Clock Polymorphisms and Circadian Rhythms Phenotypes in a Sample of the Brazilian Population

A Clock polymorphism T to C situated in the 3′ untranslated region (3′‐UTR) has been associated with human diurnal preference. At first, Clock 3111C had been reported as a marker for evening preference. However these data are controversial, and data both corroborating and denying them have been reported. This study hypothesizes that differences in Clock genotypes could be observed if extreme morning‐type subjects were compared with extreme evening‐type subjects, and the T3111C and T257G polymorphisms were studied. The possible relationship between both polymorphisms and delayed sleep phase syndrome (DSPS) was also investigated. An interesting and almost complete linkage disequilibrium between the polymorphisms T257G in the 5′ UTR region and the T3111C in the 3′ UTR region of the Clock gene is described. Almost always, a G in position 257 corresponds to a C in position 3111, and a T in position 257 corresponds to a T in position 3111. The possibility of an interaction of these two regions in the Clock messenger RNA structure that could affect gene expression was analyzed using computer software. The analyses did not reveal an interaction between those two regions, and it is unlikely that this full allele correspondence affects Clock gene expression. These results show that there is no association between either polymorphism T3111C or T257G in the Clock gene with diurnal preference or delayed sleep phase syndrome (DSPS). These controversial data could result from the possible effects of latitude and clock genes interaction on circadian phenotypes.     

Seasonal pattern in bipolar disorders and cardio-vascular risk factors: A study from the FACE-BD cohort

Seasonal pattern (SP) and metabolic syndrome (MetS) are major contributors to poor outcome in bipolar disorders (BD). Patients with seasonal bipolar depression present increased appetite, carbohydrate cravings, weight gain, and hypersomnia, which can increase the development of MetS. MetS also appears to be associated with seasonal mood changes in the general population. This study examines whether a SP in BD is associated with an increased risk of MetS and its sub-components. One thousand four hundred and seventy-one outpatients with BD were systematically enrolled from 2009 to 2016. Inclusion required a disease duration of at least 5 years, with 486 (33%) patients with SP (SP+) and 985 (67%) without (SP–) according to the DSM IV-TR criteria. When using continuous measures of metabolic components, SP+ patients, as compared to SP–, suffered from higher levels for systolic blood pressure (p = 0.01), low-density lipoprotein cholesterol (p = 0.009), fasting glucose (p = 0.007), triglycerides levels (p = 0.03), a larger abdominal circumference (p = 0.02), and a higher body mass index (p = 0.07). In the covariance analysis, adjusted for gender, age, and bipolar subtype, as well as the number of depressive and hypomanic episode, SP+ patients had a significantly higher level of fasting glucose and higher systolic blood pressure. The frequency of MetS did not differ between groups (21.2% in SP– versus 23.9% in SP+). When using categorical definitions for abnormal metabolic components (International Diabetes Federation criteria), there were no differences between groups, except that SP+ patients were more overweight/obese as compared to SP– patients (55.03% versus 46.7%, respectively; p = 0.002) and tended to have more frequently high fasting glucose (18.2% versus 14.3%, respectively; p = 0.07). MetS was frequent in patients with BD, however not associated with SP. Patients with SP appeared more vulnerable to overweight/obesity and presented with higher levels of MetS subcomponents although these parameters were mainly in the normal range. All patients with BD should benefit from early screening and targeted management of cardio-vascular risk factors.     

Validation of the French Version of the Child Post-Traumatic Stress Reaction Index: Psychometric Properties in French Speaking School-Aged Children

Background

Although the reliable and valid Child Post-Traumatic Stress Reaction Index (CPTS-RI) is a widely used measure of posttraumatic stress disorder (PTSD) symptoms in children, it has not been validated in French-speaking populations. The present study aims to assess the psychometric properties of the CPTS-RI in three samples of French-speaking school-children.

