Journal of APPLIED
BIOMEDICINEISSN 1214-0287 (on-line)
ISSN 1214-021X
(printed)
Volume 6 (2008), No 2
Advances in chronohaematology
Josef Berger
Address:
Josef Berger, Faculty of Health and Social Studies, University of South Bohemia, Emy
Destinove, 370 05 Ceske Budejovice, Czech
Republic
berger@zsf.jcu.cz
Received 26th March 2008.
Revised 25th May 2008.
Published online 2nd June 2008.
Full text article (pdf)
Abstract in xml formatSUMMARY
The circadian rhythms of the haemato-immune system seem to be synchronized by two clocks: the
hypothalamic endogenous, and the exogenous which is based on environmental stimuli. The
suprachiasmatic nucleus is not only a circadian clock, it also synchronizes peripheral oscillators and
integrates light information through the retino-hypothalamic tract. The role of the "peripheral" clock
genes in mature leucocytes still remains an unanswered question as well as the role of clock proteins in
"non-clock" physiology. The circadian rhythms may be a basis for circannual variations, although the
molecular bases of such rhythms remain a mystery. There are several hormones which have a
significant impact on haematological characteristics; the finding of a lower superoxide release from
granulocytes at higher melatonin levels opens up new research opportunities for melatonin therapy.
Discrepancies between circadian changes in mRNAs and the appropriate protein participating in
haemocoagulation and fibrinolysis may indicate that we do not know their control processes or their
genetic background well, although this problem has now opened up a new area for pharmacological
research. The endogenous clock facilitates an alternation in the immune system which counters external
attacks in daytime and induces repair and development by night.
KEYWORDS
circadian; seasonal; clock gene; haemostasis; immunity; melatonin; superoxide
INTRODUCTION
A biorhythm is a periodically repeated change in
living systems. It is a time-keeping system that
anticipates environmental alterations. The rhythms
most studied are circadian, with a period of about
24 (± 2) h. The mechanism of biorhythm control has
now been intensively studied at the molecular,
cellular and organism levels for some tens of years.
The circadian rhythms have most often been
described in terms of their phases and amplitudes,
and how these respond, in both health and disease,
to a single exposure to synchronisers.
There is a reciprocal relationship between the
robustness of the endogenous circadian timing
system and its dependency on regularly timed
synchronisers (light, physical activity, and feeding);
this relationship can be damaged during disease or
by ageing (Van Sommeren et al. 2007). Eventual
therapeutic intervention can also embrace circadian
synchronisation (cf. Lader 2007, Maharaj et al.
2007).
In addition to circadian rhythms, there are
important circannual variations and many more
new frequencies, with the newest being an 0.42
year periodicity not only in solar flares and in solar
activity generally and in sudden cardiac death
(Halberg et al. 2006), but even in the circulating
melatonin of patients.
The aim of this contribution is to choose and
highlight the advances in chronohaematology
(Halberg et al. 2003, Berger 2006) in the two years
after our last review of this topic.
Table 1. Summarizing table that conveys main areas of advances in chronohaematology during last two years
----------------------------------------------------------------------------------------------------------
Clock control
two clocks system
environmental changes
suprachiasmatic nucleus and peripheral oscillators
photic and nonphotic synchronization
Molecular timing
the role of genes in timing
per genes in cancer development
clock proteins in "non-clock" physiology
Haemato-immune rhythms
hypothalamo-immune comunication
genetic background
melatonin synchronization
correlation between activity of antioxidant enzymes and hormones
circadian changes in leucocyte and erythrocyte functions
stem cell harvest
Hemostasis
the risk state of thromboembolic events
clock genes control
----------------------------------------------------------------------------------------------------------
CLOCK CONTROL
Recent studies suggest that the control system of
the circadian rhythm is composed of two parts: the
rigid master circadian clock and the more flexible
peripheral oscillators (Berger 2004a,
Kronfeld-Schor and Dayan 2008). Mammals,
including humans, synchronize the master clock in
the brain (Ko and Tkahashi 2006) to environmental
changes through photic stimuli or the little known
non-photic entrainment (Halberg et al. 1953,
Cornelissen et al. 2007, Salazar-Juarez et al. 2007,
Challet 2007, Mendoza 2007, Novak et al. 2008).
