Circadian Acrophase Research Articles

Neuropeptide chronomics in clinically healthy young adults: circaoctohoran and circadian patterns

Endothelin-1 (ET-1) undergoes an about 8-h (circaoctohoran) rather than a circadian variation in clinical health. Herein, 24 h plasma concentrations of vasoactive intestinal peptide (VIP), substance P (SP), neuropeptide Y (NpY), and cortisol used as reference, were obtained from 20 healthy young adults starting at 07:00 or 19:00 h. Like ET-1, SP and NpY undergo a circaoctohoran variation, whereas VIP is circadian rhythmic, peaking during the night, some 8 h prior to the circadian acrophase of cortisol. Maps of circadian and extra-circadian patterns may serve for screening, diagnosis and a better understanding of mechanisms underlying the etiology of various diseases.

Neuropeptide chronomics in clinically healthy young adults: circaoctohoran and circadian patterns

Endothelin-1 (ET-1) undergoes an about 8-h (circaoctohoran) rather than a circadian variation in clinical health. Herein, 24 h plasma concentrations of vasoactive intestinal peptide (VIP), substance P (SP), neuropeptide Y (NpY), and cortisol used as reference, were obtained from 20 healthy young adults starting at 07:00 or 19:00 h. Like ET-1, SP and NpY undergo a circaoctohoran variation, whereas VIP is circadian rhythmic, peaking during the night, some 8 h prior to the circadian acrophase of cortisol. Maps of circadian and extra-circadian patterns may serve for screening, diagnosis and a better understanding of mechanisms underlying the etiology of various diseases.

Circadian periodicity of plasma lipid peroxides and anti-oxidant enzymes in pulmonary tuberculosis.

The circadian periodicity of plasma lipid peroxide levels and activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were studied in 50 clinically, bacteriologically and radiologically proven fresh cases of pulmonary tuberculosis (age: 21-45 years) and 60 age-matched healthy volunteers with diurnal activity from 06∶00 to about 22∶00 and nocturnal rest. A marked circadian variation in plasma lipid peroxide level was recorded in healthy subjects and pulmonary tuberculosis patients with significant amplitude and acrophase around 16∶21 and 17∶12 respectively. The acrophase tended to be delayed in tuberculosis patients. Furthermore, a statistically significant circadian rhythm was found in SOD, CAT and GPx activities in normal volunteers and pulmonary tuberculopsis patients. SOD and CAT enzyme activity was noted to be maximum at 06∶00 and minimum at 00∶00 in tuberculosis patients. The circadian acrophase for GPx activity was recorded at 16∶15 in normals and around 22∶45 in patients. Moreover, the activity was found to be decreased at all sampling hours during 24-hours sleep-awake period in patients in comparison to healthy counterparts. The MESOR and circadian amplitude also decreased markedly. The decreased activity of measured antioxidant enzymes in pulmonary tuberculosis patients could probably be associated with oxidative stress and/or decreased anti-oxidant defensive mechanism in such patients.

Point and interval estimations of circadian melatonin ecphasia in Smith-Magenis syndrome

An inferential statistical quantification of chronomes (time structures) in the range of everyday physiology has earlier revealed changes affecting the circadian amplitude of melatonin in the absence of changes in the chronome-adjusted mean value (MESOR) or in the acrophase. A chrono-meta-analysis of published data on patients with the Smith–Magenis syndrome herein quantifies the average extent of shift in the acrophase of the circadian melatonin rhythm, reported earlier by others time-macroscopically as an antiphase. Time-microscopically, the phase shift averages 9.6 ± 0.9 h. Circadian melatonin ecphasia complements blood pressure ecphasia in non-insulin-dependent diabetes mellitus, associated with autonomic dysfunction. The shift in phase of the peak melatonin secretion from the night into the day, associated with specific genetic findings, raises basic questions concerning the designation of melatonin as a hormone associated with darkness. Whether a resetting of the circadian acrophase beyond providing melatonin for sleep improvement can provide benefit remains to be investigated.

