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Circadian Rhythm and

its Role in Malignancy


Andrew S. Bonci, BA, DC
MSCA D-II February 2011
www.drbonci.com

Where in the World is


all of the Cancer?
www.drbonci.com

Disclosures

I work for NO special


interest or lobbying
groups nor do I
receive stipends,
consulting fees,
gratuities or honoraria
from any
pharmaceutical or
nutritional companies.

I am NOT a fan of Big


Pharma or sell-out
government officials
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3
and this may show.

Objectives

Understand the Impact of Light-Dark Cycles


on Health and Disease.
Discuss Circadian Rhythms in Light of
Malignancy.
Offer the Practicing Chiropractor Practical
Tools to Help Prevent and Co-Manage the
Phenomenon called Cancer .

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As a nation, we are sick


because we don't sleep.
We are fat and diabetic
because we don't sleep.
We are dying from cancer and
heart disease because we
don't sleep.

T. S. Wiley & B. Formby


Lights Out: Sleep, Sugar, and Survival (2000)

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Death by Endless Summer


(Artificially long
days) + (Endless
brain bath of Cortisol
+ Dopamine) +
(Food Abundance) +
(Sleep Deprivation) =
Death by Endless
Summer

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Breathe-in
Experience,
Breathe-out Poetry.

Muriel Rukeyser quotes (American Writer, 1913-1980)

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Jiddu Krishnamurti (1895


1986)
It is no measure
of health to be
well adjusted
to a profoundly
sick society.

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A Profoundly Sick Society

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A Profoundly Sick Society

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A Profoundly Sick Society

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A Profoundly Sick Society

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A Profoundly Sick Society

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A Profoundly Sick Society

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A Profoundly Sick Society

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A Profoundly Sick Society

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A Profoundly Sick Society

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A Profoundly Sick Society

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A Profoundly Sick Society

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A
Profoundly
Sick
Society

WPA Posters (Works Progress


Administration) were made during
the WWII Era between 1936 and
1943 as part of Franklin Delano
Roosevelt's New Deal.

Dr. David R. Hawkins

Man's
dilemma
now and
always has
been that he
misidentifies
his own
intellectual
artifacts as

Breathe-in
Experience,
Breathe-out Poetry.

Muriel Rukeyser quotes (American Writer, 1913-1980)

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Joseph Campbell
This thing up here, this
consciousness, thinks
it's running the shop. It's a
secondary organ. It's a
secondary organ of a
total human being, and
it must not put itself in
control. It must submit
and serve the humanity
of the body.
The Power of Myth (1988)

BJ Palmer
"But when education
becomes egotistical and
paramount and displaces
the correct values of Innate,
all else becomes
"uneducated", sub-conscious,
non-conscious, and unconscious.
Education then becomes an
impenetrable wall Innate
does not and cannot break
through."
The Bigness of the Fellow Within. p. 18.

Video Follows

We're Losing the War on


Cancer

David Angus from www.TED.com


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Why do we
think about
cancer the
way that we
do? Are We

Focused on
the Right
Things?
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Chemical Warfare Circa 1915


French troops used
xylylbromide against
German troops.
The Germans retaliated
against the French by
lobbing chlorine gas.
Mustard gas proved more
insidious.
This gas was odorless and
could be be taken deeply
into the lungs.
lungs

Davis. The Secret History of the


War on Cancer. 2007. p. 199-200.

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WBC Observations Circa 1919


A U.S. Army captain named E.B. Krumbhaar
identified a pattern in the blood of the men who had
been gassed.
gassed
The white blood cell counts of
these gassed survivors were
amazingly low.
low
Some of these men developed
lung cancer.
cancer
The conclusion: mustard gas lowers
white blood cell counts.
Davis. The Secret History of the
War on Cancer. 2007. p. 201.

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Leukemia
Some physicians
(Virchow) in the 1800's
published case reports
on patients with way too
many white blood cells.
Patients with leukemia
can have white cell
counts as high as
several
hundred
Recall that,
survivors of poison gas attacks during
thousand.
thousand
WWI,
often had close to zero WBC counts.
counts
Davis. The Secret History of the
War on Cancer. 2007. p. 201.

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Thomas Dougherty, PhD Circa


1930

The Yale anatomist asked


a question that was both
fundamental and simple:
Could poison gas be
altered so that it could kill
cancer without killing the
patient?
This was the beginning
of Chemical Warfare
directed against
pathologies.
Davis. The Secret History of the
War on Cancer. 2007. p. 201.

