User:Eugene M. Izhikevich/Proposed/Circadian rhythms
(adj. and noun, from Latin circa, about, approximately, and Latin dies, day, or rather, in current usage, roughly 24 hours) relating to biological and other variations or rhythms with a frequency of 1 cycle in 24 ± about (~) 4 hours. See also chronobiology, chronomics, diurnal.
To standardize the terminology used when discussing rhythms with periods close to 24 h, Franz Halberg (b. 1919) introduced the term circadian in 1959. His original definition follows:
"The term circadian was derived from circa (about) and dies (day); it may serve to imply that certain physiologic periods are close to 24 hours, if not of exactly that length. Herein, circadian might be applied to all 24-hour rhythms, whether or not their periods, individually or on the average, are longer or shorter, by a few minutes or hours. Circadian thus would apply to the period of rhythms under several conditions. It would describe: 1. rhythms that are frequency synchronized with 'acceptable' environmental schedules (24-hour periodic or other) as well as 2. rhythms that are 'free-running' from the local time scale, with periods slightly yet consistently different from 24 hours (e.g., in relatively constant environments). (Halberg, 1959, p. 235) (42)
"The following definition of 'circadian' was adopted in 1977 by the International Committee on Nomenclature of the International Society for Chronobiology:"Circadian: relating to biologic variations or rhythms with a frequency of 1 cycle in 24 ± 4 h; circa (about, approximately) and dies (day or 24 h). Note: term describes rhythms with an about 24-h cycle length, whether they are frequency-synchronized with (acceptable) or are desynchronized or free-running from the local environmental time scale, with periods slightly yet consistently different from 24 h … (Halberg et al., 1977)." (18)
As in physics, nomenclature is based on frequency, f (or angular frequency ω=2πf) not on its reciprocal, the period, τ, so that an f higher than 1 cycle in 20 hours is called ultradian (and is a τ shorter than 20 hours) and an f lower than 1 cycle in 28 hours (τ longer than 28 h) is infradian, Figures 1-3. The period is best estimated by the extended cosinor, relying on linear-nonlinear least squares applicable to non-equidistant data, for the derivation also of confidence intervals for each parameter: the MESOR or rhythm-adjusted average; the double amplitude, or predicted extent of change, and the acrophase, a measure of predictable timing of change within a cycle.
As new heliogeophysical cycles were discovered, it seemed logical to look for counterparts and vice versa; thus, congruent periods with overlapping CIs (95% confidence intervals) were found, among others, in 17-KS excretion, Figure 3.
a. Immediately applicable circadian marker rhythmometry for vascular disease prevention (based on automatically monitored blood pressure and heart rate, preferably for at least 7 consecutive days at 0.5 to 1.0-hour intervals, reveals risks of severe disease greater than hypertension and can be implemented with instrumentation obtained via BIOCOS (firstname.lastname@example.org) with cost reduction and analyses, also of data collected systematically with conventional sphygmomanometry.
A set of vascular variability anomalies, VVAs, is depicted in Figure 4. A chronobiologically detectable circadian overswing of blood pressure, exceeding limits set by reference values of clinically healthy gender- and age-matched peers, constituting a risk of severe disease, such as ischemic stroke, Figure 5, or nephropathy, Figure 6, greater than that associated with hypertension (2), can be treated and often eliminated. This approach reduces the number of false positive and false negative diagnoses of high blood pressure: those not in need of treatment (false positive diagnoses, often mislabeled "white-coat effect") are spared the cost, stigma and any side effects and those who need treatment (false negative diagnoses, labeled masked hypertension) are spared target organ damage and subsequent adverse cardiovascular events. Other risks of alterations of circadian endpoints are also detected. If and only if their presence is confirmed in several 7/24 records, they become vascular variability disorders, Figure 7, and some are treatable, Figure 8 (18, 49).
b. Marker rhythmometry for cancer using timing by circadian and about 7-day (circaseptan) rhythms in cancer markers such as CA130 or CA125 for patients with ovarian cancer as yet is expensive, but documented as useful (50, 51). Chronochemotherapy with unspecific marker rhythmometry (52) also seems preferable to timing by clock-hour which can fail (53), unless a rigorously validated standardized routine is ascertained. Using tumor temperature as a marker rhythm for chronoradiotherapy, 2-year disease-free survival was doubled for patients with cancers in the mouth, Figure 9 (1).
c. Susceptibility resistance cycles. In the laboratory, circadian rhythms in susceptibility make the difference between life and death, whether a stimulus was applied for seconds (like exposure to noise) or months (like implantation of a carcinogen), its effects can depend to an extremely high degree on statistically predictable circadian stages that account, among others, for the differences between high and low chances of developing a malignant tumor or of convulsions or survival from a bacterial toxin or a high dose of ethanol or of another drug, Table 1 and Figures 10-12 (47).
d. Nutrition. Relative body weight loss from a fixed or ad libitum number of dietary calories differs markedly as a function of whether all of the calories were consumed as breakfast or as dinner, Figures 13-15 (63).
Degree of generality
Because of a high degree of generality on earth (43) and in extraterrestrial space (54), circadian rhythms constitute indispensable control information. By assessing the outcome of a procedure in different circadian stages, we may find the difference between a desired and an undesired effect of any stimulus, physical, chemical, biological or other. Their neglect can be associated with blunders in experimental results that lead to false conclusions and to years or decades of wasted research. Just as light-microscopy and now molecular biology have complemented the naked eye, and just as histopathology now routinely replaces the naked eye in examining a tumor, so a circadian (and broader chronobiologic) "microscopy in time" complements today's routine experimental and clinical procedures. Circadians have served to open the "normal range" of everyday physiology. Information on their alteration is critical to disease prevention. Likewise, in much of what we measure there is a built-in circadian time structure that underlies any biological function. It represents in the background, as in the foregoing, a vast complementary system critical to whatever one singles out in medical or biological practices. In each case, a mapping of circadian characteristics in inferential statistical terms seems useful and essential to those who carry out scientific endeavors (42-47).