Circadian heart rate and blood pressure variability considered for research and patient care

Objectives: To review mechanisms of circadian variations in heart rate variability (HRV) and blood pressure variability (BPV) and mortality and morbidity due to cardiovascular diseases (CVD). Methods: Results from 7-day/24-h HRV and BPV are interpreted by gender and age-specified reference values in the context of a Medline search. Results: Abnormal HRV and BPV measured around the clock for 7 days provides information on the risk of subsequent morbid events in subjects without obvious heart disease and without abnormality outside the conventional (in the sense of chronobiologically unquantified) physiological range. Meditation, β-blockers, ACE inhibitors, n-3 fatty acids and estrogens may have a beneficial influence on HRV, but there is no definitive outcome-validated therapy. Low HRV has been associated with a risk of arrhythmias and arrhythmic death, unstable angina, myocardial infarction, progression of heart failure and atherosclerosis. BPV may be characterized by treatable circadian-hyper-amplitude-tension (CHAT), which can be transient ‘24-h CHAT’ or ‘7-day-CHAT’, MESOR-hypertension and/or an unusually-timed (odd) circadian acrophase (ecphasia), all associated with an increased risk of stroke, stroke death, myocardial infarction, and kidney disease. Conclusions: Precise insight into the patho-physiology in time of HRV and BPV is needed with development of a consensus on best measures of HRV for clinical purposes and to determine when a 7-day record interpreted chronobiologically suffices and when it does not, for detection within as well as outside the conventional normal range, for diagnostic clinical practice and to direct therapy of risk greater than that associated with hypertension, smoking or any other risk factor.

Engineering and governmental challenge: 7-day/24-hour chronobiologic blood pressure and heart rate screening: Part I.

This review provides evidence that the bioengineering community needs to develop cost-effective, fully unobtrusive, truly ambulatory instrumentation for the surveillance of blood pressure and heart rate. With available instrumentation, we document a disease risk syndrome, circadian blood pressure overswinging (CHAT, short for circadian hyper-amplitude-tension). Circadian hyper-amplitude-tension is defined as a week-long overall increase in the circadian amplitude or otherwise-measured circadian variability of blood pressure above a mapped threshold, corresponding to the upper 95% prediction limit of clinically healthy peers of the corresponding gender and age. A consistently reduced heart rate variability, gauged by a circadian standard deviation below the lower 5% prediction limit of peers of the corresponding gender and age, is an index of a separate yet additive major risk, a deficient heart rate variability (DHRV). The circadian amplitude, a measure of the extent of reproducible variability within a day, is obtained by linear curve-fitting, which yields added parameters: a midline-estimating statistic of rhythm, the MESOR (a time structure or chronome-adjusted mean), the circadian acrophase, a measure of timing of overall high values recurring in each cycle, and the amplitudes and acrophases of the 12-hour (and higher order) harmonic(s) of the circadian variation that, with the characteristics of the fundamental 24-hour component, describe the circadian waveform. The MESOR is a more precise and more accurate estimate of location than the arithmetic mean. The major risks associated with CHAT and/or DHRV have been documented by measurements of blood pressure and heart rate at 1-hour or shorter intervals for 48 hours on populations of several hundred people, but these risks are to be assessed in a 7-day/24-hour record in individuals before a physical examination, for the following reasons. (1) The average derived from an around-the-clock series of blood pressure measurements, computed as its MESOR, the proven etiopathogenetic factor of catastrophic vascular disease, can be above chronobiologic as well as World Health Organization limits for 5 days or longer and can be satisfactory for months thereafter, as validated by continued automatic monitoring. The MESOR can be interpreted in light of clock-hour-, gender-, and age-specified reference limits and thus can be more reliably estimated with a systematic account of major sources of variability than by casual time-unspecified spot checks (that conventionally are interpreted by a fixed and, thus, rhythm, gender-, and age-ignoring limit). With spot checks, in a diagnostically critical range of "borderline" blood pressures, an inference can depend on the clock-hour of the measurement, usually providing a diagnosis of normotension in the morning and of hypertension in the afternoon (for the same diurnally active, nocturnally resting patient!). Long-term treatment must not be based upon the possibility of an afternoon vs a morning appointment. Moreover, the conventional approach will necessarily miss cases of CHAT that are not accompanied by MESOR hypertension. (2) Circadian hyper-amplitude-tension indicates a greater risk for stroke than does an increase in the around-the-clock average blood pressure (above 130/80 mm Hg) or old age, whereas (3) CHAT can be asymptomatic, as can MESOR hyptertension. (4) Deficient heart rate variability, the fall below a threshold of the circadian standard deviation of heart rate, an entity in its own right, is also a chronome alteration of heart rate variability (CAHRV). Deficient heart rate variability can be present together with CHAT, doubling the relative risk of morbid events. In each case--either combined with CHAT or as an isolated CAHRV--a DHRV constitutes an independent diagnostic assessment provided as a dividend by current blood pressure monitors that should be kept in future instrumentation designs. CHAT and DHRV can be screened by systematic focus on variability, preferably by the use of automatic instrumentation and analyses, which are both available (affordably) for research in actual practice, in conjunction with the Halberg Chronobiology Center at the University of Minnesota.