The circadian rhythms of the haemato-immune
system seem to be synchronized by two clocks, the
first of which is endogenous, based on clock gene
activity in the suprachiasmatic nucleus. The second
is exogenous, based on environmental immune
stimuli (Berger 2004a). Interactions between these
two clocks can explain both the frequently observed
individual differences in circadian rhythms and the
more subtle role of the clock genes in peripheral
organs (Berger 2008).
The endogenous clock facilitates an alternation
in the immune system which counters external
attacks in daytime and induces repair and
development by night. The suprachiasmatic nucleus
is not only a circadian clock, it also synchronizes
peripheral oscillators and integrates light
information through the retino-hypothalamic tract
(Lamont et al. 2007). Shift work and jet lag, which
modify circadian rhythms, may be factors
contributing to an increase in certain cancers,
cardiovascular, gastrointestinal disease,
reproductive difficulties and mortality (Mormont et
al. 2000, Haus and Smolensky 2006, James et al.
2007a, Lamont et al. 2007).
The circadian rhythms may be the bases of
circannual variations with a period about 1 year
( 2months). Vertebrates can anticipate seasonal
changes in weather using a set of interconnected
neural elements (retina, hypothalamus, pineal
melatonin production and receptors in mammals)
and endocrine elements (prolactin secreting cells in
mammals) that govern photoperiodic responses
(Hazlerigg and Wagner 2006, Lincoln et al. 2006).
Seasonal photoperiodism facilitates transition from
winter to summer phenotypes, physiology and
behaviour (Wagner et al. 2007).
Many seasonal changes in the laboratory
characteristics (Berger 1980a, Haus 1996, Sher et
al. 2005, Kiank et al. 2007) and behaviour of both
human and animal subjects cannot however be
explained by the above mentioned circannual
mechanism. The molecular bases of the control of
circannual rhythms remain a mystery.
MOLECULAR TIMING
Some oscillator components in animals may be
related to tumour growth and it is known that per
genes can suppress tumour growth or formation (Fu
et al. 2002, Chen et al. 2005, Gery et al. 2006,
Krugluger et al. 2007, Lamont et al. 2007, Zeman et
al. 2008). Circadian proteins such as BMAL play a
role in age-related pathologies (Kondratov 2007).
The clock gene mutant in laboratory mice has
increased tumours (Fu et al. 2002). A proper
relationship between the rhythmic expression of
clock components and their absolute values may
play a role in cancer development, and their deficit
or absence may negatively influence the progress of
the disease (Zeman et al. 2008). Clock genes also
play a role in mental disorders (Lamont et al. 2007).
Historically, the molecular mechanisms of
circadian rhythms have been studied in
micro-organisms and Drosophila because the entire
circadian system can be contained in a single cell.
The transcription/translation feedback model in
micro-organisms (Lakin-Thomas and Brody 2004,
Lakin-Thomas 2006) reflects an evolutionary
conserved mechanism and may therefore give us
insight into the molecular basis in both prokaryotic
and eukaryotic organisms.
Circadian rhythms are generated by molecular
clock genes whose proteins rhythmically modulate
transcription of nearly 10% of the genome: the
so-called clock controlled' genes (Tsinkalovsky et
al. 2006, for review). Mammalian clock genes are
active in both the hypothalamus central clock and
peripheral tissues including human blood cells
(Berger 2006, Tsinkalovski 2005, 2007, James et al.
2007b, Dardente and Cermakian 2007, Haus 2007a,
for review). The second and third control points of
clock gene regulation represent post-translational
modifications of the clock proteins and chromatin
remodelling (Dardente and Cermakian 2007).
It has been hypothesized that cell cycle points
are gated to an intrinsic circadian clock for
protection from circadian exposure to mutagens,
e.g., UV radiation peaks with daylight and
dissolved genotoxins that fluctuate with feeding
periods (Shadan 2007). Perhaps, we can now
following publication of the literature summarised
above look forward to the discovery of a new role
for clock proteins in "non-clock" cellular
physiology.
