Marked Circadian Rhythm Research Articles

Interpretation of TSH results can be improved by reference values fluctuating in time.

The secretion of thyroid stimulating hormone (thyrotropin, TSH), is characterized by a marked circadian rhythm. Plasma or serum TSH values are significantly lower in the afternoon and in the evening as compared to the early morning. As in clinical practice, blood sampling time shows an important variation, a reliable assessment of thyroid status is often not an easy task for the clinician. The biological variation of TSH plays a major role in the intra-individual variability of TSH results in serum or plasma. The observed intra-day variation largely exceeds the reported inter-vendor variation and the coefficient of variation of clinical TSH assays. Therefore, a mathematical solution was sought for correcting interpretation of TSH results for sampling time. We have developed a cosinor model which allows to compensate TSH decision values for the fluctuating serum or plasma TSH concentrations throughout the day. The following mathematical function could be derived: corrected TSH cutoff_value (mIU/L)=0.40+0.24*cos(((π/12) *T)+6) in which T represents the time (hours). This mathematical function can be easily implemented into a laboratory's informatics system and furthermore allows a better tailored diagnosis of (subclinical) hyperthyroidism, regardless the blood sampling time. Implementing the corrected cut-off values result in a marked reduction of apparent (false positive) hyperthyroidism diagnosis, in particular in the afternoon.

Seasonal patterns of body temperature in response to experimental photoperiod variation in a non-hibernating ground squirrel.

Unlike numerous other members of the holarctic Tribe Marmotini of the squirrel family (Sciuridae) that typically exhibit spontaneous bouts of torpor that progress into an annual season of hibernation, members of the genus Ammospermophilus (antelope ground squirrels) do not enter torpor, and they remain active throughout the year in nature. We have experimentally evaluated seasonal patterns of variation in the circadian rhythm of body temperature in captive A. leucurus over a two-and-a-half-year period by exposing groups to either a constant daily photoperiod of 12h light or a seasonally changing photoperiod that cycled between a summer maximum of 16h per day and a winter minimum of 8h; ambient air temperature was maintained at 26°C. All squirrels showed continuous, year-round diurnal locomotor activity, and the group exposed to seasonally changing photoperiod adjusted onset and end of activity to changes in duration of the photoperiod. Animals in both groups showed a marked circadian rhythm of core body temperature with a typical daytime level of about 38°C and nighttime level of about 35°C for most of each year, but the group exposed to naturally changing daylength surprisingly reduced the level of its circadian oscillation by about 2°C at the winter seasonal extreme of shortest daily illumination to a daytime level about 36°C and a nocturnal level of about 33°C. Despite this modest experimentally induced reduction in the level of the circadian rhythm of body temperature, we conclude that A. leucurus shows an overall stable annual pattern of circadian rhythmicity of its core body temperature that is consistent with a lack of any other evidence that the species engages in torpor or hibernation.

From Filled to Empty Time Intervals: Quantifying Online Behaviors with Digital Traces

ABSTRACT Ordinary users fill some intervals on the time continuum by engaging in an online behavior and leave other intervals empty by disengaging from the behavior. Existing time-based measurements of online behaviors exclusively focus on characterizing filled time intervals and completely ignore the information embedded in empty time intervals. Empty time intervals, referring to time gaps between consecutive behaviors, carry important information on how time is organized for online behaviors. By analyzing two behavioral log files on webpage browsing and mobile application use, the study evaluates whether online behaviors characterized by empty time intervals differ from or accord with online behaviors characterized by filled time intervals. Behavioral burstiness, which measures the distribution of empty time intervals in consecutive online behaviors, is found to unveil behavioral patterns that are distinct from temporal duration that measures the overall length of the filled time intervals of online behaviors. Temporal duration is much more extended in mobile use compared with web surfing, whereas behavioral burstiness in mobile use is lower than that in web surfing. Marked circadian rhythms are observed in behavioral burstiness in web surfing and mobile use, whereas circadian rhythms are vague in temporal duration in web surfing and mobile use.

