Search

Interleukin-15 (IL-15) is a cytokine produced in the normal brain that acts on its specific receptor IL-15Ralpha and co-receptors IL-2Rbeta and IL-2Rgamma in neuronal cells. The functions of the cerebral IL-15 system, however, are not yet clear. To test the hypothesis that IL-15Ralpha regulates metabolic activity and body temperature, we quantified the specific metabolic phenotype of IL-15Ralpha knockout mice. These normal-appearing mice were leaner with lower fat composition. During the entire circadian cycle, the knockout mice had a significantly higher acrophase in locomotor activity and heat dissipation. During the light phase, there was significantly greater food intake, oxygen consumption, and carbon dioxide production. The difference in the dark and light phases suggests that IL-15Ralpha participates in circadian rhythm regulation. The higher oxygen consumption in the light phase indicates adaptive thermogenesis in the knockout mice. The body temperature of the receptor knockout mice was significantly higher than the control in the light phase, and this was mainly caused by a large difference occurring between 0600 and 0900 h. In addition to the metabolic chamber studies and circadian rhythm analyses, qPCR of hypothalamic homogenates indicated higher mRNA expression of orexin and transient receptor potential vanilloid 4 cation channels. Consistent with a direct role of IL-15Ralpha in the hypothalamus, IL-15 treatment of the wild-type mice induced c-Fos expression in the preoptic area. We conclude that activation of hypothalamic neurons by IL-15 in mice contributes to thermoregulation and modifies the metabolic phenotype.

The heart rate and axilliary temperature of 17 patients with schizophrenia were measured every 3 hours during waking for 4 days. In 28 profiles, large inter- and intra-individual variations notwithstanding, relations between the time structures (chronomes) of heart rate and axillary temperature are assessed and further examined from the viewpoint of their bearing on the severity of the patients's condition.

Adrenalectomy predisposed the C3HeB/FeJ Mouse to tumor from a low dose of tumor cells, derived from a C3H spontaneous mammary adenocarcinoma. Sham surgery had a similar effect. In contrast, ovariectomized females, intact females, and male mice did not allow the low dose of cells to develop into a tumor. In order to better understand the role of hormones on the immune system controlling tumor growth, normal C3HeB/FeJ mice were studied for the effect of corticosterone or estradiol on splenic lymphocyte surface antigen expression. Adrenalectomy and ovariectomy caused a decrease in the percentage of all T cell subclasses and an increase in absolute numbers of immunoglobulin-bearing cells. Reconstitution of ovariectomized mice with estradiol did not significantly alter lymphocyte cell surface antigen expression. In contrast, injection of corticosterone into adrenalectomized mice brought these values to normal. Further study on normal mice placed on a 12:12-hr light:dark schedule showed that the hours after lights on (HALO) had a significant effect (analysis of variance) on body temperature, percentage of splenic B cells, T pan, T helper and T suppressor cells, and absolute numbers of T pan cells. Brain dehydroepiandrosterone sulfate correlated positively with T pan lymphocytes, but showed no significant effect on HALO. In contrast, body temperature showed a strong circadian rhythm (P less than 0.001). In addition, the presentation of estrus was circadian rhythmic (P = 0.003) with 58% of mice in estrus at 16 HALO and only 8% at 4 HALO. Multiple regression analysis revealed body temperature was strongly associated with absolute numbers of splenic T lymphocytes and their subsets, as well as percentage of B lymphocytes, Thy 1.2-, and Lyt-2-bearing cells. Similarly, HALO and estrous cycle stage were associated with percentage of T helper cells. The data showed that body temperature and hormones were associated with the cell surface antigens on lymphocytes and suggest that they affect lymphocyte function.

In a stroke-prone (SP) strain of laboratory rats, aging is associated with quantifiable changes of the circadian rhythm in body core temperature: (1) its timing becomes less tight, as revealed by a larger standard error of the acrophase (the peak in the 24-hour cosine function best approximating all data) and (2) the acrophase in old SPs occurs earlier than in young ones--quite apart from (3) a decrease in circadian amplitude reported earlier. These results gain particularly in interest in the context of the recent finding that a large (approximately 90 degrees) acrophase-advance is associated with bilateral lesions of the suprachiasmatic nuclei in inbred (non-SP) Fischer rats. These observations may be of interest to those developing models of aging functions in disorders with blood pressure elevation.

A thermorhythmometric analysis was carried out on data from a patient who underwent a prophylactic subcutaneous mastectomy, subsequently to a preoperative mammogram revealing clustered small calcifications in the left breast. The patient self-measured surface temperature of each breast, above and below the nipple, at intervals of 75 +/- 10 min for 59 h while awake. In one location of each breast, the recording thermistor-probe was insulated for 21.5 h while other probe locations remained uninsulated. The overall rhythm-adjusted average surface temperature and the extent of predictable circadian variation differed with statistical significance when the two breasts were compared. The left breast exhibited a higher rhythm-adjusted mean temperature and a lower extent of predictable circadian variation, as compared to the contralateral breast. The interbreast differences of surface temperature also demonstrated a statistically significant rhythm. A review on results of rhythmometry of breast temperature was also carried out. The thermorhythmometric findings here reported must not necessarily be regarded as indicative of cancer; they may be found in non-cancerous subjects and may or may not reflect early pathology. The objective of this publication is to suggest that non-invasive mammary thermorhythmometry may complement clinical histopathology. This subject may exemplify a new principle awaiting scrutiny with much more extensive sampling and much longer follow-up, namely that chronopathology including chronoprotopathology, alongside established diagnostic procedures, may provide an indication for prophylactic intervention.