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Goodman and Gilman


Two Yale assistant professors applied the
idea of Dougherty in the 1930's and 1940's
first on rats, then on humans.
humans
They reported in a 1946 issue of JAMA that
the intravenous infusion of nitrogen
mustard kept a few terminal cancer
patients alive.
The treatment worked best for patients with
Hodgkin's lymphoma.
lymphoma
Many patients died soon after the
infusions began. www.drbonci.com

Davis. The Secret History of the


War on Cancer. 2007. p. 202.

Leukemia is Often Complicated


by Red Cell Anemias
Since leukemia was
not amenable
surgically, this
instigated a search for
factors that could:
1.Kill White Blood
Cells (vide supra)
2.Cure the Red Cell
Anemia (vide infra)
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Dr. George Minot Circa 1926


Discovered Vitamin B12
while trying to find a cure
for pernicious anemia.
Fed patients mulched
chicken livers and the
gastric contents of his
assistant.
In 1934 he was awarded
the Nobel Prize along
with two of his colleagues.
Siddhartha Mukherjee. The Emperor of all Maladies, 2010.

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Dr. Lucy Wills Circa 1929


Working to cure a
macrocytic anemia
in India, she found that
B12 didn't always
work.
Discovered a factor in
Marmite (Vegimite)
which she called Wills'
Factor (folate)
resolved this variant of
macrocytic anemia.
Siddhartha Mukherjee. The Emperor of all Maladies, 2010.

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Dr. Sidney Farber Circa 1946


A pediatric pathologist working in
Boston, became interested in the
'anemia' associated with
leukemia.
Applied the findings of Lucy Wills.
He infused synthetic folic acid
which he obtained from a colleague
into a group of leukemic children.
It 'accelerated' their disease and
killed them in a matter of days to
weeks.
This was reported in a 1948
article in NEJM that children with
leukemia were found to die more quickly when given folic acid.
acid
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Davis. The Secret History of the


War on Cancer. 2007. p. 204.

Dr. Sidney Farber Circa 1948


Given the previous disaster,
Farber reasoned that an
'antifolate' would cure the
children of leukemia.
When these children were given
agents that blocked the
utilization of folic acid
(aminopterin), their tumors were
extinguished albeit temporarily.
A boon for pharmacology and a blow to
nutrition.
Davis. The Secret History of the
War on Cancer. 2007. p. 204.

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Breathe-in
Experience,
Breathe-out Poetry.

Muriel Rukeyser quotes (American Writer, 1913-1980)

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A Brief Overview of The


Phenomenon Called Cancer

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Defining Cancer
Cancer is not
just one disease
but many
diseases.
There are more
than 100
different types
of cancer.
http://www.cancer.gov/cancertopics/what-iscancer

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Cancer is a Preventable
Disease
Only 5-10% of all cancer cases can be
attributed to genetic defects, whereas the
remaining 90-95% have their roots in the
environment and lifestyle.
Common environmental factors that lead to
cancer death include: tobacco (25-30%),
diet and obesity (30-35%), infections
(15-20%), radiation, stress, lack of physical
activity, and environmental pollutants.
Pharm Res. 2008 Sep;25(9):2097-116.

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Cause of Cancer
Cancer is
fundamentally a
disease of
regulation of tissue
growth.
In order for a normal
cell to transform into a
cancer cell, genes
which regulate cell
growth and
differentiation must be
altered.
N Engl J Med. 2008 Jan 31;358(5):502-11.
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Hmmmmmmmmmm
If cancer is a
problem of cell
growth and
regulation, then what
is required to help a
cell remain a fully
functioning, normal,
healthy cell?
How does one avoid
dysplasia or a
maturation
abnormality?
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Cellular Abnormailites
Dysplasia, a maturational abnormality, is often
indicative of an early neoplastic process.
Metaplasia is the
reversible
replacement of one
differentiated cell
type with another
mature
differentiated cell
type.
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Anaplasia
The term
anaplasia literally
means "to form
backward".
It implies
dedifferentiation,
or loss of
structural and
functional
differentiation of
normal cells.
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Cancer is a Cellular Adaptation


Cancers have been shown to be clonally
derived from a single cell, and so it does
seem that stem cells are target cells for
carcinogenesis.
The hypothesis explicitly states that
cancer is the adaptation of the aged/adult
stem cell against sustained stress.
Rejuvenation Res. 2008 Dec; 11(6): 1059-60.

