Significant Circadian Variation Research Articles

Dark Agouti and Fischer 344 rats: differential behavioral responses to morphine and biochemical differences in the ventral tegmental area

We sought to identify behavioral and biochemical differences between Dark Agouti and Fischer 344 inbred rat strains to assess whether they could serve as a model of genetically determined differences in sensitivity to drugs of abuse. We compared the strains for the following traits: morphine-induced locomotor activity and sensitization; circadian variation in plasma levels of corticosterone, a hormone reported to affect sensitivity to drugs of abuse; and several biochemical parameters in the ventral tegmental area and nucleus accumbens, brain regions implicated in the locomotor activating and reinforcing actions of drugs of abuse. Fischer 344 rats exhibited greater initial locomotor responses to morphine but, unlike Dark Agouti rats, did not develop sensitization to a second morphine exposure. Fischer 344 rats displayed a marked rise in basal plasma corticosterone levels in the late light phase and early dark phase, whereas Dark Agouti rats showed no significant circadian variation in corticosterone levels. Relative to drug-naive Fischer 344 rats, drug-naive Dark Agouti rats showed higher levels of tyrosine hydroxylase and glial fibrillary acidic protein, and lower levels of neurofilament proteins, in the ventral tegmental area. In contrast, no strain differences were found in levels of tyrosine hydroxylase, specific G protein subunits or protein kinase A in the nucleus accumbens. Together, these results demonstrate that Dark Agouti rats and Fischer 344 rats exhibit differences in specific behavioral, endocrine and biochemical parameters related to sensitivity to drugs of abuse.

Circadian Variation in the Expression of Cell-Cycle Proteins in Human Oral Epithelium

At the tissue level, there is experimental and clinical data to suggest a cytokinetic coordination of the cell cycle with a greater proportion of cycling cells entering S-phase and mitosis at specific times of the day. The association of certain cell-cycle proteins with defined events in the cell cycle is well established and may be used to study the timing of cell-cycle phases over 24 hours. In this study oral mucosal biopsies were obtained from six normal human volunteers at 4-hour intervals, six times over 24 hours. Using immunohistochemistry, the number of positive cells expressing the proteins p53, cyclin-E, cyclin-A, cyclin-B1, and Ki-67 was determined for each biopsy and expressed as the number of positive cells per mm of basement membrane. We found a statistically significant circadian variation in the nuclear expression of all of these proteins with the high point of expression for p53 at 10:56 hours, cyclin-E at 14:59 hours, cyclin-A at 16:09 hours, cyclin-B1 at 21:13 hours, and Ki-67 at 02:50 hours. The circadian variation in the nuclear expression of cyclins-E (G1/S phase), -A (G2-phase), and -B1 (M-phase) with a normal physiological progression over time suggests a statistically significant circadian variation in oral epithelial cell proliferation. The finding of a circadian variation in the nuclear expression of p53 protein corresponding to late G1 is novel. This information has clinical implications regarding the timing of chemotherapy and radiotherapy.

Circadian Variations in Natural Coagulation Inhibitors Protein C, Protein S and Antithrombin in Healthy Men: A Possible Association with Interleukin-6

Recent observations describe an increase in platelet aggregability and a decrease in fibrinolytic activity in the early morning hours. To determine whether anticoagulant proteins also show such a circadian variation we measured protein C (PC), protein S (PS), antithrombin (AT) and heparin cofactor-II (HC-II) levels on venous plasma samples taken from 10 healthy men at three-hour intervals throughout a 24-hour period. To investigate the possible temporal mapping of circadian periodicity, we also measured plasma levels of beta-thromboglobulin (beta-TG) as an indicator of platelet activation, and interleukin-6 (IL-6) as one of the possible regulatory factors that drive this rhythm. Blood samples were drawn at 6 a.m., 9 a.m., noon, 3 p.m., 6 p.m., 9 p.m. and midnight. PC, IL-6 and beta-TG were measured by ELISA, PS and AT by latex immune assay and HC-II by chromogenic substrate method. A significant circadian variation was found in PC, PS, AT, beta-TG and IL-6, but not in HC-II levels. PC, PS, IL-6 and beta-TG were at their peaks at 6 a.m., and nadirs at a time from noon to midnight. AT peak was at 6 p.m. and nadir at noon. The regression of PS on IL-6 was significant. Although the fluctuations of PS and AT were within the normal ranges during the day, some PC levels of two subjects were below the lower normal limit (0.70). These data indicate that PC, PS, and AT show a marked circadian periodicity as the other components of the blood coagulation and fibrinolytic system do. The similar trends in plasma concentrations of PC, PS, beta-TG and IL-6 may be coincidental, but could reflect a common regulatory mechanism or an effect on each other. The clinical implications of these physiological changes in coagulation inhibitors and the role of IL-6 in the anticoagulant response deserve further studies.

