Circadian Rhythms in Human Body Composition

The study investigates how the human body composition (BC) changes as a function of the day-night cycle. The BC was investigated using bioelec-trical impedance analysis (BIA) of 10 clinically healthy subjects (CHS), mon-itored in supine position (readings at 2-h intervals), avoiding mealtimes, di-etary abuses, and bladder and intestinal retention. Time series data were analyzed for their temporal characteristics and circadian rhythm (CR). Ail the variables of BC (lean body mass, fat body mass, body cell mass, total body water, intracellular and extracellular body water, sodium and potassium exchangeable pool) showed a within-day variability with nighttime crests. Such an oscillatory synchronism corroborates the hypothesis that the rest time plays a fundamental role, via its anabolic effects, in conferring the noc-turnal phase to the CR of the human BC.     

Phase-Synchronization of Daily Motor Activities Can Reveal Differential Circadian Patterns

A patient diagnosed with seasonal affective disorder (SAD) carried out prospective ratings of depression weekly for nearly a decade. A winter peak of depression and benzodiazepine intake was documented. However, over the years, the depressive episodes shifted toward spring in an apparent free-running circannual rhythm (periodogram peaks at 53 and 55 weeks). This patient may have an underlying seasonal propensity to depression no longer precisely entrained to environmental cues. (Chronobiology International, 18(2), 309–313, 2001)     

Dietary Obesity Caused by a Specific Circadian Eating Pattern

The eating pattern is altered by high-fat diet-induced obesity. To clarify whether this is dependent on the fatty acid profile of the diet, the authors conducted two studies on adult female Sprague-Dawley rats fed normal-fat chow or high-fat diets with varying fatty acid composition. Eating pattern and body weight were assessed in rats fed canola-based (low in saturated fatty acids) or lard-based (moderate in saturated fatty acids) diets for 7 days, and in animals fed chow or canola- or butter-based diets (rich in saturated fatty acids) for 43 days. These parameters were also determined when restricted amounts of low-fat canola- or butter-based diets were consumed for 25 days. Early exposure to canola or lard high-fat feeding or prolonged access to canola- or butter-based fat-rich diets (relative to chow feeding) did not alter the normal light-dark distribution of food and energy intake. All animals ingested most of their food during the dark phase. However, feeding the high-fat canola- and butter-based diets produced an altered eating pattern during the light phase characterized by a smaller number of meals, longer intermeal interval, and enhanced satiety ratio, and consumption of shorter-lasting meals than chow-fed animals. Relative to canola or chow feeding, butter-fed animals consumed a lower number of meals during the dark phase and had a higher eating rate in the light phase, but ate larger meals overall. Only butter feeding led to overeating and obesity. When given a restricted amount of low-fat canola- or butter-based diet at the start of the light phase, rats ate most of their food in that phase and diurnal rather than nocturnal feeding occurred with restriction. These findings underscore the role of saturated fatty acids and the resulting eating pattern alteration in the development of obesity. (Author correspondence: louise.thibault@mcgill.ca)     

Banding Pattern of Human Chromosomes

STUDIES of mammalian chromosomes have advanced rapidly since the introduction of the quinacrine fluorescence technique¹ and other procedures which are believed to locate repetitive DNA sequences in cytological chromosome preparations^2,3. To improve these techniques, a method has been developed which can provide further information about chromosome organization.     

Racial Differences in the Human Endogenous Circadian Period

The length of the endogenous period of the human circadian clock (tau) is slightly greater than 24 hours. There are individual differences in tau, which influence the phase angle of entrainment to the light/dark (LD) cycle, and in doing so contribute to morningness-eveningness. We have recently reported that tau measured in subjects living on an ultradian LD cycle averaged 24.2 hours, and is similar to tau measured using different experimental methods. Here we report racial differences in tau. Subjects lived on an ultradian LD cycle (1.5 hours sleep, 2.5 hours wake) for 3 days. Circadian phase assessments were conducted before and after the ultradian days to determine the change in circadian phase, which was attributed to tau. African American subjects had a significantly shorter tau than subjects of other races. We also tested for racial differences in our previous circadian phase advancing and phase delaying studies. In the phase advancing study, subjects underwent 4 days of a gradually advancing sleep schedule combined with a bright light pulse upon awakening each morning. In the phase delaying study, subjects underwent 4 days of a gradually delaying sleep schedule combined with evening light pulses before bedtime. African American subjects had larger phase advances and smaller phase delays, relative to Caucasian subjects. The racial differences in tau and circadian phase shifting have important implications for understanding normal phase differences between individuals, for developing solutions to the problems of jet lag and shift work, and for the diagnosis and treatment of circadian rhythm based sleep disorders such as advanced and delayed sleep phase disorder.     

