 16 h of wakefulness followed by deterioration during the phase of melatonin secretion. This deterioration was closely associated with an increase in SEMs. Frontal low-frequency EEG activity (1-7 Hz) exhibited a prominent increase with time awake and little circadian modulation. EEG alpha activity exhibited circadian modulation. The dynamics of SEMs and EEG activity were phase locked to changes in neurobehavioral performance and lagged the plasma melatonin rhythm. The data indicate that frontal areas of the brain are more susceptible to sleep loss than occipital areas. Frontal EEG activity and ocular parameters may be used to monitor and predict changes in neurobehavioral performance associated with sleep loss and circadian misalignment.

Time course of sleep inertia dissipation in human performance and alertness.

Alertness and performance on a wide variety of tasks are impaired immediately upon waking from sleep due to sleep inertia, which has been found to dissipate in an asymptotic manner following waketime. It has been suggested that behavioural or environmental factors, as well as sleep stage at awakening, may affect the severity of sleep inertia. In order to determine the time course of sleep inertia dissipation under normal entrained conditions, subjective alertness and cognitive throughput were measured during the first 4 h after habitual waketime from a full 8-h sleep episode on 3 consecutive days. We investigated whether this time course was affected by either sleep stage at awakening or behavioural/environmental factors. Sleep inertia dissipated in an asymptotic manner and took 2-4 h to near the asymptote. Saturating exponential functions fitted the sleep inertia data well, with time constants of 0.67 h for subjective alertness and 1.17 h for cognitive performance. Most awakenings occurred out of stage rapid eye movement (REM), 2 or 1 sleep, and no effect of sleep stage at awakening on either the severity of sleep inertia or the time course of its dissipation could be detected. Subjective alertness and cognitive throughput were significantly impaired upon awakening regardless of whether subjects got out of bed, ate breakfast, showered and were exposed to ordinary indoor room light (approximately 150 lux) or whether subjects participated in a constant routine (CR) protocol in which they remained in bed, ate small hourly snacks and were exposed to very dim light (10-15 lux). These findings allow for the refinement of models of alertness and performance, and have important implications for the scheduling of work immediately upon awakening in many occupational settings.

Psychophysiological insomnia: the behavioural model and a neurocognitive perspective.

A number of paradoxes are apparent in the assessment and treatment of psychophysiological insomnia and sleep state misperception. Three of these paradoxes exist as discrepancies between polysomnographic (PSG) measures and the subjective impressions regarding sleep quality and quantity. The remaining incongruity exists largely within the objective domain. In the case of subjective-objective discrepancies, patients with insomnia: (1) frequently identify themselves as having been awake when awakened from PSG defined sleep; (2) tend to overestimate sleep latency and underestimate total sleep time as compared with PSG measures; (3) appear to derive more benefit from pharmacotherapy that can be explained by objective gains. The remaining paradox pertains to the observation that hypnotic medications, by and large, do not normalize sleep architecture or produce a more 'sleep-like' EEG. In this paper, we review possible explanations for these various paradoxes, introduce a new perspective and suggest possible research avenues. The model introduced is based on the observation that beta and/or gamma activity (which have been found to be associated with cognitive processes) is enhanced in insomnia at or around sleep onset. We propose that this kind of high frequency EEG activity may interfere with the normal establishment of sleep onset-related mesograde amnesia. As a result, the patient with insomnia maintains a level of information and/or memory processing that blurs the phenomenological distinction between sleep and wakefulness and influences retrospective judgments about sleep initiation and duration.

Mesograde amnesia during the sleep onset transition: replication and electrophysiological correlates.

The present study was designed to explore mechanisms of amnesia for meaningful auditory material presented during the sleep onset transition. Thirty undergraduate subjects (17 female, 13 male) were presented with auditory stimuli in an oddball paradigm until sleep onset. Subjects were allowed to accumulate either 30 seconds or 10 minutes of sleep, then awakened and tested on free recall and recognition memory for the meaningful stimuli. After 10 minutes of sleep, but not after 30 seconds of sleep, subjects had profound amnesia on free recall for stimuli presented in the 4-minute window prior to sleep onset. Increased beta electroencephalograph (EEG) power during the sleep period correlated positively with recall of stimuli in the 4-minute presleep window. Event-related potential recordings provided suggestive evidence that subjects continued to process the auditory stimuli to some extent during the sleep onset transition. When allowed to sleep for 10 minutes, subjects evidenced a mixed anterograde and retrograde amnesia for auditory stimuli presented in the 4-minute window prior to sleep onset. The results are discussed in terms of stimulus encoding, consolidation, and retrieval.

