Benita Middleton - Academia.edu (original) (raw)

Papers by Benita Middleton

Neuroscience letters, Jan 23, 2002

The light levels required to maintain human circadian phase in the absence of other strong time c... more The light levels required to maintain human circadian phase in the absence of other strong time cues are not defined. We investigated circadian phase in two groups of men, living in partial temporal isolation, exposed to 12 h:12 h light:dark cycles of: (A) 200: <8 lux, broad spectrum white light for 14 days; and (B) 1000: <8lux for 14 days. The rhythm variables measured were urinary 6-sulphatoxymelatonin, rectal temperature, activity and rest (actigraphy and sleep logs). In 200: <8 lux four/six individuals showed phase delays. Exposure to 1000: <8 lux appeared to maintain synchronisation of rest-activity to 24 h, but with a significant overall phase advance of 0.81 h in temperature. These observations suggest that domestic intensity light does not maintain phase without scheduled sleep/activity, possibly due to indirect effects on behaviour influencing light exposure.

Journal of biological rhythms, 1997

In humans, the pineal hormone melatonin can phase shift a number of circadian rhythms (e.g., &quo... more In humans, the pineal hormone melatonin can phase shift a number of circadian rhythms (e.g., "fatigue", endogenous melatonin, core body temperature) together with the timing of prolactin secretion. It is uncertain, however, whether melatonin can fully entrain all human circadian rhythms. In this study, the authors investigated the effects of daily melatonin administration on sighted individuals kept in continuous very dim light. A total of 10 normal, healthy males were maintained in two separate groups in partial temporal isolation under constant dim light (< 8 lux) with attenuated sound and ambient temperature variations but with knowledge of clock time for two periods of 30 days. In these circumstances, the majority of individuals free run with a mean period of 24.3 h. In a double-blind, randomized crossover design, subjects received 5 mg melatonin at 20:00 h on Days 1 to 15 (Melatonin 1st) followed by placebo on Days 16 to 30 (Placebo 2nd) or vice versa (Placebo 1st,...

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Jan 3, 2015

Background:Night shift work has been associated with an increased risk for breast and prostate ca... more Background:Night shift work has been associated with an increased risk for breast and prostate cancer. The effect of circadian disruption on sex steroid production is a possible underlying mechanism, underinvestigated in humans. We have assessed daily rhythms of sex hormones and melatonin in night and day shift workers of both sexes. Methods: We recruited 75 night and 42 day workers, aged 22-64 years, in different working settings. Participants collected urine samples from all voids over 24 hours on a working day. Urinary concentrations of 16 sex steroid hormones and metabolites (estrogens, progestagens and androgens) and 6-sulfatoxymelatonin were measured in all samples. Mean levels and peak time of total and individual metabolite production were compared between night and day workers. Results: Night workers had higher levels of total progestagens (geometric mean ratio (GMR) 1.65; 95% confidence interval (CI) 1.17, 2.32) and androgens (GMR: 1.44; 95% CI 1.03, 2.00), compared to day...

Cancer Epidemiology Biomarkers & Prevention, 2014

Light-at-night has been shown in experimental studies to disrupt melatonin production but this ha... more Light-at-night has been shown in experimental studies to disrupt melatonin production but this has only partly been confirmed in studies of night shift workers. In this cross-sectional study, we examined the circadian variation of melatonin in relation to shift status, individual levels of light-at-night exposure, and diurnal preference, an attribute reflecting personal preference for activity in the morning or evening. One hundred and seventeen workers (75 night and 42 day) of both sexes, ages 22 to 64 years, were recruited from four companies. Participants collected urine samples from all voids over 24 hours and wore a data logger continuously recording their light exposure. Sociodemographic, occupational, lifestyle, and diurnal preference information were collected by interview. Concentrations of urinary 6-sulfatoxymelatonin (aMT6s), the main melatonin metabolite, were measured. Mean aMT6s levels were lower in night [10.9 ng/mg creatinine/hour; 95% confidence interval (CI), 9.5-12.6] compared with day workers (15.4; 95% CI, 12.3-19.3). The lowest aMT6s levels were observed in night workers with morning preference (6.4; 95% CI, 3.0-13.6). Peak time of aMT6s production occurred 3 hours later in night (08:42 hour, 95% CI, 07:48-09:42) compared with day workers (05:36 hour, 95% CI, 05:06-06:12). Phase delay was stronger among subjects with higher light-at-night exposure and number of nights worked. Night shift workers had lower levels and a delay in peak time of aMT6s production over a 24-hour period. Differences were modified by diurnal preference and intensity of light-at-night exposure. Night shift work affects levels and timing of melatonin production and both parameters may relate to future cancer risk.