Circadian Time Structure of Cardiovascular Characteristics in Human Pregnancy

Conventional time-unspecified single measurements of blood pressure and heart rate may be misleading because they may be influenced, among other factors, by the patient's emotional state, position, diet, and external stimuli. All of these effects depend on the stages of a (mathematical) spectrum of rhythms and trends with age. The evaluation of predictable variability in blood pressure and heart rate by (a) the use of fully ambulatory devices, and (b) chronobiologic data processing, assesses early cardiovascular disease risk, e.g., in pregnancy. We have used this approach to quantify changes in 24-h synchronized (circadian) characteristics of cardiovascular variables in two consecutive pregnancies of a clinically healthy woman. Blood pressure and heart rate were automatically monitored, with few interruptions, at I-h intervals, each time for at least 48 consecutive h, and for a total of 76 days of monitoring in each pregnancy. Circadian parameters of those circulatory variables were computed for each single day of measurement by the least-squares fit of a 24-h cosine curve. Regression analysis of parameters thus obtained revealed patterns of variation of circadian-rhythm-adjusted means and amplitudes with gestational age. In both pregnancies, the predictable variability of the circadian-rhythm-adjusted mean of blood pressure can be approximated by a second-order polynomial model on gestational age: a steady linear decrease in systolic, diastolic, and mean arterial blood pressure up to the 22nd week of pregnancy is followed by an increase in blood pressure up to the day of delivery. This longitudinal study confirms and extends to ambulatory everyday life conditions the predictable pregnancy-associated variability in blood pressure and heart rate and also allows the establishment of prediction and confidence limits for cardiovascular parameters in a healthy pregnancy.     

Circadian Time Structure of Cardiovascular Characteristics in Human Pregnancy

Conventional time-unspecified single measurements of blood pressure and heart rate may be misleading because they may be influenced, among other factors, by the patient's emotional state, position, diet, and external stimuli. All of these effects depend on the stages of a (mathematical) spectrum of rhythms and trends with age. The evaluation of predictable variability in blood pressure and heart rate by (a) the use of fully ambulatory devices, and (b) chronobiologic data processing, assesses early cardiovascular disease risk, e.g., in pregnancy. We have used this approach to quantify changes in 24-h synchronized (circadian) characteristics of cardiovascular variables in two consecutive pregnancies of a clinically healthy woman. Blood pressure and heart rate were automatically monitored, with few interruptions, at I-h intervals, each time for at least 48 consecutive h, and for a total of 76 days of monitoring in each pregnancy. Circadian parameters of those circulatory variables were computed for each single day of measurement by the least-squares fit of a 24-h cosine curve. Regression analysis of parameters thus obtained revealed patterns of variation of circadian-rhythm-adjusted means and amplitudes with gestational age. In both pregnancies, the predictable variability of the circadian-rhythm-adjusted mean of blood pressure can be approximated by a second-order polynomial model on gestational age: a steady linear decrease in systolic, diastolic, and mean arterial blood pressure up to the 22nd week of pregnancy is followed by an increase in blood pressure up to the day of delivery. This longitudinal study confirms and extends to ambulatory everyday life conditions the predictable pregnancy-associated variability in blood pressure and heart rate and also allows the establishment of prediction and confidence limits for cardiovascular parameters in a healthy pregnancy.     

Circadian Rhythmicity in the Activities of Phenylalanine Ammonia-Lyase from Lemna perpusilla and Spirodela polyrhiza

The oscillations in phenylalanine ammonia-lyase activity from Spirodela polyrhiza and phenylalanine ammonia-lyase and tyrosine ammonia-lyase activities from Lemna perpusilla displayed a circadian rhythm under continuous light. Rhythmicity in enzymic activity could not be detected in continuous darkness since under this condition phenylalanine ammonia-lyase activity remains at a fairly constantly low level. Results from our studies of the oscillatory pattern of the respective activities of phenylalanine and tyrosine ammonia-lyase support their “inseparability.”     

