Serum magnesium circadian rhythm in human adults with respect to age, sex and mental status

25 subjects volunteered to document circadian changes in serum magnesium. 4 groups were formed: 7 healthy young males (24.0 years +/- 3.9), 6 elderly males (82.5 years +/- 7.5), 6 elderly females 81.2 years +/- 10.7) and 6 elderly insame subjects of both sexes (80.5 years +/- 8.6). They were socially synchronized with a diurnal activity (07.00 to 21.00 for the old subjects; 07.00 to 23.00 for the young ones) and nocturnal rest. The subjects followed a spontaneous diet. Venous blood was sampled at 4-h intervals and fixed clock hours (07.45, 11.45, 15.45, 19.45, 23.45, 03.45) during 24 h. The single cosinor method was used for the statistical analysis of the time series. A statistically significant circadian rhythm is detected in three of the groups: young males, elderly males and elderly females (no rhythm detection in elderly insane subjects). The 24-h mean is higher in elderly subjects than in the young one. The rhythm amplitude is larger in elderly males than in young ones. The acrophase (peak time) location in the 24-h scale is 10.12 h for elderly females, 11.35 h for elderly males and 16.36 h for young males.     

Circadian and seasonal variations of electrolytes in aging humans

The circadian and seasonal variations of a set of routinely determined variables (chloride, sodium, potassium, calcium, inorganic phosphorus, magnesium, creatinine, urea and urate) were documented in young men (mean age ± SD: 24.0 ± 3.9 yr) and in healthy elderly men (75.3 ± 6.6) and women (78.2 ± 9.1). The same urinary variables, except magnesium, were studied in young men. The circadian variability of serum variables was between 2 and 11% except for serum inorganic phosphorus (12–22% according to the group). By contrast, urinary chloride, sodium and potassium revealed large peak-trough differences (55–75%) and the variability of urinary creatinine, urate and urea was also not negligible (20–30%). ANOVA validated seasonal variations for most of the plasma variables and for urinary calcium, phosphorus and uric acid. No age or sex difference in either 24 h means or amplitudes could be observed. These data are of interest for the concept of reference values, for the diagnosis of certain bone and renal disease as well as for chronooptimization in treatment of potential electrolytes deficiency states.     

Melatonin and 6-sulfatoxymelatonin circadian rhythms in serum and urine of primary prostate cancer patients: evidence for reduced pineal activity and relevance of urinary determinations.

The circadian rhythms of melatonin and 6-sulfatoxymelatonin (aMT6s) were analyzed in serum and urine of young men (YM, n = 8), of elderly patients with benign prostatic hyperplasia (BPH, n = 7) and of patients of similar age with primary prostate cancer (PC, n = 9). The data expressed as concentration and in urine also as hourly excreted quantity were analyzed chronobiologically by the single cosinor method and, subsequently submitted to linear regression analyses. Circadian rhythms were detected in all cases except for the excreted quantity of melatonin. The circadian patterns of melatonin and aMT6s in serum were very similar in the different groups and regression analyses showed close correlations between both variables. MESOR and amplitude were significantly depressed in PC (40-60%) as compared to BPH and YM indicating that the depression of serum melatonin in PC is due to a reduced pineal activity and is not caused by an enhanced metabolic degradation in the liver. Acrophases of serum melatonin occurred between 01:34 and 03:26 h and of serum aMT6s between 03:58 and 04:35 h. Circadian rhythms similar to those of serum melatonin and aMT6s were found in urine, particularly for aMT6s excretion as well as melatonin concentration; the determination of both parameters in overnight urine samples closely correlated with the nocturnal peak of circulating melatonin. These results imply that it is feasible to estimate changes in pineal function of prostate cancer patients by means of non-invasive determination using urinary melatonin and aMT6s.     

Food-entrained rhythmic expression of PER2 and BMAL1 in murine megakaryocytes does not correlate with circadian rhythms in megakaryopoiesis