HAEMATO-IMMUNE OSCILLATIONS
Circadian changes in circulating blood cells have
been recognized in various species and ages (Haus
1996, Berger 2004b). Cerutti and co-workers (2006)
described the creation of the circadian during
ontogenesis of calves. Circadian rhythms in the
number of mammalian leucocytes can reflect
oscillations in haematopoietic proliferation activity
in the bone marrow (Berger 1980b, Smaaland et al.
1992). Recent findings show that haematopoietic
stem cells also exit the bone marrow into the
periphery in a circadian rhythm with a peak at five
hours of light (Alcivar 2008). Clinicians may now
need to pay attention to the time of day in which
they harvest stem cells from the blood.
Last year, Ohkura with co-workers (2007a)
revealed the influence of different genetic
backgrounds on the circadian rhythmicity of
leucocytes, erythrocytes and erythropoietin.
Periodic changes in the number of peripheral blood
cells can influence their functions. The fact that the
autonomous nervous system and the neuroendocrine
system have been shown to modulate leucocyte
physiology supports the concept that circadian
timing is an important aspect of
hypothalamo-immune communication (Arjona and
Sarkar 2008).
There are several hormones which have a
significant impact on haematological characteristics
one of the more important of which is melatonin
which regulates and synchronizes many circadian
rhythms (Haus 2007a).
Circadian and circannual variations in
erythropoietin production and release, stimulate
rhythms in erythropoietic proliferation (Gunga et al.
2007) but there are some papers that demonstrate,
and others that simply did not find, a rhythm in
erythropoietin activity. Further research on this
topic is desirable.
Melatonin plays an important role in the
regulation of various body and cellular functions
including immunity. It can induce changes in the
intracellular calcium concentration that modulates
proliferation and its circadian alteration (Wronka et
al. 2008). This hormone serves as an inhibitor of
myeloperoxidase which catalyses oxidant
formation, which has been implicated in both
immune reactions and the pathogenesis of various
diseases. It modulates the formation of
myeloperoxidase intermediates (Galijasevic et al.
2008). It prevents inflammation and oxidative stress
and the circadian rhythm of the melatonin level
correlates with variations in both neutrophil
accumulation and its protective effect (Guney et al.
2007).
The endogenous level of melatonin is highest
during the night or during the second half of the
night it is the so-called nocturnal' hormone and
higher melatonin levels are associated with better
sleep. Ageing changes these rhythms; in older
individuals, treatment with melatonin and
tryptophan at the concentrations and times of
administration considered suitable for improved
nocturnal rest also reverses the
immuno-suppressory and oxidative effects
accompanying phagocytosis (Paredes et al. 2007).
Human leucocyte reactive oxygen species
show circadian variations and they might possibly
influence the occurrence of cardiovascular incidents
(Larsen and Lyberg 2006). The finding of lower
superoxide release from granulocytes at higher
melatonin levels opens up new research
opportunities for melatonin therapy (Geron et al.
2006). Some patients with low melatonin activity
may benefit from both improvement in their sleep
quality and a reduction of granulocyte mediated
oxidative stress after melatonin administration.
Superoxide dismutase activity in erythrocytes
changes the circadian rhythm in correlation with
corticosteroid levels, although other enzymes
participating in oxidative stress seem to be rather
constant (Goncharova et al. 2006). It seems that
hormones melatonin and corticosteroids play an
essential role in the regulation of superoxide
dismutase activity which is assumed to participate
in many cellular processes.
Following the dissociation of sleep from the
effects of circadian rhythms it has been documented
that sleep alone can enhance adaptive immune
responses. Sleep is associated with an increase in
pre-dendritic cells, i.e. myeloid dendritic cell
precursors, producing interleukin-12, activity of
interleukin-6 (but not the concentration of
monocytes producing this cytokine) and decreased
numbers of CD14(dim)CD16+ and interleukin-10,
producing monocytes, plasmacytoid dendritic cells
and T cells (Lange et al. 2006, Dimitrov et al. 2006,
2007). Sleep alone enhances adaptive immunity and
stimulates circadian alterations in immunity, but
high prolactin and low cortisol levels also
contribute to some of these changes during sleep.
Lymphocytes and neutrophils participate in
allergic-inflammatory processes. One of the effects
of their activation is increased binding to histamine
which reaches a peak in the afternoon for healthy
subjects' and is lowered in the night, while their
amplitude in asthmatic subjects was not significant
(Zak-Nejmark et al. 2006). The different circadian
histamine binding to leucocytes in atopic from
healthy subjects may participate in the nocturnal
exacerbation of disease symptoms.