Like nature, notably the weather and the broader climate, on earth and in space, with which it is intimately interwoven, life involves the recurrence of many cycles with vastly differing period, phase, amplitude and MESOR in about (the first circa) the same sequences of about (the second circa) the same phenomena with about (the third circa) the same extent, timing and kind of change at intervals that are about (the fourth circa), but extremely rarely all exactly the same (47). Variability during asynchronization is greater while circa-periodicities persist when organisms 1. are kept under ordinary conditions but deprived by surgery or genetics of the major transducer of the dominant synchronizing environmental cycle, such as the eyes, mediating the effect of a lighting regimen, or 2. are isolated under conditions rendered as constant as possible on earth, at least with respect to environmental light, temperature and societal interactions, e.g., living for months in a cave, and/or 3. are able to self-select the given regimen, e.g., of lighting and/or eating, or 4. are constrained to periodic regimens exceeding the range of synchronizability, whether these are, e.g., shorter than about-20-hour or longer than about-28-hour "days", implemented by the lighting regimen in the laboratory for certain rodents, e.g., light (L)/dark (D) 10:10 or LD14:14, or whether one administers regressive electric shocks at 12-hour intervals until the subject is disoriented in space and time. Under all these conditions, organisms show periods described as desynchronized, if not free-running from conditions with which they are shown to have been synchronized earlier, are resynchronized subsequently or can be compared with concomitant synchronized controls; rhythms are asynchronized if they differ with statistical significance from those found under synchronization with their environmental near (circa) match, such as a day.
Circadian includes rhythms with periods near 24 hours, whether or not they are frequency-synchronized with other cycles like society's 24-hour schedule or whether they are desynchronized if not free-running. While the primary synchronizer in the experimental laboratory is the lighting regimen for ad libitum-fed animals in the absence of a magnetic storm, there are secondary synchronizers. The timing of a diet offered with a restricted amount of calories can override the lighting regimen, and magnetic storms can influence rhythm characteristics (56) including phase (57). An abrupt shift of the primary synchronizer is followed by a gradual adjustment of circadian rhythms, that differs for various variables, is faster in the blood pressure and slower in peripheral tissue mitoses of mammals, faster with delays than with advances in schedule, and thus shorter after flights from east to west than after those from west to east, accounting for jet lags of different duration after flights in opposite directions. Adjustment can also involve polarity insofar as, in response to the same shift in routine, as after an intercontinental transmeridian flight some variables delay whereas others in the same organism advance.
Any endeavor in experimental or clinical biomedicine and beyond in transdisciplinary science benefits from the inferential statistical "isolation" of circadian and other rhythms by desirable hypothesis testing and the rejection of the zero-amplitude (no cycle) assumption and the usually indispensable estimation of characteristics of rhythms with their uncertainties, such as the period, and for each period, of measures of the extent and timing of change, the amplitude, A, and acrophase, φ, respectively, and waveform, the (A,φ) pairs of harmonics. Longer periods can also modulate circadians. These characteristics are best estimated by the extended cosinor method, Figures 16-19. As a dividend, the MESOR, a midline-estimating statistic of rhythm, the M, is obtained. As compared to an arithmetic mean, the M is usually more accurate in the case of unequidistant data, and more precise in the case of equally spaced data, Figure 16.
Some circadians are pertinent to integrative and/or molecular studies in any one of the sciences on the rim of Figure 19, including focus on mechanisms of circadian timekeeping under standardized, if not constant laboratory conditions. In each case, a mapping of circadian characteristics in inferential statistical terms seems desirable if not essential to aims such as those noted above under "Importance". Figures 21-23 are illustrative phase maps.
The partly genetic nature of circadian oscillations, apparent by 1950 from differences among inbred strains of mice, not only at a fixed circadian time, Figure 24, but also in extent of within-day differences, Figures 25 and 26 (Halberg & Visscher 1950) (67), was noted indirectly by free-running after blinding, seen time-macroscopically in Figure 27 and quantified time-microscopically in Figure 28. For human heart rate, heritability was recognized as emergenic, based on studies on twins reared apart, Figure 29 (58; cf. 59-62). For partly mapped average timing (phases) in circadian systems of populations, remove-and-replace approaches in humans and rodents lead to adrenocortical, Figure 30, and broader neuroendocrine, metabolic and other cellular mechanisms, Figure 31, that in turn led to molecular maps, Figure 32, a field in its own right.
