Lawrence E. Scheving

Toward a chronotherapy of neoplasia: Tolerance of treatment depends upon host rhythms

C h r o n o b i o l o g y L a b o r a t o r i e s , U n i v e r s i t y of M i n n e s o t a , 380 L y o n L a b o r a t o r i e s , M i n n e a p o l i s ( M i n n e s o t a 55455, U S A ) D e p a r t m e n t of A n a t o m i c a n d Cl in ica l P a t h o l o g y , St . P a u l R a m s e y H o s p i t a l , St . P a u l , M i n n e s o t a ; D e p a r t m e n t of P h a r m a c o l o g y , U n i v e r s i t y of T e n n e s s e e , M e m p h i s , T e n n e s s e e ; D e p a r t m e n t of A n a t o m y , U n i v e r s i t y of A r k a n s a s , L i t t l e R o c k , A r k a n s a s ; D e p a r t m e n t of P h y s i o l o g y a n d H e a l t h Sc ience , B a l l S t a t e U n i v e r s i t y , M u n c i e , I n d i a n a ; L o s A l a m o s Sc i en t i f i c L a b o r a t o r y of t h e U n i v e r s i t y of Ca l i fo rn ia , L o s A l a m o s , N e w M e x i c o ; a n d S l o a n K e t t e r i n g I n s t i t u t e for C a n c e r R e s e a r c h , N e w Y o r k ( N e w Y o r k , U S A ) .

Circadian characteristics of circulating interleukin-6 in men

BACKGROUND The cytokine interleukin-6 (IL-6) is a multifunctional small-peptide molecule that is produced by various types of lymphoid and nonlymphoid cells. It plays a central role in hematopoiesis, host defense mechanisms, and acute-phase reactions, including regulation of inflammatory and immune responses. METHODS Because a circadian time structure has been shown to characterize nearly every biologic function tested in human beings, including some cytokines, we sought to investigate the 24-hour pattern of circulating IL-6 in a group of 11 clinically symptom-free men (median age, 50 years; range, 46 to 72 years). Blood samples were obtained every 3 hours for 24 hours (eight samples per subject), and serum was frozen until analysis for IL-6 with a solid-phase ELISA. RESULTS Average IL-6 values ranged from 1.66 to 5.38 pg/ml, with lowest to highest values within 24 hours ranging from 1.20 to 7.58 pg/ml (120% to 531%) between subjects. On average, values were greater than the mean throughout the night, with a peak at 01:00 hours and less than the mean throughout the day, with a nadir at 10:00 hours. A significant time effect was found by analysis of variance; and a high-amplitude circadian rhythm was described by the least-squares fit of a 24-hour cosine (p < 0.001; amplitude, 41% +/- 5%; acrophase, 02:16 +/- 00:28 hours). In addition, a positive correlation between mean IL-6 levels and age was found (r = 0.63, p = 0.037). CONCLUSIONS Because monitoring of endogenous cytokine levels is suggested for assessing immune function and pathologic condition, clinical decisions and immunotherapies may be significantly influenced by the large and predictable day-night variations in endogenous cytokine production and bioactivity.

Circadian relationship of serum uric acid and nitric oxide.

To the Editor: Nitric oxide–mediated damage has been implicated in a number of neurological diseases including stroke1, 2 and multiple sclerosis (MS).3 For instance, monocytes expressing high levels of nitric oxide synthetase have been found in plaques from the brains of patients with MS.4 The proximal agent of neuronal cell damage may be peroxynitrite, which is formed in vivo from the synthesis of nitric oxide and superoxide.