Exhaled nitric oxide is higher both at day and night in subjects with nocturnal asthma.

Nitric oxide in exhaled air is thought to reflect airway inflammation. No data have been reported so far on circadian changes in NO in subjects with nocturnal asthma. To determine whether exhaled NO shows a circadian rhythm inverse to the circadian rhythm in airway obstruction in subjects with nocturnal asthma, we conducted a study involving six healthy controls, eight individuals without nocturnal asthma (4-h to 16-h variation in peak expiratory flow [PEF] <= 15%), and six individuals with nocturnal asthma (4-h to 16-h PEF variation > 15%). Smoking, use of corticosteroids, and recent respiratory infections were excluded. NO concentrations were measured at 12, 16, 20, and 24 h, and at 4, 8, and 12 h of the next day, using the single-breath method. At the same times, FEV1 and PEF were also measured. Mean NO concentrations were significantly higher in subjects with nocturnal asthma than in subjects without nocturnal asthma, and higher in both groups than in healthy controls at all time points. Mean exhaled NO levels over 24 h correlated with the 4-h to 16-h variation in PEF (r = 0.61, p < 0.01). Exhaled NO did not show a significant circadian variation in any of the three groups as assessed with cosinor analysis, in contrast to the FEV1 in both asthma groups (p < 0.05). At 4 h, mean +/- SD NO levels were higher than at 16 h in subjects with nocturnal asthma; at 50 +/- 20 ppb versus 42 +/- 15 ppb (p < 0.05); other measurements at all time points were similar. Differences in NO and FEV1 from 4 h to 16 h did not correlate with one another. We conclude that subjects with nocturnal asthma exhale NO at higher levels both at night and during the day, which may reflect more severe diurnal airway-wall inflammation. A circadian rhythm in exhaled NO was not observed. NO levels did not correspond to the circadian rhythm in airway obstruction. The small increase in NO at 4 h may indicate an aspect of inflammation, but it is not associated with increased nocturnal airway obstruction.

Expression of epithelial markers in nocturnal asthma

Background: Although the airway epithelium participates in inflammation and repair, the circadian expression of epithelial cell markers involved in these processes has not been investigated. Objective: We sought to determine whether expression of CD51 (vitronectin and fibronectin receptor), CD54 (intercellular adhesion molecule-1), HLA-DR (activation marker), CD29 (β1 integrin), CD49b (collagen receptor), and CD11b (complement receptor) exhibit a circadian rhythm in asthma. Methods: Eleven patients with nocturnal asthma (NA), 9 subjects with nonnocturnal asthma (NNA), and 10 control subjects underwent bronchoscopy at 4 pm and 4 am in a random order 1 week apart, with brushing of the proximal and distal airways. The percentage of cells staining for a particular marker was determined. Results: At 4 pm, HLA-DR in the proximal airways and CD54 in the distal airways was significantly greater in control subjects as compared with asthmatic subjects (HLA-DR, control subjects: 10.0% [range, 5.0% to 21.0%]; NNA: 8.0% [range, 4.0% to 14.5%] NA: 3.5% [range, 2.0% to 6.0%], P = .01; CD54, control subjects: 17.0% [range, 8.0% to 25.0%], NNA: 8.0% [range, 5.3% to 11.5%], NA: 7.0% [range, 4.0% to 15.0%], P = .03). At 4 am, CD51 in the distal airways was significantly greater in patients with NA as compared with patients with NNA and control subjects (control subjects, 23.0% [range, 13.8% to 30.5%]; NNA, 32.0% [range, 13.0% to 35.0%]; NA, 40.0% [range, 23.0% to 50.0%], P = .05). Expression of CD51 in the distal airways correlated with the degree of airway obstruction ( r = –0.57, P = .001). Control subjects exhibited significant circadian variation in the expression of HLA-DR in the proximal airways and CD54 in the distal airways. Conclusion: The increased CD51 at night in patients with NA may be related to increased airway inflammation and repair processes in response to injury. The circadian changes in CD54 and HLA-DR in control subjects require further study to determine their significance. (J Allergy Clin Immunol 1998;102:376-81.)

