Disturbance of circadian rhythms in analgosedated intensive care unit patients with and without craniocerebral injury

Melatonin, cortisol, heart rate, blood pressure, spontaneous motor activity, and body temperature follow stable circadian rhythms in healthy individuals. These circadian rhythms may be influenced or impaired by the loss of external zeitgebers during analgosedation, critical illness, continuous therapeutic intervention in the intensive care unit (ICU), and cerebral injury. This prospective, observational, clinical study examined 24 critically ill analgo-sedated patients, 13 patients following surgery, trauma, or acute respiratory distress (ICU), and 11 patients with acute severe brain injury following trauma or cerebral hemorrhage (CCI). Blood samples for the determination of melatonin and cortisol were obtained from each patient at 2 h intervals for 24 h beginning at 18:00 h on day 1 and ending 16:00 h on day 2. Blood pressure, heart rate, body temperature, and spontaneous motor activity were monitored continuously. Level of sedation was assessed using the Ramsey Sedation Scale. The severity of illness was assessed using the APACHE-II-score. The time series data were analyzed by rhythm analysis with the Chronos-Fit program, using partial Fourier series with up to six harmonics. The 24 h profiles of all parameters from both groups of patients were greatly disturbed/abolished compared to the well-known rhythmic 24 h patterns in healthy controls. These rhythm disturbances were more pronounced in patients with brain injury. The results of this study provide evidence for a pronounced disturbance of the physiological temporal organization in ICU patients. The relative contribution of analgosedation and/or brain injury, however, is a point of future investigation.     

Marker rhythms of circadian system function: a study of patients with metastatic colorectal cancer and good performance status

Cancer patients may exhibit normal or altered circadian rhythms in tumor and healthy tissues. Four rhythms known to reflect circadian clock function were studied in 18 patients with metastatic colorectal cancer and good performance status. Rest-activity was monitored by wrist actigraphy for 72 h before treatment, and its circadian rhythm was estimated by an autocorrelation coefficient at 24h and a dichotomy index that compared the activity level when in and out of bed. Blood samples (9-11 time points, 3-6 h apart) were drawn on day 1 and day 4 of the first course of chronochemotherapy (5-fluorouracil: 800 mg/m2/day; folinic acid: 300 mg/m2/day; oxaliplatin: 25 mg/m2/day). Group 24h rhythms were validated statistically for plasma concentrations of melatonin, 6-alpha-sulfatoxymelatonin, and cortisol and for lymphocyte counts. Significant individual 24h rhythms were displayed in melatonin by 15 patients, cortisol by seven patients, lymphocytes by five patients, and prominent circadian rhythms in activity were displayed by 10 patients; only one patient exhibited significant rhythms in all the variables. The results suggest the rhythms of melatonin, cortisol, lymphocytes, and rest/activity reflect different components of the circadian system, which may be altered differently during cancer processes. Such 24h rhythm alterations appeared to be independent of conventional clinical factors.     

Marker rhythms of circadian system function: a study of patients with metastatic colorectal cancer and good performance status

Cancer patients may exhibit normal or altered circadian rhythms in tumor and healthy tissues. Four rhythms known to reflect circadian clock function were studied in 18 patients with metastatic colorectal cancer and good performance status. Rest–activity was monitored by wrist actigraphy for 72 h before treatment, and its circadian rhythm was estimated by an autocorrelation coefficient at 24h and a dichotomy index that compared the activity level when in and out of bed. Blood samples (9–11 time points, 3–6 h apart) were drawn on day 1 and day 4 of the first course of chronochemotherapy (5-fluorouracil: 800 mg/m²/day; folinic acid: 300 mg/m²/day; oxaliplatin: 25 mg/m²/day). Group 24h rhythms were validated statistically for plasma concentrations of melatonin, 6-α-sulfatoxymelatonin, and cortisol and for lymphocyte counts. Significant individual 24h rhythms were displayed in melatonin by 15 patients, cortisol by seven patients, lymphocytes by five patients, and prominent circadian rhythms in activity were displayed by 10 patients; only one patient exhibited significant rhythms in all the variables. The results suggest the rhythms of melatonin, cortisol, lymphocytes, and rest/activity reflect different components of the circadian system, which may be altered differently during cancer processes. Such 24h rhythm alterations appeared to be independent of conventional clinical factors.     