Erythrocyte superoxidase, catalase and
glutathione peroxidise show seasonal variations
(Balog et al. 2006) which can be important in
relation to the circannual rhythm in oxidative stress
and cardiovascular events (cf. Touitou and Bogdan
2007). Circannual rhythms in the enzymes of
oxidant-antioxidant balance can be positively
influenced following regular physical activity
(Balog et al. 2006). New results (Yerer and
Aydogan 2006) have revealed rhythms in
erythrocyte deformability, one of the impact factors
participating in the rhythms of cardiovascular
events.
A significant leucocytosis after elevated
cortisol concentration has been noted several times,
recently in horses by Quaranta et al. (2006): training
programmes must consider the circadian rhythms of
cortisol as its elevated concentration can cause
stress disease and the overtraining' syndrome.
Cortisol has an important immunosuppressive
activity and its alternations could be considered to
be the ground of the circadian rhythm in the
circulating lymphocyte count. No similar
correlation was found in colorectal cancer patients
(Mussi et al. 2006).
In summary, new details concerning
oscillations in blood cells have been brought to light
in the last two years, while the chronobiology of
haematopoiesis has concentrated on clock gene
activity.
HAEMOSTASIS
The haemostatic system has multiple components in
an intricate organization; the interaction of the
rhythms of the variables participating in
haemostasis determine the transient risk states of
thromboembolic events, including myocardial
infarction and stroke, and of haemorrhage and
haemorrhagic events, each with a unique timing and
coinciding with rhythms in fibrinolytic activity
(Haus 2007b, for review). It is has been known for
many years that the myocardial infarction peak
usually occurs in the morning between 7 and
12 a.m. (Touitou and Bogdan 2007). Ohkura and
co-workers (2007b) have described circadian
rhythms in the plasma plasminogen activator
inhibitor-1 in all examined mice strains, and in
plasma antithrombin and protein C only in the
strain Jcl:ICR, whereas plasma prothrombin, factor
VII, X, prothrombin time and activated partial
thrombin time remained constant in all strains.
They also found circadian fluctuations of mRNA,
although an appropriate coagulation factor
expresses constant activity. The clock gene was
found to be involved in the regulation of
fibrinolysis through plasminogen activator
inhibitor-1 production (Oishi et al. 2005, 2006).
The CLOCK protein forms heteredimers with
BMAL1 and then activates another clock gene via
E-box elements in their promoters (Reppert and
Weaver 2002). Understanding the molecular
mechanism of plasminogen activator inhibitor-1
alterations could lead to the discovery of new
pharmaceutical targets (Oishi et al. 2006). A new
research area could be found in the mechanism of
the coagulation and fibrinolytic system.
CONCLUSION
The circadian rhythms of the haemato-immune
system are synchronized by two clocks. The
suprachiasmatic nucleus also synchronizes
peripheral oscillators and integrates light
information through the retino-hypothalamic tract.
Current findings indicate the important role of
"peripheral" clock genes in the immune system but
the role of clock genes in mature leucocytes is
unknown. The molecular bases of circannual
rhythms also remain a mystery.
Melatonin and erythropoietin have a
significant impact on rhythms. The autonomous
nervous system and the neuroendocrine system
have been shown to modulate leucocyte physiology
and this supports the concept of circadian timing as
an important aspect of hypothalamo-immune
communication. The different circadian histamine
binding to leucocytes in atopic from healthy
subjects may participate in the nocturnal
exacerbation of disease symptoms. Some oscillator
components in animals may be related to tumour
growth.
The interactions among the rhythms of the
variables participating in haemostasis determine
transient risk states of thromboembolic events.
Discrepancies between circadian changes in
mRNAs and appropriate proteins participating in
haemocoagulation and fibrinolysis indicate that we
do not know the control of these processes or their
genetic background well.
ACKNOWLEDGEMENTS
This work was partially supported by grant
no 1596/07 from the Ministry of Education of the
Czech Republic.
REFERENCES
Alcivar A: Stem cell rhythm. Nature Med. 14:252,
2008.