Repeated limited access to i.v. cocaine self-administration: conditioned autonomic rhythmicity illustrating "predictive homeostasis".

Regular cocaine self-administration may act as a "Zeitgeber" in animals and humans, and physiological rhythms may peak at the time when the drug is usually self-administered. To investigate whether or not daily sessions of cocaine self-administration for 2 weeks would synchronize autonomic rhythms to the time of daily access. Two weeks after implant of a jugular catheter and telemetry sender, each rat's heart-rate (HR) and core temperature (Tc) rhythms were well entrained to the 12:12-h light:dark cycle (lights off: 0900 hours). For the next 2 weeks rats self-administered cocaine during daily sessions at 1300 hours. The circadian and ultradian oscillations of HR and Tc recorded during the 3 days after the last self-administration (SA) session were quantified by multi-oscillator cosinor analysis. The HR and Tc were elevated during the initial 0.25 mg cocaine infusions of the daily session. This initial tachycardia disappeared as cocaine continued to be self-administered in accumulating amounts, while the locomotor activity remained elevated. After the last SA session the peak (acrophase) of the two cycles/day component in HR and Tc rhythms aligned to the time of day when cocaine self-administration had previously been scheduled. The amplitude of the circadian and ultradian HR and Tc oscillations as well as their circadian acrophase were not impacted by repeated daily time-limited cocaine self-administration. Cocaine controls the behavior and autonomic functions of rats self-administering limited amounts of cocaine during regular daily sessions, and this controlling influence extends beyond the last daily access period.

Blood Pressure and Heart Rate Rhythmicity: Differential Effects of Late Pregnancy

Arterial blood pressure (BP) and heart rate (HR) of 31 hospitalized pregnant women at low risk of hypertension were automatically monitored for 48 h at 15-min intervals. Each of the recorded 56 data series for systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and HR was chronobiologically assessed by linear–nonlinear rhythmometry. The rhythm-adjusted mean (MESOR), circadian amplitude, circadian acrophase, and best-fitting period were grouped by pregnancy trimester and further subjected to analysis of variance. BP MESOR remained unaltered, whereas HR MESOR increased significantly in middle and late pregnancy. Ultradian rhythms, with an amplitude higher than that of the circadian rhythm, were found in 25% of the SAP records in the second and third trimester. Such ultradian rhythms were not detected in the simultaneously recorded HR. Finally, the group BP and HR circadian acrophases coincided in the first trimester, but were significantly apart in mid and late pregnancy. These observations support the notion that the coordination of BP and HR rhythmicity involves different physiological mechanisms. Analysis of the individual variability in the chronobiological end points (based on the records of nine women monitored in each pregnancy trimester) revealed that only the BP MESOR was well reproducible in the course of pregnancy and may be useful in early diagnosis of gestational hypertension.

Development of Inverse Circadian Blood Pressure Pattern in Transgenic Hypertensive Tgr(mREN2)27 Rats