World Journal of Surgery, 2007

It has been suggested that circadian rhythm disturbances are present after major surgery and that... more It has been suggested that circadian rhythm disturbances are present after major surgery and that this may play a role in the development of postoperative sleep disturbances, fatigue, cognitive dysfunction and cardiovascular morbidity. The objective of this study was to examine the profile of melatonin, cortisol and core body temperature rhythms before and after major surgery. Blood samples (melatonin and cortisol) and core body temperature readings were collected every hour in the 24-h period prior to surgery and the 48 h after surgery from 11 patients undergoing major abdominal surgery. All patients had private rooms. Light exposure was controlled and monitored. Phase markers [50% dim light melatonin onset (DLMO 50%) and offset (DLMOff 50%), cortisol and core body temperature acrophase] for the three circadian rhythm profiles were calculated before and after surgery. The correlation between the melatonin rhythm and time of surgery, duration of surgery and opioid use was examined. A median delay in the onset of melatonin was seen on the first postoperative day [median DLMO 50% 22:46 hours (range: 21:15-01:08 hours) on the preoperative day compared with 23:54 hours (range: 19:09-02:46 hours) on the first postoperative day; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;/= 0.05] . A significant positive correlation existed between the duration of surgery and the time of melatonin onset (r = 0.67, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;/= 0.05) . There was a significantly reduced basal secretion of melatonin immediately after surgery, with a subsequent significant increase in maximum melatonin values on the second postoperative night. A median delay of up to 4 h was seen in the timing of the peak of the temperature rhythm on the second postoperative day. Both cortisol secretion and core body temperature were increased after surgery and did not return to preoperative values in the 48 h of the postoperative study period. No significant correlation between opioid dose and the basal or maximum melatonin levels or the time of melatonin onset was found. We found disturbances in three circadian markers after major surgery. The clinical consequences of postoperative circadian disturbances should be investigated further in the future.

PLoS ONE, 2012

Melatonin and leptin exhibit daily rhythms that may contribute towards changes in metabolic physi... more Melatonin and leptin exhibit daily rhythms that may contribute towards changes in metabolic physiology. It remains unclear, however, whether this rhythmicity is altered in obesity or type 2 diabetes (T2DM). We tested the hypothesis that 24hour profiles of melatonin, leptin and leptin mRNA are altered by metabolic status in laboratory conditions. Men between 45-65 years old were recruited into lean, obese-non-diabetic or obese-T2DM groups. Volunteers followed strict sleep-wake and dietary regimes for 1 week before the laboratory study. They were then maintained in controlled light-dark conditions, semi-recumbent posture and fed hourly iso-energetic drinks during wake periods. Hourly blood samples were collected for hormone analysis. Subcutaneous adipose biopsies were collected 6-hourly for gene expression analysis. Although there was no effect of subject group on the timing of dim light melatonin onset (DLMO), nocturnal plasma melatonin concentration was significantly higher in obese-non-diabetic subjects compared to weight-matched T2DM subjects (p,0.01) and lean controls (p,0.05). Two T2DM subjects failed to produce any detectable melatonin, although did exhibit plasma cortisol rhythms comparable to others in the group. Consistent with the literature, there was a significant (p,0.001) effect of subject group on absolute plasma leptin concentration and, when expressed relative to an individual's 24-hour mean, plasma leptin showed significant (p,0.001) diurnal variation. However, there was no difference in amplitude or timing of leptin rhythms between experimental groups. There was also no significant effect of time on leptin mRNA expression. Despite an overall effect (p,0.05) of experimental group, post-hoc analysis revealed no significant pair-wise effects of group on leptin mRNA expression. Altered plasma melatonin rhythms in weight-matched T2DM and non-diabetic individuals supports a possible role of melatonin in T2DM aetiology. However, neither obesity nor T2DM changed 24-hour rhythms of plasma leptin relative to cycle mean, or expression of subcutaneous adipose leptin gene expression, compared with lean subjects.