Arjona A, Sarkar DA: Circadian oscillations of
clock genes, cytolytic factors, and cytokines in
rat NK cells. J. Immunol. 174:7618-7624, 2005.
Arjona A, Sarkar DA: Evience supporting a
circadian control of natural killer cell function.
Brain Behav. Immunol. 20:469-476, 2006.
Arjona A, Sarkar DA: Are circadian rhythms the
code of hypothalic-immune communication?
Insight from natural killer cells. Neurochem.
Res. 33:708-718, 2008.
Balog T, Soboźanec S, ćverko V, Krolo I, Roźi†B,
Marotti M, Marotti T: The influence of season
on oxidant-antioxidant status in trained and
sedentary subjects. Life Sci. 78:1441-1447,
2006.
Berger J: Seasonal influences on circadian rhythms
in the blood picture of laboratory mice, Part I:
leucocytes and erythrocytes, Part II:
lymphocytes, eosinophils and segmented
neutrophils. Z. Versuchstierkd. 22:122-134,
1980a.
Berger J: Leucokinetic study. Morphology of the
bone marrow and blood after experimental
induction of marrow hypoplasia by
cyclophosphamide in laboratory rats. Fol.
haematol. 107:862-877, 1980b.
Berger J: Regulation of circadian rhythms. J. Appl.
Biomed. 2:131-140, 2004a.
Berger J: Chronohaematology. J. Appl. Biomed.
2:179-185, 2004b.
Berger J: Current progress in chronohaematology.
J. Appl. Biomed. 4:111-114, 2006.
Berger J: A two-clock model of circadian timing in
the immune system of mammals. Path. Biol. 56:
doi:10.1016/j.patbio.2007.10.001, 2008.
Boivin DB, James FO, Wu A, Cho-Park PF, Xiong
H, Sun ZS: Circadian clock genes oscillate in
human peripheral blood mononuclear cells.
Blood 102:4143-4145, 2003.
Cerutti RD, Scaglione MC, Tarabla HD, Boggio
JC: Biological rhythm of leukocyte
concentration in calves under natural conditions.
Biol. Rhythm Res. 37:451-454, 2006.
Challet E : Entrainment of the suprachiasmatic
clockwork in diurnal and nocturnal mammals.
Endocrinology 148:5648-5655, 2007.
Chen ST, Choo KB, Hou MF, Yeh KT, Kuo SJ,
Chang JG: Deregulated expression of the per1,
per2 and per3 genes in breast cancers.
Carcinogenesis 26:1241-1246, 2005.
Corn‚lissen G, Halberg F, Zeman M, Jozsa R,
Tarquini R, Perfetto F, Salti R, Bakken EE:
Toward a chronome (time structure) of
emlatonin. In Pandi-Perumal SR, Cardinali DP
(eds): Melatonin: from Molecules to Therapy.
Nova Biomed. Books, New York, p.135-176,
2007.
Dardente H, Cermakian N: Molecular circadian
rhythms in central and peripheral clocks in
mammals. Chronobiol. Int. 24:195-213, 2007.
Dimitrov S, Lange T, Benedict C, Nowell MA,
Jones SA, Scheller J, Rose-John S, Born J:
Sleep enhances IL-6 trans-signaling in humans.
FASEB J. 20:2174-2176, 2006.
Dimitrov S, Lange T, Nohroudi K, Born J: Number
and function of circulating human antigen
presenting cells regulated by sleep. Sleep
30:401-411, 2007.
Filipski E, King VM, Etienne MC, Li XM,
Claustrat B, Granda TG, Milano G, Hastings
MH, Levi F: Persistent twenty-four hour
changes in liver and bone marrow despite
suprachiasmatic nuclei ablaton in mice. Am. J.
Physiol. Regul. Integr. Comp. Physiol.
287:R844-851, 2004.
Fu L, Pelicano H, Liu J, Huang P, Lee C: The
circadian gene Priod2 plays an important role in
tumour suppression and DNA damage response
in vivo. Cell 111:41-50, 2002.
Fukuya H, Emoto N, Nonaka H, Yagita K,
Okamura H, Yokoyama M: Circadian
expression of clock genes in human peripheral
leukocytes. Biochem. Biophys. Res. Commun.
354:924-928, 2007.