Expression of vasoactive intestinal peptide mRNA in the suprachiasmatic nuclei of the circadian tau mutant hamster

The tau mutation of the Syrian hamster is one of only two mutations currently known to affect the circadian system in mammals. In order to investigate the molecular mechanisms associated with this mutation, we have compared the level of expression of the mRNA for vasoactive intestinal peptide (VIP) in the suprachiasmatic nuclei (SCN) and cerebral cortex of homozygous tau mutant and wild-type animals using in situ hybridization histochemistry. We observed no significant circadian variation in this message within the SCN, cingulate cortex or parietal cortex of either genotype. Comparison between genotypes indicated a significantly higher signal for VIP mRNA in the SCN of tau animals. This phenotypic effect within the SCN raises the possibility that some of the circadian consequences of the tau mutation are associated with an increased expression of the VIP gene.

Circadian variation in the timing of stroke onset: a meta-analysis.

Acute myocardial infarction and sudden death display a circadian rhythm, with a higher risk between 6 AM and noon. Some reports suggest that stroke does not follow such a circadian variation and that hemorrhagic stroke occurs more often during the evening. A meta-analysis of 31 publications reporting the circadian timing of 11,816 strokes was performed, subdividing (when possible) by the type of stroke, according to the time of onset of symptoms. When precise timing was not given, strokes were distributed evenly (that is, biasing toward the null hypothesis of lack of circadian variation). All subtypes of strokes displayed a significant (P<0.001) circadian variation in time of onset, whether divided into 3-, 4-, or 6-hour time periods. There was a 49% increase (95% confidence interval, 44% to 55%) in stroke of all types between 6 AM and noon (compared with expectations if no circadian variation was present), which is a 79% (95% confidence interval, 72% to 87%) increase over the normalized risk of the other 18 hours of the day. There were 29% fewer strokes between midnight and 6 AM, a 35% decrease compared with the other 18 hours of the day. All three subtypes of stroke had a significantly higher risk between 6 AM and noon (55% for 8250 ischemic strokes; 34% for 1801 hemorrhagic strokes, and 50% for 405 transient ischemic attacks). These data support the presence of a circadian pattern in the onset of stroke, with a significantly higher risk in the morning.

The Study of Biobehavioral Rhythms in a Psychology Laboratory Course

Eighteen students participated in an experiential exercise on circadian rhythms as part of the laboratory component of a psychology course. Participants measured their heart rate, blood pressure, mood, alertness, and visuomotor-cognitive performance. Measures showed significant circadian variation; they were strongly correlated and peaked at different times, providing support for a multioscillatory view of circadian control. Evaluation indicated students found this laboratory interesting, personally relevant, and helpful in understanding the importance of rhythms.

Chronobiology of Symptomatic Supraventricular Paroxysmal Tachycardia

The circadian, circaseptenal and circaannual occurrence of supraventricular paroxysmal tachycardias (SVPT) were examined in patients addressing an Emergency Department. Sixty-one patients, 22 men and 39 women aged 48.3+13.0 y, were eligible and investigated during a solar year. Cosinor method indicated a significant circadian SVPT variation, with an acrophase at about 6 p.m. A similar periodicity was also detected in supraventricular premature beat prevalence (acrophase at 3 h 31 min), concordant with heart rate peaking. Monday was the most frequently affected day, while the circa-annual analysis disclosed a peak in summer and autumn. Our findings provide further evidence that SVPT shows the highest occurrence during daytime, in possible connection with adrenergic influence. Moreover there are clues that cyclic stressors, e.g. the ones connected with working-activity resumption or climate influence, may partly condition SVPT appearance during the week or the year.