Oral and cervical temperatures were measured every 30 min during the time the patients were awake (0800-2200) and hourly during the night in 28 women with stage II-III cervical cancer. Data series averaged over all patients were analyzed to determine the circadian rhythmic pattern of temperatures from both sites as well as of the difference in temperature between the two sites. The characteristics of the 24-hr component, notably the amplitude-acrophase pair, were found to differ between the two sites (P less than 0.001). Harmonics of the 24-hr component were found to contribute with statistical significance to the circadian waveform. Accordingly, the acrophase is compared to the macrophase (time of maximal value) and orthophase (time of maximal value assumed by a multiple component model). The relative merits of these different endpoints should be assessed as a function of clinical outcome.

Data of core and breast surface temperature and motor activity collected automatically with ambulatory devices, reveal circadian rhythms of different prominence in these various potential chronobiologic markers. Chronobiologic serial sections further allow the study of any alterations of the circadian rhythm parameters following ambulatory surgery. An approach using miniaturized instrumentation and methods of time series analysis may signal the danger of postoperative complications and, if it prompts timely preventive measures, may increase the safety of ambulatory surgery in particular.

The circadian and circatrigintan (menstrual) system of a healthy Japanese woman has been quantified by single cosinor analyses. The results obtained at only 2 frequencies are discussed against the background of prior chronobiologic information. The paper documents different acrophase relations of rhythms with different frequencies in the same variables and includes a sketch of the position of the single cosinor method as a tool in a methodologic armamentarium of broader interest in anthropology, medicine and more generally in biology.

Plasma prolactin and cortisol were determined and breast skin temperatures measured in 8 postmenopausal diurnally active-nocturnally resting women, 7 with primary breast cancer and 1 with benign breast disease. In all subjects, prolactin peaked during the early morning hours. Cortisol and oral temperature served as internal physiological markers of anticipated rhythmicity in adrenocortical function and metabolism. In all patients studied, the tumour site had an increased mesor (midline-estimating statistic of rhythm) and reduced amplitude of the circadian breast skin temperature rhythm when compared to a similar site on the contralateral breast. Thermal asymmetry was also observed between left and right breasts. A cancer, if in the left breast, may reinforce lower amplitude and perhaps a higher mesor (associated with the healthy left breast in these particular patients), whereas if it is located in the right breast, it tends to nullify inter-mammary differences in mesor and amplitude. Screening for breast cancer appears to require subjects being monitored on at least two occasions before thermal abnormalities due to tumour or preneoplasia become discernible.

About-7-day (circaseptan) and circadian rhythms were sought and found in host-parasite relations of mice infected with Plasmodium berghei. Five inbred male DBA mice, about 18 weeks of age, were implanted with transsensors for temperature telemetry. Core temperature, monitored every 10 min for 3 days before the intravenous or intraperitoneal inoculation of 10(5) infected erythrocytes and thereafter until death, was analyzed by cosinor. A statistically highly significant circadian rhythm exhibited similarly synchronized acrophases. Core temperatures on the days immediately after malarial infection were mostly within the range of temperatures observed before injection. A mesor-hypothermic stage preceded death by several days. In a second study, 24 male BALB/c and 42 male DBA mice, 12 weeks of age, housed in three rooms on different regimens of light and darkness (alternating at 12-hr intervals), staggered by 8 hr, were inoculated ip with 10(4) infected erythrocytes, one-half at noon, the other half at midnight, within 0.5 hr of blood withdrawal. Thus, one endeavored to cover six circadian host stages (02, 06, 10, 14, 18, and 22 hr after light-on). At 54 and 51% overall mortality (irrespective of inoculation time), a circadian rhythm in susceptibility to malaria was demonstrated in these mice by the single cosinor fit of a 24-hr period (P less than 0.003 and less than 0.020, respectively). The single cosinor fit of a 7-day period further demonstrated a circaseptan rhythm (P = 0.014) in the mortality of both strains following the inoculation of P. berghei. The acrophase (360 degrees = 168 hr) was at -325 degrees from the inoculation time with 95% confidence limits extending from -276 to -378 degrees. Such predictable time relations of P. berghei to its murine host await the exploration of mechanisms underlying the circadian and infradian (7-day) rhythmicities here demonstrated and quantified with their uncertainties. Irrespective of mechanisms, information on such periodicities may also guide attempts to optimize treatment by timing according to the interactions of plasmodial virulence and host resistance that remain to be quantified separately.

