Does our DNA determine when we sleep?

The discovery and study of three kindreds with advanced sleep phase disorder shed light on how we can inherit tendencies to be early morning or late night kinds of people (pages 1062-1065).

The human phase response curve (PRC) to melatonin is about 12 hours out of phase with the PRC to light.

Melatonin's timekeeping function is undoubtedly related to the fact that it is primarily produced during nighttime darkness; that is, melatonin and light occur at opposite times. The human phase response curve (PRC) to melatonin appears to be about 12h out of phase with the PRC to light. These striking complementarities, together with light's acute suppressant effect on melatonin production, suggest that a function for endogenous melatonin is to augment entrainment of the circadian pacemaker by the light-dark cycle. The melatonin PRC also indicates correct administration times for using exogenous melatonin to treat circadian phase disorders.

Improving quality assurance through psychiatric mortality and morbidity conferences in a university hospital.

To make quality assurance more outcome oriented, the department of psychiatry in a university hospital developed a program of psychiatric mortality and morbidity conferences for reviewing cases with undesirable outcomes. The conference combines aspects of a traditional medical mortality and morbidity conference with features of utilization review and risk management. Case review is focused on mortality, morbidity, or specific indicators developed by the departmental services involved and on a determination of whether an adverse outcome was avoidable, possibly avoidable, or unavoidable. The authors summarize the 100 cases reviewed in the first seven months. They believe the focus on outcome gives the method a useful role in quality assurance; advantages include its recognizable contributions to continuing education and training.

Methylphenidate as a treatment for depression in acquired immunodeficiency syndrome: an n-of-1 trial.

BACKGROUND: Uncontrolled studies report that methylphenidate effectively treats depression in patients with acquired immunodeficiency syndrome (AIDS). Other studies report that methylphenidate improves cognition in patients with dementia stemming from human immunodeficiency virus (HIV). We performed a double-blind, placebo-controlled n-of-1 trial to learn whether methylphenidate was an effective treatment for depression in an outpatient with mild HIV dementia. METHOD: The patient received either placebo or drug in a double-blinded fashion in increasing doses in each of three 2-week phases (A = placebo, B = methylphenidate, C = placebo). Blinded outcomes of depression and cognition were measured initially and twice in each phase. Depression was measured using the Hamilton Rating Scale for Depression (HAM-D) and a mood self-assessment scale. Cognition was measured using the digit span (forward and backward subtest of the Wechsler Adult Intelligence Scale-Revised, Trail-Making Tests A and B, and the Symbol Digit Modalities Test (SDMT). RESULTS: HAM-D scores improved during the methylphenidate phase (initial = 33; A = 23, 25; B = 15, 10; C = 28, 27), as did the subjective mood assessment ratings. Digit span backward scores improved with the drug (initial = 4; A = 4, 3; B = 6, 8; C = 5, 4), as did Trail-Making Test B scores (initial = 125 seconds; A = 133, 103 seconds; B = 86, 82 seconds; C = 88, 96 seconds). Digit span forward, SDMT, and Trail-Making Test A, however, showed no drug-related trend. CONCLUSION: We conclude that methylphenidate was beneficial in the treatment of depression in this patient with AIDS.

The effects of shifting sleep two hours within a fixed photoperiod.

This study examined the effects of shifting the time of sleep within a constant photoperiod on the circadian rhythms of body temperature and melatonin secretion. Subjects lived under conditions of a long scotoperiod (dim light of less than 10 lux from 6 p.m. until 8 a.m.) for three weeks. In order to delineate dawn and dusk, subjects received one hour of bright light (2500 lux) before and after the scotoperiod (i.e., from 8 to 9 a.m. and from 5 to 6 p.m.). For the first week of the experiment they slept from 10 p.m. until 6 a.m. In the second week, sleep was advanced two hours; that is, subjects retired at 8 p.m. and arose at 4 a.m. The third week was a repeat of the first, resulting in a two-hour delay of sleep from week two to three. The six subjects who successfully completed this protocol had no significant changes in the timing of the body temperature minima and onset of secretion of melatonin. This indicates that the timing of allowed sleep has less of an immediate effect on circadian rhythms than the timing of the external light-dark cycle. The circadian effects of the timing of sleep may be due more to the light-dark cycle that is imposed by the sleep-wake cycle than from the timing of sleep itself.