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Adult/Somatic/Aged Stem Cells


Adult stem cells are
undifferentiated
cells, found
throughout the body
after embryonic
development, that
replenish dying
cells and
regenerate
damaged tissues.
www.wikipedia.org/wiki/Adult_stem_cell

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Circadian Rhythms Control


Adult Stem Cell Activites
Hemopoietic
stem cell traffic
and
hematopoiesis do
not escape the
circadian
regulation that
controls most
physiological
processes.
Current Opinion in Hematology July 2009;
16(4): 235-242

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Cancer Derived Cell Models


There is a wealth of
in vivo and in vitro
evidence implicating
the CCRP (core
circadian regulatory
proteins) in the
growth of tumors
and, by extension,
cancer
stem/progenitor
cells.
J Cell Biochem. 2009 Jul 1;107(4):569-78.

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Cancer Derived Cell Models


The Period genes
have been
associated with a
number of tumors,
including myeloid
leukemia, breast, and
lung cancers.
J Cell Biochem. 2009 Jul 1;107(4):569-78.

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Circadian Expression of Clock


and Tumor Suppressor Genes
Circadian rhythms are
daily oscillations of
multiple biological
processes driven by
endogenous clocks.
Imbalance of these
rhythms has been
associated with
cancerogenesis in
humans.
Cell Physiol Biochem. 2010;26(2):155-66.

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Circadian Clock &


Carcinogenesis
Circadian clock gene
expression is
changed in human
pathologies
including cancers.
The circadian clock
regulates the activity
of cell cycle checkpoint-related proteins
and vice versa.
Ann Med 2010 Sep; vol. 42(6) pp. 404-15.

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Father William of Ockham


Pluralitas non est ponenda sine
necessitate.
Plurality is not to be posited without necessity.

For Ockham, the only


truly necessary entity is
God.
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Breathe-in
Experience,
Breathe-out Poetry.

Muriel Rukeyser quotes (American Writer, 1913-1980)

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Cancer Statistics in Brief

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Video Follows

What are all peoples exposed


to, subject to, on a consistent
basis and global basis that
could explain cancer in
planetary terms?

Singh KB. Am J Obstet Gynecol. 1969 Apr 15;103(8):1078-83.

Induction of polycystic ovarian


disease in rats by continuous light.
Continuous light results in persistent estrus due to
disruption of the normal cycle in the reproductive
hormones.

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Kuralasov AK. Biull Eksp Biol Med. 1975 Jul;80(7):82-4.

[Modifying effect of darkness on


the growth of mammary cancer
and on the efficacy of experimental
hormone therapy]. [Article in Russian]
Darkness reduced the percentage and delayed the
growth of transplanted tumors in rat mammary glands.

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Barni S, et al. Int J Biol Markers. 1989 Jul-Sep;4(3):157-62.

The pineal gland and breast


cancer: serum levels of melatonin
in patients with mammary tumors
and their relation to clinical
characteristics.
Melatonin concentrations were highest in breast cancer
patients with the best prognosis.
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Shift-Work is Carcinogenic
(Reuters) - Shift workers
and firefighters have a
higher risk of cancer
than the general
population and such
work should be
classified as probably or
possibly carcinogenic,
the International Agency
for Research on Cancer
said on Friday.
By Maggie Fox, Health and Science Editor
WASHINGTON | Fri Nov 30, 2007 1:57pm EST
http://www.reuters.com/article/idUSN3029736520071130

Light-at-Night Disruption
We conclude that circadian disruption induced by
light-at-night accelerates aging and promotes
tumorigenesis in rats.
This observation supports
the conclusion of the
International Agency
Research on Cancer that
shift-work that involves
circadian disruption is
probably carcinogenic to
humans.
Aging (Albany NY). 2009 Oct 2;1(10):855-65.

Chronodisruption and Cancer.


[M]eta-analyses of 30
epidemiological studies
[demonstrate] that shift
workers exposed to
chronodisruption may
have increased breast
and prostate cancer
risks:

40% increase in the


risk of breast
cancer and
prostate cancer
Naturwissenschaften. 2008 May;95(5):367-82.

Circadian Disruption, Shift


Work and the Risk of Breast
Cancer

Epidemiologic studies
are now beginning to
emerge suggesting that
women who work at
night, and who
experience sleep
deprivation, circadian
disruption, and exposure
to light-at-night are at
an increased risk of
breast cancer, and
possibly colorectal
cancer as well.
Cancer Causes Control. 2006 May;17(4):539-45.

