Morning vs evening dosing of the cathepsin K inhibitor ONO-5334: effects on bone resorption in postmenopausal women in a randomized, phase 1 trial.

UNLABELLED: The cathepsin K inhibitor, ONO-5334, improves bone mineral density in postmenopausal women with osteoporosis. The effects of morning versus evening administration of ONO-5334 were investigated by measuring bone turnover marker levels in healthy postmenopausal women. Morning administration of ONO-5334 showed a more consistent suppressive effect on bone resorption than evening administration. INTRODUCTION: Bone turnover is thought to be subject to circadian variation, and the efficacy of osteoporosis treatments may be optimized by regulating the time of dosing. This study assessed whether evening administration of the cathepsin K inhibitor, ONO-5334, had a differential effect on the bone turnover marker, C-terminal telopeptide of type I collagen (CTX-I), compared with morning administration. METHODS: This was a single-center, single blind crossover study. Fourteen healthy postmenopausal women were assigned to receive ONO-5334 150 mg once daily for 5 days in each period; they were randomized to receive either evening doses in the first period and morning doses in the second or vice versa. Serum and urinary levels of CTX-I were measured throughout the study. RESULTS: Both regimens showed similar patterns of reduction in serum and urinary CTX-I; however, CTX-I suppression was more consistently >60% over 24 h following morning administration. Morning administration led to 6% greater suppression of 24-h serum CTX-I area under the effect curve (AUE; 69 vs 63%; P < .05) and 7% greater suppression of urinary CTX-I/creatinine AUE (93 vs 86%; P < .01) than evening administration. Higher plasma ONO-5334 concentrations were observed between 12 and 24 h postdose following morning administration, with mean trough concentrations for the morning and evening regimens at 9.4 and 4.0 ng/mL, respectively. There were no safety findings of concern. CONCLUSION: Morning dosing of ONO-5334 is more efficacious at reducing markers of bone turnover in healthy postmenopausal women than evening dosing. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01384188 , registered on June 27, 2011 EudraCT: 2008-006284-37.

Effect of subcutaneous insulin detemir on glucose flux, lipolysis and electroencephalography in type 1 diabetes.

The aim of the present study was to investigate the effects of subcutaneous detemir on glucose flux, lipid metabolism and brain function. Twelve people with type 1 diabetes received, in random order, 0.5 units/kg body weight detemir or NPH insulin. Glucose concentration was clamped at 5 mmol/l then increased to 10 mmol/l. Glucose production rate (glucose Ra), glucose uptake (glucose Rd) and glycerol production (glycerol Ra) were measured with a constant intravenous infusion of [6,6(2) H(2)]glucose and [(2)H(5)]glycerol. Electroencephalography direct current (DC) and alternating current (AC) potentials were measured. While detemir induced similar effects on glucose Ra, glucose Rd and glycerol Ra during euglycaemia compared with NPH, it triggered a distinct negative shift in DC potentials, with a significant treatment effect in frontal cerebrocortical channels (p < 0.001). AC spectral power showed significant differences in theta and alpha frequencies during euglycaemia (p = 0.03). Subcutaneous detemir exerts different effects on brain function when compared with NPH in people with type 1 diabetes. This may be an important mechanism behind the limitation of weight gain with detemir.

Spectral quality of light modulates emotional brain responses in humans.

Light therapy can be an effective treatment for mood disorders, suggesting that light is able to affect mood state in the long term. As a first step to understand this effect, we hypothesized that light might also acutely influence emotion and tested whether short exposures to light modulate emotional brain responses. During functional magnetic resonance imaging, 17 healthy volunteers listened to emotional and neutral vocal stimuli while being exposed to alternating 40-s periods of blue or green ambient light. Blue (relative to green) light increased responses to emotional stimuli in the voice area of the temporal cortex and in the hippocampus. During emotional processing, the functional connectivity between the voice area, the amygdala, and the hypothalamus was selectively enhanced in the context of blue illumination, which shows that responses to emotional stimulation in the hypothalamus and amygdala are influenced by both the decoding of vocal information in the voice area and the spectral quality of ambient light. These results demonstrate the acute influence of light and its spectral quality on emotional brain processing and identify a unique network merging affective and ambient light information.

