Bright light resets the human circadian pacemaker independent of the timing of the sleep-wake cycle.

Human circadian rhythms were once thought to be insensitive to light, with synchronization to the 24-hour day accomplished either through social contacts or the sleep-wake schedule. Yet the demonstration of an intensity-dependent neuroendocrine response to bright light has led to renewed consideration of light as a possible synchronizer of the human circadian pacemaker. In a laboratory study, the output of the circadian pacemaker of an elderly woman was monitored before and after exposure to 4 hours of bright light for seven consecutive evenings, and before and after a control study in ordinary room light while her sleep-wake schedule and social contacts remained unchanged. The exposure to bright light in the evening induced a 6-hour delay shift of her circadian pacemaker, as indicated by recordings of body temperature and cortisol secretion. The unexpected magnitude, rapidity, and stability of the shift challenge existing concepts regarding circadian phase-resetting capacity in man and suggest that exposure to bright light can indeed reset the human circadian pacemaker, which controls daily variations in physiologic, behavioral, and cognitive function.

An approach to studying circadian rhythms of adolescent humans.

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.

Progesterone binding by normal and abnormal human endometrium.

Cytosols from 75 normal, 36 abnormal, and 5 decidual human endometrial tissue specimens were assayed for the presence of a high affinity, progesterone-specific binding protein. Thirty of the normal and 15 of the abnormal samples were found to contain a binder which would form a high-affinity complex with progesterone but not with cortisol, 17beta-estradiol, testosterone, or 5alpha-androstane-3-,17-dione. Incubation of cytosol with trypsin or incubation for 2 hours at 37 C abolished [3H]progesterone binding by these preparations, indicating the protein nature and heat-lability of the binder. The average equilibrium constant of dissociation, Kd, of the progesterone-binder complex was 4.0 X 10(-10)M in each phase of the menstrual cycle. The concentration of the binder varied over the cycle, however, with a significant peak at mid-cycle (P = .02). The average saturation values in femtomoles (fmoles)/mg protein ranged from 21 in the early proliferative phase to 64 in the late proliferative samples, dropping to 36 in early secretory and to 3 in the late secretory phase of the cycle. No progesterone-specific binding was detected in decidual samples. Saturable binding was demonstrable in 10 of 22 endometrial hyperplasias, 80-1840 fmoles/mg protein, with high affinity, Kd 3.3 X 10(-10)M. Two other hyperplasia samples bound progesterone, but with lower affinity. Two grade I adenocarcinomas, one grade III adenosquamous carcinoma, and one grade III adenocarcinoma contained the progesterone binder, but in 9 other cancers no detectable binder was present. A benigh adenocanthomyoma was found to contain a progesterone binder (18 fmoles/mg protein with a Kd of 2.5 X 10(-10)M).

Serum estrogen and androgen levels following treatment for cervical cancer.

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)

Managing insomnia in the primary care setting: raising the issues.

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.

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.

Chronotherapy: resetting the circadian clocks of patients with delayed sleep phase insomnia.

We report here the development of a brief drug-free rescheduling treatment ("chronotherapy") for Delayed Sleep Phase (DSP) insomnia, a syndrome characterized by sleep-onset insomnia with difficulty in morning awakening. We postulated that patients with DSP insomnia had an inadequate capacity to achieve phase advance shifts of the circadian pacemaker which times the sleep-wake cycle. Chronotherapy was therefore designed to reset these patients' biological clocks by the phase delay route. This single 5-6 day treatment was tested in 5 patients with a 4-15 year history of DSP insomnia. All 5 patients reported a lasting resolution of their symptoms substantiated by systematic long-term self-reports and objective polygraphic recording before and after treatment (average follow-up of 260 days; range, 42-910 days). The average sleep onset advanced from 4:50 a.m. before treatment to 12:20 a.m. afterwards, and wake times advanced from 1:00 p.m. to 755 a.m. (for both, p less than 0.001), with no reduction in sleep efficiency. As a result, all 5 patients were able to end their chronic dependence on hypnotic medications.

Future directions in the management of insomnia.

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.

Detection and assessment of insomnia.

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.

Neuropeptide Y (NPY) and vasopressin (AVP) in the hypothalamo-neurohypophysial axis of salt-loaded or Brattleboro rats.

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)

Circadian rhythm sleep disorders: pathophysiology and treatment.

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.

Effect of running wheel availability on circadian patterns of sleep and wakefulness in mice.

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.

A circadian rhythm of hippocampal theta activity in the mouse.

Hippocampal theta activity dominates the cortical EEG of the mouse during certain behaviors. We have therefore been able to study the circadian distribution of hippocampal theta activity by means of chronic EEG implantation and computerized EEG state scoring. Observations in six mice indicate consistent and significant circadian patterns of theta-dominated EEG, both during wakefulness (theta-dominated wake, or TDW) and during sleep (REM sleep). The probability of REM rises gradually to a maximum during the sleep period and then falls abruptly at activity onset and then falls gradually. The complementary circadian patterns of REM and TDW suggest that they may be two episodes of each coincide remarkably, as do their circadian distributions. The probability of TDW rises to a very high level at activity onset and then falls gradually. The complementary circadian patterns of REM and TDW suggest that they may be two halves of a single circadian rhythm of theta probability. This concept would be relevant in interpreting the abnormally phase-advanced pattern of REM sleep observed in human depressives.

The pseudocapsule of pleomorphic adenomas (benign mixed tumors): the argument against enucleation.

The "well encapsulated" pleomorphic adenoma has at best a pseudocapsule which allows for bits of satellite tumor to be left behind at ""enucleation" surgery as well as for easy "spillage" of tumor by the overconfident surgeon. Recurrent pleomorphic adenomas then become difficult tumors to eradicate and place vital structures, such as the facial nerve, in jeopardy.

Management of recurrent salivary gland tumors.

The management of 129 patients with recurrent tumors of the salivary glands is analyzed, Principles of approaching recurrent tumors and guidelines for their management are outlined in detail. Age distribution, symptoms, time to recurrence, cases that showed possible malignant degeneration, and complications are reviewed. The surgical procedures, recurrence rate, and survival rates are recorded.

An electromyographic marker for neuroleptic-induced akathisia: preliminary measures of sensitivity and specificity.

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.

GABA and circadian timekeeping: implications for manic-depression and sleep disorders.

Circadian rhythms, evident in a wide variety of physiological and behavioural parameters, are under the control of central neural pacemakers, the best characterized of which is the suprachiasmatic nucleus of the hypothalamus. The neurophysiological mechanisms involved in central pacemaker function are unknown. Recent biochemical, pharmacological and behavioural evidence suggests that the inhibitory transmitter gamma-aminobutyric acid (GABA), present in the small interneurones of the suprachiasmatic nucleus, plays an important role in circadian timekeeping. This has enabled the formulation of strategies for treatment of patients with manic depressive illness and certain sleep disorders in which disorders of circadian timekeeping may be fundamental.

Cystic lesions of the parotid gland.

In a series of 708 parotidectomies (partial or total), we found 23 cystic lesions. Of these, 16 met the criteria for so-called "branchial cysts"; five were retention cysts of duct origin, and the remaining two were epidermal inclusion cysts. The principles of diagnosis and treatment of parotid cysts are presented.

Analysis of proteins secreted by the human endometrium in vivo and in vitro.

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.