Risk of Prostate Cancer Among


Rotating-Shift Workers
Compared with day
workers, rotatingshift workers were
significantly at risk
for prostate cancer
(relative risk = 3.0,
95% confidence
interval: 1.2, 7.7).
Am. J. Epidemiol. (15 September 2006) 164 (6): 549-555.

One in Five Americans


Approximately 15.2
million Americans
work full-time
evenings, nights,
irregular schedules
dictated by their
employers, and
rotating shifts, in
which they shift from
days to evenings,
typically on a weekly
basis.
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US Bureau of Labor Statistics & Smolensky (2000)

Shift-Work/Chronodisruption

Awake at Night

Dysregulation of Melatonin Release

Asleep During Daylight

Dysregulation of Vitamin D Production

Robert Burton (1577-1640)


Our body is like a
clock; if one wheel is
a miss, all the rest
are disordered, the
whole fabric
suffers: with such
admirable art and
harmony is a man
composed.
Robert Burton, 1577-1640
English Scholar/Author
Anatomy of Melancholy

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Melatonin, Sleep Disturbance


and Cancer Risk.
The pineal
hormone melatonin
is involved in the
circadian regulation
and facilitation of
sleep, the inhibition
of cancer
development and
growth, and the
enhancement of
immune function.
Sleep Med Rev. 2009 Aug;13(4):257-64.

Occupational Sunlight
Exposure and Risk of Cancer
Recent findings
indicate that
vitamin D obtained
from ultraviolet (UV)
exposure may
reduce the risk of
several different
cancers.
Cancer. 2010 Apr 15;116(8):2001-10.

Melatonin and Vitamin D3


Melatonin and vitamin D3
inhibit breast cancer cell
growth and induce
apoptosis.
In breast cancer cells,
melatonin together with
vitamin D3, induced a
synergistic proliferative
inhibition, with an almost
complete cell growth
arrest.
J Pineal Res. 2010 Nov 22.

No Sun Worshiper Here


Sunlight serves a
critical function: it
synchronizes the
biological clock
with planetary time.
Synchronizing, also
called entraining,
entraining
establishes
predictability and
promotes survival.
Smolensky. The body Clock. 2000; p.25

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Light-Dark Hormonal Signals


Melatonin is the hormone of
darkness

Vitamin D is the hormone of light

A Primordial Planetary Axis


Melatonin
Non-Steroid
Hormone

Cholecalciferol
Steroid Hormone
Produced in
response to light

Produced in
response to
darkness

Single Axis Hormonal


Regulation
Sophisticated
systems of
feedback requiring
one hormone and a
central nervous
system.
This is a more recent
evolutionary
development.
This is the HPA axis.
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Dual Axis Hormonal Regulation


This system of
hormonal regulation
and homeostatic
balance requires two
competitively
acting hormones.
This is a more
archaic system.

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Breathe-in
Experience,
Breathe-out Poetry.

Muriel Rukeyser quotes (American Writer, 1913-1980)

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What is Melatonin?
Melatonin also known
chemically as Nacetyl-5methoxytryptamine,
is a naturally
occurring
compound found in
animals, plants, and
microbes.
http://en.wikipedia.org/wiki/Melatonin

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Serotonin-Melatonin Pathway

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Endocrine Melatonin
Melatonin produced
in the pineal gland,
which is outside of
the blood-brain
barrier, acts as an
endocrine
hormone since it is
released into the
blood.
http://en.wikipedia.org/wiki/Melatonin

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Paracrine Melatonin
By contrast,
melatonin produced
by the retina and the
gastrointestinal (GI)
tract acts as a
paracrine
hormone.
http://en.wikipedia.org/wiki/Melatonin

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Site of Action
G protein-coupled
receptor

[Melatonin] has been


found to interact with
protein receptors
both at the cell
membrane and in the
nucleus.
[M]elatonin was
recently shown to be
a very potent
hydroxyl radical
scavenger.
J Pineal Res. 1995 Oct;19(3):123-6.

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Melatonin is Melatonin
The melatonin
circulating in your
veins is chemically
the same as that
extracted from algae,
plants, insects, frogs,
and seals.
RJ Reiter and J Robinson. Melatonin. 1995.

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Melatonin in Plants
Melatonin in plants
has multiple roles
including regulation
of the
photoperiod, in
plant defense
responses, and as a
scavenger of reactive
oxygen species.
Journal of Experimental Botany 2009; 60 (1): 5769.