Circadian Rhythmometry of Serum Interleukin-2, Interleukin-10, Tumor Necrosis Factor-α, and Granulocyte-Macrophage Colony-Stimulating Factor in Men

Serum levels of four cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-10 (IL-10)] were measured in nine diurnally active healthy adult male subjects at 3-h intervals during a 24-h period. Statistical evaluation by analysis of variance and/or the least- squares fit of a cosine model revealed significant 24-h rhythms for each cytokine. Although the amount of IL-2 in the serum was low, the levels fluctuated to form a single peak at approximately noon. In contrast, the other three cytokines exhibited a biphasic temporal pattern. In subjects with detectable TNF-alpha levels, the first peak occurred at 07:30 and the second at 13:30. IL-10 levels also exhibited a biphasic pattern, with one peak at 07:30 and the second 12 h later at 19:30. GM-CSF levels were last to rise, first peaking at approximately 13:30 and then again at 19:30. These results suggest temporal patterns that are unique for each cytokine, generally with daytime highs and nighttime lows.

REFERENCE VALUES FOR CIRCADIAN RHYTHMS OF 98 VARIABLES IN CLINICALLY HEALTHY MEN IN THE FIFTH DECADE OF LIFE

Nine clinically healthy men, 41-47 yr of age, served as subjects in a 24-hr study conducted at the Edward Hines Jr Veterans Administration Hospital in the Chicago area in May 1988. Physiologic measurements, and blood and urine samples were collected at 3-hr intervals over a single 24-hr period beginning at 1900. The number of variables measured or calculated (total = 98) included: 6 vital signs (oral temperature, pulse, blood- and intraocular pressures); 16 in whole blood (counts and differentials); 50 in serum (SMAC-24, lipids, hormones, electrophoresis of LDH and proteins); and 26 in urine (solids, proteins, creatinine, catecholamines, melatonin, cortisol, electrolytes and metals). Data were analyzed for time effect by analysis of variance (ANOVA) and for circadian rhythm by single cosinor. Individual rhythm characteristics for each variable were summarized for the group by population mean cosinor. The vast majority of variables revealed statistically significant within-day changes in values as validated by one-way ANOVA. All vital signs (except for intraocular pressures) and all serum hormones displayed a prominent circadian rhythm for the group, as did most variables in whole blood, while only about half of the variables in urine demonstrated a significant group rhythm. The results obtained are meant to: (a) document the circadian time structure; and (b) serve as reference values for circadian rhythm characteristics (range of change, mesor, amplitude and acrophase) for a defined group of individuals: clinically-healthy adult men in the prime of life.

Circadian rhythms in DNA synthesis and mitosis in normal mice and in mice bearing the Lewis lung carcinoma

Abstract Circadian rhythms in the incorporation of 3 H -Tdr into chemically isolated DNA (DNA specific activity or DNA-SA) from spleen, thymus, duodenum, bone marrow and liver were altered by the presence of the Lewis Lung Carcinoma (LLC) in BDF 1 mice standardized to a 12:12 light—dark cycle (light 0600–1800 , CST). In general, the longer the LLC was present in the host the more pronounced the changes were in the normal circadian pattern of DNA-SA in the hosts organs. Different ages ( 6, 10 or 14-day old tumors) of LLC caused different changes in (1) phasing, (2) waveform and (3) over-all level of DNA-SA in all organs examined. The circadian rhythm in the mitotic index in the corneal epithelium, however, remained unperturbed by the presence of a 6 -, 10 - or 14-day -old LLC. The LLC itself exhibited significant high-frequency fluctuation in the amount of DNA-SA during the circadian period.

Circadian interrelationships among levels of plasma fibrinogen, blood platelets, and serum interleukin-6.

