Lack of Nocturnal Blood Pressure Fall in Elderly Bedridden Hypertensive Patients With Cerebrovascular Disease

To prevent recurrence of cerebrovascular disease (CVD), adequate control of blood pressure (BP) is extremely important for the treatment of hypertensive CVD patients. As absence of the nocturnal fall of BP by the expected 10–20% from daytime levels is reported to exaggerate target organ injury, 24-h ambulatory blood pressure monitoring (ABPM) was conducted, especially to obtain data during nighttime sleep. Forty-eight elderly bedridden chronic phase CVD hypertensive patients (assessed 1–3 mo after CVD accident) participated. As a group, nocturnal BP was higher than diurnal BP, whereas nocturnal pulse rate was lower than diurnal pulse rate. The nocturnal BP fall was blunted in most (～90%) of the patients. These results suggest that to perform a rational drug treatment, it is essential to do 24-h ABPM before initiation of antihypertensive therapy in elderly bedridden hypertensive CVD patients. (Author correspondence: akiofuji@jichi.ac.jp)     

PERSPECTIVES ON THE CHRONOTHERAPY OF HYPERTENSION BASED ON THE RESULTS OF THE MAPEC STUDY

Appreciation of chronotherapy in hypertension continues to lag, despite clear demonstrations by many studies of (i) clinically relevant dosing-time differences of the beneficial and adverse effects of most blood pressure (BP) medications and (ii) significant association between reduced sleep-time BP decline of non-dippers and their heightened risk of cardiovascular disease (CVD). The Syst-Eur and HOPE outcome trials showed evening administration of nitrendipine and ramipril in these respective studies impacts sleep-time BP, converting the 24-h BP pattern to a more dipper one and in the HOPE study decreasing CVD risk. The CONVINCE study intended to compare BP control and CVD protection afforded by conventional β-blocker and diuretic medications versus a special drug-delivery verapamil formulation as a bedtime hypertension chronotherapy; however, the trial was terminated prematurely, not based on inadequate performance of the chronotherapy but on a corporate business decision. The just completed MAPEC study is the first trial specifically designed to prospectively test the hypothesis that bedtime administration of ≥1 conventional medications exerts better BP control and CVD risk reduction than the traditional approach of scheduling all medications in the morning. The results of this 5.6-yr median follow-up study establish that bedtime chronotherapy more effectively improves BP control, better decreases prevalence of non-dipping, and, most importantly, best reduces CVD morbidity and mortality. This chronotherapeutic approach to hypertension is justified by the fact that BP is usually lowest at night as is sodium excretion, but when sodium intake is excessive or its daytime excretion hampered, nocturnal BP is adjusted higher, to a level required for compensation overnight, via the pressure/natriuresis mechanism, resulting in non-dipping 24-h BP patterning. In diurnally active persons, the entire circadian BP pattern may be reset to a lower mean level and to a “more normal” day-night variation, simply by enhancing natriuresis during the night—the time-of-day when it can be most effective. A modification as simple and inexpensive as switching ≥1 hypertension medications from morning to evening may be all that is needed to normalize nighttime BP, exerting an effect exactly like sodium restriction. Current clinical concepts such as “normotensive non-dipper” (with higher CVD risk than a hypertensive dipper), broad recommendation of pharmacotherapy with exclusively high “smoothness index” medications (without attention to individual patient needs defined by the features of the 24-h BP pattern), and reliance upon static daytime diagnostic BP thresholds based solely on single office cuff assessment necessitate urgent reconsideration. (Author correspondence: prf@unife.it)     

THE RESPONSE OF PER1 TO LIGHT IN THE SUPRACHIASMATIC NUCLEUS OF THE DIURNAL DEGU (OCTODON DEGUS)

Several studies suggest that the circadian systems of diurnal mammals respond differently to daytime light than those of nocturnal mammals. We hypothesized that the photosensitive “clock” gene Per1 would respond to light exposure during subjective day in the suprachiasmatic nucleus of the diurnal rodent, Octodon degus. Tissue was collected 1.5–2?h after a 30?min light pulse presented at five timepoints across the 24?h day and compared to controls maintained under conditions of constant darkness. Per1 mRNA was quantified using in situ hybridization. Results showed that the rhythmicity and photic responsiveness of Per1 in the degu resembles that of nocturnal animals. (Author correspondence: hagenaue@umich.edu)     