Circadian Variation in Plasma Levels of Free-Form Tissue Facter Pathway Inhibitor Antigen in Patients With Coronary Spastic Angina

Tissue factor pathway inhibitor (TFPI) is known to inhibit the initial reaction in the tissue factor-mediated coagulation pathway. We measured plasma free-form TFPI antigen levels and monitored 24-h Holter recordings at 06.00, 14.00 and 22.00 h in 15 patients with coronary spastic angina, 13 patients with stable exertional angina, and 11 control subjects. There was a significant circadian variation in plasma free-form TFPI antigen levels in patients with coronary spastic angina (25.8+/-2.0 ng/ml at 06.00 h, 21.1+/-1.6 ng/ml at 14.00 h, and 20.2+/-1.4 ng/ml at 22.00 h; p<0.01). Furthermore, free-form TFPI antigen levels at 06.00 h were significantly higher in coronary spastic angina patients than in patients with stable exertional angina or control subjects (p<0.01). Free-form TFPI antigen levels increased after the ischemic attacks in coronary spastic angina (p<0.01). This circadian variation correlated with the frequency of attacks, with the peak level occurring between midnight to early morning in patients with coronary spastic angina.

Circadian Variation of Urinary Type I Collagen Crosslinked C-Telopeptide and Free and Peptide-Bound Forms of Pyridinium Crosslinks

This study was performed to investigate the circadian variation of urinary CrossLaps (CTx), which was the type I collagen peptide released during bone matrix degradation, and peptide-bound and free forms of urinary pyridinium crosslinks. Urine was obtained during the 24 h of the study in seven separate collections as follows: from 23:00 h to the first void (FV) followed by FV at 11:00, 11:00–14:00, 14:00–17:00, 17:00–20:00, 20:00–23:00, and 23:00 h to FV the next morning. Total, free, and peptide-bound pyridinoline (Pyr) and deoxypyridinoline (Dpyr) excretion measured by high-performance liquid chromatography (HPLC) and CTx measured by enzyme-linked immunosorbent assay in nine premenopausal women aged 22–40 years and nine osteoporotic women aged 65–83 years was analyzed. Among three parameters of Pyr measured by HPLC, a significant day and night difference was found only in total Pyr (21.9% higher at night than during the day in premenopausal women and 24.0% in osteoporotic women, whereas no significant day and night variation was found in free and peptide-bound Pyr in either group. In contrast, total and peptide-bound Dpyr were significantly (37.9% and 66.9%) higher at night than those during the day in premenopausal women (38.0%) and osteoporotic women (48.8%). For free Dpyr, there were no day and night differences in the two groups. The day and night variances were significantly greater in peptide-bound Dpyr than with total Dpyr in both groups. In urinary CTx, a significant circadian variation with a peak at night and a nadir at 17:00 h was found ( p < 0.0001) (premenopausal was 54.0% higher at night than during the day; osteoporotic was 38.4%). In conclusion, urinary CTx represented remarkable circadian variation compared with urinary pyridinium crosslinks measured by HPLC. Furthermore, free pyridinium crosslinks did not undergo a circadian variation. Peptide-bound crosslinks might contribute mostly to the circadian variation of total excretion of pyridinium crosslinks.

Is there circadian variation of plasma endothelin (ET-1) in patients with systemic scleroderma (SSc)?