TGR(mREN2)27 (TGR) rats are transgenic animals with an additional mouse renin gene, which leads to overactivity of the renin-angiotensin system. Adult TGR rats are characterized by fulminant hypertension, hypertensive end-organ damage, and an inverse circadian blood pressure pattern. To study the ontogenetic development of cardiovascular circadian rhythms, telemetric blood pressure transmitters were implanted in male Sprague-Dawley (SPRD, n = 5) and heterozygous, transgenic TGR rats before 5 weeks of age. The TGR received either drinking water or enalapril 10 mg/L in drinking water (n = 5 per group). Drug intake was measured throughout the study by computerized monitoring of drinking volume. Circadian patterns in blood pressure and heart rate were analyzed from 5 to 11 weeks of age. In the first week after transmitter implantation, blood pressure did not differ among SPRD, untreated, and enalapril-treated TGR rats. In parallel with the rise in blood pressure of untreated TGR rats, a continuous delay of the circadian acrophase (time of fitted blood pressure maximum) was observed, leading to a complete reversal of the rhythm in blood pressure at an age of 8 weeks. Enalapril reduced blood pressure at night, but was less effective during the day, presumably due to the drinking pattern of the animals, which ingested about 90% of their daily water intake during the nocturnal activity period. After discontinuation of treatment, blood pressure returned almost immediately to values found in untreated TGR rats. In conclusion, the inverse circadian blood pressure profile in TGR rats develops in parallel with the increase in blood pressure. Direct effects of the brain renin-angiotensin system may be involved in the disturbed circadian rhythmicity in TGR(mREN2)27 rats.

Experimental separation of time of day and homeostatic influences on sleep.

The purpose of the present study was to evaluate the simultaneous effects on sleep of prior time awake (PRW) and time of day (TOD). Eight male subjects spent 13 days in an isolated sleep lab and had three 8-h baseline sleeps and then 18 4-h sleeps, distributed to provide three sleeps starting at 2400, 0400, 0800, 1200, 1600, and 2000. The three sleeps were preceded by 4, 8, and 12 h of PRW, respectively. ANOVA showed that TST and subjective sleepiness increased with PRW and with closeness to the trough of the circadian rhythm of rectal temperature, whereas sleep latency showed the opposite pattern, and rapid eye movement sleep (REM) latency strongly decreased with PRW and with closeness to the trough. Slow-wave sleep (SWS) increased with PRW, whereas SWS latency and final time awake decreased. REM sleep increased with closeness to the circadian trough, and time awake decreased. Multiple-regression analysis showed that REM latency was closely related to increased SWS in the first sleep cycle, reduced SWS latency, and increased PRW [a short PRW before sleep at noon yielded an extremely short (14 min) REM latency]. Sleep latency and final time awake showed almost exactly the same relationship to TOD and PRW. It is concluded that both homeostatic and circadian influences simultaneously affect sleep, that REM latency is very sensitive to the need for SWS, and that the circadian acrophase strongly interferes with sleep. It should be emphasized that the conclusions should not be extrapolated to longer (> 12 h) wake spans.

Melatonin excretion is not related to sleep in the elderly.

We examined the association between 6-sulphatoxymelatonin (6-SMT) excretion and sleep in 68 volunteers 60-79 years of age who complained of insomnia or depression. An Actillume wrist monitor was worn for 5-7 consecutive days and nights in home-living conditions. Activity was used to estimate total sleep time (TST) and wake after sleep onset (WASO). Throughout two 24 hr periods, urine was collected approximately every 2 hr during the day and after any voidings during the sleep period. During the next week, subjects spent 5 nights and 4 days in the laboratory. Sleep was measured and scored with standard polysomnographic techniques. Urine was collected, as for home recording, on days 1 and 4. Urinary concentrations of 6-SMT were assayed. Cosine-fitting of urine data across both days at home and both laboratory collections established the mesors and amplitudes of 24 hr 6-SMT excretion rhythms, but neither was significantly correlated with sleep. Mean and peak 6-SMT excretion during the sleep period was also determined. Significant correlations were found between mean 6-SMT during the laboratory sleep period and TST and WASO. However, these associations were not independent of circadian timing: sleep was better when sleep occurred near the circadian acrophase of 6-SMT excretion. These data indicate that low melatonin production may not be an important factor in insomnia among the elderly.

Effect of forward rapidly rotating shift work on circadian rhythms of arterial pressure, heart rate and oral temperature in air traffic controllers.