Human Circadian Time Structure in Subjects of Different Gender and Age

Most human variables exhibit rhythms with an about 24 hour (circadian) period. Each rhythm can be characterized by its acrophase (calculated peak time of the cosine curve best fitting to the data), its amplitude and rhythm adjusted mean (MESOR). The sequential array of the rhythms' acrophases represents the temporal order of the human time structure. In the present work we used circadian rhythms of 24 chemical and 15 hormonal variables extracted from published studies which were done in a defined area of southeastern Europe (Romania). All studies had a comparable experimental design and were analyzed biochemically and statistically in the same laboratory. The acrophases of these rhythms obtained from both genders of different age groups (from the 2nd to the 9th decade of age) were subjected to multiple correlation test, cluster and principal coordinates analyses. The results show that the temporal order is affected both by gender and age, and evaluate the degree of the effect, offer a “chronbiologic fingerprint” for the examined groups and assist in dissecting rhythm variability among populations.     

Modelling and Analysis of the Feeding Regimen Induced Entrainment of Hepatocyte Circadian Oscillators Using Petri Nets

Circadian rhythms are certain periodic behaviours exhibited by living organism at different levels, including cellular and system-wide scales. Recent studies have found that the circadian rhythms of several peripheral organs in mammals, such as the liver, are able to entrain their clocks to received signals independent of other system level clocks, in particular when responding to signals generated during feeding. These studies have found SIRT1, PARP1, and HSF1 proteins to be the major influencers of the core CLOCKBMAL1:PER-CRY circadian clock. These entities, along with abstracted feeding induced signals were modelled collectively in this study using Petri Nets. The properties of the model show that the circadian system itself is strongly robust, and is able to continually evolve. The modelled feeding regimens suggest that the usual 3 meals/day and 2 meals/day feeding regimens are beneficial with any more or less meals/day negatively affecting the system.     

人外周血淋巴细胞核心钟基因Clock和Bmal1的昼夜节律性表达

探讨自然光制下正常成年人外周血淋巴细胞钟基因Clock和Bmal1的昼夜节律性表达。用实时定量RT-PCR方法,测定不同昼夜时点(ZT)受试者外周血淋巴细胞总RNA中核心钟基因Clock和Bmal1的mRNA表达量,通过余弦法和Clock Lab软件获取节律参数,并经振幅检验分析是否存在昼夜节律。结果发现正常成年人外周血淋巴细胞钟基因Clock和Bmal1的mRNA表达呈昼夜节律性振荡(P0.05),Clock的峰时和谷时分别位于ZT13和ZT1,Bmal1的峰时和谷时分别位于ZT12和ZT24;两个基因在所检测的各个昼夜时点中表达水平均有明显差异(P0.05),Bmal1的表达水平较Clock降低;二者表达的峰值相位、振幅、峰时和谷时相一致(P0.05),但Bmal1转录的中值水平以及峰时mRNA水平和谷时mRNA水平降低(P0.05)。提示正常成年人外周血淋巴细胞钟基因Clock和Bmal1的表达存在同步化的昼夜节律性转录特征。     

植物生命活动与人类健康

与人类健康最密切的是食物和生存环境,文章讨论了植物生命活动与人类的食物和生存环境间的基本关系。     

The Daily Melatonin Pattern in Djungarian Hamsters Depends on the Circadian Phenotype

Djungarian hamsters (Phodopus sungorus) bred at the Institute of Halle reveal three different circadian phenotypes. The wild type (WT) shows normal locomotor activity patterns, whereas in hamsters of the DAO (delayed activity onset) type, the activity onset is continuously delayed. Since the activity offset in those hamsters remains coupled to “light-on,” the activity time becomes compressed. Hamsters of the AR (arrhythmic) type are episodically active throughout the 24?h. Previous studies showed that a disturbed interaction of the circadian system with the light-dark (LD) cycle contributes to the phenomenon observed in DAO hamsters. To gain better insight into the underlying mechanisms, the authors investigated the daily melatonin rhythm, as it is a reliable marker of the circadian clock. Hamsters were kept individually under standardized laboratory conditions (LD 14:10, T?=?22°C?±?2°C, food and water ad libitum). WT, DAO (with exactly 5?h delay of activity onset), and AR hamsters were used for pineal melatonin and urinary 6-sulfatoxymelatonin (aMT6s) measurement. Pineal melatonin content was determined at 3 time points: 4?h after “light-off” [D?+?4], 1?h before “light-on” [L???1], and 1?h after “light-on” [L?+?1]). The 24-h profile of melatonin secretion was investigated by transferring the animals to metabolic cages for 27?h to collect urine at 3-h intervals for aMT6s analysis. WT hamsters showed high pineal melatonin content during the dark time (D?+?4, L???1), which significantly decreased at the beginning of the light period (L?+?1). In contrast, DAO hamsters displayed low melatonin levels during the part of the dark period when animals were still resting (D?+?4). At the end of the dark period (L???1), melatonin content increased significantly and declined again when light was switched on (L?+?1). AR hamsters showed low melatonin levels, comparable to daytime values, at all 3 time points. The results were confirmed by aMT6s data. WT hamsters showed a marked circadian pattern of aMT6s excretion. The concentration started to increase 3?h after “light-off” and reached daytime values 5?h after “light-on.” In DAO hamsters, in contrast, aMT6s excretion started about 6?h later and reached significantly lower levels compared to WT hamsters. In AR animals, aMT6s excretion was low at all times. The results clearly indicate the rhythm of melatonin secretion in DAO hamsters is delayed in accord with their delayed activity onset, whereas AR hamsters display no melatonin rhythm at all. Since the regulatory pathways for the rhythms of locomotor activity and melatonin synthesis (which are downstream from the suprachiasmatic nucleus [SCN]) are different but obviously convey the same signal, we conclude that the origin of the phenomenon observed in DAO hamsters must be located upstream of the SCN, or in the SCN itself. (Author correspondence: weinert@zoologie.uni-halle.de)     