Morning vs evening light treatment for winter depression. Evidence that the therapeutic effects of light are mediated by circadian phase shifts.

Bright light exposure has been found to alleviate the symptoms of recurrent winter depression in many patients. The mechanism of light therapy may involve shifts in the timing (phase) of circadian rhythms. In this study, morning light exposure (which shifts rhythms earlier) was compared with evening light exposure (which shifts rhythms later) in a double-blind, crossover design. The onset of melatonin secretion in the evening was measured under dim light conditions as a marker for circadian timing (phase) before and after each treatment. Eight patients with winter depression and five control subjects were studied. Morning light was found to be significantly better than evening light in reducing depressive symptoms. At baseline, there was a trend for the onset of melatonin production to be later in the patients than in the controls. Morning light shifted the melatonin onset significantly earlier in the patients but not the controls. Our findings suggest that patients with winter depression have circadian rhythms that are abnormally delayed and that bright light therapy benefits winter depression by providing a corrective advance.

Physician exposure to ionizing radiation during trauma resuscitation: a prospective clinical study.

A prospective study of emergency physician whole body and extremity exposure to ionizing radiation during trauma resuscitation over a three-month period was conducted. Radiation film badges and thermoluminescent dosimeter finger rings were permanently attached to leaded aprons worn by emergency medicine residents during all trauma resuscitations. One set of apron and finger ring dosimeters was designated for the resident who managed the airway and stabilized the neck, when necessary, during cervical spine radiography (A-CS resident). A separate set of dosimeters was designated for the resident supervising the resuscitation. During the study period, 150 major trauma patients requiring 481 radiographic studies were treated. The mean monthly cumulative whole body exposures were 136.7 +/- 85.0 and 103.3 +/- 60.3 mrem for A-CS and supervising residents, respectively. The mean weekly cumulative extremity exposures were 523.3 +/- 611.0 and 46.7 +/- 18.6 mrem for A-CS and supervising residents, respectively. Calculated whole body exposures per patient were 2.7 mrem for the A-CS resident and 2.1 mrem for the supervising resident. Calculated extremity exposures per patient were 41.9 +/- 48.9 and 3.7 +/- 1.5 mrem, respectively. To exceed the annual whole body exposure limit established by the National Council of Radiologic Protection, the A-CS resident, working 200 shifts per year, would have to treat 9.2 trauma patients per shift. To exceed the annual extremity exposure limit, the A-CS resident would have to treat 5.9 trauma patients per shift. Of note, European exposure limits are 10% of current US limits. We conclude that significant exposures may occur to physicians working in trauma centers and that the use of shielding devices is indicated.

Exposure of emergency medicine personnel to ionizing radiation during cervical spine radiography.

We studied the potential hazard of ionizing radiation exposure to health care workers who routinely stabilize the necks of trauma patients during cervical spine radiography. A clinical trauma model was developed using an Alderson RANDO Phantom artificial torso to simulate an actual patient. A radiation monitor was placed where a health care worker's fingers, hands, arms, and thyroid gland would be, and standard cervical spine radiographs were taken. The exposures to the finger positions then were repeated with the monitor inside a 0.5 mm lead-equivalent glove. The mean exposure to the finger for a single cross-table lateral radiograph was 174.5 mrem. The use of leaded gloves reduced this exposure to 0.3 mrem a 99.9% reduction). For a single series of lateral, anteroposterior, odontoid, and swimmer's views, the total mean measured unprotected exposure to the finger of the hand positioned nearest the radiographic tube was 681 mrem and the exposure to the finger of the opposite hand was 230 mrem. If these simulated exposures are indicative of actual patient situations, a health care worker who holds the head of a trauma patient four times each week with unshielded hands would receive more than twice the maximum allowable annual occupational radiation exposure to the extremities recommended by the National Council of Radiation Protection and Measurements. We conclude that health care workers who routinely stabilize the necks of trauma patients during cervical spine radiography may incur a radiation exposure risk and that 0.5-mm lead-equivalent gloves provide an effective barrier to ionizing radiation.