Twenty-four-hour records of arterial pressure (AP), heart rate (HR), oral temperature (OT) and physical and mental performance were obtained in air traffic controllers during morning (n = 16), afternoon (n = 17) and night (n = 19) shifts. Data were analyzed by the cosinor method. The results obtained during the morning shift were as follows (mesor/amplitude/acrophase): systolic AP (mm Hg)--113.6/10.0/16:03 h; diastolic AP--71.1/8.2/15:19 h; mean AP--85.6/8.8/15:41 h; HR (beats/min)--77.5/8.9/16:00 h; OT (dg C)--36.71/0.21/15:49 h; right-hand grip strength (kg)--49.8/2.0/17:43 h; left-hand grip strength--46.1/2.0/16:08 h; mental performance (calculations/min)--14.9/1.1/16:39 h. During the night shift either no change of the circadian acrophases (HR, right-hand grip strength) or acrophase delays ranging from about 2 h (systolic AP, OT, mental performance) up to 3 h (diastolic and mean AP, left-hand grip strength) were observed. Our data suggest that the shift system studied does not significantly alter the circadian rhythms, and does not induce a desynchronization, particularly as concerns arterial pressure and oral temperature.

Blood Pressure Circadian Rhythm and Variability in Essential Hypertensives without End-organ Damage

The aim of the study was to evaluate the 24-hour Blood Pressure (BP) profile in essential hypertensives without end-organ damage using a two-step method proposed by Staessen and his group: the existence of a circadian rhythm is first tested using Siegel’s Runs-Test, then a Fourier multiple harmonic analysis allows an adequate parametrical representation of the 24-hour BP profile. Sixty-five newly diagnosed, untreated mild-to-moderate essential hypertensives without end-organ damage (HYP) were compared to 29 normal control subjects (NORM). No significant differences have been found between the two groups when considering the existence of a BP circadian rhythm and acrophase parameters, as distinct from amplitudes (p<0.01). Furthermore, as expected, BP mean values were found higher in the HYP group as compared with the NORM group. In conclusion, according to our results, essential hypertensives without end-organ damage present a preserved BP profile, showing a circadian rhythm, but, as compared to normal subjects, increased BP variability (BPV) as expressed by amplitude values. The present study is consistent with the hypothesis that BPV, even though related, is not a consequence of end-organ damage.

Rewards in practice from chrono-meta-analyses ‘recycling’ heart rate, ectopy, ischemia and blood pressure information

Previously published average curves of heart rate and duration of ischemia in patients with coronary artery disease, studied while on placebo or on treatment with either atenolol or diltiazem, are re-analysed for the assessment of about-daily (circadian) and about-weekly (circaseptan) changes in these variables and of any treatment effect on rhythm characteristics. In addition to circadians, a circaseptan pattern characterizes the duration of ischemia in all three aforementioned study stages. Both drugs decrease the duration of ischemia, atenolol, but not diltiazem, also affects the circadian amplitude and acrophase of this variable. A circaseptan pattern is also found for heart rate on placebo and on treatment with atenolol, but not with diltiazem. Both drugs lower heart rate and the circadian amplitude and 24-h standard deviation of heart rate, atenolol much more markedly than diltiazem. Circadian and circaseptan rhythm characteristics and their alterations with treatment serve to optimize treatment by timing its administration. Chronobiologic surveillance of variables that are being readily monitored as-one-goes by modern implantable devices can also serve for the validation of the effectiveness of drug and electrical therapy. Rhythm alterations, in turn, can provide the earliest warnings of an elevated disease risk and lead to an improved diagnosis.

Stress induced disorganization of circadian and ultradian rhythms: Comparisons of effects of surgery and social stress

Persistent autonomic disturbances following stressful events suggest that the rhythmical nature of homeostatic functioning may be disrupted by these experiences. We assessed the effects of two different stressors on circadian and ultradian rhythms of Long-Evans rats by using nonlinear multi-oscillator cosinor analysis. Heart rate and intraperitoneal temperature were monitored continuously in 5-min intervals in two groups of animals via radio-telemetry for 15 days after surgery ( n = 9) and 15 days following social defeat ( n = 6). Circadian amplitude of heart rate and temperature increased significantly for the first nine days of the recovery from surgery but only circadian temperature amplitude increased following social defeat. Circadian acrophase of temperature but not heart rate changed significantly for a similar period following the surgery but not after the social defeat. A mathematical model incorporating the first five harmonics of the circadian rhythm was found to fit the data significantly better than a circadian model alone with rhythms of 3 and 5 cycles/day in temperature and heart rate entraining significantly to the light-dark schedule. Full recovery of the circadian and ultradian rhythms did not occur until a minimum of nine to twelve days after surgery or social defeat. The results suggest that rhythms with multiple periodicities are involved in homeostatic functioning and that models incorporating these rhythms may aid in understanding an organisms adaptive response to surgical intervention and social defeat, long after the challenges have terminated.