In vivo marker of brainstem myelin is associated to quantitative sleep parameters in healthy young men.

The regional integrity of brain subcortical structures has been implicated in sleep-wake regulation, however, their associations with sleep parameters remain largely unexplored. Here, we assessed association between quantitative Magnetic Resonance Imaging (qMRI)-derived marker of the myelin content of the brainstem and the variability in the sleep electrophysiology in a large sample of 18-to-31 years healthy young men (N = 321; ~ 22 years). Separate Generalized Additive Model for Location, Scale and Shape (GAMLSS) revealed that sleep onset latency and slow wave energy were significantly associated with MTsat estimates in the brainstem (pcorrected ≤ 0.03), with overall higher MTsat value associated with values reflecting better sleep quality. The association changed with age, however (MTsat-by-age interaction-pcorrected ≤ 0.03), with higher MTsat value linked to better values in the two sleep metrics in the younger individuals of our sample aged ~ 18 to 20 years. Similar associations were detected across different parts of the brainstem (pcorrected ≤ 0.03), suggesting that the overall maturation and integrity of the brainstem was associated with both sleep metrics. Our results suggest that myelination of the brainstem nuclei essential to regulation of sleep is associated with inter-individual differences in sleep characteristics during early adulthood. They may have implications for sleep disorders or neurological diseases related to myelin.

Psychological distress, cardiometabolic diseases and musculoskeletal pain: A cross-sectional, population-based study of syndemic ill health in a Dutch fishing village.

BACKGROUND: Disease clustering is a growing public health concern and is increasingly linked to adverse socioeconomic conditions. Few population-based studies have focussed on interaction between non-communicable diseases. In this cross-sectional study, we examine clustering of, and synergistic interactions between, frequently occurring non-communicable diseases in Katwijk, a former fishing village in the Netherlands. Additionally, our study identifies contextual variables associated with these clusters of non-communicable diseases. METHODS: In a survey among adults (>19 years) living in the former fishing village Katwijk, Netherlands, were asked about non-communicable diseases, psychological distress, self-rated health scores and contextual factors, eg, socio-demographic, psychosocial and health behavior characteristics. Interaction was measured on the additive and the multiplicative scale. We used generalized ordered logistic regression analysis to examine associations with contextual variables. RESULTS: Three disease clusters were found to be most prevalent among the study participants (n = 1408). Each cluster involved a combination of frequently occurring conditions in this population: psychological distress (n = 261, 19%), cardiometabolic diseases (n = 449, 32%) and musculoskeletal pain (n = 462, 33%). These three diseases interact synergistically on the additive scale to increase the odds of reporting a low self-rated health. None of the disease clusters showed a statistically significant positive interaction on a multiplicative scale. Multiple contextual factors were associated with these disease clusters, including gender, loneliness, experiencing financial stress, and a BMI≥30. CONCLUSION: Our findings imply that psychological distress, cardiometabolic diseases and musculoskeletal pain synergistically interact, leading to a much lower self-rated health than expected. Several contextual factors are related to this interaction emphasizing the importance of a multicomponent, ecological approach.

The Usefulness of Electronic Health Records From Preventive Youth Healthcare in the Recognition of Child Mental Health Problems.

Background and Objectives: Early identification of child mental health problems (MHPs) is important to provide adequate, timely treatment. Dutch preventive youth healthcare monitors all aspects of a child's healthy development. We explored the usefulness of their electronic health records (EHRs) in scientific research and aimed to develop prediction models for child MHPs. Methods: Population-based cohort study with anonymously extracted electronic healthcare data from preventive youth healthcare centers in the Leiden area, the Netherlands, from the period 2005-2015. Data was analyzed with respect to its continuity, percentage of cases and completeness. Logistic regression analyses were conducted to develop prediction models for the risk of a first recorded concern for MHPs in the next scheduled visit at age 3/4, 5/6, 10/11, and 13/14 years. Results: We included 26,492 children. The continuity of the data was low and the number of concerns for MHPs varied greatly. A large number of determinants had missing data for over 80% of the children. The discriminatory performance of the prediction models were poor. Conclusions: This is the first study exploring the usefulness of EHRs from Dutch preventive youth healthcare in research, especially in predicting child MHPs. We found the usefulness of the data to be limited and the performance of the developed prediction models was poor. When data quality can be improved, e.g., by facilitating accurate recording, or by data enrichment from other available sources, the analysis of EHRs might be helpful for better identification of child MHPs.