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Melatonin in Animals

[Melatonin] serves as a
biological signal for the
organization of
photoperiodic seasonal
functions such as
reproduction, behavior,
coat growth and
camouflage coloring in
www.drbonci.com
seasonal animals. 91

Melatonin Toxicity
Melatonin has a very low
toxicity in rats.
Rat maternal toxicity: the
no observable adverse
effect level (NOAEL) and
lowest observed adverse
effect level (LOAEL) were
100 and 200 mg/kg/day,
respectively, and the
developmental toxicity
NOAEL was >= 200
mg/kg/day.
Toxicological Sciences 1999;50(2):271-9.

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Anti-Cancer Effects of
Melatonin

antioxidant effects

regulation of the
estrogen receptor
expression

modulation of the
enzymes involved in
the local synthesis of
estrogens
modulation of cell
cycle and induction of
apoptosis

inhibition of
telomerase activity
inhibition of
metastasis
prevention of
circadian disruption
antiangiogenesis
stimulation of cell
differentiation
activation of the
immune system.
Curr Med Chem. 2010 Nov 10.

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Melatonin as Antioxidant
Melatonin can easily
cross cell membranes
and the blood-brain
barrier.
Endocrine. 2005 Jul;27(2):119-30.

Is a suicidal or terminal
antioxidant which
distinguishes it from
the opportunistic
antioxidants.
Biol Signals Recept. 2000 May-Aug;9(3-4):137-59.

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An Established Antioxidant
Worthy of Use in Clinical Trials
Accumulating
evidence suggests
that this nontoxic
indolamine may be
useful either as a
sole treatment or in
conjunction with
other treatments for
inhibiting the
biohazardous actions
of nitrooxidative
stress.
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Melatonin Estrogen Receptor


Melatonin has been
shown to inhibit the
proliferation of
estrogen receptor
(ER)-positive human
breast cancer cells in
vitro and suppress
the growth of
carcinogen-induced
mammary tumors in
rats.
J Pineal Res. 2010 Oct;49(3):210-21.

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Melatonin & Aromatase


Melatonin inhibits aromatase promoter
expression by regulating cyclooxygenase
expression and activity in breast cancer
cells.
Br J Cancer. 2009 Nov 3;101(9):1613-9.

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Melatonin Regulates Apoptosis


Melatonin treatment substantially
prevents CCl(4)-induced apoptosis and
oxidative damage in the liver.
Toxicol Ind Health. 2008 May;24(4):201-8.

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Melatonin & Telomerase


Activity
Melatonin exhibits
oncostatic properties.

Melatonin inhibits
telomerase activity in the
MCF-7 tumor cell line both in
vivo and in vitro.

Vitamin D slows the


rate of telomere
shortening.
www.telomerase.org

Telomerase is an enzyme
responsible of telomere
elongation and is activated
in most human cancers.
J Pineal Res. 2003 Oct;35(3):204-11.

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MMP, ICAM & Melatonin


Melatonin inhibits
Matrix
Metalloproteinase
activity while
stabilizing
intercellular adhesion
molecules.
J Pineal Res. 2010 Oct 22.

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Melatonin Suppresses Tumor


Angiogenesis.

J Pineal Res. 2010 Mar;48(2):178-84.

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Melatonin & Immunity


Melatonin stimulates
the production of
progenitor cells for
granulocytes and
macrophages.
It also stimulates the
production of
natural killer cells
and CD4+ cells and
inhibits CD8+ cells.
Neuroimmunomodulation. 2008;15(4-6):272-8.

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NSAIDS Effect on Melatonin


Nonsteroidal
antiinflammatory
drugs alter
body
temperature
and suppress
melatonin in
humans.
Physiol Behav. 1996 Jan;59(1):133-9.

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Beta Blockers Block Melatonin


Beta-blockers
decrease
melatonin
release via
specific
inhibition of
adrenergic
beta1-receptors.
Eur J Clin Pharmacol. 1999 Apr;55(2):111-5.

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Caffeine Lowers Melatonin


Melatonin secretion
is controlled by
neurotransmitters
that can be affected
by caffeine.
Consumption of
caffeine decreases
6sulphoxymelatonin
excretion.
Sleep Med. 2002 May;3(3):271-3.

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Agomelatine: New Drug.


Agomelatine, a
melatonin receptor
agonist, is approved in
the European Union for
the treatment of
depression.