Methods

Data was obtained from three samples. Sample 1 was composed of 106 children (mean (SD) age = 11.7(0.7), 50% females) victims of an industrial disaster. Sample 2 was composed of 50 children (mean (SD) age = 10.8(2.6), 44% females) who had received an orthopaedic surgical procedure after an accident. Sample 3 was composed of 106 children (mean (SD) age = 11.7(2.2), 44% females) admitted to an emergency department after a road traffic accident. We tested internal consistency using Cronbach''s alpha. We examined test-retest reliability using intraclass correlation coefficient. In order to assess the convergent validity of the French version of the CPTS-RI and the Clinician Administered PTS Scale-Child and Adolescent (CAPS-CA), spearman-correlation coefficient was computed. To verify the validity of the cut-off scores, a ROC curve was constructed which evaluated the sensitivity and specificity of each score compared to the diagnosis with the CAPS-CA. We also used principal components analysis with varimax rotation to study the structure of the French version of the CPTS-RI.

Results

Cronbach''s alpha coefficient was 0.87 for the French version of the CPTS-RI. Two-week test-retest intraclass correlation coefficient (n = 30) was 0.67. The French version of the CPTS-RI was well correlated with the CAPS-CA (r = 0.76, p<0.001). Taking the CAPS-CA as the diagnostic reference, with a diagnostic cut-off of >24 for the CPTS-RI, the sensitivity and specificities were 100% and 62.6%, respectively. The French version of the CPTS-RI demonstrated a three-factor structure.

Conclusions

The CPTS-RI is reliable and valid in French-speaking children.     

Circadian Uses of Melatonin in Humans

Melatonin in humans can be an independent or dependent variable. Measurement of endogenous melatonin levels under dim‐light conditions, particularly the dim‐light melatonin onset (DLMO), has received increasing attention among researchers, and for clinicians it may soon become a convenient test that can be done at home using saliva collections in the evening, without interfering with sleep. Melatonin, even at low physiological doses, can cause advances (shifts to an earlier time) or delays (shifts to a later time) depending on when it is administered on its phase‐response curve (in most sighted people, these times are approximately in the p.m. and in the a.m., respectively). Although both bright light and melatonin can be used separately or together in the treatment of circadian phase disorders in sighted people—such as advanced and delayed sleep phase syndromes, jet lag, shift‐work maladaptation, and winter depression (seasonal affective disorder, or SAD)—melatonin is the treatment of choice in totally blind people. These people provide a unique opportunity to study the human circadian system without the overwhelming effects of ocularly mediated light, thus permitting us to establish that all blind free‐runners (BFRs) studied under high resolution appear to have phase‐advancing and phase‐delaying responses to as yet unidentified zeitgebers (time givers) that are usually too weak to result in entrainment.     

Altered Myelination of the Hippocampal Formation in Subjects with Schizophrenia and Bipolar Disorder

Myelination of the frontal and temporal lobes occurs at a similar time period as symptom onset in schizophrenia. To assess this potential relationship, we compared myelination and oligodendrocyte numbers in the hippocampal formation of controls and matched subjects with schizophrenia and bipolar disorder. The levels and distribution of the myelin marker myelin basic protein (MBP) and the oligodendrocyte marker adenomatous polyposis coli (APC) were measured using immunocytochemistry. MBP immunoreactivity (IR) was increased in several hippocampal subregions of control females versus control males. Female subjects with schizophrenia and bipolar disorder exhibited decreased myelination in the hippocampal formation while male subjects with bipolar disorder showed increased MBP levels in the superior medullary lamina. In contrast, the number of APC immunoreactive cells did not differ in any disorder or region. Our results demonstrate an interaction between gender, mental illness, and myelination, and may be related to cognitive deficits seen in schizophrenia and bipolar disorder.     