The circadian intracranial pressure would be a prognostic factor in traumatic brain injury?

Traumatic brain injury (TBI) generally influences circadian rhythms and has been implicated changes in circadian rhythm. Whether TBI-induced changes in circadian rhythm may affect the prognosis or recovery from TBI remains to be investigated. Sixty-two patients with TBI were continuously monitored for intracranial pressure (ICP) during the first 24 hours after the implantation of ICP monitor. The data from each patient were analyzed using the least squares fit of a 24-h cosine function by single cosinor method. Parameters of circadian A (Amplitude)/M (MESOR) were used to evaluate the circadian rhythm of the patients. Student’s t-test and Pearson’s chi-squared test were utilized to analyze the differences between good prognosis group and poor prognosis. A linear regression analysis was then applied to calculate the correlation between circadian A/M of ICP and Glasgow Coma Scale (GCS) before discharge, the Extended Glasgow Outcome Scale (GOS-E), the dosage of mannitol, and time spent in the intensive care unit (ICU), respectively. The results demonstrated that circadian A/M of patients’ ICP exhibited a positive correlation with GCS scores taken before discharge, GOS-E scores, and was negatively correlated with the amount of mannitol, and time spent in the ICU. We conclude that changes in the ICP circadian rhythm in TBI patients could reflect an internal signal of brain damage and, therefore, may be useful to predict a patient’s prognosis and recovery from TBI.     

Circadian rhythms of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), cortisol, and melatonin in women with breast cancer

Background: Circadian rhythms in plasma concentrations of many hormones and cytokines determine their effects on target cells. Methods: Circadian variations were studied in cortisol, melatonin, cytokines (basic fibroblast growth factor [bFGF], EGF, insulin-like growth factor-1 [IGF-1]), and a cytokine receptor (insulin-like growth factor binding protein-3 [IGFBP-3]) in the plasma of 28 patients with metastatic breast cancer. All patients followed a diurnal activity pattern. Blood was drawn at 3h intervals during waking hours and once during the night, at 03:00. The plasma levels obtained by enzyme-linked immunoassay (ELISA) or radioimmunoassay (RIA) were evaluated by population mean cosinor (using local midnight as the phase reference and by one-way analysis of variance (ANOVA). Results: Cortisol and melatonin showed a high-amplitude circadian rhythm and a superimposed 12h frequency. bFGF showed a circadian rhythm with an acrophase around 13:00 with a peak-to-trough interval (double amplitude) of 18.2% and a superimposed 12h frequency. EGF showed a circadian rhythm with an acrophase around 14:20, a peak-to-trough interval of 25.8%, and a superimposed 12h frequency. IGF-1 showed a high value in the morning, which is statistically different t test) from the low value at 10:00, but a regular circadian or ultradian rhythm was not recognizable as a group phenomenon. IGFBP-3 showed a low-amplitude (peak-to-trough difference 8.4%) circadian rhythm with the acrophase around 11:00 and low values during the night. Conclusions: (1) Circadian periodicity is maintained in hospitalized patients with metastatic breast cancer. (2) Ultradian (12h) variations were superimposed on the circadian rhythms of the hormones and several of the cytokines measured. (3) Studies of hormones and cytokines in cancer patients have to take their biologic rhythms into consideration. (4) The circadian periodicity of tumor growth stimulating or restraining factors raises questions about circadian and/ or ultradian variations in the pathophysiology of breast cancer. (Chronobiology International, 18(4), 709-727)     

Hypoxic alterations of cortisol circadian rhythm in man after simulation of a long duration flight