Circadian clock genes and sleep homeostasis.

Circadian and sleep-homeostatic processes both contribute to sleep timing and sleep structure. Elimination of circadian rhythms through lesions of the suprachiasmatic nuclei (SCN), the master circadian pacemaker, leads to fragmentation of wakefulness and sleep but does not eliminate the homeostatic response to sleep loss as indexed by the increase in EEG delta power. In humans, EEG delta power declines during sleep episodes nearly independently of circadian phase. Such observations have contributed to the prevailing notion that circadian and homeostatic processes are separate but recent data imply that this segregation may not extend to the molecular level. Here we summarize the criteria and evidence for a role for clock genes in sleep homeostasis. Studies in mice with targeted disruption for core circadian clock genes have revealed alterations in circadian rhythmicity as well as changes in sleep duration, sleep structure and EEG delta power. Clock-gene expression in brain areas outside the SCN, in particular the cerebral cortex, depends to a large extent on prior sleep-wake history. Evidence for effects of clock genes on sleep homeostasis has also been obtained in Drosophila and humans, pointing to a phylogenetically preserved pathway. These findings suggest that, while within the SCN clock genes are utilized to set internal time-of-day, in the forebrain the same feedback circuitry may be utilized to track time spent awake and asleep. The mechanisms by which clock-gene expression is coupled to the sleep-wake distribution could be through cellular energy charge whereby clock genes act as energy sensors. The data underscore the interrelationships between energy metabolism, circadian rhythmicity, and sleep regulation.

Stability, precision, and near-24-hour period of the human circadian pacemaker.

Regulation of circadian period in humans was thought to differ from that of other species, with the period of the activity rhythm reported to range from 13 to 65 hours (median 25.2 hours) and the period of the body temperature rhythm reported to average 25 hours in adulthood, and to shorten with age. However, those observations were based on studies of humans exposed to light levels sufficient to confound circadian period estimation. Precise estimation of the periods of the endogenous circadian rhythms of melatonin, core body temperature, and cortisol in healthy young and older individuals living in carefully controlled lighting conditions has now revealed that the intrinsic period of the human circadian pacemaker averages 24.18 hours in both age groups, with a tight distribution consistent with other species. These findings have important implications for understanding the pathophysiology of disrupted sleep in older people.

Wavelength-dependent modulation of brain responses to a working memory task by daytime light exposure.

In addition to classical visual effects, light elicits nonvisual brain responses, which profoundly influence physiology and behavior. These effects are mediated in part by melanopsin-expressing light-sensitive ganglion cells that, in contrast to the classical photopic system that is maximally sensitive to green light (550 nm), is very sensitive to blue light (470-480 nm). At present, there is no evidence that blue light exposure is effective in modulating nonvisual brain activity related to complex cognitive tasks. Using functional magnetic resonance imaging, we show that, while participants perform an auditory working memory task, a short (18 min) daytime exposure to blue (470 nm) or green (550 nm) monochromatic light (3 x 10(13) photons/cm2/s) differentially modulates regional brain responses. Blue light typically enhanced brain responses or at least prevented the decline otherwise observed following green light exposure in frontal and parietal cortices implicated in working memory, and in the thalamus involved in the modulation of cognition by arousal. Our results imply that monochromatic light can affect cognitive functions almost instantaneously and suggest that these effects are mediated by a melanopsin-based photoreceptor system.

Favourable outcomes of a preventive screening and counselling programme for older people in underprivileged areas in the Netherlands: The PRIMUS project.