Forty-three patients with systemic scleroderma (SSc), 10 with non-SSc (6 cases of systemic lupus erythematosus and 4 cases of dermatomyositis), 14 cases of mild- or non-sclerotic type of scleroderma with capillaroscopic abnormalities of nailfolds (SSD; scleroderma spectrum disorders) and 10 healthy volunteers (HC) were subjected to examination of plasma levels of endothelin-1 (ET-1). The sex ratios (male/female) in the patients with SSc, non-SSc and HC were 7:36, 4:6 and 0:10, and the ranges of their ages were 22–74, 19–78 and 33–62 years old, respectively. The plasma levels of ET-1 in SSD, SSc (Barnett I;15), SSc (Barnett II;16), SSc (Barnett III;12 cases), non-SSc and HC were 1.67±0.37, 2.04±0.58, 2.04±0.68, 1.85±0.41, 1.91±0.7 and 1.31±0.34 pg/ml, respectively, confirming previous results from other laboratories. The plasma levels of ET-1 statistically differ between each collagen disease (SSD, SSc and non-SSc) and HC using Student's t-test ( P<0.05). Although a statistically significant difference was obtained in the plasma levels of ET-1 between the SSc group (6 cases) and HC (6 cases) measured at 06:00, 12:00, 18:00 and 24:00 h, there was no significant circadian variation of plasma levels of ET-1 at these times in both the SSc group and HC. The present study revealed that (1) the ET-1 level in HC showed no circadian fluctuation, and remained at a low level (0.8–1.6 pg/ml). (2) When compared to HC, ET-1 in blood plasma of patients with SSc was elevated (0.3–3 pg/ml) throughout the day and night ( P<0.05). (3) ET-1 tended to increase more at midnight (24:00 h) in the SSc group without PSL treatment, though no statistical significance was obtained. (4) TAT showed a significant increase at noon (12:00 h) suggesting coagulation activity in patients with SSc, but PIC did not show a significant increase compared to HC. In conclusion, the observed increase of vasoconstrictive ET-1 in the patients with SSc throughout the day and night may make maintenance of peripheral blood flow more difficult, may have some biological origin and should be further investigated.

Serum bone alkaline phosphatase isoenzyme levels in normal children and children with growth hormone (GH) deficiency: a potential marker for bone formation and response to GH therapy.

Serum bone alkaline phosphatase (B-ALP) has been considered to be a good marker for bone formation. Recently, a specific immunoradiometric assay for serum B-ALP has been developed. Using this system, we measured the serum levels of B-ALP in 363 normal children (207 males and 156 females, age 0-18 yr) and in 20 GH-deficient children (age 5-13 yr) who showed significant bone growth during GH therapy. We found the following results. 1) There were no significant circadian variations in serum B-ALP levels (coefficients of variation: 2.10-9.66%). 2) In normal children, serum B-ALP levels were high in infants and gradually declined and increased again during puberty. During the pubertal period, the highest serum B-ALP values were observed at midpuberty (stage 3 of breast and pubic hair development and 4-12 mL of testicular volume). 3) Serum B-ALP levels were significantly correlated with levels of the carboxy-terminal propeptide of type 1 procollagen (r = 0.447, P < 0.0001) and osteocalcin (r = 0.433, P < 0.0001). 4) After beginning GH therapy, serum B-ALP levels increased significantly; a 26% increase in serum B-ALP level was observed after 3 months of GH therapy. 5) The ratio between serum B-ALP level after 3 months of GH therapy and before GH therapy was positively correlated with the GH-induced improvement in the height SD score (height SD score after 1 yr of GH therapy minus that before GH therapy) and improvement in the height velocity SD score (height velocity SD score during GH therapy minus before GH therapy) (r = 0.531, P < 0.05 and r = 0.608, P < 0.01, respectively). 6) The increment of SD score in serum B-ALP level after 1 yr of GH treatment was also significantly correlated with that for bone mineral density after 1 yr of GH therapy (r = 0.663, P < 0.005). These results show that B-ALP levels are a useful marker for bone formation because B-ALP levels increased when the growth rate accelerated. Serum B-ALP is a potential predictor of the effectiveness of GH therapy, because the serum level after 3 months of GH therapy reflects the outcome of 1 yr of GH therapy.

Psychophysiological measures of anesthetic depth

The effects of isoflurane at three different doses (0.75, 1.68, and 2.17 MAC) were examined in 12 male rats at two different times of day on baseline and in response to a tactile stimulus (tailpinch) and an auditory stimulus (click). Dependent measures included anterior-parietal and posterior-parietal electrocorticograms (ECoGs), heart rate (HR), respiration, and gross body movement. The ECoG was the measure most sensitive in distinguishing anesthetic dose, whereas gross body movement exhibited the least sensitivity. Finally, although there were significant circadian variations in the ECoG, HR, and respiration for baseline doses of isoflurane, circadian variation in anesthetic action was not demonstrated. The data support the notion that animals can experience stimuli under anesthesia to which they do not, or cannot, exhibit motor responses.