Galijasevic S, Abdulhamid I, Abu-Soud HM:
Melatonin is a potent inhibitor for
myeloperoxidase. Biochemistry 47:2668-2677,
2008.
Geron R, Shurtz-Swirski R, Sela S, Gurevitch Y,
Tanasijtschouk T, Orr ZS, Shkolnik GS,
Tanhilevski O, Kristal B: Polymorphonuclear
leucocyte priming in long intermittent nocturnal
haemodialysis patients is melatonin a player?
Nephrol. Dial. Transplant. 21:3196-3201, 2006.
Gery S, Komatu N, Baldjyan L, Yu A, Koo D,
Koeffler HP: The circadian gene Per1 plays an
important role in cell growth and DNA damane
control in human cancer cells. Mol. Cell.
22:375-382, 2006.
Goncharova ND, Shmaliy AV, Bogatyrenko TN,
Koltover VK: Correlation between activity of
antioxidant enzymes and circadian rhythms of
corticosteroids in Macaca mulatta monkeys of
different age. Exp. Gerontol. 41:778-783, 2006.
Guney Y, Hicsonmez A, Uluoglu C, Guney HZ,
Turkcu UO, Tak‚ G, Yucel B, Caglar G,
Bilgihan A, Erdogan D, Andreu MN,
Kurtman C, Zengil H: Melatonin prevents
inflammation and oxidative stress caused by
abdominopelvic and total body irradiation of rat
small intestine. Braz. J. Med. Biol. Res.
40:1305-1314, 2007.
Gunga HC, Kirsch KA, Roecker L, Kohlberg,
Tiedemann J, Steinach M, Schobersberger W:
Erythropoietin regulation in humans under
different environmental and experimental
conditions. Resp. Physiol. Neurobiol.
158:287-297, 2007.
Halberg F, Visscher MB, Bittner JJ: Eosinophil
rhythm in mice: range of occurrence; effects of
illumination, feeding and adenalectomy. Am. J.
Physiol. 174:109-122, 1953.
Halberg F, Corn‚lissen G, Katinas G, Syutkina EV,
Sothern RB, Zslavskaya R, Halberge Francine,
Watanabe Y, Schwarzkopff O, Otsuka K,
Tarquini R, Frederico P, Siggelov J:
Transdisciplinary unifying implications of
circadian findings in the 1950s. J. Circadian
Rhythms 1:2(p.1-61), 2003.
Halberg F, Corn‚lissen G, Katinas G, Tvildiani L,
Gigolashvili M, Janashia K, Toba T, Revilla M,
Regal P, Sothern RB, Wendt HW, Wang Z,
Zeman M, Jozsa R, Singh RB, Mitsutake G et
al.: Chronobiology's progress. Part I, season's
appreciations 2004 2005: time-, frequency-,
phase-, variable-, individual-, age- and site-
specific chronomics. J. Appl. Biomed. 4:1-38,
2006.
Haus E.: Biologic rhythms in hematology. Pathol.
Biol. 44:618-630, 1996.
Haus E: Chronobiology in the endocrine system.
Adv. Drug Delivery Rev. 59:985-1014, 2007a.
Haus E: Chronobiology of hemostasis and
inferences for the chronotherapy of coagulation
disorders and thrombosis prevention. Adv. Drug
Deliv. Rev. 59:966-984, 2007b.
Haus E, Smolensky M: Biological clocks and shift
work: circadian dysregulation and potential
long-term effects. Cancer Causes Control
17:489-500, 2006.
Hazlerigg DG, Wagner GC: Seasonal
photoperiodism in vertebrates: from coincidence
to amplitude. Trends Endocrinol. Metab.
17:83-91, 2006.
James FO, Cermakian N, Boivin DB: Circadian
rhythnms of melatonin, cortisol, and clock gene
expression during simulated night shift work.
Sleep 30:1427-1436, 2007a.
James FO, Boivin DB, Charbonneau S, B‚langer V,
Cermakian N: Expression of clock genes in
human peripheral blood mononuclear cells
throughout the sleep/wake and circadian cycles
Chronobiol. Int. 24:1009-1034, 2007b.
Kiank C, Koerner Pia, Ke3ler W, Traeger T,
Maier S, Heidecke CD, Schuett C: Seasonal
variations in inflammatory responses to sepsis
and stress in mice. Crit. Care Med.