Zeitgeber Hierarchy in Humans: Resetting the Circadian Phase Positions of Blind People Using Melatonin

Four blind individuals who were thought to be entrained at an abnormal circadian phase position were reset to a more normal phase using exogenous melatonin administration. In one instance, circadian phase was shifted later. A fifth subject who was thought to be entrained was monitored over four years and eventually was shown to have a circadian period different from 24 h. These findings have implications for treating circadian phase abnormalities in the blind, for distinguishing between abnormally entrained and free‐running blind individuals, and for informing the debate over zeitgeber hierarchy in humans.     

Circadian Variations in the Number of Actively Secreting Sebaceous Follicles and Androgen Circadian Rhythms

Sebum excretion has been shown to demonstrate a circadian rhythm using a gravimetric method (cigarette paper). With the newly introduced method of Sebutape, we confirmed this periodicity and showed that the elevation in sebum excretion is correlated with an increase in the number of secreting follicles. We found, furthermore, that the number of secreting follicles on the forehead showed a distinct and statistically significant circadian rhythmicity, in contrast to those of the chest, which remained almost constant. The quantification in plasma levels of cortisol, melatonin, δ-4-androstenedione, dehydroepiandrosterone sulphate, and free testosterone showed no correlation with sebum excretion at either site. These observations suggest that local factors are involved in control of sebum secretion.     

哺乳动物昼夜节律调节的神经基础——昼夜光感受器

哺乳动物昼夜光感受器为一组具有直接感光功能的特殊视网膜神经节细胞 ,其基本感光色素为黑视素 .昼夜光感受器具有直接、广谱和稳定感受昼夜光变化的功能特点 .昼夜光感受器的功能是通过导引作用 ,使下丘脑视交叉上核内的昼夜节律活动与外界明 暗周期变化同步     

Circadian preferences in young adults: Psychometric properties and factor structure of the Portuguese version of the Preferences Scale (PS-6)

Morningness is a trait-like variable which has been extensively studied within chronobiology. Despite the number of existing measures to assess morningness, there is a need for brief instruments that are psychometrically sound to be used in applied settings. Accordingly, the modified version of the Preferences Scale (PS-6) comprises six items and was reported to have adequate reliability and satisfactory validity indicators. In this article, the psychometric properties of the Portuguese version of the PS-6 are reported. A total of 700 students attending medical school were recruited, and this sample was randomly divided into two groups. In the first group (n = 352), we assessed the internal consistency calculations and conducted a principal component analysis of the posited structure. In the second group (n = 348), we conducted a confirmatory factor analysis (CFA) using structural equation modeling. Overall, the results indicated that the PS-6 has adequate reliability (α = .75) and is constituted by two components: (I) preferred cognitive activities timings and (II) preferred sleeping–eating timings, respectively. In conclusion, the Portuguese version of the PS seems suitable for use in research and applied settings such as shift work schedules management. However, the applicability of the PS-6 in other samples and further validity indicators should be both investigated. The use of actigraphy and biological measures should also be collected to enhance the robustness of the PS-6.     

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)     

Circadian rhythms in the blowfly, Phormia terraenovae: control of phase within the range of entrainment

ABSTRACT Locomotor activity of individual blowflies, Phormia (= Protophormia) terraenovae R.D. (Diptera, Calliphoridae) was recorded by means of running wheels. A few days after emergence, adult flies were placed in the wheels and exposed to at least two of four light-dark cycles (LD) differing in cycle duration T (LD 11:11, 12:12, 13:13 and 14:14 h). The intensity of illumination was 400 lux in L and 2 lux in D. From the actograms, phase-angle differences were read off between onset of activity and light-on (ψ/_onset), and between end of activity and light-off (ψend)- Within the range of entrainment, ψ changed systematically from negative values in T =22 h to positive values in T =28 h: the mean change in ψ per hour change in T , expressed in degree of the full circadian cycles, was 20^o. Standard deviations of ψ around its mean were computed for ten-cycle intervals; in ψ_onset and in ψ_end standard deviation was minimal when 4ψ was close to zero, and increased steadily with increasing negative or positive ψ -values.     