Fatigue is often reported after long duration flights. Mild hypobaric hypoxia caused by pressurisation may be involved in this effect through disruption of circadian rhythms, independently of the number of time zones crossed. In this controlled crossover study, we assessed the effects of two levels of hypoxia equivalent to 8000 and 12,000 ft on the circadian rhythm of plasma cortisol, a marker of the circadian time structure. Sixteen healthy young male volunteers (23-39 years) were exposed in a hypobaric chamber for 8 h (08:00-16:00 h) to 8000 ft, followed 4 weeks later to 12,000 ft. Plasma cortisol was assayed during two 24-h cycles (control and hypoxic exposure) every 2h in all subjects. We found a significant change in the pattern of cortisol secretion during both hypoxic exposures, with an initial fall in cortisol followed by a transient rebound, whereas the phase and the 24-h mean level remained unchanged. The change in cortisol pattern followed the alterations in autonomic balance assessed by heart rate variability (HRV) spectral analysis. The normalised high frequencies and the low-to-high frequencies ratio showed a significant shift toward sympathetic dominance with some differences in time course for both altitudes studied. HRV analysis improved the interpretation of cortisol 24-h profiles. Our data, which strongly suggest that prolonged mild hypoxia alters the expression of cortisol circadian rhythm, should be taken into account to interpret secretory rhythm changes after transmeridian flights.     

Daily rhythms of pituitary-ovarian function in the immature hamster are independent of adrenal and pineal influence

In female hamsters, the daily rhythm of LH appeared on the 15th or 16th day after birth with a peak occurring at about 16:00 h (14L:10D, lights on 06:00 h). Progesterone concentrations increased and became rhythmic a few days later. In serum samples collected at 14, 16, 18, 20, 25, 30, 40 and 60-62 days of age between 13:00 and 23:00 h, significant rhythms of serum cortisol and corticosterone concentrations were not detected before 25 days of age; furthermore, the phase of the rhythms did not stabilize to the adult pattern until about 40 days of age. As in the adult, significant rhythms were present in both sexes and the levels of cortisol were greater than those of corticosterone. Injection of pig ACTH (50 i.u./kg body wt, i.p.) significantly increased serum cortisol by 10 days of age, but corticosterone did not respond until 25 days of age. Thus, for cortisol at least, the appearance of 24-h rhythms in the serum is probably not dependent on the ability of the adrenal to respond to ACTH. Ovariectomy had no effect on the late afternoon surge of serum cortisol; similarly, adrenalectomy of immature females did not abolish the surge of LH. Ovariectomy did not alter the daily rhythm of pineal melatonin content and pinealectomy had no effect on the daily afternoon surge of LH. These results demonstrate functional independence of circadian rhythms in the pituitary-gonadal axis and the pituitary-adrenal axis of the immature hamster and also independence of daily rhythms of pineal melatonin and pituitary release of LH.     

Alteration of the Circadian Rhythm in Peak Expiratory Flow of Nocturnal Asthma Following Nighttime Transdermal β2‐adrenoceptor Agonist Tulobuterol Chronotherapy