Circadian periodicity and effect of gender, age, diet and smoking on circulating plasma lipid peroxides and antioxidant enzymes in healthy Indians of different age groups

ABSTRACT This study aims at assessing circadian rhythm characteristics of oxidants and antioxidants, testing for any effect of gender, age, diet and smoking status. Blood samples from clinically healthy Indians (103 males and 59 females, 7–75 years of age) were collected at 6-hour intervals for 24 hours for determination of MDA, SOD, CAT, GPx and GR. Data were analyzed by the single and population-mean cosinor to estimate circadian rhythm characteristics. The latter were further analyzed by multi-factor analysis of variance. A marked circadian rhythm was documented for all variables. Its parameters were found to undergo marked changes as a function of age. Males differed from females in terms of the rhythm-adjusted mean (MESOR) of CAT and GPx and of the 24-hour amplitude of GR. The MESOR of GPx differed between vegetarians and omnivores. Smoking status affected the MESOR of MDA and CAT and the 24-hour amplitude of CAT. As oxidative stress is being reported for most diseases, the mapping of circadian rhythms in oxidant and antioxidant enzymes in health may help refine reference values, thereby allowing the early detection of pathophysiological conditions, prompting the early institution of treatment. Abbreviations CAT: Catalase; FRAP: Ferric Reducing Antioxidant Power; GPx: Glutathione Peroxidase; GR: Glutathione Reductase; GSH: Glutathione; MDA: Malondialdehyde; MESOR: Midline Estimating Statistic Of Rhythm; ROS: Reactive Oxygen Species; SCN: Suprachiasmatic Nuclei; SOD: Superoxide Dismutase; TBARs: Thiobarbituric acid reactive substances; XPA: Xeroderma Pigmentosum, Complementation Group A (DNA Damage Recognition And Repair Factor)

The study of the effect of light intensity, temperature and feeding conditions changes on the cardiac activity of crayfish-bioindicators in bioelectronic systems for surface water quality monitoring

Heart rate of crayfish species Astacus leptodactylus (Esch.) was measured continually in the real-time regime during 2 months. Measurements were carried out with non-invasive fiber optic method under laboratory conditions and under factory conditions during the bioindication of the Neva river water quality at the waterworks intake of the water supply station. The effect of light intensity and feeding conditions changes on the crayfish heart rate is studied at 2 temperature values. It is shown that after the acclimation period of crayfish species Astacus leptodactylus a marked circadian rhythm is settled, it has bimodal formation that is connected with the artificial lighting regime «day — night». It is established that 1.5-hour shifts in the lighting regime, feeding and temperature rise from 10 to 18 °С don’t affect circadian periodicity of the rhythm. In this temperature range the temperature value affects only amplitude characteristics of the heart rate rhythm. Feeding causes the short-term rise of the heart rate, that doesn’t impact on the heart rate dynamics of an animal during next 24-hour period. Refs 28. Figs 3. Tables 1.

Circadian Time Structure of Circulating Plasma Lipid Components in Healthy Indians of Different Age Groups.

The circadian rhythm of human circulating lipid components was studied under nearnormal tropical conditions in 162 healthy volunteers (103 males and 59 females; 7 to 75years of age). They followed a diurnal activity from about 06:00 to about 22:00 and nocturnal rest. These volunteers were divided into four groups: Group A (7-20years), Group B (21-40years), Group C (41-60years) and Group D (61-75years), comprising 42, 60, 35 and 25 participants, respectively. A marked circadian rhythm was demonstrated for each studied variable in each group by population-mean cosinor analysis (almost invariably p<0.001). Furthermore, circadian rhythm characteristics were compared among the 4 groups by parameter tests and regressed as a function of age, separately for males and females. A second-order polynomial characterized the MESOR of HDL cholesterol, phospholipids and total lipids, as well as the 24-h amplitude of total cholesterol and phospholipids. The 24-h amplitude of total lipids decreased linearly with age. The 24-h acrophase of the oldest age group (Group D) was advanced in the case of total cholesterol, HDL cholesterol, and total lipids, whereas that of phospholipids was delayed. Mapping the circadian rhythm (an important component of the broader time structure or chronome, which includes a. o., trends with age and extra-circadian components) of lipid components is needed to explore their role in the aging process in health.