Circadian cell cycle variations of erythro- and myelopoiesis in humans.

By use of a multiparameter flow cytometric method with specific surface markers, circadian (24-h) variations in cell cycle distribution have been studied in 19 healthy male volunteers by sampling bone marrow (BM) every 4-5 h during 24-h periods. Admixture of peripheral blood during the sampling was specifically adjusted for, and the fractions of cells in DNA synthetic phase were measured for different hemopoietic cell lineages. Significant circadian variations in DNA S-phase were demonstrated both in myelo- and erythropoiesis of the human BM, with 75% (myeloid) and 80% (erythroid) of the volunteers showing highest activity (values) of DNA S-phase during the day and lowest activity (values) between midnight and 04:00 h. A temporal relationship in the circadian variation of S-phase and G2/M-phase was demonstrated between the myeloid and erythroid cell lineages. The highest fractions of S-phase cells were found in erythropoiesis, while the highest circadian stage dependent variation was found in myelopoiesis. The existence of a similar phasing in DNA synthetic activity for myelopoietic and erythropoietic cells in the human bone marrow indicates that the circadian rhythmicity of hemopoiesis may be caused by a common regulatory mechanism. These findings may be relevant with regard to optimizing the use of cytotoxic drugs and hemopoietic growth factors by taking into consideration the intrinsic (endogenous) circadian variation in proliferative activity of human BM subpopulations.

Chronobiologic evolution of luteinizing hormone secretion in adolescence: developmental patterns and speculations on the onset of the polycystic ovary syndrome

Objective: To investigate the long-term evolution of the LH circadian profile in adolescent women with anovulatory cycles and normal or elevated LH levels in the first evaluation. Design: Prospective controlled clinical study. Setting: Reproductive endocrinology unit of an academic medical center. Patient(s): Twelve healthy anovulatory adolescent girls aged 12 to 17 years (5 subjects with high plasma LH level and 7 subjects with normal LH level) and four ovulatory subjects as controls. Intervention(s): Blood samples were drawn every 20 minutes for 24 hours beginning at 10:00 A.M. at early and late gynecologic ages. Main Outcome Measure(s): Luteinizing hormone, FSH, E 2, T, androstenedione, ovarian volume. Result(s): In the first evaluation, the highest plasma LH levels and greatest pulse amplitude were found early in the morning in the normal-LH group and late in the afternoon in the high-LH group. Controls did not display any significant circadian variation in LH secretion. The second evaluation revealed ovulatory cycles in six of seven subjects (85.7%) in the normal-LH group with the disappearance of the circadian rhythm. Two of five (40%) patients with high LH in the first evaluation became ovulatory with a significant decrease of mean LH levels and the disappearance of the circadian rhythm. Girls of both groups who remained anovulatory still displayed the accentuated circadian profiles that were seen at the first evaluation. Conclusion(s): An accentuated 24-hour LH periodicity is typical of puberty but disappears in adulthood. The persistence of these rhythms in persistently anovulatory adolescents may indicate a maturational arrest. In particular, the persistence of the high LH circadian profile with the highest values during the day is very similar to that found in polycystic ovary syndrome.

Attenuation or absence of circadian and seasonal rhythms of acute myocardial infarction.

OBJECTIVES: To examine the circadian, seasonal, and weekly rhythms of acute myocardial infarction, and to identify subgroups in whom the rhythms are attenuated or absent to provide further information about...

Morning or evening administration of nasal calcitonin? Effects on biochemical markers of bone turnover