Time-dependent sensitization of heart rate and blood pressure over multiple laboratory sessions in elderly individuals with chemical odor intolerance.

In this study, we tested the hypothesis that low-level chemical odor intolerance (i.e., "cacosmia") is a manifestation of heightened sensitizability to environmental stimuli. We examined supine heart rate and blood pressure of elderly individuals, who were classified as either having a higher degree of chemical odor intolerance (n = 12) or a lower degree of chemical odor intolerance (n = 13), upon awakening in a sleep research laboratory on 6 different days during an 8-wk protocol. During the 2 initial wk, they consumed a customary baseline diet (including ad lib milk and other dairy products), followed by 3 wk each of nondairy-containing and dairy-containing diets in randomly assigned, counterbalanced order. Measurements were made on 3 pairs of successive days, distributed over a 6-wk period, and on which different diets were consumed. The high-intolerance group had significantly higher mean supine systolic and diastolic blood pressures than did the low-intolerance group. Although subjects consumed milk products during both the initial baseline and subsequent dairy diet periods, the high-intolerance group had significantly higher heart rates and diastolic blood pressures later in the study than at baseline, especially when they were on the dairy diet. In contrast, the cardiovascular measures of the low-intolerance group lowered on average with time. The high-intolerance subjects had an increased mean diastolic blood pressure on the second days versus the first days in the laboratory (averaged across all diets). Collectively, the data suggest that elderly individuals with a high degree of chemical odor intolerance evidence (a) increased sympathetic tone in the cardiovascular system at rest over multiple measurements; and (b) greater sensitizability and/or lesser habituation of heart rate and diastolic blood pressure over time as a function, in part, of repeated environmental stressor exposures (i.e., a novel laboratory contextual setting and/or specific dietary constituents). Consistent with a sensitization model, the findings emphasize the need for two or more identical sessions at least 24 h apart in physiological studies of individuals with a high degree of intolerance for chemical odors versus normal individuals. The results of the blood pressure observations suggest that the possibility of abnormally labile autonomic function and cognitive sequelae in individuals with a high degree of intolerance for chemical odor increases with age.

Objective assessment of sleep and alertness in medical house staff and the impact of protected time for sleep.

We studied 26 physicians in postgraduate medical training ("house staff") to objectively quantify their sleep, alertness, and psychomotor performance while working on call. This study provided precise data on the extent of sleep deprivation during a typical call night, the workload factors predictive of sleep loss, and the extent to which protected time for sleep within the call night can ameliorate sleep loss and consequent daytime sleepiness. We used ambulatory EEG recording equipment and a standardized computer-based performance test to monitor sleep and alertness over the course of a 36-hour call day. Comparisons were made between interns provided with 4 hours of protected time for sleep by a covering resident ("night-float") and interns without such coverage. As anticipated, we found evidence that hospital interns were severely sleep-deprived, to an extent even greater than prior behavioral observations have suggested. Interns in both conditions spent an average of less than 5 hours (295.4 minutes) in bed attempting to sleep and obtained an average of 3.67 hours (220.1 minutes) of sleep (range 37.4-358.4 minutes). Provision of the night-float for 4 hours did not significantly change total sleep time (TST) (212.8 minutes covered vs. 224.9 minutes uncovered), but sleep efficiency was significantly improved (86.5% vs. 70.3%; p = 0.001). Covered interns also obtained significantly more slow-wave sleep than the uncovered interns (65.4 minutes vs. 51.1 minutes; p = 0.05). However, measures of alertness and performance were not significantly different between the two groups and were only weakly related to TST. These data suggest that significant chronic sleep deprivation is relatively unaffected by sleep obtained in the hospital and that provision of protected time for sleep does not significantly improve TST.

A polysomnographic study of sleep disturbance in community elderly with self-reported environmental chemical odor intolerance.

Subjective sleep complaints and food intolerances, especially to milk products, are frequent symptoms of individuals who also report intolerance for low-level odors of various environmental chemicals. The purpose of the present study was to evaluate the objective nature of nocturnal sleep patterns during different diets, using polysomnography in community older adults with self-reported illness from chemical odors. Those high in chemical odor intolerance (n = 15) exhibited significantly lower sleep efficiency (p = .005) and lower rapid-eye-movement (REM) sleep percent (p = .04), with a trend toward longer latency to REM sleep (p = .07), than did those low in chemical intolerance (n = 15), especially on dairy-containing as compared with nondairy (soy) diets. The arousal pattern of the chemical odor intolerant group differed from the polysomnographic features of major depression, classical organophosphate toxicity, and subjective insomnia without objective findings. The findings suggest that community elderly with moderate chemical odor intolerance and minimal sleep complaints exhibit objectively poorer sleep than do their normal peers. Individual differences in underlying brain function may help generate these observations. The data support the need for similar studies in clinical populations with chemical odor intolerance, such as multiple chemical sensitivity patients and perhaps certain veterans with "Persian Gulf Syndrome."