Relationships of Circadian Rhythms and Physical Activity With Objective Sleep Parameters in Lung Cancer Patients.

Lung cancer patients undergo various treatments leading to sleep problems, rest-activity circadian rhythms disruption, and reduced levels of physical activity. It is important to understand the relationships among these variables. Appropriate interventions can possibly be implemented to improve sleep quality in lung cancer patients. The objective of this study was to examine the relationships of circadian rhythms and physical activity with objective sleep parameters in 106 of Taiwanese lung cancer patients. This study used a cross-sectional design. The instruments included an actigraph to measure the objective sleep parameters (total sleep time [TST], sleep efficiency, and sleep-onset latency [SOL]), rest-activity circadian rhythms (r24 [24-hour autocorrelation coefficient] and I < O [in-bed less than out-of-bed dichotomy index]), and physical activity frequency (UP activity mean). The daily physical activity amount in minutes was measured by the Bouchard 3-day physical activity record. Patients performing light-intensity physical activity of 295 min/d or greater had better values for the TST, sleep efficiency, SOL, r24, and I < O than those performing less than 295 min/d (all P < .05). Significant predictors of the TST included age (β = -.31), I < O (β = .32), and UP activity mean (β = -.42). Predictors of the SOL included current treatment (β = .20), I < O (β = -.28), UP activity mean (β = .51), and 24-hour light-activity minutes (β = -.23). Marked circadian rhythms and adequate light-intensity physical activity may improve sleep quality in lung cancer patients. Adequate light-intensity physical activity can be an effective intervention to improve sleep quality in lung cancer patients.

Homeobox genes and melatonin synthesis: regulatory roles of the cone-rod homeobox transcription factor in the rodent pineal gland.

Nocturnal synthesis of melatonin in the pineal gland is controlled by a circadian rhythm in arylalkylamine N-acetyltransferase (AANAT) enzyme activity. In the rodent, Aanat gene expression displays a marked circadian rhythm; release of norepinephrine in the gland at night causes a cAMP-based induction of Aanat transcription. However, additional transcriptional control mechanisms exist. Homeobox genes, which are generally known to encode transcription factors controlling developmental processes, are also expressed in the mature rodent pineal gland. Among these, the cone-rod homeobox (CRX) transcription factor is believed to control pineal-specific Aanat expression. Based on recent advances in our understanding of Crx in the rodent pineal gland, we here suggest that homeobox genes play a role in adult pineal physiology both by ensuring pineal-specific Aanat expression and by facilitating cAMP response element-based circadian melatonin production.

Effect of Monochromatic Light on Melatonin Secretion and Arylalkylamine N‐Acetyltransferase mRNA Expression in the Retina and Pineal Gland of Broilers

The goal of this study is to investigate the effects of various monochromatic lights on plasma melatonin (MT) levels and the expression of arylalkylamine N-acetyltransferase (AANAT) mRNA in the pineal gland and retina. A total of 160 newly hatched (posthatching day 1, P1) broilers, including intact, sham-operated, and pinealectomized groups were exposed to blue light (BL), green light (GL), red light (RL), and white light (WL) by light emitting diode (LED) system for short term (24 hr) or long term (2 weeks), separately. For intact and sham-operated birds, the plasma MT level exhibited marked circadian rhythms at P7 and P14 regardless of short-term and long-term exposure to four monochromatic lights. However, WL and BL showed a faint suppression of MT secretion in contrast to GL and RL at either light or dark time points, with the following rank order: GL < RL < WL < BL. Larger circadian amplitude of MT levels was observed in GL group versus BL group (at P14: 87.70 pg/mL vs. 19.85 pg/mL, respectively). Pinealectomy disturbed the MT rhythm under different light colors, especially in RL. Additionally, consistent with the alteration of plasma MT levels, we observed increased AANAT mRNA expression and immunoreactive cell numbers of proliferating cell nuclear antigen (PCNA) and c-Fos in the pineal gland or retina in GL than that of BL, whereas 5-HT immunoreactive cell number was significantly decreased in GL. These data suggested that GL enhanced chick pinealocytes and retinal cells to express AANAT mRNA and to secrete MT, which may be depended on promoting c-Fos expression and cell proliferation.