35:2352-2358, 2007.
Ko CH, Takahashi JS: Molecular components of
the mammalian circadian clock. Hum. Mol.
Genet. 15:R271-R277, 2006.
Kondratov RV: A role of the circadian system and
circadian proteins in aging. Ageing Res. Rev.
6:12-27, 2007.
Kronfeld-Schor N, Dayan T: Activity patterns of
rodents: the physiological ecology of biological
rhythms. Biol. Rhythm Res. 39:193-211, 2008.
Krugluger W, Brandstaetter A, KÂ llay E,
Schueller J, Krexner E, Kriwanek S, Bonner E,
Cross HS: Regulation of genes of the circadian
clock in human colon cancer: reduced period-1
and dihydropyrimidine dehydrogenase
transcription correlates in high-grade tumors.
Cancer Res. 67:7917-7922, 2007.
Lader M: Limitations of current medical treatments
for depression: disturbed circadian rhythms as a
possible therapeutic target. Eur.
Neuropsychopharmacol. 17:743-755, 2007.
Lakin-Thomas PL: New model for circadian
systems in microorganisms. FEMS Microbiol.
Lett. 259:1-6, 2006.
Lakin-Thomas PL, Brody S: Circadian rhythms in
microoranisms: new complexities. Annu. Rev.
Microbiol. 58: 489-519, 2004.
Lamont EW, Legault-Coutu D, Cermakian N,
Boivin DB: The role of circadian clock genes in
mental disorders. Dialogues Clin. Neurosci.
9:333-342, 2007.
Lange T, Dimitrov S, Fehm HL, Westermann J,
Born J: Shift of monocyte function toward
cellular immunity during sleep. Arch. Intern.
Med. 166:1695-1700, 2006.
Larssen KS, Lyberg T: Oxidative status - Age- and
circadian variations? A study in
leukocytes/plasma. Neuroendocrinol. Lett.
27:445-452, 2006.
Lincoln GA, Clarke IJ, Hut RA, Hazlerigg DG:
Characterizing a mammalian circannual
pacemaker. Science 314:1941-1944, 2006.
Maharaj DS, Glass BD, Daya S: Melatonin: new
places in therapy. Biosci. Rep. 27:299-320,
2007.
Mendoza J: Circadian clocks: setting time by food.
J. Neuroendocrinol. 19:127-137, 2007.
Mormont MC, Waterhouse J, Bleuzen P,
Giacchetti S Jami A, Bodan A, Lellouch J,
Misset JL, Touitou Y, Levi F: Marked 24-h
rest/activity rhythms are associated with better
quality of life, better response, and longer
survival in patients with metastatic colorectal
cancer and good performance status. Clin.
Cancer Res. 6:3038-3045, 2000.
Mussi C, Crippa S, Bonardi C, Fontana A,
Caprotti R, Uggeri F: Endocrine and
immunological alterations during cancer
processes. Int. Surg. 91:68-71, 2006.
Novak CM, Ehlen JC, Albers HE: Photic and
nonphotic inputs to the diurnal circadian clock.
Biol. Rhythm Res. 39:291-304, 2008.
Ohkura N, Oishi K, Sekine Y, Atsumi G, Ishida N,
Matsuda J, Horie S: Comparative study of
circadian variations in numbers of peripheral
blood cells among mouse strains: unique feature
of C3H/HeN mice. Biol. Pharm. Bull.
30:1177-1180, 2007a.
Ohkura N, Oish K, Sakata T, Kadota K,
Kasmatsu M, Fukushirna N, Kurata A, Tamai Y,
Shira H, Atsumi GI, Ishida N, Matsuda J, Horie
S: Circadian variations in coagulation and
fibrinolytc factors among four different strains
of mice. Chronobiol. Int. 24:651-669, 2007b.
Oishi K, Ohkura N, Amagai N, Ishida N:
Involvement of circadian clock gene Clock in
diabetes-induced circadian augmentation of
plasminogen activator inhibitor-1 (PAI-1)
expression in the mouse heart. FENS Lett.
579:3555-3559, 2005.