The Lancet, 1996

Melatonin and fragmented sleep patterns. By - Benita A Middleton, Barbara M Stone, Josephine Arendt.

Journal of Sleep Research, 1996

The light/dark (L/D) cycle is a major synchronizer of human circadian rhythms. In the absence of ... more The light/dark (L/D) cycle is a major synchronizer of human circadian rhythms. In the absence of a strong L/D cycle, synchrony with 24 hours can nevertheless be maintained in a socially structured environment, as shown in Polar regions (Broadway et al. 1987) and by some blind subjects . The relative contribution of other time cues to entrainment in dim light has not been fully explored. The present study investigated the behaviour of melatonin (assessed as 6-sulphatoxymelatonin); rectal temperature; activity and sleep (actigraphy and logs) in constant dim light (L/ L) with access to a digital clock. 6 normal healthy males were maintained as a group in partial temporal isolation with attenuated sound and ambient temperature for 21 days. All 6 subjects showed free-running periodicity for 6-sulphatoxymelatonin and 5/6 subjects for temperature, activity and sleep offset. The average period (tau) was 24.26±0.049, substantially shorter than in previous experiments with a self selected L/D cycle but similar to a recent study conducted in very dim light. One subject maintained a rigid sleep/wake cycle throughout whilst his 6-sulphatoxymelatonin rhythm free-ran. Total sleep time, from actigraph data, did not change but sleep efficiency decreased during the experiment. The subjects did not show group synchronization.

Journal of Hepatology, 2006

The Journal of Clinical Endocrinology & Metabolism, 1998

The Journal of Clinical Endocrinology & Metabolism, 2003

The pineal hormone melatonin is a popular treatment for sleep and circadian rhythm disruption. Me... more The pineal hormone melatonin is a popular treatment for sleep and circadian rhythm disruption. Melatonin administered at optimal times of the day for treatment often results in a prolonged melatonin profile. In photoperiodic (day length-dependent) species, changes in melatonin profile duration influence the timing of seasonal rhythms. We investigated the effects of an artificially prolonged melatonin profile on endogenous melatonin and cortisol rhythms, wrist actigraphy, and reproductive hormones in humans. Eight healthy men took part in this double-blind, crossover study. Surge/sustained release melatonin (1.5 mg) or placebo was administered for 8 d at the beginning of a 16-h sleep opportunity (1600 h to 0800 h) in dim light. Compared with placebo, melatonin administration advanced the timing of endogenous melatonin and cortisol rhythms. Activity was reduced in the first half and increased in the second half of the sleep opportunity with melatonin; however, total activity during the sleep opportunities and wake episodes was not affected. Melatonin treatment did not affect the endogenous melatonin profile duration, pituitary/gonadal hormone levels (24-h), or sleepiness and mood levels on the subsequent day. In the short term, suitably timed sustained-release melatonin phase-shifts circadian rhythms and redistributes activity during a 16-h sleep opportunity, with no evidence of changes in the duration of endogenous melatonin secretion or pituitary/gonadal hormones.