The effect of four-day round trip flights over 10 time zones on the circadian variation of salivary melatonin and Cortisol in airline flight attendants

The effects of four-day round flights (Helsinki-Los Angeles-Seattle-Helsinki) were studied on the circadian rhythms of salivary melatonin (MT) and cortisol (COR) in 35 flight attendants. The mean age of the subjects was 33 +/- 7 years (median 34, range 21-50). Five 24 h profiles of unstimulated saliva were collected at 2 h intervals (except at 04:00) before, during, and after the four day flight. Salivary MT and COR were determined by radioimmunoassay. Both MT and COR exhibited a clear circadian rhythm with acrophases before the flight at 03:03 (MT) and 09:08 (COR). Two days after the westward flight from Helsinki to Los Angeles, the MT rhythm (circadian acrophase) had delayed 4 h 51 min and the COR rhythm 3 h 55 min compared to the control day before the flight. Two days later, during the last day in the USA, the MT rhythm had delayed 5 h 59 min and the COR rhythm 5 h 29 min as compared to the situation before the flight. After four days of the eastward flight from Seattle to Helsinki, the circadian acrophase of MT was still 1 h 35 min delayed compared to the control day before the westward flight. The results indicate that the restitution time of five days at the home base is on the average proper for recovery, if a four day round flight over 10 time zones takes four days or less. The resynchronization rate of salivary hormones after westward, outgoing flights is faster than the resynchronization rate after the eastward return flights.

The meaning of good sleep: a longitudinal study of polysomnography and subjective sleep quality.

The present study sought to investigate the meaning of subjectively good sleep, using a longitudinal and intraindividual design. Eight subjects slept in an isolation unit according to an irregular schedule of 6 h sleeps and 1 h naps, designed to give normal amounts of time in bed (1/3 of total), but variable sleep quality. Eight sleeps and eight naps were used for longitudinal simple and multiple regression analyses with standard polysomnographical sleep variables as predictors and subjective sleep quality as dependent variables. The results showed that subjective sleep quality (and related variables) was closely related to sleep efficiency, but not sleep stages. At least 87% efficiency was required for ratings of 'rather good' sleep. In addition, sleep quality ratings improved with closeness (of the awakening) to the circadian acrophase (17.00-21.00 hours) of the rectal temperature rhythm. The subjective ease of awakening differed from most other other variables in that it was related to low sleep efficiency. Objective and subjective homologues of sleep length and sleep latency showed high mean intraindividual correlations (r = 0.55 and 0.64, respectively). It was concluded that objective measures of sleep continuity were closely reflected in perceived sleep quality and that sleep quality essentially means sleep continuity.

Circadian profiles of blood pressure with respect to age

The effects of ageing on nocturnal blood pressure (BP) and the circadian rhythm of BP were studied. Ambulatory BP and heart rate (HR) were monitored at 30-minute intervals for 24 hours, in 326 normotensive volunteers aged 15-83. The following groups were monitored: young: < 40 yrs, n = 177; middle: 40 yrs < or = - < 60 years, n = 100; old: 60 yrs < or =, n = 49 Firstly, the ratio of nocturnal fall (RONF) of BP (or HR) was calculated as follows: [(average day time BP (or HR)-average night time BR (or HR)]/averaged whole day BP (or HR) x 100. Then we calculated 2 measurements: 1. The dipper (RONF of BP (or HR) > or = 10% 2. The non-dipper. (RONF of BP (or HR) < 10%. A cosine fitting technique using the least-squares method was employed to find the circadian rhythm of BP and HR. The results of the study showed that the incidence of the non-dipper on systolic BP (SBP) was higher for old subjects than for young subjects. In addition, the nocturnal BP and HR were higher for old subjects than for young subjects. The circadian amplitude of HR was lower in old subjects. The circadian midline estimating statistic of rhythm (MESOR) or SBP increased with age. The circadian acrophase of BP and HR increased with age. non-dippers of BP and HR were observed in any age groups. The frequency of BP and HR non-dipper was greater for old subjects than young subjects. This result may suggest the clinical significance of nocturnal BP and HR for the evaluation of hypertensive subjects.