The effect of timing of teriparatide treatment on the circadian rhythm of bone turnover in postmenopausal osteoporosis

We hypothesized that with the administration of teriparatide (TPTD) treatment at different times, we would be able to modify the physiological circadian rhythm of bone turnover. The concentration of serum C-terminal telopeptide of collagen type I (βCTX), serum N-terminal propeptide of procollagen type I (P1NP), serum ionized calcium (iCa), and plasma PTH were measured every 3 h over a 24 h period in 14 postmenopausal osteoporotic women (aged 72.4±9.3 years) treated with 20 μg TPTD for long term, given at different times of the day. General linear model-repeated measurements (GLM RM) were performed to analyze the circadian rhythms as well as intergroup comparisons. GLM-RM for both related groups showed a significant influence of time of day on all measured variables except P1NP. The analysis for each group separately provided a powerful model for βCTX (P<0.001, η(2)=0.496), serum iCa (P<0.001, η(2)=0.423), plasma PTH (P<0.001, η(2)=0.283), and serum PINP (P<0.001, η(2)=0.248). While the evening TPTD treatment showed a marked circadian rhythm for serum βCTX, the morning TPTD treatment rather suggested circasemidian rhythm. The P1NP rhythm followed a much smaller amplitude of the rhythm than βCTX. Changes in serum iCa were positively related to changes in serum βCTX (P<0.001) and negatively related to changes in PTH (P<0.001). Timing of TPTD administration may significantly change the 24 h variation in bone turnover markers as well as calcium-parathyroid axis in postmenopausal osteoporotic women.

Circadian melatonin profiles during single 24-h shifts in anesthetists

It has been shown that shift work constitutes a great health hazard, particularly when chronodisruption is involved. Anesthetists are used to working for a certain number of 24-h shifts every month. The work-related lack of sleep in combination with light exposure is suspected to alter melatonin courses. The main aim of the present study was to analyze circadian melatonin profiles before, during, and after a 24-h shift in anesthetists and medical students (controls). Furthermore, we evaluated possible differences in melatonin profiles between the groups. Interactions between specific parameters were calculated. Over three consecutive days, including a 24-h shift, urine samples were collected daily at five time points. 6-Sulfateoxymelatonin (aMT6-s) courses were assayed using a commercially available competitive immunoassay kit. Ten anesthetists aged between 29 and 35 years and ten medical students aged between 25 and 31 years were included in the study. aMT6-s fluctuated between nocturnal values of (mean [range]) 2.2 (1.4; 3.0) pg/ml and morning values of 25.5 (12.1; 39.0) pg/ml. A marked circadian rhythm of aMT6-s courses was observed in both groups. Analyses of variance showed an effect of the factor "time" on aMT6-s concentrations but not of the factor "anesthetists versus students". Correlations between aMT6-s, the amount of sleep, and the time since the last extended duration shift could be found. The results show no evidence for a single 24-h shift having a great impact on circadian disruption as evidenced by a similar melatonin profile for both groups over the study phase.