The First Melatonergic Antidepressant

In summary,
agomelatine has
unproven efficacy and
poorly documented
adverse effects.
Prescrire Int. 2009 Dec;18(104):241-5.

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ROZEREM (r-Zair-em) (ramelteon)


Another Melatonin
Receptor Agonist

http://www.rozerem.com

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Pharmakos (Greek: )
The term "pharmakos"
later became the term
"pharmakeus" which
refers to "a drug, spellgiving potion, druggist,
poisoner, by extension
a magician or a
sorcerer."
Jim Lynn, The Miracle of Healing in Your Church Today. p.93

Scapegoat
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Believing that a
pharmaceutical can heal your
body ...

Is like believing this vehicle


works best with a space-saver
tire.
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Breathe-in
Experience,
Breathe-out Poetry.

Muriel Rukeyser quotes (American Writer, 1913-1980)

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111

What is Vitamin D?
Vitamin D (calciferol)
comprises a group of fat
soluble seco-sterols
found naturally only in a
few foods, such as fish-liver
oils, fatty fish, mushrooms,
egg yolks, and liver.
The two major
physiologically relevant
forms of vitamin D are D2
(ergocalciferol) and D3
(cholecalciferol).
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112

Where is Vitamin D
Synthesized?

Vitamin D from the skin or


diet is only short-lived in
circulation (with a halflife of 12 days), as it is
either stored in fat cells or
metabolized in the liver
(Mawer 1972).
In circulation, vitamin D is
bound to vitamin Dbinding protein and
transported to the liver,
where it is converted to
25-hydroxyvitamin D
[25(OH)D] (DeLuca 1984).

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113

Vitamin D is a Hormone
Active vitamin D functions as a hormone, and its main
biologic function in people is to maintain serum calcium and
phosphorus concentrations within the normal range by
enhancing the efficiency of the small intestine to absorb
these minerals from the diet (DeLuca 1988; Reichel 1989).

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114

Canonical Vitamin D
1.Skin-LiverKidney
Activation
2.Endocrine
Function
3.Enteric
Calcium
Binding
Protein

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4.Enteric
Calcium
Channel

115

Non-Canonical Vitamin D
1.Peripheral Tissue
Activation
2.Paracrine Function
3.Human ProtonCoupled Folate
Transporter

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116

Vitamin D Improves Folate


Status
Vitamin D3 and its nuclear
receptor increase the
expression and activity
of the human protoncoupled folate transporter.
Mol Pharmacol. 2009 Nov;76(5):1062-71.

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117

Folic Acid, Folate or Vitamin B9


Folic acid (also known as
vitamin B9 or folacin)
and folate (the
naturally occurring
form), as well as
pteroyl-L-glutamic acid,
pteroyl-L-glutamate, and
pteroylmonoglutamic
acid are forms of the
water-soluble vitamin
B9.
http://en.wikipedia.org/wiki/Folic_acid

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118

Role of Folate
Folate is necessary
for the
production and
maintenance of
new cells, for DNA
synthesis and RNA
synthesis, and for
preventing
changes to DNA,
and, thus, for
preventing
cancer.
www.drbonci.com

Semin Oncol. 1997 Oct;24(5 Suppl 18):S1830-S18-39.

119

Vitamin D-Folate-Melatonin

J Nutr. 2002 Sep;132(9):2781-4.

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120

Betaine/Betaine-Homocysteine
Methyltransferase

The original betaine (bee' ta een), N,N,Ntrimethylglycine, was named after its discovery in
sugar beets (Beta vulgaris) in the 19th century.
Intracellular accumulation of
betaine protects protein structure
and membrane integrity while
preventing cellular dehydration.
It is also a methyl donor of
increasing significance.
http://en.wikipedia.org/wiki/Betaine

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121

S-Adenosyl Methionine

A common co-substrate involved in


methyl group transfers.
The methyl group (CH3) attached to the
methionine sulfur atom in SAM is
chemically reactive.
http://en.wikipedia.org/wiki/SAM-e

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122

HIOMT/Hydroxylindole-O-Methyltransferase
HIOMT mRNA displays a day/night
variation,with a 2-fold increase in
nighttime levels.
This day/night variation persists under
constant darkness and is abolished
by light applied at night, indicating that
HIOMT gene expression is
controlled by the endogenous clock.

Endocrinology. 1999 Mar;140(3):1375-84.