Slowed reaction time performance on a divided attention task in elderly with environmental chemical odor intolerance.

Previous research has suggested an association between the subjective report of illness from environmental chemical odors and poorer cognitive task performance in persons with industrial levels of xenobiotic exposures. The present study investigated baseline morning performance on a computerized divided attention task in active retired adults without occupational exposures or clinical disorders who nonetheless rated themselves currently high versus low in episodic illness from the odor of certain environmental chemicals. The chemically intolerant group showed slower reaction times in registering both centrally and peripherally placed stimuli, but no difference in making target tracking errors. Measures of negative affect did not account for these findings. Taken together with evidence for heightened neurobehavioral sensitization in this population, the data suggest disturbances in allocation of attention and related cognitive functions.

Sleep onset is associated with retrograde and anterograde amnesia.

The purpose of the present study was to examine explicit and implicit memory for auditory events presented immediately prior to sleep onset. The results of the present study suggest subjects allowed 10 minutes of sleep demonstrate deficient explicit memory for auditory stimuli presented immediately prior to sleep onset. Subjects showed severe free recall deficits for word pairs presented 3 minutes prior to sleep onset and recognition deficits for stimuli from 1 minute prior to sleep onset. Implicit memory for word pairs presented prior to sleep onset seemed intact, and no recency effect was observed. In contrast to the 10-minute condition, subjects allowed 30 seconds of sleep demonstrated no equivalent explicit memory deficits. Memory performance in both delay conditions, however, appeared globally impaired relative to control data from subjects who remained awake. The results are interpreted in terms of elaboration of stimulus encoding, interruption of consolidation and retrograde versus anterograde amnesia.

Sarcomatoid renal cell carcinoma. An immunohistochemical study of 18 cases.

Malignant spindle cell neoplasms are a diagnostic challenge regardless of their location. In the retroperitoneum a major consideration in the differential diagnosis is sarcomatoid renal cell carcinoma; if an epithelial component cannot be recognized histologically, special studies may be required to reach the correct diagnosis. In an attempt to better characterize this entity, 23 cases of sarcomatoid renal cell carcinoma (6.3%) were identified from a review of 363 renal cell carcinomas. Blocks were available for immunohistochemical analysis in 18 cases. The epithelial and sarcomatoid portions were studied with a panel of antibodies directed against cytokeratin (AE1/AE3, CAM 5.2, and 34 beta E12), epithelial membrane antigen, Leu-M1, muscle-specific actin, S100 protein, desmin, and vimentin. The epithelial nature of the spindle cell component was best demonstrated by positive reactivity with the anti-cytokeratin AE1/AE3 (in 17 [94%] of the 18 cases). The other epithelial markers stained the spindle cell component less frequently: cytokeratin CAM 5.2 in seven cases (39%); epithelial membrane antigen in nine cases (50%); and high-molecular-weight cytokeratin 34 beta E12 in no cases (0%). In 10 cases (56%) vimentin positivity and in six cases (33%) actin positivity was seen in the spindled areas. The spindle cell component stained for Leu-M1 in four cases (22%) and for S100 protein in one case (6%) and did not react for desmin in any case. From this study we conclude that in the majority of sarcomatoid renal cell carcinomas the epithelial nature of the spindle cells, as indicated by cytokeratin expression, can be documented using immunohistochemical methods.

Primary rhabdomyosarcoma of the kidney. A light microscopic, immunohistochemical, and electron microscopic study.

Primary rhabdomyosarcoma of the kidney is a rare and highly aggressive tumor in the adult population. A case is reported in a 70-year-old woman with the diagnosis confirmed by immunohistochemistry and electron microscopy. This is the first case studied using the immunoperoxidase technique and the second with electron microscopic examination. To make a diagnosis of primary sarcoma, of the kidney, three criteria must be met: (1) a metastatic sarcoma must be ruled out; (2) the tumor must arise from renal parenchyma; and (3) a sarcomatoid variant of renal cell carcinoma needs to be excluded. The literature is reviewed and available clinical and pathologic details are summarized.