Muscleblind‐like 2: circadian expression in the mammalian pineal gland is controlled by an adrenergic‐cAMP mechanism

Muscleblind-like 2 (Mbnl2) is a zinc finger protein first identified in Drosophila. It appears to be essential for photoreceptor development and to be involved in RNA splicing. Here we report that Mbnl2 is strongly expressed in the rat pineal gland. The abundance of pineal Mbnl2 transcripts follows a marked circadian rhythm with peak levels approximately sevenfold higher at night than day levels. Mbnl2 protein exhibits a similar rhythm. In vitro studies indicate that the abundance of Mbnl2 transcripts and protein are controlled by an adrenergic/cAMP mechanism.

Daily and circadian melatonin release in vitro by the pineal organ of two nocturnal teleost species: Senegal sole ( Solea senegalensis) and tench ( Tinca tinca)

This research aimed to investigate melatonin rhythms in the pineal organ of two nocturnal fish species, sole and tench, which show high sensitivity to light. Pineal organs were cultured in vitro under an LD (12 h light:12 h dark) cycle to study the daily rhythmicity of melatonin release. In addition, the in vitro culture was performed under conditions of constant darkness (DD) to study the endogenous control of the rhythm. In the pineal organs cultured under an LD cycle, rhythmic melatonin release was evident in both species, with low values observed during the photophase (15.6 ± 7.2 and 22.6 ± 2.6 pg/mL for sole and tench, respectively) and high values coinciding with the scotophase (74.0 ± 8.2 and 82.1 ± 9.1 pg/mL, for sole and tench, respectively). Under LD, the rhythm had a period of 24 h ( p < 0.001) and presented similar acrophases for both species, located around 9–10 h after lights off (2 and 3 h before the end of the dark phase). When the pineal organs were cultured under DD, the results differed between the species studied. A marked circadian rhythm in melatonin release by the pineal was registered in tench, with lower values during the subjective day, i.e. the period that was previously day (6.2 ± 1.6 pg/mL) and higher values during the subjective night, i.e. the period that was previously night (20.4 ± 5.5 pg/mL). The rhythm had a mean tau of 24.1 h ( p < 0.01) and the acrophase was located around 12 h after lights off (the beginning of the subjective day), slightly later than that registered under LD conditions. In contrast, melatonin values in sole remained high during darkness (around 92.0 ± 6.9 pg/mL) for four consecutive days, including subjective day periods. In short, these findings revealed that the rhythm of melatonin release in tench is under endogenous control by a circadian oscillator within the pineal organ, while no such pacemaker was evident in sole, which melatonin rhythm appeared to be exclusively light-driven.

Shell gaping behaviour of Pinna nobilis L., 1758: circadian and circalunar rhythms revealed by in situ monitoring

Gaping activity of bivalve molluscs is closely related to physiological process such as breathing, nutrition, responses to environmental stimuli and follows rhythmic cycles in many species. Although the alternation of Sun and Moon is the major entraining agent for the daily living clock-driven rhythms, cyclic extrinsic environmental factors can also modulate gaping activity. Therefore, laboratory experimental conditions can alter the natural behaviour of bivalves, hindering the interpretation of observations. Many features of Pinna nobilis physiology are poorly known, gaping activity not being an exception. To reduce the knowledge gap on this regard, we performed a study on the species gaping activity. The research was designed to be carried out in situ, in order to avoid the interference of laboratory conditions in the observations. To this end, we designed and fabricated a new electronic system composed by a data logger and a sensor formed by multiple reed switches activated by a single magnet. The system is autonomous and can record gaping activity of subtidal bivalves in potentially any type of subtidal environment. Furthermore, it requires little framework for the installation. With this system, we monitored 10 individuals in periods ranging between 3 and 21 days, for up to a total of 98 days. The records have shown that far from being all day open, as previously suggested, P. nobilis follows marked circadian and circalunar rhythms of gaping activity. Individuals usually close the valves during night, sometimes for more than 12 h. The repetition of patterns observed made it possible to distinguish between two main behaviours: (1) night-closing related with sunset and (2) night-opening related with the Moon visible in the sky with the disc illuminated more than 50%. Another two less common trends were also observed: (3) day-closing and (4) night-opening with no visible Moon.