Circadian rhythmicity in dopamine content of mammalian retina: role of the photoreceptors

Dopamine, the predominant retinal catecholamine, is a neurotransmitter and neuromodulator known to regulate light-adaptive retinal processes. Because dopamine influences several rhythmic events in the retina it is also a candidate for a retinal circadian signal. Using high performance liquid chromatography (HPLC), we have tested whether dopamine and its breakdown products are rhythmic in Royal College of Surgeons (RCS) rats with normal and dystrophic retinas. In both normal and mutant animals entrained to a 12-h light/12-h dark cycle, we found robust daily rhythms of dopamine and its two major metabolites. To address circadian rhythmicity of dopamine content, rats were entrained to light/dark cycles and released into constant darkness, using the circadian rhythm of wheel-running activity as a marker of each individual's circadian phase. Circadian rhythms of dopamine and metabolite content persisted in both wild type and retinally degenerate animals held for two weeks in constant darkness. Our results demonstrate for the first time clear circadian rhythms of dopamine content and turnover in a free-running mammal, and suggest that rods and cones are not required for dopamine rhythmicity.     

Circadian Determinants of the Postlunch Dip in Performance

This study compared rectal temperature rhythms in groups of subjects who either did (n = 5) or did not (n - 7) show a clear postlunch dip in performance at a monotonous (25-30 min) vigilance task. Performance was tested every 2h in a standardized routine with lunch replaced by hourly liquid food supplements. Those showing the postlunch performance dip had a higher amplitude and later peaking 12h component to their rectal temperature rhythm that those who did not, resulting in flat, rather than rising, temperatures over the 10:00-15:00 time interval. The effect could not be explained by intergroup differences in prior sleep, morningness, or gender, although there was a trend (p = 0.09) for the “dip” group to be slightly younger (21.8y vs. 24.2y). The postlunch dip appears to be an endogenous phenomenon individually determined, but related to the strength of the (12h) harmonic of the circadian system.     

Circadian Rhythms of Locomotor Activity in the Nile Tilapia Oreochromis niloticus

Behavioral rhythms of the Nile tilapia were investigated to better characterize its circadian system. To do so, the locomotor activity patterns of both male and female tilapia reared under a 12:12 h light-dark (LD) cycle were studied, as well as in males the existence of endogenous rhythmicity under free-running conditions (DD and 45 min LD pulses). When exposed to an LD cycle, the daily pattern of activity differed between individuals: some fish were diurnal, some nocturnal, and a few displayed an arrhythmic pattern. This variability would be typical of the plastic circadian system of fish. Moreover, reproductive events clearly affected the behavioral rhythms of female tilapia, a mouth-brooder teleost species. Under DD, 50% (6 of 12) of male fish showed circadian rhythms with an average period (τ) of 24.1±0.2 h, whereas under the 45 min LD pulses, 58% (7 of 12) of the fish exhibited free-running activity rhythms with an average τ of 23.9±0.5 h. However, interestingly in this case, activity was always confined to the dark phase. Furthermore, when the LD cycle was reversed, a third of the fish showed gradual resynchronization to the new phase, taking 7–10 days to be completely re-entrained. Taken together, these results suggest the existence of an endogenous circadian oscillator that controls the expression of locomotor activity rhythms in the Nile tilapia, although its anatomical localization remains unknown.     

An Investigation of Natural Genetic Variation in the Circadian System of Drosophila melanogaster: Rhythm Characteristics and Methods of Quantification

Variation in four characteristics of the circadian locomotor activity rhythm was investigated in 24 true-breeding strains of Drosophila melanogaster with a view to establishing methods of phenotypic measurement sufficiently robust to allow subsequent biometric analysis. Between them, these strains formed a representative sample of the genetic variability of a natural population. Period, phase, definition (the degree to which a rhythmic signal was obscured by noise), and rhythm waveform were all found to vary continuously among the strains, although within each strain the rhythm phenotype was remarkably consistent. Each characteristic was found to be sufficiently robust to permit objective measurement using several different methods of quantification, which were then compared.     