We investigated the efficacy of nighttime transdermal tulobuterol (β₂‐adrenoceptor agonist) chronotherapy for nocturnal asthma by assessing changes both in the frequency of symptoms and features of the circadian rhythm in peak expiratory flow (PEF), a measure of airway caliber. Thirteen patients with nocturnal asthma were evaluated before and during tulobuterol patch chronotherapy, applied once daily in the evening for 6 consecutive days. Patients were asked to record their PEF every 4 h between 03:00 and 23:00 h for one day. Circadian rhythms in PEF were examined by group‐mean cosinor analysis. The group average PEF at 03:00 h, the time during the 24 h when PEF is generally the poorest, before the application of the chronotherapy, when asthma was unstable and nocturnal symptoms frequent, was 276±45 L/min. Application of the tulobuterol patch at nighttime significantly increased (p<0.001) the 03:00 h group average PEF to 363±67 L/min. Significant circadian rhythms in PEF were observed during the span of study when nocturnal symptoms were frequent as well as with the use of the tulobuterol patch. Before the initiation of tulobuterol chronotherapy, the bathyphase (trough time of the circadian rhythm) in PEF narrowed to around 04:00 h, and the group circadian amplitude was 28.8 L/min. In contrast, the group circadian amplitude significantly (p<0.01) decreased to 10.4 L/min, and the 24 h mean PEF increased significantly with tulobuterol patch chronotherapy. These changes indicate that tulobuterol chronotherapy significantly increased both the level and stability of airway function over the 24 h. The circadian rhythm in PEF varied with the severity and frequency of asthmatic symptoms with and without the nighttime application of the tulobuterol patch medication. We conclude that the parameters of the circadian rhythm of PEF proved useful both in determining the need for and effectiveness of tulobuterol chronotherapy for nocturnal asthma.     

Circadian placebo and ACTH effects on urinary cortisol in arthritics

The effect of placebo and ACTH-1-17 (Synchrodyn®, Hoechst) upon urinary free cortisol was examined at 5 different circadian stages on 10 men with Steinbrocker Stage II–III rheumatoid arthritis. A mean cosinor analysis of urinary cortisol data from the subjects prior to treatment with either ACTH or placebo revealed a statistically highly-significant rhythm. A circadian variation in a response of urinary free cortisol to a placebo was also seen. Moreover, the response of the midline-estimating statistic of rhythm (rhythm-adjusted circadian average) of urinary free cortisol to ACTH-1-17 by patients with rheumatoid arthritis is circadian rhythmic. This reactivity rhythm is out of phase with the spontaneous rhythm in urinary cortisol acrophases—in the tests limited thus far to midsummer. The further assessment of the circadian component in the context of broader interactions by rhythms with other frequencies in various conditions in health and disease is warranted by the demonstration of rhythms here presented for men with rheumatoid arthritis.     

Time Dependency in the Regenerative Response to Injury of the Rat Corneal Epithelium

In the present study a central corneal epithelial defect (diameter 3.5 mm) was made in both eyes at 12:00 h in one group of rats and at 24:00 h in another group to see if the regenerative proliferation is influenced by circadian rhythms. The labeling index and the mitotic rate were registered at 4-h intervals in the perilimbal conjunctiva, the limbal area, and different parts of the cornea from the following morning until noon the day after that. The most pronounced regenerative proliferation was seen in the midperipheral and peripheral cornea. The regenerative response occurred in both groups 24-28 h after the injury, but was highly influenced by the normal circadian rhythms, especially with regard to the mitotic rate. The results support the theory that even regeneration is influenced by a circadian proliferative factor.     

Alteration of the circadian rhythm in peak expiratory flow of nocturnal asthma following nighttime transdermal beta2-adrenoceptor agonist tulobuterol chronotherapy

We investigated the efficacy of nighttime transdermal tulobuterol (beta2-adrenoceptor agonist) chronotherapy for nocturnal asthma by assessing changes both in the frequency of symptoms and features of the circadian rhythm in peak expiratory flow (PEF), a measure of airway caliber. Thirteen patients with nocturnal asthma were evaluated before and during tulobuterol patch chronotherapy, applied once daily in the evening for 6 consecutive days. Patients were asked to record their PEF every 4h between 03:00 and 23:00 h for one day. Circadian rhythms in PEF were examined by group-mean cosinor analysis. The group average PEF at 03:00 h, the time during the 24 h when PEF is generally the poorest, before the application of the chronotherapy, when asthma was unstable and nocturnal symptoms frequent, was 276 +/- 45 L/min. Application of the tulobuterol patch at nighttime significantly increased (p < 0.001) the 03:00 h group average PEF to 363 +/- 67 L/min. Significant circadian rhythms in PEF were observed during the span of study when nocturnal symptoms were frequent as well as with the use of the tulobuterol patch. Before the initiation of tulobuterol chronotherapy, the bathyphase (trough time of the circadian rhythm) in PEF narrowed to around 04:00h, and the group circadian amplitude was 28.8 L/min. In contrast, the group circadian amplitude significantly (p < 0.01) decreased to 10.4 L/min, and the 24 h mean PEF increased significantly with tulobuterol patch chronotherapy. These changes indicate that tulobuterol chronotherapy significantly increased both the level and stability of airway function over the 24 h. The circadian rhythm in PEF varied with the severity and frequency of asthmatic symptoms with and without the nighttime application of the tulobuterol patch medication. We conclude that the parameters of the circadian rhythm of PEF proved useful both in determining the need for and effectiveness of tulobuterol chronotherapy for nocturnal asthma.     