Altered Circadian Rhythm of Melatonin Concentrations in Hypocretin-Deficient Men

Hypocretin deficiency causes narcolepsy. It is unknown whether melatonin secretion is affected in this sleep disorder. Therefore, in both narcolepsy patients and matched controls, the authors measured plasma melatonin levels hourly for 24?h before and after 5 days of sodium oxybate (SXB) administration. Although mean melatonin concentrations were similar between patients and controls, in narcoleptics the percentage of 24-h melatonin secreted during the daytime was significantly higher, and melatonin secretion exhibited a weaker coupling to sleep. SXB did not affect melatonin secretion. These findings suggest that hypocretin deficiency might disturb both the circadian control of melatonin release and its temporal association with sleep. (Author correspondence: c.e.h.m.donjacour@lumc.nl)     

Chronotherapy With Valsartan/Hydrochlorothiazide Combination in Essential Hypertension: Improved Sleep-Time Blood Pressure Control With Bedtime Dosing

Administration of angiotensin receptor blockers at bedtime results in greater reduction of nighttime blood pressure than dosing upon awakening, independent of the terminal half-life of each individual medication. To obtain blood pressure (BP) target goals most patients require treatment with more than one hypertension medication. However, the potential differing effects on BP regulation of combination therapy depending on the time-of-day of administration have scarcely been investigated. Accordingly, the authors prospectively evaluated the administration-time-dependent BP-lowering efficacy of valsartan/hydrochlorothiazide (HCTZ) combination therapy. The authors conducted a randomized, open-label, blinded-endpoint trial on 204 subjects with essential hypertension (95 men/109 women), 49.7?±?11.1 (mean?±?SD) yrs of age. The BP of participants in this trial was not properly controlled with respect to published ambulatory BP criteria after initially randomized to valsartan monotherapy (160?mg/day), whether routinely ingested upon awakening by one group or at bedtime by another group for 12 wks. Thus, HCTZ (12.5?mg/day) was added to valsartan as a single-pill formulation, maintaining the original treatment-time, i.e., upon awakening or at bedtime, of participants of the two groups, for another 12 wks. BP was measured by ambulatory monitoring for 48?h at inclusion and after each 12-wk span of therapy. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately define the beginning and end of daytime activity and nocturnal sleep so that the respective BP means for every participant at each evaluation could be precisely determined. Combination therapy resulted in a similar statistically significant reduction of the 48-h BP mean from baseline for both treatment-time groups (17.0/11.5?mm Hg in systolic/diastolic BP after combination therapy on awakening; 17.9/12.1?mm Hg reduction after combination treatment at bedtime; p?>?.542 between groups). The awake BP mean was reduced to a comparable extent in both treatment-time groups (p?>?.682). However, bedtime compared to morning dosing better reduced the asleep means of systolic BP (20.1 vs. 16.0?mm Hg; p?=?.015) and pulse pressure (6.5 vs. 4.0?mm Hg; p?=?.007 between groups). Accordingly, the proportion of subjects with a baseline non-dipper BP profile was significantly reduced from 59% to 23% only after bedtime combination treatment (p?<?.001). Moreover, the proportion of subjects with properly controlled ambulatory BP after combination therapy was significantly greater with bedtime than upon-awakening treatment (55 vs. 40%, p?=?.037). The improved efficacy in lowering the asleep BP mean, increased sleep-time relative BP decline, and greater proportion of controlled patients suggest that valsartan/HCTZ combination should be preferably administered at bedtime for treatment of subjects with essential hypertension requiring combination therapy to achieve proper BP control. (Author correspondence: rhermida@uvigo.es)     

Orcadian Rhythm of Serotonin Binding in Rat Brain—I. Effect of the Light-Dark Cycle