An aging population is associated with an increased prevalence of diabetes, cardiovascular diseases and depression. Important aspects of programmes targeted at older people are: to reach those at risk, effective screening, optimising advice, and referral to local interventions. We examined the effect of a preventive health consultation (PRIMUS), a multi-behavioural screening programme for persons aged 55-74 years in primary care. In a multi-centre randomised controlled trial, the effects of participating in the PRIMUS intervention were compared to a comparison group receiving personalised summaries and advice by postal mail, both preceded by a health risk assessment via a questionnaire. The intervention consisted of a baseline health risk assessment, followed by a preventive health consultation (after 4 weeks), and a follow-up visit (2 weeks later) in the primary care centre. A newly developed web-based computer-tailored programme supported the nurse practitioner during the consultation. Main outcomes measures were awareness of, and compliance with referral advice for changing unhealthy lifestyles. The PRIMUS preventive health consultation was successful in older people at risk for cardio metabolic diseases compared to the comparison group (compliance: RR 1.43; 95% CI 1.12-1.79; p < 0.05). The intervention was less successful in older people at risk for mental health problems. This preventive health consultation for older people resulted in positive changes in unhealthy behaviours by optimising reach, raising awareness, motivating and assisting individuals to change, and referring to local interventions.

Complex interaction of the sleep-wake cycle and circadian phase modulates mood in healthy subjects.

BACKGROUND: Several studies of healthy volunteers have revealed that subjective mood may vary with the duration of prior wakefulness and with the time of day. However, in these studies, the effects of extended wakefulness and circadian phase remained confounded, and the interaction of these 2 processes could not be assessed quantitatively. METHODS: In the present study, a total of 24 healthy young subjects (16 men, 8 women) lived on a 30-hour sleep-wake schedule for 19 to 23 days or on a 28-hour sleep-wake schedule for 33 to 36 days; both schedules induced desynchrony between the subjects' sleep-wake cycle and their endogenous circadian pacemaker. Subjective mood was assessed by 2 types of visual analog scales, which were administered twice every 2 hours and every 20 minutes, respectively, during all scheduled wakefulness episodes. A circadian phase and an interval elapsed since awakening were attributed to each data point, and circadian and wake-dependent fluctuations of mood were assessed. RESULTS: A significant variation of mood with circadian phase was observed, but no reliable main effect of the duration of prior wakefulness was found. A statistically significant interaction of circadian and wake-dependent fluctuations was evident; when the analysis was restricted to specific circadian phases, mood improved, deteriorated, or remained stable with the duration of prior wakefulness. CONCLUSIONS: These results indicate that, in healthy young subjects, subjective mood is influenced by a complex and nonadditive interaction of circadian phase and duration of prior wakefulness. The nature of this interaction is such that moderate changes in the timing of the sleep-wake cycle may have profound effects on subsequent mood.

Melatonin and the circadian regulation of sleep initiation, consolidation, structure, and the sleep EEG.

The endogenous circadian rhythm of melatonin, driven by the suprachiasmatic nucleus, exhibits a close association with the endogenous circadian component of the sleep propensity rhythm and the endogenous circadian component of the variation in electroencephalogram (EEG) oscillations such as sleep spindles and slow waves. This association is maintained even when the sleep-wake cycle is desynchronized from the endogenous circadian rhythm of melatonin. Administration of melatonin during the day increases daytime sleep propensity as indexed by both the latency to sleep onset and sleep consolidation. The EEG during daytime sleep after melatonin administration exhibits characteristics reminiscent of the nocturnal sleep EEG, that is, increased sleep spindle activity and reduced slow-wave sleep and slow-wave activity, as detected by quantitative EEG analysis. Administration of higher doses of melatonin (5 mg or more) prior to nocturnal sleep results in an increase in rapid eye movement (REM) sleep. These data demonstrate that melatonin exerts effects on the main characteristics of human sleep, that is, latency to sleep onset, sleep consolidation, slow waves, sleep spindles, and REM sleep. There is a need for further studies using physiological doses and delivery systems that generate physiological plasma melatonin profiles to firmly establish the role of the endogenous circadian rhythm of melatonin in the circadian regulation of sleep.