Experimental background to the coining of "circadian"
By 1950, Franz Halberg (FH) had compared two groups of mice that happened to have rhythms with different phases, Figure 32, and two other groups exhibiting rhythms with different frequencies, Figures 26 and 27. In each case, he identified the difference in phase or frequency and avoided publishing the statistically highly significant but opposite, nonsensical differences on top of Figure 32). The ready chronobiologic interpretation of the findings on top of this figure indicated the importance of identifying circadian rhythms in cancer research and more broadly in any biological investigations. One must invariably look for any phase, frequency or other differences in parameters between the rhythms of two groups being compared. The top row of Figure 32 is a warning for investigators of stress or allergy whose research can be greatly misled if rhythms are not assessed. Thus, by 1950 it became clear that once-daily concomitant controls were not enough if a comparable stage of any rhythmic variable was not ascertained. Also at the outset, FH found further puzzling opposite differences between blinded and sham-operated mice at various times after surgery that were due to different average periods, Figure 26 and top row of Figure 27. By using rectal temperature as a marker rhythm, FH found ~23.5-hour periods in rectal temperature of mice after blinding, shown time-macroscopically in Figure 26 and time-microscopically in section I B-C and the left half of D in Figure 27. It became clear, as an important dividend, that the uncoupling from the lighting regimen by the loss of the eyes suggested a partly built-in nature of the rhythms, subsequently documented by the isolation of clock genes in mice and by studies of twins reared apart.
Longer-than-24-hour periods (frequencies lower than precisely 1 cycle in 24 hours) are usually seen for humans' activity-rest, rectal temperature and hormone excretion, Figure 20, Section ID, and for many other variables, i.a., blood pressure, heart rate, time estimation during isolation from society, e.g., in caves for up to several hundred days. The differences among inbred strains in extent of within-day change in counts of circulating blood eosinophil cells, hinted by 1950 at built-in rhythms and were major reasons prompting the "circa" in "circadian": blinded mice happened to have periods different than 24 hours, and the desynchronized periods varied further among some of the mice themselves, Section 3C in Figure 20. The methodological and intrinsic importance of circadian systems became apparent further from reactive rhythms, Figure 28 (middle and bottom sections); timing along the 24-hour scale accounted for the difference between inhibiting and stimulating DNA labeling.
History of semantics
Originally, FH had proposed, for synchronized vs. desynchronized rhythms, the terms dian vs. circadian at meetings of nomenclature committees in Basel in 1953 and later. In the absence of an environmental 24-hour synchronizer, different variables can assume different free-running periods. Even under 24-hour synchronized conditions, on the right side at the bottom, Section 2, of Figure 24 shows a drifting phase on top for blood pressure and a synchronized rhythm in activity/rest (sleep/wakefulness) in the same organism, one more reason for the use of the term in describing all synchronized, asynchronized or desynchronized rhythms under the concept of a circadian system. In Section 1 (left) at the bottom of Figure 34, a 95% confidence interval of the period, the small shaded box on the right end of the horizontal line visualizing the period, shows another major reason, namely that uncertainty, often large, is almost invariably involved in basic or applied studies of circadian rhythms.
Circadian time, HALO time, zeitgeber time and location
In investigations in the field, the use of local time is appropriate when the geographic locality is given (e.g., "tests were conducted at 1530 hours [3:30 pm] Eastern Time in New York, NY, USA"). It is essential to report the calendar date and location of each study so that any environmental factor, local as well as global, such as a magnetic storm or an extreme magnetic quiet or solar activity, can be looked up from routinely recorded physical databases. There can be geographic differences in environmental magnetic effects and, of course, the duration of the nocturnal photofractions differs with latitude. For laboratory studies involving cyclic regimens of alternating light (L) and darkness (D) as synchronizers, the expression "Hours After Light Onset" (HALO) is recommended and is applicable to nonphotic synchronizers, with appropriate change in abbreviation.
Equivalent is "Zeitgeber Time" (ZT). 0 HALO or ZT 0 correspond to the time of light onset, so that, for instance, ZT 15.5 or 15.5 HALO refer to a time point 15.5 hours after the lights are turned on. Synchronizers are clock-time or calendar-time givers but not physiological-time givers. When the length of the light-dark cycle is different from 24 hours, the HALO and ZT denominations allow for correction of the duration of each hour (thus, ZT 15.5 or 15.5 HALO under a 28-hour light-dark cycle refers to 15.5 synchronizer hours after light onset, even though this corresponds to 18.1 clock hours after light onset).
The recommended way to describe free-running circadian, circannual or other rhythms consists of assessing their periods by inferential statistical means, and of expressing the phases when they reach the periodically recurring overall highest values (acrophases) in degrees, 360 degrees being equated to the given period's length, and 0 degrees being set to a given reference time such as the time of release of experimental animals or plants into special, e.g., constant lighting conditions. This inferential statistical approach leads to objective indications of timing in degrees, radians or fractions of a cycle, each with 95% confidence intervals. Circadian or other cycle times are thus amenable to mapping in a succinct yet generally applicable and reproducible way, Figures 14-16.
Remaining semantic problem
Koukkari and Sothern write: "To standardize the terminology used when discussing rhythms with periods close to 24 h, Franz Halberg … introduced the term circadian in 1959 [as noted above under Origin]." The same book which cites exact definitions as an essay, however, restricts the use of "circadian" to presumably free-running rhythms. Some scholars (at this time a minority unfamiliar with the history of the field or with biomedical practice) prefer to use daily, diurnal or nycthemeral for a 24-hour synchronized rhythm and restrict the use of circadian to desynchronized rhythms. If this practice were generally followed in health care, the designation of a rhythm as synchronized or desynchronized from a given, e.g., 24-hour routine would be cumbersome insofar as it would require prior long-term monitoring in special environments and, in that case, perhaps more than one term, e.g., dian vs. circadian could be reconsidered. New technology for automatic monitoring of physiological functions and software for as-one-goes analysis may render such a dichotomy implementable, albeit not soon in general health care practice. At this time, in the majority of biomedical articles, circadian is used for both the synchronized and the desynchronized cases in biology and medicine and diurnal is mostly restricted to daytime, but the need to arrive at a consensus in all of science, including in particular physics, remains, unless one follows the practice of using a definition of terms in each report and allows these definitions to vary from one report to the next. The community of physicists has traditionally used diurnal to mean, "performed in or occupying one day; daily", notably in an astronomical context. But even in reference to physical matters such as environmental temperature, it seems awkward to read "a diurnal temperature rise during the day and diurnal fall at night". Usage of circadian or at least dian may also be more appropriate in this case, may also account for day-to-day variability, and may prompt reference to "a nocturnal temperature fall" instead.