Moving rapidly from a supine to a standing posture is a common daily activity, yet a significant physiological challenge. Syncope can result from the development of initial orthostatic hypotension (IOH) involving a transient fall in systolic/diastolic blood pressure (BP) of >40/20?mm Hg within the first 15 s, and/or a delayed orthostatic hypotension (DOH) involving a fall in systolic/diastolic BP of >20/10?mm Hg within 15?min of posture change. Although epidemiological data indicate a heightened syncope risk in the morning, little is known about the diurnal variation in the IOH and DOH mechanisms associated with postural change. The authors hypothesized that the onset of IOH and DOH occurs sooner, and the associated cardiorespiratory and cerebrovascular changes are more pronounced, in the early morning. At 06:00 and 16:00?h, 17 normotensive volunteers, aged 26?±?1 yrs (mean?±?SE), completed a protocol involving supine rest, an upright stand, and a 60° head-up tilt (HUT) during which continuous beat-to-beat measurements of middle cerebral artery velocity (MCAv), mean arterial BP (MAP), heart rate, and end-tidal Pco₂ (P_ETco₂) were obtained. Mean MCAv was ～12% lower at baseline in the morning (p?≤?.01) and during the HUT (p?<?.01), despite a morning elevation in P_ETco₂ by ～2.2?mm Hg (p?=?.01). The decline in MAP during initial standing (morning vs. afternoon: 50%?±?4% vs. 49%?±?3%) and HUT (39%?±?3% vs. 38%?±?3%) did not vary with time-of-day (p?>?.30). In conclusion, although there is a marked reduction in MCAv in the morning, there is an absence of diurnal variation in the onset of and associated physiological responses associated with IOH and DOH. These responses, at least in this population, are unlikely contributors to the diurnal variation in orthostatic tolerance. (Author correspondence: N.C.Lewis@2004.ljmu.ac.uk)     

Photic Resetting in Night-Shift Work: Impact on Nurses' Sleep

The objective of this study was to quantify daytime sleep in night-shift workers with and without an intervention designed to recover the normal relationship between the endogenous circadian pacemaker and the sleep/wake cycle. Workers of the treatment group received intermittent exposure to full-spectrum bright light during night shifts and wore dark goggles during the morning commute home. All workers maintained stable 8-h daytime sleep/darkness schedules. The authors found that workers of the treatment group had daytime sleep episodes that lasted 7.1?±?.1?h (mean?±?SEM) versus 6.6?±?.2?h for workers in the control group (p?=?.04). The increase in total sleep time co-occurred with a larger proportion of the melatonin secretory episode during daytime sleep in workers of the treatment group. The results of this study showed reestablishment of a phase angle that is comparable to that observed on a day-oriented schedule favors longer daytime sleep episodes in night-shift workers. (Author correspondence: diane.boivin@douglas.mcgill.ca)     

EARLY PROGRAMMING OF ASTROCYTE ORGANIZATION IN THE MOUSE SUPRACHIASMATIC NUCLEI BY LIGHT

The principal pacemaker in mammals, controlling physiology and behavior, is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Early photic experience has long-term effects on the animal's rhythmic behavior, as indicated by alterations in the phase shift induced by a light pulse, and in the expression of the circadian rhythm of locomotor activity under light-dark (LD), constant light (LL), and constant darkness (DD) environments. However, the brain substrates targeted by early light have not yet been identified. Possible candidates are astrocytes, as they develop postnatally in parallel to the circadian system, and are involved in SCN function by modulating intercellular communication and mediating photic input. Here, we reared three groups of mice under different light environments (LD, LL, and DD) during the suckling period. Later on, all mice were entrained to LD, and we determined associated astrocytic modifications by examining the expression of glial fibrillary acidic protein (GFAP) in the SCN. We observed that although LL-reared mice showed lowest GFAP expression in the SCN, as determined by quantification of immunostaining levels, the number of GFAP-positive cells was highest in this group, suggesting structural remodelling of SCN astrocytes by early light experience. These results indicate the postnatal light environment has long-term effects on the astrocytic population of the SCN. We argue that these neurochemical and structural alterations may affect clock function, which may in turn modify animal behavior (Author correspondence: maria.canal@manchester.ac.uk, Jose.Rodriguez-arellano@manchester.ac.uk).     

PHOTOPERIOD AT BIRTH DOES NOT MODULATE THE DIURNAL PREFERENCE IN ASIAN POPULATION

Two research groups reported that diurnal preference in Canadian and South European populations was modulated by the season of birth. The aim of the present study was to examine this association in the Japanese population. In this study, 1156 college students were administered the Morningness-Eveningness Questionnaire and asked the date and place of birth. Our results demonstrated that neither photoperiod nor season of birth modulated diurnal preference in the Japanese population. Two biological differences are reported to exist between Caucasians and Asians: polymorphisms of circadian clock genes and difference in ocular photosensitivity. These ethnic differences might characterize the circadian photosensitivity in infancy. (Author correspondence: takao@keyaki.cc.u-tokai.ac.jp).     