Some emotional disorders are associated with alterations of biological rhythm characteristics ('echronism'). Chronotherapy aims empirically to 1. optimize the kind and timing of conventional psychopharmacologic treatment and, need be, to use such old or new molecules in the rational endeavor to 2. correct (disease-determining) rhythm alteration directly. With respect to the first aim, a reduction by timing of undesired pharmacodynamic effects, as well as an amplification of empirically desired ones, can be dramatically illustrated by circadian rhythms in tolerance to many drugs affecting the central nervous system of rodents. A more rational approach is aimed at correcting ecchronism. The new antidepressant drug, nomifensine, achieves this task in rats with bilateral suprachiasmatic lesions, exhibiting in the telemetered core temperature an echronism of varying degrees. In this model system for the chronobiotic treatment of ecchronism, the properly timed administration of nomifensine speeds the adjustment of bilaterally (suprachiasmatically) lesioned rats to a shift in the synchronizing light-dark schedule. With methodologic provisions, notably for treatment timed by pertinent marker rhythms, nomifensine deserves clinical tests in psychochronotherapy.

Statistically significant and biologically interesting changes (no decrease and even an increase) with age may characterize peak expiratory flow. This variable and others were investigated in the same persons by dense measurements for several years. A possible health benefit from the monitoring of personal health thus becomes apparent. The relative prominence of changes in body core temperature and 2-min estimation with circadian rhythms, as compared to those with aging is of basic interest. The population-based presumption that aging necessarily involves an increase in overall-systolic and diastolic blood pressure is here aligned with an unusually well documented exception to this view.

We explored the circadian variation of core temperature, heart rate and blood pressure in hypothyroid and euthyroid male Sprague-Dawley rats. A circadian rhythm was quantified by the population mean-cosinor method for the core temperature of both hypothyroid and intact rats, whereas for the blood pressure and heart rate values a circadian rhythm was validated by rejection of the zero-amplitude assumption only in the hypothyroid rats. Whether hypothyroid rats adjust to new schedules at a rate different from euthyroid animals is an inference from these studies awaiting scrutiny.

Widrow's adaptive line enhancer (ALE) was applied to human rectal temperatures at 12-min intervals for 9 days. Changes along the scale of 9 days in circadian pattern suggested the occurrence of infradian variation, resolved by analyses of the entire series by linear-nonlinear rhythmometry. Once the original signal is filtered to extract the circadian component, ultradian components appear. A wide peak with a period of about 100 min, seen each day, may reflect a consistent ultradian component. Other peaks at lower ultradian frequencies (around a period of approximately 8 hr) are unsteady and may correspond to harmonics of the partially extracted circadian oscillation. Ultradian components with periods of approximately 131 and approximately 68 min were also suggested independently by population-mean cosinor summarizing data collected over a total of 158 days. Results show the ability of ALE to detect and reconstruct periodic components in noise and to track their changes in frequency, notably when other methods are also used to assess separately the components and the corresponding uncertainties involved.

Rectal temperatures were measured automatically every 10 min for part or most of two menstrual cycles in ten clinically healthy young women, 20-30 years of age, with a wearable instrument, the Polychronor. Occasional malfunction of the instrumentation resulted in corresponding gaps in the series. Data were examined by chronograms, plexograms, and chronobiologic serial sections computed with the fit of a 24-hr period, population-mean cosinor, and linear-nonlinear least-squares analyses. Single cosinor-derived circadian parameters were next fitted with a cosine curve of a period equal to the number of days of the corresponding intermenstruum. Second-order infradian inferential statistics were calculated next; the first day of menstruation was used as acrophase reference. A population-mean cosinor at the intermenstrual period yields a temperature acrophase of -279 degrees, with the 95% confidence interval extending from -254 degrees to -312 degrees. Since the intermenstruum differs in different subjects and/or in different menstrual cycles of a given woman, this acrophase corresponds to different time intervals from the first day of menstruation in different cases. This acrophase thus indicates the relative timing within the menstrual cycle of overall high rectal temperatures. On four subjects in four stages of their menstrual cycle, plasma was also obtained at 2-hr intervals around the clock. Ten hormones were determined. The sparse endocrine sampling along the menstrual cycle notwithstanding, a circatrigintan rhythm in all hormones investigated was demonstrated for a woman 26 years of age. At the period corresponding to the intermenstrual interval, the acrophases for T3, cortisol, FSH, testosterone, DHEA-S, T4, and LH occurred before the circatrigintan rectal temperature acrophase, whereas the acrophases for prolactin, estradiol, and progesterone occurred near or shortly after the rectal temperature acrophase. Whereas earlier circatrigintan mapping of adult women had been summarized on a group basis, this study allows individualized circatrigintan rhythm assessment. Circatrigintan, like circadian and circannual, acrophase and amplitude relations do not necessarily imply causal relations, yet they are an indispensable quantitative reference standard for the study of basic mechanisms and for diagnosis and intervention, including endeavors in planned parenthood that might take into account the organism's dynamics with multiple frequencies.