References to books
Available free of charge on the Internet
1. Cornélissen G, Halberg F. Introduction to Chronobiology. Medtronic Chronobiology Seminar #7. Minneapolis: Medtronic Inc.; April 1994, 52 pp. (Library of Congress Catalog Card #94-060580; URL http://www.msi.umn.edu/~halberg/)
2. Halberg F, Cornélissen G, International Womb-to-Tomb Chronome Initiative Group: Resolution from a meeting of the International Society for Research on Civilization Diseases and the Environment (New SIRMCE Confederation), Brussels, Belgium, March 17-18, 1995: Fairy tale or reality ? Medtronic Chronobiology Seminar #8, April 1995. Minneapolis: Medtronic Inc.; 1995. 12 pp. text, 18 ﬁgures. URL http://www.msi.umn.edu/~halberg/resol.html
- - - Other: 3. Ahlgren A, Halberg F. Cycles of Nature: An Introduction to Biological Rhythms. Washington DC: National Science Teachers Association; 1990. 87 pp.
4. Ajuriaguerra J de (ed). Symposium Bel-Air III. Cycles biologiques et psychiatrie / publié sous la direction du professeur J. de Ajuriaguerra. Geneva: Georg / Paris: Masson et Cie; 1968. 423 pp.
5. Aschoff J, Ceresa F, Halberg F, editors. Chronobiological aspects of endocrinology. 8th Capri Conference, 1974. Chronobiologia 1, Suppl. 1. Milan: Il Ponte; 1974. 509 pp.
6. Aschoff J, Ceresa F, Halberg F, editors. Chronobiological aspects of endocrinology. 8th Capri Conference, 1974. Stuttgart/New York: Schattauer; 1974. 463 pp.
7. Birkenhäger WH, Halberg F, Prikryl P, editors. Proc. Int. Symp. on Hypertension, Brno, Czechoslovakia, April 9-10, 1990. Brno: Masaryk University, 1990. 182 pp.
8. Carandente F, Halberg F, editors. Chronobiology of blood pressure in 1985. Chronobiologia 1984; 11: #3. p. 189-341.
9. Cornélissen G (editor), Schwartzkopff O, Niemeyer-Hellbrügge P, Halberg F (co-editors). Time structures -- chronomes -- in child development. International Interdisciplinary Conference, Nov. 29-30, 2002, Munich, Germany. Neuroendocrinol Lett 2003; 24 (Suppl 1). 256 pp.
10. Cornélissen G, Halberg E, Bakken E, Delmore P, Halberg F, eds. Toward phase zero preclinical and clinical trials: chronobiologic designs and illustrative applications. University of Minnesota Medtronic Chronobiology Seminar Series, #6, September 1992. Minneapolis: Medtronic Inc.; 1992. 411 pp. Second extended edition, February 1993.
11. Cornélissen G, Halberg E, Haus E, O'Brien T, Berg H, Sackett-Lundeen L, Fujii S, Twiggs L, Halberg F, International Womb-to-Tomb Chronome Initiative Group: Chronobiology pertinent to gynecologic oncology. University of Minnesota/Medtronic Chronobiology Seminar Series, #5, July 1992. Minneapolis: Medtronic Inc.; 1992. 25 pp. text, 7 tables, 30 ﬁgures.
12. Dunlap JC, Loros JJ, DeCoursey PJ, eds. Chronobiology: Biological Timekeeping. Sunderland, MA: Sinauer Associates; 2004. 406 pp.
13. Ferin M, Halberg F, Richart RM, Vande Wiele R, eds. Biorhythms and Human Reproduction. New York: John Wiley & Sons; 1974. 665 pp.
14. Foster R, Kreitzman L. Rhythms of Life: The Biological Clocks That Control the Daily Lives of Every Living Thing. London: Profile; 2004. 320 pp.
15. Graeber RC, Gatty R, Halberg F, Levine H. Human eating behavior: preferences, consumption patterns and biorhythms. NATICK/TR-78/022 Technical Reports. Natick, Mass.: U.S. Army; 1978, 287 pp.
16. Halberg F, editor. Proc. XII Int. Conf. International Society for Chronobiology, Washington, DC, August 10-15, 1975. Milan: Il Ponte; 1977. 782 pp.
17. Halberg F, Breus TK, Cornélissen G, Bingham C, Hillman DC, Rigatuso J, Delmore P, Bakken E, International Womb-to-Tomb Chronome Initiative Group: Chronobiology in space. University of Minnesota/Medtronic Chronobiology Seminar Series, #1, December 1991. Minneapolis: Medtronic Inc.; 1991. 21 pp. of text, 70 ﬁgures.
18. Halberg F, Carandente F, Cornélissen G, Katinas GS. Glossary of chronobiology. Chronobiologia 1977; 4 (Suppl. 1), 189 pp.
19. Halberg F, Cornélissen G, Halberg E, Halberg J, Delmore P, Shinoda M, Bakken E. Chronobiology of human blood pressure. Medtronic Continuing Medical Education Seminars, 4th ed. Minneapolis: Medtronic Inc.; 1988. 242 pp.