Circadian rhythms in myocardial metabolism and contractile function: influence of workload and oleate

Multiple extracardiac stimuli, such as workload and circulating nutrients (e.g., fatty acids), known to influence myocardial metabolism and contractile function exhibit marked circadian rhythms. The aim of the present study was to investigate whether the rat heart exhibits circadian rhythms in its responsiveness to changes in workload and/or fatty acid (oleate) availability. Thus, hearts were isolated from male Wistar rats (housed during a 12:12-h light-dark cycle: lights on at 9 AM) at 9 AM, 3 PM, 9 PM, and 3 AM and perfused in the working mode ex vivo with 5 mM glucose plus either 0.4 or 0.8 mM oleate. Following 20-min perfusion at normal workload (i.e., 100 cm H(2)O afterload), hearts were challenged with increased workload (140 cm H(2)O afterload plus 1 microM epinephrine). In the presence of 0.4 mM oleate, myocardial metabolism exhibited a marked circadian rhythm, with decreased rates of glucose oxidation, increased rates of lactate release, decreased glycogenolysis capacity, and increased channeling of oleate into nonoxidative pathways during the light phase. Rat hearts also exhibited a modest circadian rhythm in responsiveness to the workload challenge when perfused in the presence of 0.4 mM oleate, with increased myocardial oxygen consumption at the dark-to-light phase transition. However, rat hearts perfused in the presence of 0.8 mM oleate exhibited a markedly blunted contractile function response to the workload challenge during the light phase. In conclusion, these studies expose marked circadian rhythmicities in myocardial oxidative and nonoxidative metabolism as well as responsiveness of the rat heart to changes in workload and fatty acid availability.

Circadian Variation of Angiotensin II and Aldosterone in Nocturnal Enuresis: Relationship to Arterial Blood Pressure and Urine Output

We investigated the circadian rhythm of solute excretion and regulating hormones as well as blood pressure in patients with monosymptomatic nocturnal enuresis. We included 15 patients with a mean age +/- SE of 13.4 +/- 0.9 years who had monosymptomatic nocturnal enuresis with at least 3 wet nights weekly and a control group of 10 healthy children with a similar age and sex distribution. During inpatient circadian studies urine was collected during 6 periods and blood was drawn at 7 time points during 24 hours. Heart rate and blood pressure was recorded with an ambulatory blood pressure monitor every 30 to 60 minutes. The total patient group excreted a significantly larger nocturnal urine volume than controls (p <0.01). Five patients had marked nocturnal polyuria (nocturnal urine volume greater than the mean in the control group +2 SD), whereas urine output in the remaining patients without polyuria were similar to controls. Nocturnal polyuria was caused mainly by increased nocturnal solute excretion, especially Na. Serum aldosterone and plasma angiotensin II showed a marked circadian rhythm in normal children with a nocturnal increase concomitant with a significant decrease in mean arterial blood pressure during sleep. In contrast, the group of patients with nocturnal polyuria showed a lack of circadian rhythm in all excretion variables as well as an attenuated rhythm in plasma angiotensin II and mean arterial blood pressure. Interestingly this group had normal circadian rhythms of the circadian rhythm markers plasma cortisol and heart rate. The study suggests that an abnormally large nocturnal excretion of Na caused by selectively attenuated circadian rhythms of Na regulating hormones might be an important pathogenic factor in monosymptomatic nocturnal enuresis.