Commentary: models of sleep regulation: successes and continuing challenges.

Quantitative models have been developed to describe salient aspects of human sleep regulation. The two-process model of sleep regulation and the thermoregulatory model of sleep control highlight the interaction between sleep homeostasis and circadian rhythmicity and the association between sleep and temperature regulation, respectively. These models have been successful and inspiring, but continuing progress remains dependent on rigorous testing of some of their basic assumptions. Whereas it has been established that EEG slow-wave activity is a marker of sleep homeostasis, its causal role in regulating the timing of sleep and wakefulness remains to be demonstrated conclusively. Likewise, the causal role of the temperature regulatory system in sleep timing requires further investigation. In both models, many parameters have yet to be associated with specific physiologic processes. This makes it challenging, at least within the framework of these models, to account for interindividual differences or age-related changes in such features as sleep duration and sleep timing, as well as changes in the phase angle between the sleep-wake cycle and accepted markers of the circadian pacemaker, such as the body temperature or melatonin rhythm. Although the models may describe adequately global sleep patterns and their circadian modulation, detailed modeling of the frequent short awakenings from, and the subsequent transitions back to, sleep, as well as the variation of the propensity to awaken across the ultradian non-REM-REM cycle, is not addressed. Incoporation of these aspects of sleep in mathematical models of sleep regulation may further our understanding of a key aspect of sleep regulation, that is, its timing.

EEG power density during nap sleep: reflection of an hourglass measuring the duration of prior wakefulness.

The relation between the duration of prior wakefulness and EEG power density during sleep in humans was assessed by means of a study of naps. The duration of prior wakefulness was varied from 2 to 20 hr by scheduling naps at 1000 hr, 1200 hr, 1400 hr, 1600 hr, 1800 hr, 2000 hr, and 0400 hr. In contrast to sleep latencies, which exhibited a minimum in the afternoon, EEG power densities in the delta and theta frequencies were a monotonic function of the duration of prior wakefulness. The data support the hypothesis that EEG power density during non-rapid eye movement sleep is only determined by the prior history of sleep and wakefulness and is not determined by clock-like mechanisms.

Light treatment for sleep disorders: consensus report. I. Chronology of seminal studies in humans.

Examination of the influence of the light-dark cycle on circadian rhythmicity has been a fundamental aspect of chronobiology since its inception as a scientific discipline. Beginning with Bünning's hypothetical phase response curve in 1936, the impact of timed light exposure on circadian rhythms of literally hundreds of species has been described. The view that the light-dark cycle was an important zeitgeber for the human circadian system, as well, seemed to be supported by early studies of blind and sighted subjects. Yet, by the early 1970s, based primarily on a series of studies conducted at Erling-Andechs, Germany, the notion became widely accepted that the light-dark cycle had only a weak influence on the human circadian system and that social cues played a more important role in entrainment. In 1980, investigators at the National Institute of Mental Health reported that bright light could suppress melatonin production in humans, thereby demonstrating unequivocally the powerful effects of light on the human central nervous system. This finding led directly to the use of timed bright light exposure as a tool for the study and treatment of human circadian rhythms disorders.

Light treatment for sleep disorders: consensus report. II. Basic properties of circadian physiology and sleep regulation.