20. Halberg F, Kenner T, Fiser B, editors. Proceedings, Symposium: The Importance of Chronobiology in Diagnosing and Therapy of Internal Diseases. Faculty of Medicine, Masaryk University, Brno, Czech Republic, January 10-13, 2002. Brno: Masaryk University, 2002, 206 pp.
21. Halberg F, Kenner T, Fiser B, Siegelova J, editors. Proceedings, Cardiovascular Coordination in Health and Blood Pressure Disorders. Brno, Czech Republic: Medical Faculty, Masaryk University; May 24, 1996. 65 pp.
22. Halberg F, Kenner T, Fiser B, Siegelova J, eds. Proceedings, Symposium, Noninvasive Methods in Cardiology. Brno, Czech Republic: Department of Functional Diagnostics and Rehabilitation, Faculty of Medicine, Masaryk University; 2006. 90 pp.
23. Halberg F, Kenner T, Siegelova J, editors. Proceedings, Symposium, Chronobiological Analysis in Pathophysiology of Cardiovascular System. Brno: Masaryk University; 2003. 186 pp.
24. Halberg F, Reale L, Tarquini B. (eds.). Proc. 2nd Int. Conf. Medico-Social Aspects of Chronobiology, Florence, Oct. 2, 1984, Istituto Italiano di Medicina Sociale, Rome, 1986, 791 pp.
25. Halberg F, Scheving LE, Powell EW, Hayes DK, eds. Chronobiology, Proc. XIII Int. Conf. Int. Soc. Chronobiol., Pavia, Italy, September 4-7, 1977. Milan: Il Ponte; 1981. 394 pp.
26. Halberg F, Watanabe H. (eds.). Workshop on Computer Methods on Chronobiology and Chronomedicine. 20th Int. Cong. Neurovegetative Research, Tokyo, Sept. 10-14, 1990. Medical Review, Tokyo, 1992, 297 pp.
27. Hayes DK, Pauly JE, Reiter RJ, eds. Chronobiology: Its Role in Clinical Medicine, General Biology, and Agriculture, Parts A and B. New York: Wiley-Liss; 1990. (Progress in Clinical and Biological Research 1990; 341A & B.) A: 822 pp. B: 940 pp.
28. Hillman DC, Cornélissen G, Scarpelli PT, Otsuka K, Tamura K, Delmore P, Bakken E, Shinoda M, Halberg F, International Womb-to-Tomb Chronome Initiative Group: Chronome maps of blood pressure and heart rate. University of Minnesota/Medtronic Chronobiology Seminar Series, #2, December 1991. Minneapolis: Medtronic Inc.; 1991. 3 pp. of text, 38 ﬁgures.
29. Koukkari WL, Sothern RB. Introducing Biological Rhythms: A primer on the temporal organization of life, with implications for health, society, reproduction and the natural environment. New York: Springer; 2006. 655 pp.
30. Otsuka K, Cornélissen G, Halberg F (eds). Chronocardiology and Chronomedicine: Humans in Time and Cosmos. Tokyo: Life Science Publishing; 1993. 147 pp.
31. Pauly JE, Scheving LE, eds. Advances in Chronobiology, Parts A and B, Proc. XVII Int. Conf. Int. Soc. Chronobiol., Little Rock, Ark., USA, Nov. 3-7, 1985. New York: Alan R. Liss; 1987. (Progress in Clinical and Biological Research 1987; 227A & B.) A: 528 pp. B: 613 pp.
32. Prikryl P, Siegelova J, Cornélissen G, Dusek J, Dankova E, Fiser B, Vacha J, Ferrazzani S, Tocci A, Caruso A, Rao G, Fink H, Halberg F, International Womb-to-Tomb Chronome Initiative Group: Chronotherapeutic pilot on 6 persons may guide tests on thousands: Toward a circadian optimization of prophylactic treatment with daily low-dose aspirin. University of Minnesota/Medtronic Chronobiology Seminar Series, #3, December 1991. Minneapolis: Medtronic Inc.; 1991. 4 pp. text, 4 ﬁgures.
33. Refinetti R. Circadian Physiology. 2nd ed. Boca Raton, FL: CRC Press; 2006. 700 pp.
34. Reinberg A, Halberg F, editors. Chronopharmacology. Oxford/New York: Pergamon Press, 1979, 429 pp.
35. Reinberg A, Smolensky MH. Biological rhythms and medicine. Cellular, metabolic, physiopathologic, and pharmacologic aspects. New York: Springer; 1983. 305 pp.
36. Scheving LE, Halberg F, editors. Chronobiology: Principles and Applications to Shifts in Schedules. Alphen aan den Rijn, Netherlands: Sijthoff & Noordhoff; 1980. 572 pp.
37. Scheving LE, Halberg F, Ehret CF, editors. Chronobiotechnology and Chronobiological Engineering. Dordrecht, The Netherlands: Martinus Nijhoff; 1987. 453 pp.
38. Scheving LE, Halberg F, Pauly JE, editors. Chronobiology, Proc. Int. Soc. for the Study of Biological Rhythms, Little Rock, Ark. Stuttgart: Georg Thieme Publishers/Tokyo: Igaku Shoin Ltd.; 1974. 784 pp.
39. Smolensky MH, Reinberg A, McGovern JP, eds. Proceedings, Symposium on Chronobiology in Allergy and Immunology, X Int Cong Allergology, Jerusalem, Israel, 11 Nov 1979. Oxford/New York: Pergamon Press; 1980. 358 pp.