Summary.  Background:  Circadian rhythms control a vast array of biological processes in a broad spectrum of organisms. The contribution of circadian rhythms to the development of megakaryocytes and the regulation of platelet biology has not been defined. Objectives:  This study tested the hypothesis that murine megakaryocytes exhibit hallmarks of circadian control. Methods:  Mice expressing a PER2::LUCIFERASE circadian reporter protein and C57BI/6 mice were used to establish if megakaryocytes expressed circadian genes in vitro and in vivo . Mice were also subjected to 3 weeks on a restricted feeding regime to separate food-entrained from light-entrained circadian rhythms. Quantitative real time polymerase chain reaction (PCR), flow cytometry and imunohistochemistry were employed to analyse gene expression, DNA content and cell-cycle behavior in megakaryocytes collected from mice over a 24-h period. Results:  Megakaryocytes exhibited rhythmic expression of the clock genes mPer2 and mBmal1 and circadian rhythms in megakaryopoiesis. mPer2 and mBmal1 expression phase advanced 8 h to coincide with the availability of food; however, food availability had a more complex effect on megakaryopoiesis, leading to a significant overall increase in megakaryocyte ploidy levels and cell-cycle activity. Conclusions:  Normal megakaryopoiesis requires synchrony between food- and light-entrained circadian oscillators.     

Serum concentration and circadian profiles of cathepsins B, H and L, and their inhibitors, stefins A and B, in asthma

Background: In order to determine the effect of asthma on serum concentrations of cathepsins B, H and L, and stefins A and B, the circadian and concentration profiles were followed in steroid-independent and steroid-dependent asthmatics before and after 1-week treatment with methylprednisolone and cyclosporin A. Methods: Serum samples were taken at 4-h intervals throughout a 24-h period. Cathepsin and stefin concentrations were assayed using specific ELISAs. Data were analysed by one-way ANOVA and least squares fit of 24-h cosine. Results: Temporal analysis of these proteins revealed little or no significant changes with time over a 24-h period. In comparison to normal sera, cathepsin H concentrations were elevated in all asthmatic patients, concentrations of both stefins were decreased in steroid-independent asthmatics, and stefin A concentrations were increased in steroid-dependent asthmatics before therapy. The effect of methylprednisolone treatment was demonstrated on decreased cathepsin B and increased cathepsin L concentrations in post-therapy serum samples. On the other hand, cyclosporin A treatment led to increased concentrations of cathepsins H and L. However, concentrations of stefins A and B were unaffected. Conclusions: This study associated alterations in balance of serum cysteine proteinases and their inhibitors in asthmatic patients, which has raised the possibility of their involvement in asthma pathogenesis. Validated rhythms of cathepsins and stefins in asthmatic sera exhibited temporal differences, which are too small to influence the time of sampling for their quantitative measurement over the course of a day.     

A circadian rhythm of proteinuria in patients with a nephrotic syndrome

Circadian variations in proteinuria were studied in 17 patients with different types of glomerulopathies. During 3-4 successive days urine was collected over periods of 3 h under standardized conditions. Thirteen of the 17 patients showed a circadian rhythm of their proteinuria with a maximum excretion in daytime around 16.00 hours and a minimum excretion at night around 03.00 hours. In the majority of patients the urinary excretory rhythms of albumin, transferrin and immunoglobulin G were 'in phase' with each other and with the circadian rhythm of total protein excretion. Nine patients had a larger degree of rhythmicity for immunoglobulin G than for transferrin excretion. In eight of them a circadian rhythm of the selectivity index of proteinuria was seen with the lowest index at night. No relation was observed between the circadian rhythm of proteinuria and the type of glomerulopathy.     

Circadian rhythms and seasonally dependent variability of arterial pressure in patients with arterial hypertension in the Khanty-Mansiysky region

Key parameters of 24-h blood pressure monitoring (BPM) in 46 18-50-year-old patients (men and women) with arterial hypertension (AH) stage I, II and 33 healthy persons living in the Tyumen North (Khanty-Mansiysky Region, the town of Nyagan) were investigated. The comparison group consisted of 55 patients with AH stage I, II and 33 healthy persons living in moderate climate (Tyumen) matched by sex, age, duration of AH, office systolic and diastolic arterial pressure (SAP, DAP). General patterns of 24-h and seasonal rhythms of AP fluctuations in healthy northerners and citizens of moderate climatic zone and mismatch of these rhythms in AH patients more evident in the northerners are shown. Paired correlations were obtained which indirectly confirm the priority role of daily AP rhythm in development of visceral lesions irrespective of the season of the year and climatic load. In the North, when winter meets spring, a surge of SAP, DAP and mean AP occurs as well as an increase in heart rate, number of patients with disturbed circadian profile of AP. In moderate climate these changes are more typical for summer period. The results of the study necessitate design of programs of additional pharmacological and preventive measures for hypertensive northerners with consideration of AP seasonal rhythms and climatic load.     