Circadian Pattern of Ambulatory Blood Pressure in Hypertensive Patients With and Without Type 2 Diabetes

There is strong association between diabetes and increased risk of end-organ damage, stroke, and cardiovascular disease (CVD) morbidity and mortality. Non-dipping (<10% decline in the asleep relative to awake blood pressure [BP] mean), as determined by ambulatory BP monitoring (ABPM), is frequent in diabetes and consistently associated with increased CVD risk. The reported prevalence of non-dipping in diabetes is highly variable, probably due to differences in the study groups (normotensive subjects, untreated hypertensives, treated hypertensives), relatively small sample sizes, reliance only on a single, low-reproducibility, 24-h ABPM evaluation per participant, and definition of daytime and nighttime periods by arbitrary selected fixed clock-hour spans. Accordingly, we evaluated the influence of diabetes on the circadian BP pattern by 48-h ABPM (rather than for 24?h to increase reproducibility of results) during which participants maintained a diary listing times of going to bed at night and awakening in the morning. This cross-sectional study involved 12 765 hypertensive patients (6797 men/5968 women), 58.1?±?14.1 (mean?±?SD) yrs of age, enrolled in the Hygia Project, designed to evaluate prospectively CVD risk by ABPM in primary care centers of northwest Spain. Among the participants, 2954 (1799 men/1155 women) had type 2 diabetes. At the time of study, 525/3314 patients with/without diabetes were untreated for hypertension, and the remaining 2429/6497 patients with/without diabetes were treated. Hypertension was defined as awake systolic (SBP)/diastolic (DBP) BP mean ≥135/85?mm Hg, or asleep SBP/DBP mean ≥120/70?mm Hg, or BP-lowering treatment. Hypertensive patients with than without diabetes were more likely to be men and of older age, have diagnoses of microalbuminuria, proteinuria, chronic kidney disease, obstructive sleep apnea, metabolic syndrome, and/or obesity, plus higher glucose, creatinine, uric acid, and triglycerides, but lower cholesterol and estimated glomerular filtration rate. In patients with diabetes, ambulatory SBP was significantly elevated (p?<?.001), mainly during the hours of nighttime sleep and initial hours after morning awakening, independent of presence/absence of BP-lowering treatment. Ambulatory DBP, however, was significantly higher (p?<?.001) in patients without diabetes, mainly during the daytime. Differing trends for SBP and DBP between groups resulted in large differences in ambulatory pulse pressure (PP), it being significantly greater (p?<?.001) throughout the entire 24?h in patients with diabetes, even after correcting for age. Prevalence of non-dipping was significantly higher in patients with than without diabetes (62.1% vs. 45.9%; p?<?.001). Largest difference between groups was in the prevalence of the riser BP pattern, i.e., asleep SBP mean greater than awake SBP mean (19.9% vs. 8.1% in patients with and without diabetes, respectively; p?<?.001). Elevated asleep SBP mean was the major basis for the diagnosis of hypertension and/or inadequate BP control among patients with diabetes; thus, among the uncontrolled hypertensive patients with diabetes, 89.2% had nocturnal hypertension. Our findings document significantly elevated prevalence of a blunted nocturnal BP decline in hypertensive patients with diabetes. Most important, prevalence of the riser BP pattern, associated with highest CVD risk among all possible BP patterns, was more than twice as prevalent in diabetes. Patients with diabetes also presented significantly elevated ambulatory PP, reflecting increased arterial stiffness and enhanced CVD risk. These collective findings indicate that diabetes should be included among the clinical conditions for which ABPM is recommended for proper CVD risk assessment. (Author correspondence: rhermida@uvigo.es)     