Entrainment of a free-running human with bright light?

The case of a 40-year-old sighted woman with free-running sleep-wake and melatonin rhythms is presented. The subject was studied for 102 days. During the pre-treatment period, both the sleep-wake and melatonin rhythms had a period of 25.1 hr, similar to the average period of humans living in temporal isolation. Treatment consisted of bright artificial light exposure (2500 lx Vita-Lite) for 2 hr each day upon awakening. Clock time of light exposure was held constant for 6 days and then slowly advanced until the subject was arising at her desired time of day. The subject continued the light treatment at home and was able to live on a 24-hr day for the 30-day follow-up study. While other factors may be operating in this situation, it is possible that the light treatment caused the stabilization of the free-running rhythms, advancement to a normal phase and entrainment to the 24-hr day. We suspect that the tendency to free-run was related to sleep onsets that were abnormally delayed relative to the circadian phase response curve for light. By scheduling a 2-hr pulse of bright light each morning, this tendency to delay would be counteracted by light-induced advances, resulting in normal entrainment.

The use of plasma melatonin levels and light in the assessment and treatment of chronobiologic sleep and mood disorders.

Using the highly accurate and sensitive gas chromatographic-negative chemical ionization mass spectrometric assay for plasma melatonin we have measured plasma melatonin in humans as a biological marker for 24-hour (circadian) and seasonal rhythms and the effects of light on these rhythms. We propose that there are at least three critical parameters for light to be chronobiologically active in humans: intensity, wavelength and timing. With regard to timing, we have found that bright light exposure in the morning advances circadian rhythms (shifts them to an earlier time) and bright light in the evening delays them (shifts them to a later time). We have suggested that chronobiologic sleep and mood disorders be "phase typed" into either the phase advance subtype or the phase delayed subtype and that these disorders can then be treated with either evening light (for phase advanced disorders) or morning light (for phase delayed disorders). Regarding the function of melatonin in humans, we have preliminary evidence that it may participate in the regulation of the circadian rhythm of intraocular pressure.

Human melatonin production decreases with age.

The purpose of this study was to investigate the effects of time of year and demographic variables on the amplitude of melatonin production in normal human subjects. Melatonin production was estimated by measuring the overnight excretion of its major urinary metabolite, 6-hydroxymelatonin. Urine was collected on three consecutive nights in the summer from a sample of 60 normal subjects balanced for sex and age. The collections were repeated in a subgroup during the winter. Melatonin production clearly declined with age but was not influenced by other demographic variables or by season of the year.

Melatonin, light and chronobiological disorders.

Human plasma melatonin concentrations can be measured accurately and sensitively by gas chromatography-negative chemical ionization mass spectrometry. With this assay, we have shown that: in rats and in humans, plasma melatonin is exclusively derived from the pineal gland; propranolol and clonidine reduce melatonin levels in human; some blind people appear to have free-running melatonin secretory circadian rhythms; bright light can acutely suppress human melatonin production according to a linear fluence-response relationship; manic-depressive patients appear to be supersensitive to light, even when they are well; melatonin levels are greater in manic patients than in depressed patients; in experiments to test the clock-gate model and the hypothesized phase-response curve, two different effects of light appear to present in humans: an acute suppressant effect (mainly in the evening during long photoperiods) and an entrainment effect (particularly during the morning but also in the evening). When blood is sampled for measuring melatonin levels as a marker for circadian phase position, bright light should be avoided after 5 p.m. (the dim light melatonin onset). Bright-light exposure in the morning appears to advance circadian rhythms, whereas bright-light exposure in the evening appears to delay them. Once a patient has been 'phase typed' (phase-advanced vs. phase-delayed), predictions can be made about whether morning or evening light would be more effective in treating the sleep or mood disorder.