A classification of circadian blood pressure profiles using a cumulative chi-squared technique

Non-invasive ambulatory blood pressure monitoring has been used to assess circadian rhythms in blood pressure in a qualitative fashion. However, there are no established methods for assessing circadian changes in blood pressure in a quantitative fashion. In this study, we developed a quantitative method to evaluate the circadian rhythm based on profile analysis and a cumulative chisquare technique. This method was used to analyse the circadian blood pressure variations in 100 normotensive volunteers and 127 hypertensive patients. Three blood pressure profiles were identified for the normotensive group, while four were identified for the hypertensive group. Furthermore, there was a relationship between the discriminate blood pressure profiles and the severity of hypertension. We conclude that profile analysis of 24-h ambulatory blood pressure monitoring may be used to stratify patients with regard to the risk of complications of hypertension.     

A classification of circadian blood pressure profiles using a cumulative chi-square technique

Non-invasive ambulatory blood pressure monitoring has been used to assess circadian rhythms in blood pressure in a qualitative fashion. However, there are no established methods for assessing circadian changes in blood pressure in a quantitative fashion. In this study, we developed a quantitative method to evaluate the circadian rhythm based on profile analysis and a cumulative chi-square technique. This method was used to analyse the circadian blood pressure variations in 100 normotensive volunteers and 127 hypertensive patients. Three blood pressure profiles were identified for the normotensive group, while four were identified for the hypertensive group. Furthermore, there was a relationship between the discriminate blood pressure profiles and the severity of hypertension. We conclude that profile analysis of 24-h ambulatory blood pressure monitoring may be used to stratify patients with regard to the risk of complications of hypertension.     

The Circadian Clock: From Molecules to Behaviour

Circadian rhythms are a cardinal feature of living organisms. The stereotypical organization of homeostatic, endocrine and behavioural variables around the 24-hour cycle constitutes one of the most conserved attributes among species. It is now well established that circadian rhythmicity is not a learned behaviour, but is genetically transmitted and therefore subject to genetic manipulations. Recent advances in the circadian field have demonstrated that circadian oscillations are cell autonomous, that the circadian mechanism operates through a negative feedback loop and that a growing number of genes is under circadian control. Furthermore, single-gene mutations have been isolated in mammals that have profound effects on circadian behaviour. The production and mapping of one of these mutations in the mouse, an organism about which there exists a wealth of genetic information, should accelerate the elucidation of the molecular events involved in the generation of circadian rhythms in mammals.     

Diurnal changes of biochemical metabolic markers in healthy young males – the Bispebjerg study of diurnal variations

Background. To examine whether time of the day has an effect on the circulating levels of metabolism parameters. Methods. Venous blood samples were obtained under standardized conditions from 24 healthy young men every third hour through 24 hours. The metabolic markers and melatonin were examined at each time-point and data were analyzed by rhythmometric statistical methods. Results. The normal 24-h rhythms of the participants were confirmed by significant oscillation of melatonin (p < 0.0001). Cosinor analysis revealed significant diurnal 24-h rhythms of five of the seven examined markers: Total cholesterol (p = 0.01, amplitude (amp) = 0.18 mmol/L) peaking in the early afternoon, Glucose (p < 0.0001, amp = 0.35 mmol/L) peaking around midnight, C-peptide (p < 0.001, amp = 360 pmol/L), triglyceride (p < 0.0001, amp = 0.37 mmol/L) peaking in the afternoon and low-density lipoprotein cholesterol (p = 0.003, amp = 0.16 mmol/L) peaking in the morning. C-peptide, triglyceride, and glucose had the highest 24-h oscillations in proportion to the reference ranges of the parameters for healthy young men. Glycated haemoglobin (HbA1c) (p = 0.07, amp = 0.57 mmol/L) and high-density lipoprotein (p = 0.09, amp = 0.06 mmol/L) did not show significant oscillations. Conclusions. When diagnosing and monitoring metabolic disorders compensation for the 24-h variation of the biochemical metabolic markers is needed especially C-peptide, triglyceride and glucose. Furthermore, the stable HbA1c level through 24 h makes it an accurate diagnostic test for diabetes mellitus.     