Human Gut Bacteria Are Sensitive to Melatonin and Express Endogenous Circadian Rhythmicity

Circadian rhythms are fundamental properties of most eukaryotes, but evidence of biological clocks that drive these rhythms in prokaryotes has been restricted to Cyanobacteria. In vertebrates, the gastrointestinal system expresses circadian patterns of gene expression, motility and secretion in vivo and in vitro, and recent studies suggest that the enteric microbiome is regulated by the host’s circadian clock. However, it is not clear how the host’s clock regulates the microbiome. Here, we demonstrate at least one species of commensal bacterium from the human gastrointestinal system, Enterobacter aerogenes, is sensitive to the neurohormone melatonin, which is secreted into the gastrointestinal lumen, and expresses circadian patterns of swarming and motility. Melatonin specifically increases the magnitude of swarming in cultures of E. aerogenes, but not in Escherichia coli or Klebsiella pneumoniae. The swarming appears to occur daily, and transformation of E. aerogenes with a flagellar motor-protein driven lux plasmid confirms a temperature-compensated circadian rhythm of luciferase activity, which is synchronized in the presence of melatonin. Altogether, these data demonstrate a circadian clock in a non-cyanobacterial prokaryote and suggest the human circadian system may regulate its microbiome through the entrainment of bacterial clocks.     

Modelling Human Granulopoiesis under Poly-chemotherapy with G-CSF Support

Cytotoxic drugs administered in polychemotherapy cause a characteristic neutropenic period depending on the schedule of the drugs, which can partly be prevented by G-CSF growth factor support. To quantify these effects and to gain a deeper insight into the dynamics of bone marrow recovery after such suppressing and stimulating disturbances, we construct a biomathematical compartment model of human granulopoiesis under polychemotherapy with G-CSF support. The underlying assumptions and mathematical techniques used to obtain the model are explained in detail. A large variety of biological and clinical data as well as knowledge from a model of murine haematopoiesis are evaluated to construct a physiological model for humans.Particular emphasis is placed on estimating the influence of chemotherapeutic drugs on the granulopoietic system. As a result, we present an innovative method to estimate the bone marrow damage caused by cytotoxic drugs with respect to single identifiable cell stages only on the basis of measured peripheral blood leukocyte dynamics. Conversely, our model can be used in a planning phase of a clinical trial to estimate the haematotoxicity of regimens based on new combinations of drugs already considered and with or without growth factor support.Acknowledgement This paper was supported by the DFG (Deutsche Forschungsgemeinschaft) in the framework of the project Aufbau von Simulationsmodellen der h{\a}matopoetischen Dynamik nach konventioneller und hochdosierter Chemotherapie und Zytokingabe beim Menschen (Nr. LO 342/8-2). We would like to thank the German High Grade Non-Hodgkins-Lymphoma Study Group and the German Hodgkins Lymphoma Study Group for the kind provision of data.     

Simultaneous Recording of Circadian Rhythms of Brain and Intraperitoneal Temperatures and Locomotor and Drinking Activities in the Rat

In order to investigate the circadian oscillatory system, the present study performed simultaneous and continuous recordings of brain and intraperitoneal temperatures, drinking and locomotion in rats under light-dark (LD) cycles and continuous dim illumination (dim LL) for a total period of 16 days. Compared to circadian amplitudes under LD, those under dim LL were significantly reduced by 34% for drinking and 50% for locomotion, but were not for brain and intraperitoneal temperatures. On the other hand, means of steady circadian periods during last 10 days under dim LL were all within a close range between 24.2 and 24.3 h in these rhythms. Besides the steady periods, one rat exhibited weak circadian period of 23.7 and 24.6 h, but these multiple frequencies were also equally observed in the four rhythms. The similarity in the periodicities suggests that these temperature and activity rhythms might be driven by a common oscillatory system. Therefore differential reductions in the amplitudes of drinking and loc omotor rhythms might be caused by a masking effect of dim LL on their rhythm output-pathways. Hence rats may temporally coordinate various physiological and behavioral functions by such clock system under time cue free environment.