Journal of Biological Rhythms, 2006

Numerous factors influence the increased health risks of seamen. This study investigated sleep (b... more Numerous factors influence the increased health risks of seamen. This study investigated sleep (by actigraphy) and the adaptation of the internal clock in watch-keeping crew compared to day workers, as possible contributory factors. Fourteen watch keepers, 4 h on, 8 h off (0800-1200/2000-2400 h, 1200-1600/2400-0400 h, 1600-2000/0400-0800 h) (fixed schedule, n = 6; rotating by delay weekly, n = 8), and 12 day workers participated during a voyage from the United Kingdom to Antarctica. They kept daily sleep diaries and wore wrist monitors for continuous recording of activity. Sleep parameters were derived from activity using the manufacturer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s software and analyzed by repeated-measures ANOVA using SAS 8.2. Sequential urine samples were collected for 48 h weekly for 6-sulphatoxymelatonin measurement as an index of circadian rhythm timing. Individuals working watches of 1200-1600/2400-0400 h and 1600-2000/0400-0800 h had 2 sleeps daily, analyzed separately as main sleep (longest) and 2nd sleep. Main sleep duration was shorter in watch keepers than in day workers (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). Objective sleep quality was significantly compromised in rotaters compared to both day workers and fixed watch keepers, the most striking comparisons being sleep efficiency (percentage desired sleep time spent sleeping) main sleep (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) and sleep fragmentation (an index of restlessness) main sleep (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). The 2nd sleep was substantially less efficient than was the main sleep (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) for all watch keepers. There were few significant differences in sleep between the different watches in rotating watch keepers. Circadian timing remained constant in day workers. Timing of the 6-sulphatoxymelatonin rhythm was later for the watch of 1200-1600/2400-0400 h than for all others (1200-1600/2400-0400 h, 5.90 +/- 0.85 h; 1600-2000/0400-0800 h, 1.5 +/- 0.64 h; 0800-1200/ 2000-2400 h, 2.72 +/- 0.76 h; days, 2.09 +/- 0.68 h [decimal hours, mean +/- SEM]: ANOVA, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). This study identifies weekly changes in watch time as a cause of poor sleep in watch keepers. The most likely mechanism is the inability of the internal clock to adapt rapidly to abrupt changes in schedule.

Journal of Biological Rhythms, 1997

Melatonin has chronobiotic properties in humans. It is able to phase shift strongly endogenous rh... more Melatonin has chronobiotic properties in humans. It is able to phase shift strongly endogenous rhythms, such as core temperature and its own endogenous rhythm, together with the sleep-wake cycle. Its ability to synchronize free-running rhythms has not been fully investigated in humans. There is evidence for synchronization of the sleep-wake cycle, but the available data suggest that it is less effective with regard to endogenous melatonin and core temperature rhythms. When suitably timed, most studies indicate that fast release preparations are able to hasten adaptation to phase shift in both field and simulation studies of jet lag and shift work. Both subjective and objective measures support this statement. However, not all studies have been successful. Careful evaluation of the effects on work-related performance is required. When used to alleviate the non-24-h sleep-wake disorder in blind subjects, again most studies report a successful outcome using behavioral measures, albeit in a small number of individuals. The present data suggest, however, that although sleep-wake can be stabilized to 24 h, entrainment of other rhythms is exceptionally rare.