40. Takahashi R, Halberg F, Walker C, editors. Toward Chronopharmacology, Proc. 8th IUPHAR Cong. and Sat. Symposia, Nagasaki, July 27-28, 1981. Oxford: Pergamon Press, 1982, 444 pp.
41. Touitou Y, Haus E, editors. Biological Rhythms in Clinical and Laboratory Medicine. Berlin: Springer-Verlag; 1992. 730 pp.
When no reference in this entire entry is given, see foregoing books and specifically:
42. Halberg F. Physiologic 24-hour periodicity; general and procedural considerations with reference to the adrenal cycle. Z. Vitamin-, Hormon-u Fermentforsch 1959; 10: 225-296 (introducing term);
43. Halberg F. Chronobiology. Annu Rev Physiol 1969; 31: 675-725 (scope of term);
44. Cornélissen G, Halberg F. Introduction to Chronobiology. Medtronic Chronobiology Seminar #7, April 1994, 52 pp. (Library of Congress Catalog Card #94-060580; URL http://www.msi.umn.edu/~halberg/) (scope of term);
45. Halberg F. Chronobiology: methodological problems. Acta med rom 1980; 18: 399-440 (method);
46. Refinetti R, Cornélissen G, Halberg F. Procedures for numerical analysis of circadian rhythms. Biological Rhythm Research 2007; 38 (4): 275-325. http://dx.doi.org/10.1080/09291010600903692 (method);
47. Halberg Franz, Cornélissen G, Katinas G et al. Transdisciplinary unifying implications of circadian findings in the 1950s. J Circadian Rhythms 2003; 1: 2. 61 pp. www.JCircadianRhythms.com/content/pdf/1740-3391-2-3.pdf (history).
48. Cornélissen G, Halberg F, Otsuka K, Singh RB, Chen CH. Chronobiology predicts actual and proxy outcomes when dipping fails. Hypertension 2007; 49: 237-239. doi:10.1161/01.HYP.0000250392.51418.64.
49. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T, Revilla M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB, Mitsutake G, Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O, Delmore P, Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group. Chronobiology's progress: Part II, chronomics for an immediately applicable biomedicine. J Applied Biomedicine 2006; 4: 73-86. http://www.zsf.jcu.cz/vyzkum/jab/4_2/halberg2.pdf.
50. Halberg F, Cornélissen G, Bingham C, Fujii S, Halberg E. From experimental units to unique experiments: chronobiologic pilots complement large trials. in vivo 1992; 6: 403-428.
51. Kennedy BJ. A lady and chronobiology. Chronobiologia 1993; 20: 139-144.
52. Halberg F, Prem K, Halberg F, Norman C, Cornélissen G. Cancer Chronomics I: Origins of timed cancer treatment: early marker rhythm-guided individualized chronochemotherapy. J Exp Ther Oncol 2006; 6: 55-61.
53. Hrushesky W, Wood P, Levi F, Roemeling R v, Bjarnason G, Focan C, Meier K, Cornélissen G, Halberg F. A recent illustration of some essentials of circadian chronotherapy study design [letter]. J Clin Oncol 2004; 22: 2971-2972.
54. Halberg F, Vallbona C, Dietlein LF, Rummel JA, Berry CA, Pitts GC, Nunneley SA. Circadian circulatory rhythms of men in weightlessness during extraterrestrial flight as well as in bedrest with and without exercise. Space Life Sci 1970; 2: 18-32.
55. Klein JL. Statistical Visions in Time: A History of Time Series Analysis, 1662-1938. Cambridge, UK: Cambridge University Press; 1997. 345 pp.
56. Jozsa R, Halberg F, Cornélissen G, Zeman M, Kazsaki J, Csernus V, Katinas GS, Wendt HW, Schwartzkopff O, Stebelova K, Dulkova K, Chibisov SM, Engebretson M, Pan W, Bubenik GA, Nagy G, Herold M, Hardeland R, Hüther G, Pöggeler B, Tarquini R, Perfetto F, Salti R, Olah A, Csokas N, Delmore P, Otsuka K, Bakken EE, Allen J, Amory-Mazaudier C. Chronomics, neuroendocrine feedsidewards and the recording and consulting of nowcasts forecasts of geomagnetics. Biomedicine & Pharmacotherapy 2005; 59 (Suppl 1): S24-S30.
57. Chibisov SM, Cornélissen G, Halberg F. Magnetic storm effect on the circulation of rabbits. Biomedicine & Pharmacotherapy 2004; 58 (Suppl 1): S15-S19.
58. Hanson BR, Halberg F, Tuna N, Bouchard TJ Jr, Lykken DT, Cornélissen G, Heston LL. Rhythmometry reveals heritability of circadian characteristics of heart rate of human twins reared apart. Cardiologia 1984; 29: 267-282.
59. Li CC. A genetical model for emergenesis. Am J Human Genetics 1987; 41: 517-523.
60. Lykken DT. Research with twins: the concept of emergenesis. Psychophysiology 1982; 19: 361-373.
61. Lykken DT. The mechanism of emergenesis. Behavior 2006; 5: 306-310.
62. Lykken DT, McGue M, Tellegen A, Bouchard TJ Jr. Emergenesis: genetic traits that may not run in families. Am Psychologist 1992; 47: 1565-1577.
