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Research on insomnia has provided a number of important new insights, but fundamental deficits in our understanding remain. In considering priorities for future research, 3 areas warrant immediate attention. First, a causal relationship between insomnia and the adverse outcomes seen in insomnia patients needs to be established. Second, currently available symptomatic therapies need to be optimized. Recent data suggest that some benzodiazepine receptor agonists produce their hypnotic effect without side effects that were presumed to be inherent to sedation. Understanding the neuropharmacology underlying this differential effect would allow substantial improvements in the risk-benefit ratio for these drugs. Finally, the mechanisms of insomnia need to be better understood. Several lines of evidence suggest that physiologic arousal is important to the clinical presentation of primary insomnia. It remains unclear, however, whether this activation is primary or secondary to the insomnia itself. If physiologic hyperarousal causes primary insomnia, it would provide new approaches to the management of this disorder.

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The optimal management of insomnia in the primary care setting should be viewed as a public health problem that will require specific attention. Important recent strides in the understanding of insomnia, its consequences, and its treatment do not always provide a basis for management strategies in a setting with distinct practical limitations. A somewhat different research focus will be needed if the scientific advances are to be translated into practical improvements in therapy. In primary care today, multiple agendas compete for the physician's time. Therefore, it is necessary to view diagnosis and management in terms of both what is efficient and what is optimally effective. Much can be learned from experience with medical risk factors of broad prevalence, such as hypercholesterolemia and hypertension. Large outcome trials demonstrating the benefits of drug therapy were required before pharmacologic management became standard care in the primary care setting. For insomnia, specific issues that must be addressed include the components of diagnosis that will guide therapy and affect prognosis. How can the 10% of adults with insomnia in the primary care practice be subdivided to identify those most in need of therapy? Stated another way, what are the features of insomnia that predict risk? Is duration important? Severity? Frequency? Which treatments are most effective? Which are most efficient in terms of the time required of patient and practitioner? Do treatments for insomnia produce patient satisfaction? Do they prevent adverse outcomes, such as depression and automobile accidents? Studies are now addressing many of these questions. In selecting research priorities, however, the practical application of this information in the clinical setting is important if the ultimate goal is to reduce the number of patients suffering from insomnia and its consequences.

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The "long nights" protocol was designed to evaluate sleep processes and circadian rhythm parameters in young humans. A total of 19 children (10 boys, ages 11.2 to 14.1 years [mean = 12.7 +/- 1.0], and 9 girls, ages 12.2 to 14.4 years [mean = 13.1 +/- 0.7]) took part in the study. Sleep/wake initially was assessed at home using actigraphy and diary for 1 week on each child's self-selected schedule followed by an 8-night fixed light-dark (LD) condition, while sleeping from 22:00 to 08:00 h and wearing an eye mask to exclude as much light as possible. Phase measurements included 4-night mean actigraphically estimated sleep onset and offset as well as 1-night dim light salivary melatonin onset (DLSMO) phase at the end of each condition. Subjects then lived in the laboratory for 6 consecutive cycles: Day 1 LD = 14:10 h, lights out 22:00 to 08:00 h; Days 2-4 LD = 6:18 h, lights out 18:00 to 12:00 h; Days 5-6 = constant routine in continuous dim light (about 20 lux); Night 6 = 14 h recovery sleep. Phase markers (sleep onset, sleep offset, DLSMO) were significantly less dispersed after the fixed LD as compared to the self-selected condition, indicating efficacy of the LD protocol. Phase markers were correlated at the self-selected assessment (sleep onset vs. sleep offset r = .72; DLSMO vs. sleep onset r = .82; DLSMO vs. sleep offset r = .76) but not on the fixed schedule, probably due to restricted range. The constant routine provided additional phase markers, melatonin offset and midphase. Offset phase of melatonin secretion was significantly correlated with age (r = .62) and Tanner stage (r = .62). In conclusion, these preliminary data indicate a relationship between adolescent development and circadian phase. Thus, the long nights protocol is a feasible way in which to assess circadian parameters in young humans as well as to examine intrinsic sleep processes.

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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.

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Previous polysomnographic (PSG) investigations have reported a rhythmic electromyographic (EMG) pattern (0.5-3.0 cps) of leg movement activity in a subset of patients with neuroleptic-induced akathisia (NIA). It has been suggested that this EMG pattern may represent a pathophysiological correlate of NIA and thus have clinical utility as an objective marker for this condition. We present preliminary measures of sensitivity and specificity for this EMG pattern as a diagnostic marker for NIA for 26 neuroleptic-treated patients. The EMG marker yielded a diagnostic sensitivity of 68.9% and a specificity of 70.0%, falling just short of statistical significance (Fisher's exact test p = 0.06). Quantitative analysis of the EMG pattern revealed a significant positive correlation between the percentage of time the NIA marker occurred during wakefulness and corresponding chlorpromazine equivalent levels. Clinical demographic findings for true-positive, false-positive, true-negative, and false-negative groups are discussed. Overall findings suggest that this particular pattern of EMG marker activity observed in neuroleptic-treated patients during PSG and EMG studies is valuable in facilitating the diagnosis and monitoring treatment.