The CLOCK Gene and Mood Disorders: A Case-Control Study and Meta-analysis

The clock gene (CLOCK) is considered to be a good candidate gene for the pathophysiology of mood disorders, including bipolar disorder (BP) and major depressive disorder (MDD). rs1801260 (T3111C) has been detected at position 3111 in the CLOCK mRNA 3' untranslated region, and was reported to be associated with a substantial delay in preferred timing for activity and sleep in a human study. As for function, rs1801260 has been speculated to affect mRNA. Therefore, the authors investigated the association between the three tagging single-nucleotide polymorphisms (SNPs) (rs3736544, rs1801260, and rs3749474) in CLOCK and risk of BP (n?=?867) and MDD (n?=?139) compared to controls (n?=?889) in the Japanese population. In addition, we also performed an updated meta-analysis of nine published, genetic association studies investigating the relationship between rs1801260 and mood disorder risk, comprising 3321 mood disorders cases and 3574 controls. We did not detect any associations between tagging SNPs in CLOCK and BP or MDD in the allele, genotype, or haplotype analysis (global p_BP?=?.605 and global p_MDD?=?.211). Moreover, rs1801260 was also not associated with BP, MDD, or any mood disorders in the meta-analysis. In conclusion, these data suggest that CLOCK does not play a major role in the pathophysiology of mood disorders. (Author correspondence: tarok@fujita-hu.ac.jp)     

A Honey Bee (Apis mellifera) Light Phase Response Curve

The authors report a phase response curve (PRC) for individual honey bees (Apis mellifera) to single 1-h light pulses (1000 lux) using an Aschoff Type 1 protocol (n?=?134). The bee PRC is a weak (Type 1) PRC with a maximum advance of 1.5?h between circadian time (CT) 18 and 3 and a maximum delay of 1.5?h between CT 12 and 18. This is the first published honey bee light PRC and provides an important resource for chronobiologists and honey bee researchers. It may also have practical applications for what is an economically important species frequently transported across different time zones. (Author correspondence: G.warman@auckland.ac.nz)     

Short- and Long-day Responses in the Pre-adult Developmental Duration of Two Species of Camponotus Ants

We assessed the effect of different day/night lengths on the pre-adult developmental time of two species of Camponotus ants that normally develop in dark underground nests. We assayed larval (egg-to-pupal formation), pupal (pupal formation-to-adult emergence), and pre-adult (egg-to-adult emergence) durations in these ants under three different light/dark (LD) cycles of 12:12?h, 10:14?h, and 14:10?h. We observed that the pre-adult development time of ants under these day lengths was significantly different. Although both species developed fastest under 12:12?h LD, when asymmetric LD cycles were compared, night-active species (Camponotus compressus) developed faster under short days (10:14?h) and day-active species (C. paria) developed faster under long days (14:10?h). This day/night-length-mediated difference in pre-adult developmental duration was mostly due to modulation of larval duration; however, in day-active species it was also via altered pupal duration. These results thus indicate that the two species of Camponotus ants respond differently to short and long days, suggesting that seasonal timers regulate pre-adult development time in tropical ant species living in dark underground nests. (Author correspondence: vsharma@jncasr.ac.in/vksharmas/gmail.com)     

Seasonal Effect on Infants' Sleep Regulation: A Preliminary Study in a Mediterranean Climate

Infants' sleep-wake rhythms are influenced by multiple factors, including developmental and contextual aspects, as well as circadian cycles. Empirical studies that address the seasonal impact on infants' sleep are scarce. The present study examined aspects of sleep schedule and quality, comparing summer and winter months in a Mediterranean climate. This report is based on a convenience sample of 34 healthy 7-mo-olds, an age in which sleep is well consolidated and regulated compared with the first few months of life. Sleep was measured with actigraphy, in the home context. It was found that compared with winter, in the summer months, sleep onset occurred at a later hour, and more motor activity during sleep was detected. Although the overall sleep quality, as defined by sleep efficiency score, was similar in the two seasons, in the summer, more active sleep was observed. The authors discuss the finding in terms of circadian rhythms, developmental characteristics, as well as possible environmental factors and family routines, and call for more studies, in different climates and geographical zones, and in different developmental periods. (Author correspondence: cohen.dini@gmail.com or anats@edu.haifa.ac.il)     

Robustness of Circadian Timing Systems Evolves in the Fruit Fly Drosophila melanogaster as a Correlated Response to Selection for Adult Emergence in a Narrow Window of Time