63. Halberg F, Haus E, Cornélissen G. From biologic rhythms to chronomes relevant for nutrition. In: Marriott BM, editor. Not Eating Enough: Overcoming Underconsumption of Military Operational Rations. Washington DC: National Academy Press; 1995. p. 361-372. http://books.nap.edu/books/0309053412/html/361.html#pagetop
64. Shinagawa M, Kubo Y, Otsuka K, Ohkawa S, Cornélissen G, Halberg F. Impact of circadian amplitude and chronotherapy: relevance to prevention and treatment of stroke. Biomedicine & Pharmacotherapy 2001; 55 (Suppl 1): 125s-132s.
65. Halberg F. Biological as well as physical parameters relate to radiology. Guest Lecture, Proc. 30th Ann. Cong. Rad., January 1977, Post-Graduate Institute of Medical Education and Research, Chandigarh, India, 8 pp.
66. Halberg F, Cornélissen G, Wang ZR, Wan C, Ulmer W, Katinas G, Singh Ranjana, Singh RK, Singh Rajesh, Gupta BD, Singh RB, Kumar A, Kanabrocki E, Sothern RB, Rao G, Bhatt MLBD, Srivastava M, Rai G, Singh S, Pati AK, Nath P, Halberg Francine, Halberg J, Schwartzkopff O, Bakken E, Shastri VK. Chronomics: circadian and circaseptan timing of radiotherapy, drugs, calories, perhaps nutriceuticals and beyond. J Exp Therapeutics Oncol 2003; 3: 223-260.
67. Halberg F, Visscher MB. Regular diurnal physiological variation in eosinophil levels in five stocks of mice. Proc Soc exp Biol (N.Y.) 1950; 75: 846-847.
As of January 2006, PubMed (the U.S. National Library of Medicine’s biomedical database) contained 50,000 abstracts of journal articles that could be retrieved by the keyword circadian three times as many as those catalogued 20 years earlier (33) for a term published in 1959 (42).
|1952, 1953||2800-fold increase in sensitivity of a corticosteroid assay by accounting for circadian stage (Figure 1 in 2 vs. 1)||Halberg (1, 2)|
|1955||Circadian susceptibility rhythm to noise||Halberg, Bittner, Gully, Albrecht & Brackney (3)|
|1955||Circadian susceptibility rhythm to an endotoxin||Halberg, Spink, Albrecht & Gully (4)|
|1958||Manipulability of a susceptibility rhythm by lighting regimen||Halberg, Jacobson, Wadsworth & Bittner (5)|
|1958||Detection of (growth) hormone effect on mitoses depends on circadian stage||Litman, Halberg et al. (6)|
|1959||Effect of ethanol depends on circadian stage||Haus, Hanton & Halberg (7)|
|1959||Individualized sequential testing||Johnson, Haus, Halberg & Wadsworth (8)|
|1959||Circadian susceptibility rhythm to a drug (ouabain)||Halberg & Stephens (9)|
|1960||LD50 to whole-body X-irradiation depends on circadian stage||Halberg (10, discussion)|
|1961||Circadian susceptibility rhythm to Librium||Marte & Halberg (11)|
|1963||Circadian susceptibility rhythm to acetylcholine||Jones, Haus & Halberg (12)|
|1964||Circadian susceptibility rhythm to fluothane||Matthews, Marte & Halberg (13)|
|1967||Cosinor method||Halberg, Tong & Johnson (14)|
|1969||Methodological and conceptual context||Halberg (15)|
|1969||Chronotherapy with penicillin||Reinberg et al. (16)|
|1970, 1972||Chronotherapy with arabinosyl cytosine (ara C)||Cardoso et al. (17), Haus et al. (18)|
|1973||Rhythm in chronotherapeutic indices of hydrochlorothiazide and adriamycin||Halberg et al. (19), Levine et al. (20), Shiotsuka et al. (21)|
|1974, 1975||Formulation of rules of chronopharmacology and chronotherapy; demonstration of shift of susceptibility rhythm to adriamycin by meal timing||Halberg (22-24)|
|1977||Doubling of 2-year survival by timing radiotherapy||Halberg (25)|
|1979||Ara-C chronotherapy brings about cancer cures||Halberg, Nelson, Cornélissen, Haus, Scheving & Good (26)|
|1979||More antihypertensive chronotherapy||Güllner, Bartter & Halberg (27)|
|1992||Individualized cancer marker-guided chronochemotherapy||Halberg et al. (28)|
|1995||More antihypertensive chronotherapy and its optimization by timing||Halberg et al. (29)|
|1997||Individualized sequential testing of chronotherapy||Cornélissen, Halberg, Hawkins, Otsuka & Henke (30)|
|2006||Toxicity marker-guided chronochemotherapy||Halberg et al. (31)|
References to Table 1: 1. Halberg F. Some correlations between chemical structure and maximal eosinopenia in adrenalectomized and hypophysectomized mice. J Pharmacol exp Ther 1952; 106: 135-149.
2. Halberg F. Some physiological and clinical aspects of 24-hour periodicity. Journal-Lancet (Minneapolis) 1953; 73: 20-32. See Figure 1.
3. Halberg F, Bittner JJ, Gully RJ, Albrecht PG, Brackney EL. 24-hour periodicity and audiogenic convulsions in I mice of various ages. Proc Soc exp Biol (NY) 1955; 88: 169-173.
4. Halberg F, Spink WW, Albrecht PG, Gully RJ. Resistance of mice to brucella somatic antigen, 24-hour periodicity and the adrenals. J clin Endocrinol 1955; 15: 887.
5. Halberg F, Jacobson E, Wadsworth G, Bittner JJ. Audiogenic abnormality spectra, 24-hour periodicity and lighting. Science 1958; 128: 657-658.