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123

Vitamin D-Folate-Melatonin
Connection

During the Light


Cycle

Vitamin D levels
increase
Folate absorption
Increases
Melatonin
Precursors
Assemble

During the Dark


Cycle

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Melatonin is

124

Sunlight & Season on


Serotonin
Summer sunlight
increases brain
serotonin levels twice
as much as winter
sunlight, a finding
compatible with both
bright light in the
visible spectrum and
vitamin D affecting
mood.
Lancet. 2002 Dec 7;360(9348):1840-2.

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125

Breathe-in
Experience,
Breathe-out Poetry.

Muriel Rukeyser quotes (American Writer, 1913-1980)

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126

Vitamin D and Cancer

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Video Follows

The Gift

Stacey Kramer from www.TED.com


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128

Vibe is a 7 years old girl from


Denmark who was diagnosed
with an inoperable tumor in
2007. Vibe has received 30
radiation treatments, four
chemotherapy treatments, and
three high dosage
chemotherapy treatments.

http://bop.nppa.org/2009/still_p
hotography/winners/?
cat=UPS&place=3rd&item=14
0479

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129

In January
2009, Vibe lost
the fight
against cancer.
At the time of
her death she
was seven
years old.

http://www.bitemagazine.ne
t/2010/08/24/a-family-lifebetween-hospitalizationsand-chemotherapy/

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130

It is projected that raising the minimum year-around serum 25(OH)D level


to 40 to 60 ng/mL would prevent approximately 58,000 new cases of
breast cancer and 49,000 new cases of colorectal cancer each year, and
three fourths of deaths from these diseases in the United States and
Canada, based on observational studies combined with a randomized
trial.
Such intakes also are expected to reduce case-fatality rates of patients
who have breast, colorectal, or prostate cancer by half.
The time has arrived for nationally coordinated action to substantially
increase intake of vitamin D and calcium.
www.drbonci.com

Because of the convincing evidence for benefit and the strong


evidence of safety, we urge those who have the ability to support
public healththe media, vitamin manufacturers, and policy makers
to undertake new initiatives that will have a realistic chance of
making a difference in terms of vitamin D nutrition.
nutrition
We call for international agencies such as the Food and Nutrition
Board and the European Commissions Health and Consumer
Protection Directorate-General to reassess as a matter of high
priority their dietary recommendations for vitamin D, because the
formal nationwide advice from health agencies needs to be
changed.
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Is Sun exposure
Worth the Skin Cancer Risk?
The U.S. economic
burden due to vitamin
D insufficiency from
inadequate exposure
to solar UVB irradiance,
diet, and supplements
was estimated at $4056 billion in 2004,
whereas the economic
burden for excess UV
irradiance was
estimated at $6-7
billion.
billion
www.drbonci.com
Photochem Photobiol. 2005 Nov-Dec;81(6):1276-86.

Deficiency Death Toll


We estimate that
50,000-63,000
individuals in the
United States and
19,000-25,000 in
the UK die
prematurely from
cancer annually due
to insufficient
vitamin D.
Photochem Photobiol. 2005 Nov-Dec;81(6):1276-86.

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An Ethical Question?
The recent discovery that
supplemental cholecalciferol
(vitamin D) significantly
reduces all-cause mortality
emphasizes the medical,
ethical, and legal
implications of promptly
diagnosing and adequately
treating vitamin D deficiency.
Altern Med Rev. 2008 Mar;13(1):6-20.

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Prevalence of Low Vitamin D


40

In this study of vitamin


D status in 512 women:

37.5% were deficient


38.5% were insufficient
24% were adequate

Percentage

37.5

Adequate is 30 ng/mL or
higher (73 nmol/L).

CA: A Cancer Journal for Clinicians. 2008


Sep/Oct;58:264-265.

38.5

n = 512

30

24

20

10

Deficient Insufficient Adequate

Vitamin D Status
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Vitamin D and Breast Cancer


Survival
Women with breast
cancer who had
adequate serum
vitamin D levels
(30+ ng/mL)
ng/mL had
nearly twice the
survival rate after
12 years of follow-up
than vitamin D
deficient (<20
ng/mL)
women.
ng/mL
CA: A Cancer Journal for Clinicians. 2008

2.0

Cancer Free Survival (RR)

n = 512,
12 yrs

1.94

1.5

1.0
1.00
0.5

0.0

Sep/Oct;58:264-265.