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The prediction that abnormalities of circadian clock function in humans would manifest principally as sleep/wake disruption led to the description of the first circadian sleep/wake disorders almost 20 years ago. Since then, formal classification of sleep pathology has expanded this category to include six specific disorders. In this review, the physiology of mammalian circadian clocks is summarized with emphasis on the role of light and hormonal signals in circadian adjustment and entrainment. Each of the circadian sleep disorders-time zone change (jet lag) syndrome, shift work sleep disorder, irregular sleep/wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome, and non-24-h sleep wake disorder-is reviewed. Presenting characteristics, approaches to diagnosis, models of pathophysiology, and methods of treatment are summarized for each sleep disorder. Developments in the understanding of circadian physiology offer promise for important advances in the diagnosis and treatment of these sleep disorders.

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Endogenous sex hormones seem to influence the risk of several common and debilitating diseases. With a view toward better understanding the effects of surgical removal of the ovaries and high-dose pelvic radiotherapy on plasma sex hormone levels, we measured estrogen and androgen concentrations cross-sectionally among 147 women who had been treated for cervical cancer 0.3-18.5 years previously. Pelvic radiotherapy (mean dose to ovaries, 50 Gy) and bilateral ovariectomy were associated with similarly reduced hormone concentrations relative to levels among nonirradiated women with intact ovaries, most of whom had had early-stage disease and were treated by hysterectomy. There was little evidence that radiotherapy in addition to ovariectomy further lowered concentrations below levels associated with ovariectomy alone, such as might be expected if radiation was suppressing adrenal endocrine function. Among women age 50 years or older at the time of blood drawing, the removal or irradiation of the ovaries was associated with approximately 45% lower concentrations of estradiol (mean ratio [MR], 0.55; 95% confidence interval [CI], 0.32-0.95) and testosterone (MR, 0.57; 95% CI, 0.32-0.99), and 25-30% lower concentrations of estrone (MR, 0.69; 95% CI, 0.44-1.09) and androstenedione (MR, 0.76; 95% CI, 0.47-1.23), relative to the hysterectomy-only group. Among women younger than 50, ovariectomy and radiotherapy, alone or in combination, were associated with 83% lower estradiol concentrations (MR, 0.17; 95% CI, 0.09-0.31), 46% lower estrone concentrations (MR, 0.54; 95% CI, 0.37-0.81), 23% lower androstenedione concentrations (MR, 0.77; 95% CI, 0.57-1.04), and 14% lower testosterone levels (MR, 0.86; 95% CI, 0.64-1.15).(ABSTRACT TRUNCATED AT 250 WORDS)

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Many elderly people complain of disturbed sleep patterns but there is not evidence that the need to sleep decreases with age; it seems rather that the timing and consolidation of sleep change. We tried to find out whether there is a concurrent change in the output of the circadian pacemaker with age. The phase and amplitude of the pacemaker's output were assessed by continuous measurement of the core body temperature during 40 h of sustained wakefulness under constant behavioural and environmental conditions. 27 young men (18-31 years) were compared with 21 older people (65-85 years; 11 men, 10 women); all were healthy and without sleep complaints. The mean amplitude of the endogenous circadian temperature oscillation (ECA) was 40% greater in young men than in the older group. Older men had a lower mean temperature ECA than older women. The minimum of the endogenous phase of the circadian temperature oscillation (ECP) occurred 1 h 52 min earlier in the older than in the young group. Customary bedtimes and waketimes were also earlier in the older group, as was their daily alertness peak. There was a close correlation between habitual waketime and temperature ECP in young men, which may lose precision with age, especially among women. These findings provide evidence for systematic age-related changes in the output of the human circadian pacemaker. We suggest that these changes may underlie the common complaints of sleep disturbance among elderly people. These changes could reflect the observed age-related deterioration of the hypothalamic nuclei that drive mammalian circadian rhythms.