Circadian placebo and ACTH effects on urinary cortisol in arthritics

The effect of placebo and ACTH-1-17 (Synchrodyn®, Hoechst) upon urinary free cortisol was examined at 5 different circadian stages on 10 men with Steinbrocker Stage II–III rheumatoid arthritis. A mean cosinor analysis of urinary cortisol data from the subjects prior to treatment with either ACTH or placebo revealed a statistically highly-significant rhythm. A circadian variation in a response of urinary free cortisol to a placebo was also seen. Moreover, the response of the midline-estimating statistic of rhythm (rhythm-adjusted circadian average) of urinary free cortisol to ACTH-1-17 by patients with rheumatoid arthritis is circadian rhythmic. This reactivity rhythm is out of phase with the spontaneous rhythm in urinary cortisol acrophases—in the tests limited thus far to midsummer. The further assessment of the circadian component in the context of broader interactions by rhythms with other frequencies in various conditions in health and disease is warranted by the demonstration of rhythms here presented for men with rheumatoid arthritis.     

Changes in salivary cortisol concentrations during a 24-hour period in dogs.

The purpose of this investigation was to clarify whether salivary cortisol secretion in dogs had a circadian rhythm. Saliva sampling during a 24-hour period was performed in 4 non-consecutive days. Eight adult beagle dogs (4 males and 4 females) were divided into 4 groups, and 2 dogs (1 male and 1 female) were used for each repetition. Saliva samples were taken at 1 h intervals from 9:00 a. m. to 9:00 a. m. of the following day. Salivary cortisol concentrations were determined using enzyme-linked immunosorbent assay. No circadian rhythm was detected for salivary cortisol, and the differences among salivary cortisol concentrations measured every hour were not demonstrated during a 24-hour period in dogs.     

Circadian Rhythm Variation in Attempted Suicide by Deliberate Self-Poisoning, and in Completed Suicide, in Central Nepal

Daily rhythms are described in almost every variable that can be measured, including suicide rate. The present study aims to find if circadian rhythm exist in suicidal poisoning and completed suicide due to poisoning in central Nepal. The study included all the attempted suicide cases admitted in Patan Hospital and all the completed suicide cases by poisoning reported to Kathmandu District Police during March 2002 to April 2003. The time was grouped into 24 increments of 1 hour. The data were analysed by Kolmogorov-Smirnov test and cosinor analysis. The circadian rhythm of attempted suicide by deliberate self poisoning exhibits a peak at 18:00 h, whereas no circadian rhythm is seen in completed suicides by poisoning although it is bimodal in distribution (6:00-12:00 and 15:00-20:00) with peaks at 7:00 and 18:00 h.     