Chronomics of circulating plasma lipid peroxides and anti-oxidant enzymes and other related molecules in cirrhosis of liver: In the memory of late Shri Chetan Singh

Background.The chronome (from chronos, time, and nomos, rule; time structure) of lipid peroxidation and anti-oxidant defense mechanisms may relate to the efficacy and management of preventive and curative chronotherapy.Patients and methods.Thirty patients with liver cirrhosis, 25–45 years of age, and 60 age-matched clinically healthy volunteers were synchronized for 1 week with diurnal activity from about 06:00 to about 22:00 and nocturnal rest. Breakfast was around 08:30, lunch around 13:30 and dinner around 20:30. Drugs known to affect the free-radical system were not taken. Blood samples were collected at 6-h intervals for 24 h under standardized, presumably 24-h synchronized conditions. Determinations included plasma lipid peroxides, in the form of malondialdehyde (MDA), blood superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) activities, and serum total protein, albumin, ascorbic acid, and uric acid concentrations.Results.A marked circadian variation was demonstrated for each variable in each group by population-mean cosinor (P < 0.01). In addition to anticipated differences in overall mean value (MESOR), patients differed from healthy volunteers also in terms of their circadian pattern.Conclusion.Mapping the broader time structure (chronome) with age and multifrequency rhythm characteristics of antioxidants and pro-oxidants is needed for exploring their putative role as markers in the treatment and management of liver cirrhosis.     

Continuous administration of synthetic ovine corticotropin-releasing factor in man. Physiological and pathophysiological implications.

The continuous 24-h infusion of a maximally stimulating dose (1 micrograms/kg per h) of ovine corticotropin-releasing factor (CRF) in man caused a modest elevation of plasma cortisol (17.2 +/- 1.4 micrograms/dl) and urinary-free cortisol (173 +/- 43 micrograms/24 h) concentrations, which was far less than that seen with a maximally stimulating dose of ACTH (50.4 +/- 2.2 micrograms/dl and 1,200 +/- 94 micrograms/24 h, respectively). The circadian rhythms of plasma ACTH and cortisol were preserved during CRF administration. An intravenous bolus injection of 1 microgram/kg of ovine CRF given to normal volunteers under basal conditions resulted in elevated plasma ACTH and cortisol peak levels (28 +/- 6 pg/ml and 15.0 +/- 1.0 micrograms/dl, respectively). However, no plasma ACTH and cortisol responses were observed when an identical CRF stimulation test was given at the end of the continuous infusion. These findings suggest that the stimulatory activity of exogenous CRF on the ACTH-secreting cells of the pituitary gland is restrained by the negative feedback of cortisol. The persistent circadian rhythm of ACTH, despite a constant level of plasma CRF during the infusion, suggests that the circadian variation in the activity of the hypothalamic-pituitary-adrenal axis cannot be explained solely by circadian periodicity of the endogenous CRF stimulus.     

Circadian phase resetting in older people by ocular bright light exposure.

BACKGROUND: Aging is associated with frequent complaints about earlier bedtimes and waketimes. These changes in sleep timing are associated with an earlier timing of multiple endogenous rhythms, including core body temperature (CBT) and plasma melatonin, driven by the circadian pacemaker. One possible cause of the age-related shift of endogenous circadian rhythms and the timing of sleep relative to clock time is a change in the phase-shifting capacity of the circadian pacemaker in response to the environmental light-dark cycle, the principal synchronizer of the human circadian system. METHODS: We studied the response of the circadian system of 24 older men and women and 23 young men to scheduled exposure to ocular bright light stimuli. Light stimuli were 5 hours in duration, administered for 3 consecutive days at an illuminance of approximately 10,000 lux. Light stimuli were scheduled 1.5 or 3.5 hours after the CBT nadir to induce shifts of endogenous circadian pacemaker to an earlier hour (phase advances) or were scheduled 1.5 hours before the CBT nadir to induce shifts to a later hour (phase delays). The rhythms of CBT and plasma melatonin assessed under constant conditions served as markers of circadian phase. RESULTS: Bright light stimuli elicited robust responses of the circadian timing system in older people; both phase advances and phase delays were induced. The magnitude of the phase delays did not differ significantly between older and younger individuals, but the phase advances were significantly attenuated in older people. CONCLUSIONS: The attenuated response to light stimuli that induce phase advances does not explain the advanced phase of the circadian pacemaker in older people. The maintained responsiveness of the circadian pacemaker to light implies that scheduled bright light exposure can be used to treat circadian phase disturbances in older people.     