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BACKGROUND AND PURPOSE: The causes of volume depletion and hyponatremia after subarachnoid hemorrhage are not fully understood but may be in part due to natriuresis or "cerebral salt wasting." Because previous studies using infrequent hormone sampling have given inconsistent results, we determined if elevations in atrial natriuretic factor concentrations preceded negative sodium and fluid balances. METHODS: We measured diurnal atrial natriuretic factor and vasopressin concentrations and sodium balance for 5 days in 14 consecutive patients after aneurysmal subarachnoid hemorrhage. RESULTS: Plasma concentrations of atrial natriuretic factor on admission were elevated in subarachnoid hemorrhage patients (mean +/- SD 106 +/- 59 pg/ml) compared with acutely ill controls (39 +/- 30 pg/ml). In eight patients, high peak concentrations of atrial natriuretic factor, greater than 300 pg/ml or a twofold increase above baseline, were followed by natriuresis and a negative sodium balance. Three patients, two of whom became hyponatremic, developed cerebral infarcts after natriuresis. Vasopressin concentrations were slightly elevated just after hemorrhage but subsequently declined to normal values. CONCLUSIONS: A markedly increased atrial natriuretic factor concentration precedes natriuresis in some patients and, with other abnormalities of water handling possibly including a relatively diminished vasopressin concentration, may cause volume depletion. Patients with natriuresis appear to be at increased risk for delayed cerebral infarction after subarachnoid hemorrhage.

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Insomnia is one of the most common complaints encountered by the primary care physician. Yet, in many cases, physicians treat the symptom of insomnia rather than evaluating and treating the underlying causes of insomnia. Because the subjective complaint of insomnia does not always correlate with evidence of objective sleep disruption, a careful history and evaluation are required. Assessment of the duration of insomnia and quantification of the impact of nocturnal sleep disruption on daytime functioning provide the most reliable indices of severity. Primary insomnia may be due to a number of different causes, such as poor sleep hygiene or circadian rhythm disruption. Insomnia may also be the presenting symptom of other primary sleep disorders, such as sleep apnea syndrome or nocturnal myoclonus, or of a variety of medical or psychiatric illnesses. The treatment of the patient with insomnia should address the underlying cause, when identifiable. When the cause cannot be identified, treatment should be conservative; nonpharmacologic therapies should be used whenever possible. When pharmacologic approaches are indicated, short-acting benzodiazepines should be administered in concordance with strict prescribing guidelines. Frequent follow-up is necessary to ensure continued therapeutic efficacy of the prescribed therapy.

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We have recently identified a uterine progesterone-dependent 25 kD protein (protein #27) secreted by endometrial epithelial cells but not stroma. Protein #27 was originally isolated from human luteal phase uterine fluids and partially purified by two-dimensional gel-electrophoresis and electroelution. It could not be detected in serum. We here report the further purification and amino terminal sequence of this protein, obtained from in vitro luteal phase endometrial tissue incubation media. Protein #27 was purified by a one-step method using reverse-phase high performance liquid chromatography. Amino acid compositional analysis confirms a high content of nonpolar and hydrophobic residues (40 mol%) and reveals a preponderance of acidic amino acids, consistent with its isoelectric point (5.9-6.3 pH). The amino terminal sequence obtained from a single individual reveals 85% homology with that of pregnancy-associated alpha 2-globulin from pooled cytosolic fractions from pregnancy endometria. We propose that protein #27, secreted by the endometrial epithelium, is an excellent candidate for a marker to be used to study pathological processes of the endometrium such as endometriosis and invasive carcinoma.

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A close anatomical relationship between nerve terminals containing neuropeptide Y (NPY) and vasopressin (AVP) has been demonstrated in the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON). Furthermore, injections of NPY into the SON increased plasma concentrations of AVP in the rat. These data suggest a potential involvement of hypothalamic NPY in fluid homeostasis in the rat. Therefore, we have studied the effect of elevated plasma osmolality on the concentration of NPY and AVP in the hypothalamus and neurointermediate lobe (NIL) of the pituitary gland. Furthermore, we measured the concentration of NPY in the AVP-deficient Brattleboro rat, which suffers from diabetes insipidus and hyperosmolality. Salt-loading increased plasma osmolality and the concentration of AVP from 2.0 +/- 0.5 to 4.1 +/- 0.6 pg/ml after 7 days. The concentration of NPY in the NIL doubled after 7 days of salt-loading, from 7.9 +/- 0.6 ng/mg protein to 15.2 +/- 1.4 ng/mg protein, whereas AVP concentrations fell from 2285.7 +/- 210.9 ng/mg protein to 187.5 +/- 2.5 ng/mg protein. AVP concentrations in the ME increased transiently after 2 days of salt-loading and returned to control levels after 7 days. In contrast, NPY concentrations in the ME were unchanged at 2 days and were increased 61% after 7 days. NPY concentrations also were significantly elevated after 7 days of salt-loading in the preoptic area (POA) and mediobasal hypothalamus (MBH). The concentration of NPY in the NIL of the homozygous Brattleboro rat was 2-fold greater than in the heterozygous Brattleboro rat and 4-fold greater than in Sprague-Dawley rats used as controls.(ABSTRACT TRUNCATED AT 250 WORDS)