Rhythmic cortisol secretion in the equine: Analysis and physiological mechanisms

Abstract

Four Thoroughbred mares (no. 1–4) were maintained under constant temperature (24°C) and controlled light (L/D:12/12 with lights on at 06.00 hr) conditions. They were fed and watered ad libitum with fresh feed and water given at 09.00 hr. After a 45‐day pre‐conditioning period, blood samples were obtained by veinipuncture at 4‐hr intervals for 14 days to determine circadian and day‐to‐day variation. The horses exhibited a circadian rhythm with maximum values attained at about 12.00 hr, however, there are periods of days in which no rhythm is distinguishable. Ultradian rhythms with mean periods of 105 to 128 and 24 to 31 min are superimposed upon the circadian rhythm. The individual rhythms are quite variable from horse to horse and within the same horse. During periods of decline in plasma cortisol with metabolic half‐lives of approximately 70 min, secretion of cortisol was very low or had ceased. During periods of increasing plasma concentration, secretion was occurring at a faster rate than degradation. Rapid decreases in plasma concentration (metabolic half‐life of approximately 30 min) was accompanied by a rise in specific activity indicating cortisol with a high specific activity was entering the plasma pool from other storage pools.     

Consistent changes in the circadian rhythms of blood pressure and atrial natriuretic peptide in congestive heart failure.

We demonstrated in previous works that the circadian rhythms of blood pressure (BP) and atrial natriuretic peptide (ANP) are antiphasic in normal subjects and in essential hypertension. The aim of the present study was to assess the circadian rhythms of BP and ANP in 20 patients with stable congestive heart failure (CHF), divided into two groups of 10 according to their New York Heart Association functional class. A matched control group of 10 normal volunteers was also studied. Noninvasive BP monitoring at 15-min intervals was performed for 24 h. Peripheral blood samples were also obtained at 4-h intervals starting from 08:00 h. The mean (+/- SEM) circadian mesors of ANP plasma levels were 13.4 +/- 1.7 pmol/L in the control group, 28.6 +/- 2.4 pmol/L in the group of 10 patients in class II, and 81.5 +/- 12 pmol/L in the group of 10 patients in class III-IV. In normal subjects, plasma ANP concentration was highest at 04:00 h (21.5 +/- 2.7 pmol/L) and lowest at 16:00 h (8.8 +/- 2.4 pmol/L; p less than 0.01). Both groups of patients with CHF showed no significant circadian change in the plasma levels of ANP and also a significantly blunted circadian rhythm of BP. Cosinor analysis confirmed the loss of the circadian rhythms of ANP and BP in CHF patients. Our findings support the existence of a causal relationship between the circadian rhythms of ANP and BP.     

Neuro-endocrine correlations of hypothalamic-pituitary-thyroid axis in healthy humans

Neuro-endocrine hormone secretion is characterized by circadian rhythmicity. Melatonin, GRH and GH are secreted during the night, CRH and ACTH secretion peak in the morning, determining the circadian rhythm of cortisol secretion, TRH and TSH show circadian variations with higher levels at night. Thyroxine levels do not change with clear circadian rhythmicity. In this paper we have considered a possible influence of cortisol and melatonin on hypothalamic-pituitary-thyroid axis function in humans. Melatonin, cortisol, TRH, TSH and FT4 serum levels were determined in blood samples obtained every four hours for 24 hours from ten healthy males, aged 36-51 years. We correlated hormone serum levels at each sampling time and evaluated the presence of circadian rhythmicity of hormone secretion. In the activity phase (06:00 h-10:00 h-14:00 h) cortisol correlated negatively with FT4, TSH correlated positively with TRH, TRH correlated positively with FT4 and melatonin correlated positively with TSH. In the resting phase (18:00 h-22:00 h-02:00 h) TRH correlated positively with FT4, melatonin correlated negatively with FT4, TSH correlated negatively with FT4, cortisol correlated positively with FT4 and TSH correlated positively with TRH. A clear circadian rhythm was validated for the time-qualified changes of melatonin and TSH secretion (with acrophase during the night), for cortisol serum levels (with acrophase in the morning), but not for TRH and FT4 serum level changes. In conclusion, the hypothalamic-pituitary-thyroid axis function may be modulated by cortisol and melatonin serum levels and by their circadian rhythmicity of variation.     