An Investigation of Natural Genetic Variation in the Circadian System of Drosophila melanogaster: Rhythm Characteristics and Methods of Quantification

Variation in four characteristics of the circadian locomotor activity rhythm was investigated in 24 true-breeding strains of Drosophila melanogaster with a view to establishing methods of phenotypic measurement sufficiently robust to allow subsequent biometric analysis. Between them, these strains formed a representative sample of the genetic variability of a natural population. Period, phase, definition (the degree to which a rhythmic signal was obscured by noise), and rhythm waveform were all found to vary continuously among the strains, although within each strain the rhythm phenotype was remarkably consistent. Each characteristic was found to be sufficiently robust to permit objective measurement using several different methods of quantification, which were then compared.     

The Use of Salivary Steroids to Monitor Circadian Rhythmicity on Expeditions in the Arctic

The circadian variation in salivary Cortisol concentration was investigated in four men during a traverse on foot, of the Greenland ice cap and of salivary Cortisol and testosterone on a summer expedition to Spitzbergen. In both instances circadian rhythmicity was demonstrated both before leaving the U.K. and throughout the expedition. The acrophase of the rhythms followed the changes in activity patterns on both expeditions although there was a dissociation between the Cortisol and testosterone following an acute 8 hr phase shift in Spitzbergen. The mesor of Cortisol in both instances tended to be higher than in the U.K. but the difference was never statistically significant. This work demonstrates the feasibility of using salivary steroid concentrations to investigate their circadian rhythmicity in circumstances where frequent blood sampling would be precluded.     

Norepinephrine Turnover in the Hypothalamus of Adult Male Rats: Alteration of Circadian Patterns by Semistarvation

Norepinephrine (NE) turnover, as estimated by 3-methoxy-4-hydroxyphenylethyleneglycol concentration, was studied in the mediobasal hypothalamus of control and semistarved adult male rats at eight time points of a 24-h period. The marked circadian periodicity of NE turnover with a peak in the dark phase in control rats is completely suppressed in semistarved rats. The average 24-h concentration of the NE precursor tyrosine in brain and of tyrosine flow into brain (calculated from plasma amino acid concentrations) is reduced in semistarved rats, but both brain tyrosine and tyrosine flow show continuing circadian fluctuations.     

Evidence for Circadian Variations of Thyroid Hormone Concentrations and Type II 5'-Iodothyronine Deiodinase Activity in the Rat Central Nervous System

Abstract: The 24-h patterns of tissue thyroid hormone concentrations and type II 5'- and type III 5-iodothyronine deiodinase (5'D-II and 5D-III, respectively) activities were determined at 4-h intervals in different brain regions of male euthyroid rats entrained to a regular 12-h light/12-h dark cycle (lights on at 6:00 a.m.). Activity of 5'D-II, which catalyzes the intracellular conversion of thyroxine (T₄) to 3,3',5-triiodo- l -thyronine (T₃) in the CNS, and the tissue concentrations of both T₄ and T₃ exhibited significant daily variations in all brain regions examined. Periodic regression analysis revealed significant circadian rhythms with amplitudes ranging from 9 to 23% (for T₃) and from 15 to 40% (for T₄ and 5'D-II) of the daily mean value. 5'D-II activity showed a marked nocturnal increase (1.3–2.1-fold vs. daytime basal value), with a maximum at the end of the dark period and a minimum between noon and 4:00 p.m. 5D-III did not exhibit circadian patterns of variation in any of the brain tissues investigated. Our results disclose circadian rhythms of 5'D-II activity and thyroid hormone concentrations in discrete brain regions of rats entrained to a regular 12:12-h light-dark cycle and reveal that, in the rat CNS, T₃ biosynthesis is activated during the dark phase of the photoperiod. For all parameters under investigation, the patterns of variation observed were in part regionally specific, indicating that different regulatory mechanisms may be involved in generating the observed rhythms.