Robustness is a fundamental property of biological timing systems that is likely to ensure their efficient functioning under a wide range of environmental conditions. Here we report the findings of our study aimed at examining robustness of circadian clocks in fruit fly Drosophila melanogaster populations selected to emerge as adults within a narrow window of time. Previously, we have reported that such flies display enhanced synchrony, accuracy, and precision in their adult emergence and activity/rest rhythms. Since it is expected that accurate and precise circadian clocks may confer enhanced stability in circadian time-keeping, we decided to examine robustness in circadian rhythms of flies from the selected populations by subjecting them to a variety of environmental conditions comprising of a range of photoperiods, light intensities, ambient temperatures, and constant darkness. The results revealed that adult emergence and activity/rest rhythms of flies from the selected stocks were more robust than controls, as they displayed enhanced stability under a wide variety of environmental conditions. These results suggest that selection for adult emergence within a narrow window of time results in the evolution of robustness in circadian timing systems of the fruit fly D. melanogaster. (Author correspondence: vsharma@jncasr.ac.in or vksharmas@gmail.com)     

Circadian Rhythms in the Efficacy of Intravenous Alteplase in Patients With Acute Ischemic Stroke and Middle Cerebral Artery Occlusion

Circadian rhythm interactions of hemostatic factors can modify tissue plasminogen activator (tPA) effects. We assess the relationship of the time frame of intravenous tPA administration with the outcome of patients with acute ischemic stroke (AIS). We studied 135 consecutive patients with AIS and transcranial duplex documented middle cerebral artery (MCA) occlusion treated with intravenous tPA. Complete recanalization was defined as total improvement on thrombolysis in brain ischemia (TIBI) grades 2?h after tPA infusion. Clinical response was evaluated by the modified Rankin scale at 90 days. We determined plasminogen activator inhibitor-1 (PAI-1) levels in 33 patients with available plasma samples before treatment. Our results are follows: 92 (68.1%) patients were treated in the diurnal (9:00–21:00) and 43 (31.8%) in the nocturnal period (21:00–9:00). Complete recanalization was recorded in 52/135 (38.5%) patients. Both the rate of complete recanalization (45.6% vs. 23.2%; p?=?.01) and good clinical outcome (64.1% vs. 44.2%; p?=?.02) were significantly higher in the group of diurnal tPA administration compared with those treated in the nocturnal period. The adjusted odds ratio (OR) of diurnal tPA treatment for complete MCA recanalization was 2.37 (95% confidence interval [CI], 1.02–5.52; p?=?.045). Diurnal tPA infusion significantly improved the overall distribution of scores on the modified Rankin scale, as compared with nocturnal treatment (OR, 2.07; 95% CI, 1.16–4.64 by ordinal regression analysis). Low PAI-1 levels were associated with complete recanalization but did not significantly differ between the two time frames. In conclusion, diurnal administration of tPA is associated with complete MCA recanalization and better functional outcome at 90 days in patients with AIS. (Author correspondence: mgomis.germanstrias@gencat.cat, meritxellgomis@gmail.com)     

Effect of "no added salt diet" on blood pressure control and 24 hour urinary sodium excretion in mild to moderate hypertension

Background

The incidence of Hypertension as a major cardiovascular threat is increasing. The best known diet for hypertensives is 'no added salt diet'. In this study we evaluated the effect of 'no added salt diet' on a hypertensive population with high dietary sodium intake by measuring 24 hour urinary sodium excretion.

Methods

In this single center randomized study 80 patients (60 cases and 20 controls) not on any drug therapy for hypertension with mild to moderate hypertension were enrolled. 24 hour holter monitoring of BP and 24 hour urinary sodium excretion were measured before and after 6 weeks of 'no added salt diet'.

Results

There was no statistically significant difference between age, weight, sex, Hyperlipidemia, family history of hypertension, mean systolic and diastolic BP during the day and at night and mean urinary sodium excretion in 24 hour urine of case and control groups. Seventy eight percent of all patients had moderate to high salt intake. After 6 week of 'no added salt diet' systolic and diastolic BP significantly decreased during the day (mean decrease: 12.1/6.8 mmhg) and at night (mean decrease: 11.1/5.9 mmhg) which is statistically significant in comparison to control group (P 0.001 and 0.01). Urinary sodium excretion of 24 hour urine decreased by 37.1 meq/d ± 39,67 mg/dl in case group which is statistically significant in comparison to control group (p: 0.001). Only 36% of the patients, after no added salt diet, reached the pretreatment goal of 24 hour urinary sodium excretion of below 100 meq/dl (P:0.001).

Conclusion

Despite modest effect on dietary sodium restriction, no added salt diet significantly decreased systolic and diastolic BP and so it should be advised to every hypertensive patient.

Trial Registration

Clinicaltrial.govnumber NCT00491881     

Does the Modern Urbanized Sleeping Habitat Pose a Breast Cancer Risk?