CIRCADIAN RHYTHM IN PEAK EXPIRATORY FLOW: ALTERATION WITH NOCTURNAL ASTHMA AND THEOPHYLLINE CHRONOTHERAPY*

We investigated changes in the circadian rhythm of peak expiratory flow (PEF) in seven persons with nocturnal asthma for a 24h span when (1) they were symptom free and their disease was stable, (2) their asthma deteriorated and nocturnal symptoms were frequent, and (3) they were treated with theophylline chronotherapy. Subjects recorded their PEF every 4h between 07:00 and 23:00 one day each period. Circadian rhythms in PEF were assessed using the group-mean cosinor method. The circadian rhythm in PEF varied according to asthma severity. Significant circadian rhythms in PEF were detected during the period when asthma was stable and when it was unstable and nocturnal symptoms were frequent. When nocturnal symptoms were present, the bathyphase (trough time) of the PEF rhythm narrowed to around 04:00; during this time of unstable asthma, the amplitude of the PEF pattern increased 3.9-fold compared to the symptom-free period. No significant group circadian rhythm was detected during theophylline chronotherapy. Evening theophylline chronotherapy proved to be prophylactic for persons whose symptoms before treatment had occurred between midnight and early morning. Changes in the characteristics of the circadian rhythm of PEF, particularly amplitude and time of bathyphase, proved useful in determining when to institute theophylline chronotherapy to avert nocturnal asthma symptoms. (Chronobiology International, 17(4), 513–519, 2000)     

Circadian rhythm in peak expiratory flow: alteration with nocturnal asthma and theophylline chronotherapy

We investigated changes in the circadian rhythm of peak expiratory flow (PEF) in seven persons with nocturnal asthma for a 24h span when (1) they were symptom free and their disease was stable, (2) their asthma deteriorated and nocturnal symptoms were frequent, and (3) they were treated with theophylline chronotherapy. Subjects recorded their PEF every 4h between 07:00 and 23:00 one day each period. Circadian rhythms in PEF were assessed using the group-mean cosinor method. The circadian rhythm in PEF varied according to asthma severity. Significant circadian rhythms in PEF were detected during the period when asthma was stable and when it was unstable and nocturnal symptoms were frequent. When nocturnal symptoms were present, the bathyphase (trough time) of the PEF rhythm narrowed to around 04:00; during this time of unstable asthma, the amplitude of the PEF pattern increased 3.9-fold compared to the symptom-free period. No significant group circadian rhythm was detected during theophylline chronotherapy. Evening theophylline chronotherapy proved to be prophylactic for persons whose symptoms before treatment had occurred between midnight and early morning. Changes in the characteristics of the circadian rhythm of PEF, particularly amplitude and time of bathyphase, proved useful in determining when to institute theophylline chronotherapy to avert nocturnal asthma symptoms. (Chronobiology International, 17(4), 513-519, 2000)     

Circadian rhythm in prostatic acid phosphatase (PAP): a potential tumor marker rhythm in prostatic cancer (PCa)

In order to define circadian states for an earlier diagnosis and for optimal response to treatment, the possibility of a circadian rhythm in serum PAP was investigated in subjects with and without prostatic cancer. Two groups of subjects were investigated: a. 12 patients affected by PCa, further subdivided in two subgroups: 1. without metastasis (6 patients) and 2. with metastatic disease (6 patients); b. 9 age-matched healthy control subjects. Controls and PCa patients were synchronized before starting the study with standardized meal times and nocturnal rest (22(00) to 06(00) ). Venous blood samples were drawn at prearranged hours (00(00), 04(00), 08(00), 12(00), 16(00), 20(00) ) for 24 consecutive hours. Each serum sample was assayed for PAP. Data on each group and subgroup were evaluated by conventional statistical analysis and by 'single' and 'population mean cosinor' to define rhythm parameters. PCa patients, as a single group, did not show a significant circadian PAP rhythm. A statistically significant circadian PAP rhythm was however detected in the subgroup without metastasis, on the contrary no rhythm was detected in the subgroup with metastatic disease. The potential of these rhythms as marker of cancer is noted.