Circadian (24 h) rhythms of fibrinogen, interleu kin-6 (IL-6), and platelet levels were studied in 11 males ages 46 to 72 years. Since there is a known circadian rhythm for fibrinogen and IL-6, we postulated that the peak level (acro phase) of fibrinogen would follow the acrophase of IL-6, based on the fact that IL-6 is the stimulus for fibrinogen production in the liver. Platelet levels were measured to show whether there was any correlation with the IL-6 acrophase because it has been reported that IL-6 affects megakaryocytes and platelets in dogs. We found that the acrophase for IL-6 occurred at 02:03 h and the acrophase for fibrinogen occurred at 09:16 h. Platelet counts peaked at 16:56 h. Thus, there was a positive correlation between IL-6 and fibrinogen acrophases and a negative corre lation of each with the acrophase for platelets. The positive linkage of IL-6 with fibrinogen in this study suggests that sup pression of IL-6 production would lower those peak fibrinogen levels that occur in the morning in association with arterial ischemic events. This could result in fewer arterial ischemic events, especially in the morning. Key Words: Circadian— Fibrinogen—Interleukin—6 (IL-6)—Platelets—Arterial ischemia.

Temporal (Circadian) and Functional Relationship Between Atrial Natriuretic Peptides and Blood Pressure

Long-acting natriuretic peptide, vessel dilator, and atrial natriuretic factor consisting of amino acids (a.a.) 1 to 30, 31 to 67, and 99 to 126 of the 126-a.a. atrial natriuretic factor (ANF) prohormone, respectively, circulate in humans and have potent vasodilatory properties. To determine if these atrial natriuretic peptides are directly related to blood pressure in clinically healthy normotensive humans, we obtained 24-h profiles of vessel dilator, long-acting natriuretic peptide, ANF, and blood pressure in 10 men in 1988 and 11 men in 1993 (seven men were studied twice) to compare circulating concentrations of atrial natriuretic peptides with naturally occurring changes in blood pressure. Overall, vessel dilator, long-acting natriuretic peptide, and ANF each had significant (p<0.001) circadian rhythms, with peak concentrations late during sleep (at 04:00 h) being nearly twice their concentrations in the afternoon and evening. This high-amplitude circadian change allowed for the refinement of normal limits for ANF peptides by computing 3-hourly tolerance intervals (chronodesms) against which to compare time-specified single samples for normality. Systolic, diastolic, and mean arterial blood pressure also had significant circadian rhythms (p<0.001) with peaks and troughs that were exactly opposite those of the ANF peptides. In addition to this inverse temporal relationship, there was a significant inverse correlation between absolute values for blood pressure and each ANF peptide (p<0.001), implying a functional relationship. These data suggest that in addition to other well-established neurochemical factors, the ANF peptides (vessel dilator, long-acting natriuretic peptide, and ANF) are important for the maintenance of blood pressure and modulation of its circadian rhythm.

Meal timing dominates the lighting regimen as a synchronizer of the eosinophil rhythm in mice.

Mouse eosinophils undergo circadian fluctuation, and the phasing of the rhythm normally is synchronized to the environmental light-dark cycle if food always is available. This study was undertaken to determine whether or not the same rhythm could be synchronized to restricted feeding schedules. It was found that if food is available ad libitum for only short spans (in this case, 4 h during each 24 h period), the rhythm becomes synchronized to the feeding schedule. In addition, restricting food to certain 4 h spans causes the amplitude of the eosinophil rhythm to increase significantly over that of normal, light-dark synchronized animals. Not all rhythmic variables synchronize to restricted feeding schedules. Some remain synchronized to the light-dark cycle; the phasing of others seems to be the result of an interaction between both the light-dark cycle and the feeding schedule. These studies help dispel the popular misconception that all body functions react in the same manner to different synchronizers and emphasize that one must not generalize about the synchronizing effect of feeding or lighting.

Chronopharmacokinetics of ethanol

SummaryA male human subject administered single, oral doses of ethanol was examined repeatedly for venous ethanol levels. Four separate trials, begun at 03.00, 09.00, 15.00, and 21.00 h, on different days yielded four different estimates of the slope of the apparently linear ethanol disappearance curve. The slopes appeared to exhibit circadian rhythmicity. In a second study of the same subject, the slope was estimated 7 times over a period of 26 h following repeated oral doses. These slopes also appeared to vary in a daily fashion. These preliminary results suggest that pharmacokinetic parameters may not be invariable with time of day.