The purpose of this study was to examine the effect of intranasal salmon calcitonin (sCT) administration (200 IE), given either in the morning (8:00) or evening (21:00), on the known circadian variation in biochemical markers of bone turnover. An open, placebo-controlled, randomized, crossover study, with three 24 h studies of blood samples drawn every third hour and urine collected in 3 h aliquots was undertaken. Subjects consisted of nine healthy postmenopausal women, aged 58 ± 7 years. Urinary CrossLaps (a measure of bone resorption) was measured by ELISA and corrected for creatinine (Cr). Serum osteocalcin (sOC) was measured by radioimmunoassay (RIA). The first 24 h study was performed without intervention. Prior to this control study the participants were randomized to either morning (8:00) or evening (21:00) sCT (200 IE). sCT administrations were given 4–5 days prior to and during the second study. After a washing-out period of 2 weeks the participants were given 200 IE of sCT at the reverse time of the day 5 days prior to and during the third study. At all timepoints, urinary CrossLaps/Cr exhibited a significant ( p < 0.001) circadian rhythm with its zenith in early morning and nadir in late afternoon. Both morning and evening administration of sCT significantly decreased the urinary excretion of CrossLaps/Cr approximately 3–6 h after administration with a subsequent rebound effect. sOC did not exhibit a significant circadian variation and was not affected by the calcitonin. The 24 h mean urinary CrossLaps/Cr and sOC remained unchanged. Both morning and evening sCT significantly decreased the urinary excretion of CrossLaps/Cr 3–6 h after administration, with a rebound effect approximately 12 h later. However, the present study does not indicate that neither evening nor twice-daily administration is superior to morning administration.

Patterns and behavior of transient myocardial ischemia in stable coronary disease are the same in both men and women: A comparative study

Objectives. This study sought to compare the circadian variations in transient ischemic activity, mean heart rate and ischemic threshold between women and men with coronary artery disease.Background. There is a circadian variation in ischemic activity, onset of myocardial infarction and sudden cardiac death in patients with coronary artery disease, but studies assessing ischemia have incorporated predominantly male subjects.Methods. Thirty-one women and 45 men underwent at least 48 h of ambulatory ST segment monitoring.Results. There was a similar and significant circadian variation in ischemic activity in both women and men (p < 0.001 and p < 0.0001, respectively), with a trough at night, a surge in the morning and a peak between 1 and 2 pm, corresponding to a similar circadian variation in mean hourly heart rate (p < 0.0001) that was not different between men and women (p = 0.28, power to detect a shift 99.9%). Mean heart rate at onset of ischemia (ischemia threshold) had similar variability in women and men (p = 0.96), and harmonic regression analysis confirmed a significant circadian variation (p < 0.0001), with a trough at night and a peak during activity hours. Heart rate increased significantly in the 5 min before ischemia throughout the 24 h (p < 0.0001), with no gender differences in the pattern of preonset to onset heart rate changes over time (p = 0.52); the smallest differences were recorded in the middle of the night. The majority of ischemic episodes (80%) had a heart rate increase >5 beats/min in the 5 min before ischemia, but there were no gender differences.Conclusions. Women with coronary artery disease have a pattern of ischemic activity and underlying pathophysiologic mechanisms very similar to men. The importance of increase in myocardial oxygen demand in the genesis of ischemia in both men and women is reflected by similar magnitude of heart rate increases before ischemia. The lower ischemic threshold during the nocturnal hours, when blood pressure is also lower, is consistent with a circadian variation is underlying coronary vascular tone.

Circadian rhythm of the urinary crosslinks pyridinoline and deoxypyridinoline in normal human and involutional osteoporosis

Urinary pyridinoline (Pyr) and deoxypyridinoline (Dpyr) are collagen crosslinks found in bone and cartilage and are sensitive bone resorption markers. In this study, values of urinary Pyr and Dpyr during 24-h periods in 6 normal men, 10 normal women, and 10 osteoporotic patients were measured. In these three groups, urinary Pyr and Dpyr showed significant circadian variations only in normal men. Neither urinary Pyr nor Dpyr showed significant circadian variations in normal women or osteoporotic subjects, although they had the same trend as the diurnal changes of urinary crosslinks in normal men. Comparing the values of urinary crosslinks in the daytime (11:00–20:00 h) and at night (20:00–11:00 h), the latter were significantly higher than the former in both normal and osteoporotic subjects. Furthermore, the nighttime and daytime difference of urinary Pyr in osteoporotic subjects was significantly larger than those in normal subjects. Urinary Pyr and Dpyr were 22.6% and 10.7% higher, respectively, at night compared to during the day in normal women, while in osteoporotic patients, the values were 51.2% and 25.5% higher at night than during the day, respectively. In conclusion, the acceleration of bone resorption at night may be one of the etiologies of involutional osteoporosis.