Regulation of Sleep and Naps on an Irregular Schedule

For many occupational groups there is an implicit requirement that sleep be taken according to very irregular schedules. The purpose of this study was to investigate the effects of an irregular sleep schedule on sleep and to determine if such effects could be attributed to the timing of sleep. Eight subjects slept in an isolation unit according to an irregular schedule comprising four 8-hour sleep periods, 12 6-hour sleep periods and 12 1-hour naps. The schedule was designed to give normal amounts of time (1/3 of total) in bed. Large variations in mean sleep efficiency (100-46%) were observed, which in individual cases frequently involved a complete absence of sleep. In 6-hour sleep periods the loss was due to an inability to maintain sleep, whereas in naps the loss was due to an inability to initiate sleep. The major causes of reduced sleep were short prior time awake and bedtime close to the circadian acrophase of rectal temperature (i.e. late afternoon). These two components accounted for 46% of the intraindividual variance of total sleep time (TST). TST increased by 9.2 minutes for each hour of prior time awake and by 10 minutes for each hour of deviation from the circadian acrophase of rectal temperature. Prior time awake also exerted a strong influence on slow-wave sleep (SWS), and circadian phase exerted a similar influence on rapid eye movement sleep. We concluded that irregular sleep patterns strongly affect sleep and that circadian and homeostatic influences are clearly discernible despite the irregularity.(ABSTRACT TRUNCATED AT 250 WORDS)

Robustness of the male lactotropic axis to the hyperprolactinemic stimulus of primary thyroidal failure.

Primary hypothyroidism is a presumptive proximate basis for increased serum PRL concentrations. However, most studies to date have been performed in females and do not address the possible effect of sex differences. In the present study we investigated the 24-h patterns of pulsatile PRL release in 10 hypothyroid men (24-h mean +/- SEM: total T4, 35 +/- 8 nmol/L; TSH, 55 +/- 10 mU/L) by sampling blood at 10-min intervals for 24 h. The study was repeated in 5 men, 5-7 months and again 14-36 months after treatment with levothyroxine. The control group consisted of 7 normal age-matched euthyroid men. The mean 24-h serum PRL concentration of 4.9 +/- 0.6 micrograms/L in 10 hypothyroid men was not significantly different from the value of 4.9 +/- 0.5 micrograms/L found in the normal group (P greater than 0.5). Pulsatile features of PRL release were evaluated by Cluster analysis, which revealed normal mean PRL peak frequency (12.6 +/- 0.7 vs 13.4 +/- 0.6 pulses/24 h; P greater than 0.5), maximal peak amplitude (6.1 +/- 0.7 vs. 6.7 +/- 0.6 micrograms/L; P greater than 0.5), peak increment (2.2 +/- 0.3 vs. 2.6 +/- 0.3 micrograms/L; P = 0.3), mean valley (4.2 +/- 0.6 vs. 4.4 +/- 0.4 micrograms/L; P greater than 0.5), and prepeak nadir (3.6 +/- 0.5 vs. 3.6 +/- 0.4 micrograms/L; P greater than 0.5) PRL concentrations. Five to 7 months of T4 therapy in 5 hypothyroid men caused significant decreases in the mean 24-h (2.9 +/- 0.5 vs. 6.1 +/- 1.2 micrograms/L; P less than 0.05), interpulse valley (2.5 +/- 0.4 vs. 5.2 +/- 1.1 micrograms/L; P less than 0.05), and prepeak nadir (2.3 +/- 0.3 vs. 4.6 +/- 1.0 micrograms/L; P less than 0.05) PRL concentrations. These values returned to normal after 14-36 months of treatment. Cosinor analysis revealed preserved circadian PRL rhythmicity during hypothyroidism, with a normal circadian mesor (mean), amplitude, and acrophase. In summary, we have demonstrated normal mean 24-h serum PRL concentrations as well as normal pulsatile and circadian patterns of PRL release in men with primary hypothyroidism. These results stand in contrast to previous reports of increased serum PRL concentrations observed predominantly in hypothyroid premenopausal women. The foregoing disparity suggests the possibility of a role for estrogen in enhancing the effect of hypothyroidism on PRL release.(ABSTRACT TRUNCATED AT 400 WORDS)