Mechanistic modeling of the effects of glucocorticoids and circadian rhythms on adipokine expression

A mechanism-based model was developed to describe the effects of methylprednisolone (MPL), circadian rhythms, and the glucose/free fatty acid (FFA)/insulin system on leptin and adiponectin expression in white adipose tissue in rats. Fifty-four normal Wistar rats received 50 mg/kg MPL intramuscularly and were sacrificed at various times. An additional set of 54 normal Wistar rats were sacrificed at 18 time points across the 24-h light/dark cycle and served as controls. Measurements included plasma MPL, glucocorticoid receptor (GR) mRNA, leptin mRNA, adiponectin mRNA, plasma leptin, adiponectin, glucose, FFA, and insulin. MPL pharmacokinetics was described by a two-compartment model with two absorption components. All measured plasma markers and mRNA expression exhibited circadian patterns except for adiponectin and were described by Fourier harmonic functions. MPL caused significant down-regulation in GR mRNA with the nadir occurring at 5 h. MPL disrupted the circadian patterns in plasma glucose and FFA by stimulating their production. Plasma glucose and FFA subsequently caused an increase in plasma insulin. Furthermore, MPL disrupted the circadian patterns in leptin mRNA expression by stimulating its production. This rise was closely followed by an increase in plasma leptin. Both leptin mRNA and plasma leptin peaked at 12 h after MPL and eventually returned back to their circadian baselines. MPL and insulin had opposing effects on adiponectin mRNA expression and plasma adiponectin, which resulted in biphasic pharmacodynamic profiles. This small systems model quantitatively describes, integrates, and provides additional insights into various factors controlling adipokine gene expression.     

Circasemidian rather than circadian variation of circulating osteoprotegerin in clinical health

Osteoprotegerin (OPG) serves as a soluble decoy receptor for RANKL to inhibit osteoclast formation and activity. Hormones such as PTH and glucocorticoids have been reported to decrease OPG concentrations, while estrogens, transforming growth factor b, related bone morphogenic factor and thrombopoietin reportedly enhance the OPG production in the osteoblastic and bone stromal cells. Since bone turnover shows a prominent circadian rhythm in laboratory animals and humans, with bone resorption increasing at night, we investigated the time structure of circulating OPG concentrations in a group of nine healthy subjects (six women and three men; in the age range of 26–49 years). Blood samples for OPG determination were collected every 4 h for 24 h on the same day, starting at 08:00 in the morning. Data were analyzed by inferential statistical procedures, including the single and population-mean cosinor. A 12-h component was found to characterize serum OPG concentrations (P = 0.038) with peak concentrations around noon and midnight. No statistically significant circadian rhythm of OPG concentrations could be found by cosinor in our study population. The mean 24-h OPG concentration was higher in women than in men (mean ± S.E.: 3.13 ± 0.44 vs. 1.94 ± 0.26 pmol/l, Student t = 2.325, P = 0.053). Since PTH concentrations also exhibit a bimodal pattern along the 24-h scale, PTH may be tested as a putative determinant of the observed changes in serum concentrations of osteoprotegerin.     

Characteristics of infradian and circadian rhythms in the persistent vegetative state

This retrospective study investigated the circadian and infradian characteristics of blood pressure and heart rate in 26 patients with traumatic head injury in a persistent vegetative state (PVS). Systolic and diastolic blood pressures and heart rate were measured every hour for the first 240 h (10 days) following hospital admission. These data were analysed for the presence of circadian and infradian rhythms using the least-squares fit of the cosine function with the single cosinor method. Infradian rhythms were defined as biological rhythms with a period of approximately 7 days (circaseptan rhythms). All the patients studied had circadian and circaseptan rhythms of systolic and diastolic blood pressures and heart rate. The amplitudes of all the circaseptan rhythms were significantly greater than those of the corresponding circadian rhythms. It was concluded that there was an altered association between circadian and infradian blood pressure and heart rate rhythms in patients in a PVS. Circadian and infradian rhythms were present, but the infradian rhythm had a greater amplitude than the circadian rhythm.     

Circadian variation of cardiac autonomic regulation during 24-h bed rest

Summary. We examined the effect of circadian variation on cardiac autonomic regulation in 11 young and middle-aged, healthy men during 24-h bed rest. Cardiac parasympathetic regulation expressed significant circadian variation: sensitivity of baroreceptor reflex, standard deviation of R-R intervals and the power of high frequency component of R-R interval variability (HFP) increased during the evening (2000–2100 h), were highest during the night (0200–0300 h), and gradually decreased again towards afternoon (1400–1500 h). Cardiac sympathetic regulation, the power of medium frequency component of R-R interval variability (MFP), did not show any significant circadian variation. The autonomic response to orthostatic stress changed after the 24-h bed rest; the sympathetic dominance in response to assuming upright position was before bed rest principally attributable to increased sympathetic activity (MFP increase), whereas after bed rest this was due to withdrawal of parasympathetic activity (HFP decrease). We conclude that the effect of circadian variation must be taken into account, while assessing cardiac autonomic regulation in patients with acute cardiovascular disorders.