Due to its disruptive effects on circadian rhythms and sleep deprivation at night, shiftworking is currently recognized as a risk factor for breast cancer (BC). As revealed by the present analysis based on a comparative case-control study of 1679 women, exposure to light-at-night (LAN) in the “sleeping habitat” is significantly associated with BC risk (odds ratio [OR]?=?1.220, 95% confidence interval [CI]?=?1.118–1.311; p?<?.001), controlling for education, ethnicity, fertility, and alcohol consumption. The novelty of the present research is that, to the best of the authors' knowledge, it is the first study to have identified an unequivocal positive association between bedroom-light intensity and BC risk. Thus, according to the results of the present study, not only should artificial light exposure in the working environment be considered as a potential risk factor for BC, but also LAN in the “sleeping habitat.” (Author correspondence: ahaim@research.haifa.ac.il)     

PREDICTING HUMAN NOCTURNAL NONVISUAL RESPONSES TO MONOCHROMATIC AND POLYCHROMATIC LIGHT WITH A MELANOPSIN PHOTOSENSITIVITY FUNCTION

The short-wavelength (blue) light sensitivity of human circadian, neurobehavioral, neuroendocrine, and neurophysiological responses is attributed to melanopsin. Whether melanopsin is the sole factor in determining the efficacy of a polychromatic light source in driving nonvisual responses, however, remains to be established. Monochromatic (λ_max 437, 479, and 532?nm administered singly and in combination with 479?nm light) and polychromatic (color temperature: 4000 K and 17000 K) light stimuli were photon matched for their predicted ability to stimulate melanopsin, and their capacity to affect nocturnal melatonin levels, auditory reaction time, and subjective alertness and mood was assessed. Young, healthy male participants aged 18–35 yrs (23.6?±?3.6 yrs [mean?±?SD]; n?=?12) participated in 12 overnight sessions that included an individually timed 30-min nocturnal light stimulus on the rising limb of the melatonin profile. At regular intervals before, during, and after the light stimulus, subjective mood and alertness were verbally assessed, blood samples were taken for analysis of plasma melatonin levels, and an auditory reaction time task (psychomotor vigilance task; PVT) was performed. Proc GLM (general linear model) repeated-measures ANOVA (analysis of variance) revealed significantly lower melatonin suppression with the polychromatic light conditions (4000 and 17000 K) compared to the “melanopsin photon-matched” monochromatic light conditions (p?<?.05). In contrast, subjective alertness was significantly lower under the 479?nm monochromatic light condition compared to the 437 and 532?nm monochromatic and both polychromatic light conditions. The alerting responses more reflected the total photon content of the light stimulus. The demonstration that the melatonin suppression response to polychromatic light was significantly lower than predicted by the melanopsin photosensitivity function suggests this function is not the sole consideration when trying to predict the efficacy of broadband lighting. The different spectral sensitivity of subjective alertness and melatonin suppression responses may imply a differential involvement of the cone photopigments. An analysis of the photon densities in specific wavelength bands for the polychromatic lights used in this and the authors' previous study suggests the spectral composition of a polychromatic light source, and particularly the very short-wavelength content, may be critical in determining response magnitude for the neuroendocrine and neurobehavioral effects of nocturnal light. (Author correspondence: v.revell@surrey.ac.uk)     

Association Between Phase Shifts,Expression Levels,and Amplitudes in Peripheral Circadian Clocks

Data analyses examining the relationship between circadian phase shifts and amplitudes are scarce. The aim of this data analysis was to explore the association between the phase shifts of gene expression, their amplitudes, and daily levels as a result of a given treatment under ad libitum or restricted feeding (RF) conditions. Two hundred forty data sets of gene expression (clock and metabolic genes) from various tissues and treatments were statistically analyzed. The data revealed a significant association between phase delays and increased amplitudes. Moreover, upon subgroup analyses, separating the RF from the non-RF groups, phase delays were significantly correlated with increased amplitudes and phase advances with decreased amplitudes. This picture was also achieved when clock genes, but not metabolic genes, were analyzed. In contrast, under RF, increased amplitude of metabolic genes correlated with phase advances. Moreover, phase advances under RF led to increased average daily levels in clock genes, but not in metabolic genes. In summary, these data demonstrated statistically significant association between phase shifts, daily levels, and amplitudes in circadian gene expression in peripheral tissues under timed versus ad libitum feeding conditions. (Author correspondence: oren.froy@mail.huji.ac.il)