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Protein secretion by the human endometrium was studied in vitro in medium after incubation of tissue minces (n = 10) or glands isolated by collagenase digestion (n = 4) from tissues obtained at the time of curettage from normal women. Samples were incubated in a serum-free medium for 24 h at 38 degrees C in the presence of radiolabeled methionine. Dialyzed medium from each sample was subjected to two-dimensional gel separation, and detected by protein staining. Although 5 of the 27 proteins were considered to be present in the labeling experiments by only one of the three observers, there was agreement about the presence of the 22 others. In addition, the observers categorized the proteins into three groups for purposes of analysis: a) those associated with the follicular phase of the cycle; b) those associated with the luteal phase; and c) those not cycle-related. One protein triplet, labeled #27, showed a significant relation to the luteal phase (p less than 0.01). A complete lack of similarity between the pattern of labeled proteins obtained from the medium and labeled proteins obtained from lysates of cells incubated in the same experiments makes it unlikely that cellular lysis, as opposed to secretion, contributed to the pattern of proteins studied in these experiments.

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A substantial and growing percentage of the U.S. work force now works on a rotating shift schedule. The repeated changes in sleep-wake, meal and work times inherent in such schedules conflict with the dictates of the internal biological clock and have adverse consequences for the health of the shiftworker population. An important consequence of this conflict is impaired performance, both on and off the job, as indexed by the increased incidence of motor vehicle accidents in shift workers. In this paper we report the results of a survey administered to rotating shift and straight day workers at a manufacturing plant in the eastern U.S. This survey documents an increased incidence of motor vehicle accidents or "near misses" in which sleepiness was implicated as a cause by the respondent. Complaints of poor sleep and increased sleepiness were also significantly more common in shiftworkers than day workers. Last, shiftworkers reported higher caffeine and alcohol consumption, and were more likely to use alcohol as a sleep aid. Although causal links cannot be established using these associative observations alone, previously reported experience with alteration of shift schedules, improvement of levels of alertness, and reduction in adverse performance outcomes corroborate the possibility of a causal link and suggest potential interventions.

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Sleep/wake expression in mice varies predictably with circadian phase. Such circadian rhythms are known to depend on intact suprachiasmatic nuclei (SCN) in the hypothalamus, but the mechanism by which SCN activity modulates sleep/wake expression is unknown. This paper examines the possibility that circadian patterns of sleep/wake derive partly from circadian timing of waking behaviors that are incompatible with sleep, such as locomotor activity. Voluntary locomotor activity was restricted in five mice adapted to a running wheel by locking the wheel in place. Continuous electrographic monitoring of sleep and wakefulness over multiple circadian cycles revealed: (1) during the active phase, shorter wake bouts and more frequent bouts of sleep, resulting in greater sleep/wake fragmentation and more time spent asleep; (2) during the rest phase, a small compensatory reduction in NREM sleep; (3) reduced amplitude of circadian sleep/wake rhythms and a greater amount of sleep overall. Thus, voluntary locomotor activity has an important influence on sleep/wake expression in mice, and the normal circadian pattern of sleep/wake depends on circadian timing of activity. Previous reports of damped circadian sleep/wake rhythms in rodents may therefore be explained by coincident diminutions in locomotor activity associated with age or health status. Our results also support analogous findings in human subjects, and we propose that elderly humans may benefit from therapies that augment daytime activity.

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Human uterine luminal fluids contain over two dozen proteins distinct from those of serum as detected by two dimensional gel electrophoresis and silver-type protein staining. Eighty-one percent of these uterine fluid proteins can be detected in vitro by radiolabeled methionine incorporation studies and the vast majority of these products are epithelial in origin. The major recognizable menstrual cycle phase-dependent change in the protein pattern in these gels was the appearance of a protein group (number 27) of approximately 25,000 mw and pI of 5.8 - 6.3. This group of proteins was found in nearly all mid- and all late secretory phase fluids or culture media and in none obtained earlier in the cycle. As yet, however, it has not been possible to induce these proteins in proliferative specimens in vitro by the addition of estrogens and/or progestins, though studies along these lines are continuing. Although we cannot be certain, it appears as though protein group number 27 is distinct from, but similar in several respects to, other proteins of human endometrium reported in the literature.

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