6. Litman T, Halberg F, Ellis S, Bittner JJ. Pituitary growth hormone and mitoses in immature mouse liver. Endocrinology 1958; 62: 361-364.
7. Haus E, Hanton EM, Halberg F. 24-hour susceptibility rhythm to ethanol in fully-fed, starved and thirsted mice and the lighting regimen. Physiologist 1959; 2: 54.
8. Johnson EA, Haus E, Halberg F, Wadsworth GL. Graphic monitoring of seizure incidence changes in epileptic patients. Minn Med 1959; 42: 1250-1257.
9. Halberg F, Stephens AN. Susceptibility to ouabain and physiologic circadian periodicity. Proc Minn Acad Sci 1959; 27, 139-143.
10. Halberg F. Temporal coordination of physiologic function. Cold Spr Harb Symp quant Biol 1960; 25: 289-310. Discussion on LD50, p. 310.
11. Marte E, Halberg F. Circadian susceptibility rhythm of mice to librium. Fed Proc 1961; 20, 305.
12. Jones F, Haus E, Halberg F. Murine circadian susceptibility-resistance cycle to acetylcholine. Proc Minn Acad Sci 1963; 31: 61-62.
13. Matthews JH, Marte E, Halberg F. A circadian susceptibility-resistance cycle to fluothane in male B1 mice. Canadian Anaesthetists' Society J 1964; 11: 280-290.
14. Halberg F, Tong YL, Johnson EA. Circadian system phase—an aspect of temporal morphology; procedures and illustrative examples. Proc. International Congress of Anatomists. In: Mayersbach H v, ed. The Cellular Aspects of Biorhythms, Symposium on Biorhythms. New York: Springer-Verlag; 1967. p. 20-48.
15. Halberg F. Chronobiology. Annu Rev Physiol 1969; 31: 675-725.
16. Reinberg A, Zagula-Mally ZW, Ghata J, Halberg F. Circadian reactivity rhythm of human skin to house dust, penicillin and histamine. J Allergy 1969; 44: 292-306.
17. Cardoso SS, Scheving LE, Halberg F. Mortality of mice as influenced by the hour of the day of drug (ara-C) administration. Pharmacologist 1970; 12: 302.
18. Haus E, Halberg F, Scheving L, Pauly JE, Cardoso S, Kühl JFW, Sothern R, Shiotsuka RN, Hwang DS. Increased tolerance of leukemic mice to arabinosyl cytosine given on schedule adjusted to circadian system. Science 1972; 177: 80-82.
19. Halberg F, Haus E, Cardoso SS, Scheving LE, Kühl JFW, Shiotsuka R, Rosene G, Pauly JE, Runge W, Spalding JF, Lee JK, Good RA. Toward a chronotherapy of neoplasia: Tolerance of treatment depends upon host rhythms. Experientia (Basel) 1973; 29: 909-934.
20. Levine H, Thompson D, Shiotsuka R, Krzanowski M, Halberg F. Autorhythmometrically determined blood pressure ranges and rhythm of 12 presumably healthy men during an 18-day span. Int J Chronobiol 1973; 1: 337-338.
21. Shiotsuka R, Halberg F, Haus E, Lee JK, McHugh R, Simpson H, Levine H, Ratte J, Najarian J. Results bearing on the chronotherapy of hypertension: saluresis and diuresis without kaluresis can be produced by properly timing chlorothiazide administration according to circadian rhythms. Int J Chronobiol 1973; 1: 358.
22. Halberg F. Protection by timing treatment according to bodily rhythms: an analogy to protection by scrubbing before surgery. Chronobiologia 1974; 1 (Suppl. 1): 27-68.
23. Halberg F. Quando trattare /When to treat. Hæmatologica (Pavia) 1975; 60: 1-30.
24. Halberg F. When to treat. Indian J. Cancer 1975; 12: 1-20.
25. Halberg F. Biological as well as physical parameters relate to radiology. Guest Lecture, Proc. 30th Ann. Cong. Rad., January 1977, Post-Graduate Institute of Medical Education and Research, Chandigarh, India, 8 pp.
26. Halberg F, Nelson W, Cornélissen G, Haus E, Scheving LE, Good RA. On methods for testing and achieving cancer chronotherapy. Cancer Treatment Rep 1979; 63: 1428-1430.
27. Güllner HG, Bartter FC, Halberg F. Timing antihypertensive medication. The Lancet, September 8, 1979: 527.
28. Halberg F, Cornélissen G, Bingham C, Fujii S, Halberg E. From experimental units to unique experiments: chronobiologic pilots complement large trials. in vivo 1992; 6: 403-428.
29. Halberg F, Cornélissen G, International Womb-to-Tomb Chronome Initiative Group: Resolution from a meeting of the International Society for Research on Civilization Diseases and the Environment (New SIRMCE Confederation), Brussels, Belgium, March 17-18, 1995: Fairy tale or reality ? Medtronic Chronobiology Seminar #8, April 1995, 12 pp. text, 18 figures. URL http://www.msi.umn.edu/~halberg/
30. Cornélissen G, Halberg F, Hawkins D, Otsuka K, Henke W. Individual assessment of antihypertensive response by self-starting cumulative sums. J Medical Engineering & Technology 1997; 21: 111-120.
31. Halberg F, Prem K, Halberg F, Norman C, Cornélissen G. Cancer Chronomics I: Origins of timed cancer treatment: early marker rhythm-guided individualized chronochemotherapy. J Exp Ther Oncol 2006; 6: 55-61.