The rationale for the treatment of sleep disorders by scheduled exposure to bright light in seasonal affective disorder, jet lag, shift work, delayed sleep phase syndrome, and the elderly is, in part, based on a conceptual framework developed by nonclinical circadian rhythm researchers working with humans and other species. Some of the behavioral and physiological data that contributed to these concepts are reviewed, and some pitfalls related to their application to bright light treatment of sleep disorders are discussed. In humans and other mammals the daily light-dark (LD) cycle is a major synchronizer responsible for entrainment of circadian rhythms to the 24-h day, and phase response curves (PRCs) to light have been obtained. In humans, phase delays can be induced by light exposure scheduled before the minimum of the endogenous circadian rhythm of core body temperature (CBT), whereas phase advances are induced when light exposure is scheduled after the minimum of CBT. Since in healthy young subjects the minimum of CBT is located approximately 1 to 2 h before the habitual time of awakening, the most sensitive phase of the PRC to light coincides with sleep, and the timing of the monophasic sleep-wake cycle itself is a major determinant of light input to the pacemaker. The effects of light are mediated by the retinohypothalamic tract, and excitatory amino acids play a key role in the transduction of light information to the suprachiasmatic nuclei. LD cycles have direct "masking" effects on many variables, including sleep, which complicates the assessment of endogenous circadian phase and the interpretation of the effects of light treatment on sleep disorders. In some rodents motor activity has been shown to affect circadian phase, but in humans the evidence for such a feedback of activity on the pacemaker is still preliminary. The endogenous circadian pacemaker is a major determinant of sleep propensity and sleep structure; these, however, are also strongly influenced by the prior history of sleep and wakefulness. In healthy young subjects, light exposure schedules that do not curtail sleep but induce moderate shifts of endogenous circadian phase have been shown to influence the timing of sleep and wakefulness without markedly affecting sleep structure.

Light treatment for sleep disorders: consensus report. III. Alerting and activating effects.

In addition to the well-established phase-shifting properties of timed exposure to bright light, some investigators have reported an acute alerting, or activating, effect of bright light exposure. To the extent that bright light interventions for sleep disturbance may cause subjective and/or central nervous system activation, such a property may adversely affect the efficacy of treatment. Data obtained from patient samples and from healthy subjects generally support the notion that exposure to bright light may be associated with enhanced subjective alertness, and there is limited evidence of objective changes (EEG, skin conductance levels) that are consistent with true physiological arousal. Such activation appears to be quite transient, and there is little evidence to suggest that bright light-induced activation interferes with subsequent sleep onset. Some depressed patients, however, have experienced insomnia and hypomanic activation following bright-light exposure.

Light treatment for sleep disorders: consensus report. IV. Sleep phase and duration disturbances.

Advanced and delayed sleep phase disorders, and the hypersomnia that can accompany winter depression, have been treated successfully by appropriately timed artificial bright light exposure. Under entrainment to the 24-h day-night cycle, the sleep-wake pattern may assume various phase relationships to the circadian pacemaker, as indexed, for example, by abnormally long or short intervals between the onset of melatonin production or the core body temperature minimum and wake-up time. Advanced and delayed sleep phase syndromes and non-24-h sleep-wake syndrome have been variously ascribed to abnormal intrinsic circadian periodicity, deficiency of the entrainment mechanism, or--most simply--patterns of daily light exposure insufficient for adequate phase resetting. The timing of sleep is influenced by underlying circadian phase, but psychosocial constraints also play a major role. Exposure to light early or late in the subjective night has been used therapeutically to produce corrective phase delays or advances, respectively, in both the sleep pattern and circadian rhythms. Supplemental light exposure in fall and winter can reduce the hypersomnia of winter depression, although the therapeutic effect may be less dependent on timing.

Light treatment for sleep disorders: consensus report. V. Age-related disturbances.

Sleep maintenance insomnia is a major complaint among the elderly. As a result, an inordinate proportion of sleeping pill prescriptions go to individuals over 65 y of age. Because of the substantial problems associated with use of hypnotics in older populations, efforts have been made to develop nondrug treatments for age-related sleep disturbance, including timed exposure to bright light. Such bright light treatments are based on the assumption that age-related sleep disturbance is the consequence of alterations in the usual temporal relationship between body temperature and sleep. Although studies are limited, results strongly suggest that evening bright light exposure is beneficial in alleviating sleep maintenance insomnia in healthy elderly subjects. Less consistent, but generally positive, findings have been reported with regard to bright light treatment of sleep and behavioral disturbance in demented patients. For both groups, it is likely that homeostatic factors also contribute to sleep disturbance, and these may be less influenced by bright light interventions.