Timing and Type of Glucocorticoid Replacement in Adult Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is one of the commonest inherited diseases. Treatment during childhood is directed towards obtaining normal growth. There is an extensive literature on management of CAH during childhood but little published on how patients should be treated as adults. CAH results in increased adrenocorticotropic hormone levels driving the adrenal to produce cortisol and thereby excessive cortisol precursors which are predominantly androgenic. In normal individuals there is a marked circadian rhythm in cortisol release with the lowest levels occurring shortly after midnight and rising between 02.00 and 03.00 h to peak at around 06.00–08.00 h after waking. The treatment of choice for children with CAH is hydrocortisone three times daily. There is no consensus on treating adults. A recent survey by the UK Society for Endocrinology showed that hydrocortisone was the most popular steroid, followed by dexamethasone and then prednisolone. Sixty percent of respondents used a reverse circadian pattern of glucocorticoid treatment and only 16% used a dose based on weight or surface area. In a recent study we demonstrated that the most important variable determining hydrocortisone bioavailability is weight and we advocated a weight-related dosing regimen monitored using a nomogram for serum cortisol.

Potential Role of Pancreatic and Enteric Hormones in Regulating Bone Turnover

Potential Role of Pancreatic and Enteric Hormones in Regulating Bone Turnover

Directed movements and diel burrow fidelity patterns of red tilefish Branchiostegus japonicus determined using ultrasonic telemetry

Wild red tilefish Branchiostegus japonicus were tracked and/or monitored for up to nearly 3 months in Western Wakasa Bay and Maizuru Bay, Japan, using ultrasonic telemetry to examine their movements and burrow fidelity patterns. In Western Wakasa Bay, it is guessed that fish released in relatively shallow waters, about 30 m deep, actively moved into more suitable deeper habitats after their release. In Maizuru Bay, the fish did not undertake large-scale movements and showed burrow fidelity about 1 month after their release. That is, the fish primarily remained in the burrow, which was constructed in the sea-bottom, during the night and moved outside the burrow during the day. The marked circadian rhythm from Fourier analysis indicated a clear diel movement pattern of the red tilefish.

Circadian rhythm of bone turnover markers in breast cancer patients with bone metastases and in control subjects

737 Background: Circadian rhythmicity is an essential feature of bone metabolism. The assessment of diurnal variation in bone resorption and formation markers in cancer patients with bone metastases could provide further insights on tumour induced derangement in bone turnover. Methods: 21 ambulatory breast cancer patients with bone metastases and 20 age-matched controls entered the study. Blood and urine specimens in both groups were collected starting at 8 am every 4 hours till midnight and every 2 hours till 8 am to assess alkaline phosphatase (ALP), Calcium, (Ca), albumin (ALB), cortisol, osteocalcin, cross-laps (CTX) and parathyroid hormone (PTH) in blood and deoxy-pyridinoline (DPD) and n-telopeptide (NTX) in urine. Results: Serum cortisol showed a marked circadian rhythm either in controls or in patients: MESOR 116 ng/dl vs 103.1 ng/dl, amplitude 60.9 ng/dl vs 54.8 ng/dl, acrophase at 6.00 am, (p<0.001) vs at 11.00 am, (p<0.001) respectively. Urinary DPD expressed as variation from individual MESOR showed a significant circadian rhythm either in patients: amplitude 15.4% and acrophase at 9h59 (p<0.001) or in controls: amplitude 13.9%, acrophase at 8h12 (p<0.001). Also urinary NTX showed a diurnal rhythm either in patients: amplitude 11.4%, acrophase at 4h49 (p<0.001) or in controls: amplitude 30.9% at 7h25 (p<0.001). A marked rhythmicity was evident for serum CTX in controls: amplitude 37%, acrophase at 5h55 (p<0.001) and in patients: amplitude 25,2%, acrophase at 2h40 (p<0.001).A significant trend of rhythmicity was evident in cancer patients for osteocalcin (amplitude 5.3%, acrophase 4h50, p=0.08) and PTH (amplitude 18%, acrophase 15h37, p=0.05). No significant circadian rhythm was found for Ca and ALP. Conclusions: Bone resorption markers maintain a circadian rhythmicity in cancer patients. On the basis of these results a randomised trial comparing Zoledronic acid administration day versus night has been conducted. Forty four patients have been enrolled, data on changes in bone turnover markers between the 2 treatment arms will be provided at the meeting. No significant financial relationships to disclose.