Journal of Biological Rhythms, 2009

Reduced sensitivity to short-wavelength (blue) light with age has been shown for light-induced me... more Reduced sensitivity to short-wavelength (blue) light with age has been shown for light-induced melatonin suppression. The current research aimed to determine if a similar age-related reduction occurs in subjective alertness, mood, and circadian phase-advancing responses. Young (n = 11, 23.0 +/- 2.9 years) and older (n = 15, 65.8 +/- 5.0 years) healthy males participated in laboratory sessions that included a 2-h intermittent monochromatic light exposure, individually timed to begin 8.5 h after their dim light melatonin onset (DLMO) determined in a prior visit. In separate sessions, pupil-dilated subjects were exposed to short-wavelength blue (lambda max 456 nm) and medium-wavelength green (lambda max 548 nm) light matched for photon density (6 x 1013 photons/cm2/sec). Subjective alertness, sleepiness, and mood were verbally assessed every 15 to 30 min before, during, and up to 5 h after the light exposure. The magnitude of phase advance was assessed as the difference in plasma melatonin rhythm phase markers before and after light exposure. Following blue light exposure, responses in older men were significantly diminished compared with young men for subjective alertness (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001), sleepiness (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001), and mood (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) during and after light exposure. There was no significant effect of age on these parameters following green light exposure. The phase advances to both blue and green light were larger in the young than older subjects, but did not reach statistical significance. In general, phase advances to blue light were slightly larger than to green light in both young and old, but did not reach statistical significance. The current results add to previous findings demonstrating reduced responsiveness to the acute effects of blue light in older people (melatonin suppression, alertness). However, under the study paradigm, the phase-advancing response to light does not appear to be significantly impaired with age.

Journal of sleep research, 2007

Heart rate (HR) and heart rate variability (HRV) undergo marked fluctuations over the 24-h day. A... more Heart rate (HR) and heart rate variability (HRV) undergo marked fluctuations over the 24-h day. Although controversial, this 24-h rhythm is thought to be driven by the sleep-wake/rest-activity cycle as well as by endogenous circadian rhythmicity. We quantified the endogenous circadian rhythm of HR and HRV and investigated whether this rhythm can be shifted by repeated melatonin administration while exposed to an altered photoperiod. Eight healthy males (age 24.4 +/- 4.4 years) participated in a double-blind cross-over design study. In both conditions, volunteers were scheduled to 16 h-8 h rest : wake and dark : light cycles for nine consecutive days preceded and followed by 29-h constant routines (CR) for assessment of endogenous circadian rhythmicity. Melatonin (1.5 mg) or placebo was administered at the beginning of the extended sleep opportunities. For all polysomnographically verified wakefulness periods of the CR, we calculated the high- (HF) and low- (LF) frequency bands of th...

Journal of sleep research, 2008

Antarctic Base personnel live for 3 months in winter with no natural sunlight. This project compa... more Antarctic Base personnel live for 3 months in winter with no natural sunlight. This project compared sleep, by actigraphy, during periods of increased exposure to white light or blue enriched light in 2003. The primary aim was to help define the optimum spectral composition and intensity of artificial environmental light. Nine men and one woman (33 +/- 7 years, mean +/- SD), wore activity and light monitors continuously from 28.2 to 9.10, and kept sleep diaries. Extra light was provided by light boxes (standard white, 5300 K, or prototype blue enriched, 10,000 K, Philips Lighting), which were turned on in bedrooms and in communal/work areas approximately 08.00-18.00 hours. After a no-treatment control period, 28.2-20.3, sequential 4-5 week periods of first white, then blue light, were imposed with a further control period 19.9-9.10. A limited baseline study in 2002 (no interventions) similarly measured light and activity in seven men and one woman (30 +/- 7 years). Daily light expos...

Journal of hepatology, 2009

Sleep-wake abnormalities are common in patients with cirrhosis but their evaluation is time consu... more Sleep-wake abnormalities are common in patients with cirrhosis but their evaluation is time consuming and laborious. The aim of this study was to assess the validity of a simple Sleep Timing and Sleep Quality Screening questionnaire (STSQS) against an established sleep quality questionnaire and daily sleep diaries.

Liver international : official journal of the International Association for the Study of the Liver, 2009

Sleep-wake disturbances are common in patients with cirrhosis and are generally attributed to the... more Sleep-wake disturbances are common in patients with cirrhosis and are generally attributed to the presence of hepatic encephalopathy.