Oishi K, Ohkura N, Wakabaashi M, Shirai H,
Sato K, Matsuda J, Atsumi G, Ishida N: Clock
is involved in obesity-induced disordered
fibrinolysis in ob/ob mice by regulating PAI-1
gene expression. J. Thromb. Haemost. 4:
1774-1780, 2006.
Paredes SD, Terron MP, Marchena AM, Barriga C,
Pariente JA, Reiter RJ, Rodriguez AB: Effect of
exogenous melatonin on viability, ingestion
capacity, and free-radical scavenging in
heterophils from young and old ringdoves
(Streptopelia risoria). Mol. Cell. Biochem.
304:305-314, 2007.
Quaranta A, Tateo A, Siniscalchi M, Padalino B,
Iacoviello R, Centoducati P: Influence
oftraining on cortisol plasma levels and other
hematic parameters in standardbred trotters.
Ippologia 17:5-10, 2006.
Reppert SM, Weaver DR: Coordination of circadian
timing in mammals. Nature 418:935-941, 2002.
Salazar-Juarez A, Parra-Gamez L, Mendez SB, Leff
P, Anton B: Non-photic entrainment.
Physiological mechanism. Part II. (in Spanish)
Salud Mental 30:69-79, 2007.
Shadan FF: Circadian tempo: a paradigm for
genome stability? Med. Hypoth. 68:883-891,
2007.
Sher L, Oquendo MA, Galfalvy HC, Zalsman G,
Cooper TB, Mann JJ: Higher cortisol levels in
spring and fall in patients with major
depression. Progr. Neuro-Psychopharmacol.
Biol. Psychiatry 29:529-534, 2005.
Smaaland R, Lacrum O, Sothern R, Sletvold O,
Bjerknes R, Lote K: Colony forming
unit-granulocyte-macrophage and DNA synthesi
of human bone marrow are circadian
stage-dependent and show covariation. Blood
79:2281-2287, 1992.
Touitou Y, Bohdan A: Circadian and seasonal
variations of physiological and biochemical
determinats of acute myocardial infarction. Biol.
Rhythm Res. 38:169-179, 2007.
Tsinkalovsky O, Rosenluind B, Lacrum OD,
Eiken HG: Clock gene expression in purified
mouse hematopoietic stem cells. Exp. Hematol.
33:100-107, 2005.
Tsinkalovsky O, Filipski E, Rosenlund B, Sothern
RB, Eiken HG, Wu MW, Claustrat B, Bayer J,
L‚vi F, Laerum OD: Circadian expression of
clock genes in purified hematopoietic stem cells
is developmentally regulated in mouse bone
marrow. Exp. Hematol. 34:1249-1261, 2006.
Tsinkalovsky O, Smaaland R, Rosenlund B,
Sothern RB, Hirt A, Steine S, Badiee A,
Abrahamsen JF, Eiken HG, Lacrum OD:
Circadian variations in clock gene expression of
human bone marrow CD34(+) cells. J. Biol.
Rhythms 22:140-150, 2007.
Van Someren EJW, Riemersma-Van Der Lek RF :
Live to the rhythm, slave to the rhythm. Sleep
Med. Rev. 11:465-484, 2007.
Wagner GC, Johnson JD, Clarke IJ, Lincoln GA,
Hazlerigg DG: Redefining the limits of day
length responsiveness in a seasonal mammal.
Endocrinology 149:32-39, 2007.
Wronka M, Maleszewska, Stepiäska U,
Markowska M: Diurnal differences in melatonin
effets on intracellulat Ca2+ concentration in
chiscken spleen leukocytes in vitro. J. Pineal
Res. 44:134-140, 2008.
Yerer MB, Aydogan S: The importance of circadian
rhythm alterations in erythrocyte deformability.
Clin. Hemorheol. Microcirc. 35:143-147, 2006.
Zak-Nejmark T, Nowak IA, Kraus-Filarska M:
Circadian variations of histamine binding to
lymphocytes and neutrophils and skin reactivity
to histamine in atopic and healthy subjects.
Arch. Immunol. Ther. Exper. (Warsz.)
54:283-287, 2006.
Zeman M, Vican M, Monosˇkov J, Herichov I:
Deregulated expression of the per2 gene in
human colorectal carcinoma. Mol. Med. Rep. 1:
in press, 2008.
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