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Low

Adequate

Serum Vitamin D Status

Breast Cancer

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Colorectal Cancer

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Vitamin D and Cancer


Prevention
http://www.grassrootshealth.net/media/download/disease_incidence_prev_chart_101608.pdf

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DINOMIT Theory of Cancer


Disjunction
Initiation (genetic variation)
Natural selection
Overgrowth
Metastasis (spread)
Involution (cancer stops or slows)
Transition (becomes chronic
condition)
Ann Epidemiol. 2009 Jul;19(7):468-83.

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Disjunction
[D]isjunction,
consist[s] of
substantial
weakening or
loss of adherence
between epithelial
cells within a tissue
compartment.
Ann Epidemiol. 2009 Jul;19(7):468-83.

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Disjunction
Existence of the
capability of human
cells for disjunction
and rapid
autonomous
proliferation is not
surprising, since it is
needed for growth
and healing of
injuries.
Cell. 1996;84:345357.

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Disjunction
DNA may facilitate
the capability of the
human cell for
autonomous
decoupling from a
basement
membrane, and the
mobility that is
needed for
reproduction and
functioning of the
www.drbonci.com
cellular immune

Initiation
The critical events
are most likely
uncorrected errors
that occur during
DNA replication or, at
times, action on the
DNA of alkylating
agents, ionizing
radiation, or
epigenetic factors.
Br J Cancer. 2009;100:571577.

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Natural Selection
This phase consists
of selection of the
fastest reproducing,
most aggressive
cells.
It is a well described
process of evolution,
yet occurring on a
microscopic scale.
Land RB. Genetics and reproduction. In: Austin CR, Short
RV, eds. Reproduction in mammals: reproductive fitness.
Cambridge: Cambridge University Press; 1985:3

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Natural Selection
Since the driver of evolution
is the gene, a stem cell
having a gene associated
with faster reproduction or
aggression against other
cells in competition for
limited resources, will
eventually be
overrepresented in the
tissue compartment.
Dawkins R. The selfish gene. New York: Oxford University Press;
2006.
Nutr Rev. 2007;65:S9195.

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Overgrowth
The next phase is
clonal expansion, or
overgrowth of the
tumor outside the
basement
membrane of the
tissue and into the
stromal layer; it
occurs for unknown
reasons.
Ann Epidemiol. 2009 Jul;19(7):468-83.

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Overgrowth
Aggressive cells near
the basement
membrane may
begin to dissolve it
enzymatically or by
changing
extracellular pH, in
order to obtain
needed amino acids.
Ann Epidemiol. 2009 Jul;19(7):468-83.

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Metastasis
The next phase is
metastasis, which may
be regarded as
analogous to
colonization of a
remote range by an
organism.
Invasion of distal tissues
could be facilitated by
disjunction in the
remote tissue, reducing
its barrier function.
www.drbonci.com
Ann Epidemiol. 2009 Jul;19(7):468-83.

Involution
The next phase is
involution, which occurs
when vitamin D status
is restored by a
seasonal rise in
25(OH)D; it consists of
a temporary arrest of
growth of metastases
and other progeny of
the primary tumor
whose VDR is intact.
Ann Epidemiol. 2009 Jul;19(7):468-83.

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Involution
During the involution
phase, malignant cells
remain in the
metastases, but
intercellular
junctions may be reestablished in cells
that have functional
VDR.
Ann Epidemiol. 2009 Jul;19(7):468-83.

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Transition
If vitamin D and
calcium deficiency
persist and the
metastatic lesions do
not irretrievably
harm a vital organ,
the metastatic
cancer will make a
transition to
carcinomatosis, or
disseminated
malignancy.
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Transition
If vitamin D and
calcium are
repleted to
adequate levels,
some evidence
suggests that there
may be a
transition from an
acute to a chronic
disease.
Ann Epidemiol. 2009 Jul;19(7):468-83.

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Transition
[T]he VDR receptorligand complex
activates signaling
pathways that
induce E-cadherin
and other proteins
that adhere cells to
one another,
including zona
occludens proteins 1
and 2.
J Cell Biol. 2008;183:697710.
Anticancer Res. 2008;28:26132623.

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D, Season and Survivability


Patients diagnosed during
the summer and
autumn had the best
prognosis (Ralative risk
(RR) death 0.8; 95% CI
0.75-0.85).
The seasonal effect on
prognosis may be
related to the seasonal
variations of calcidiol (the
marker of vitamin D
status).
www.drbonci.com

J. Prostate. 2007 Sep 1;67(12):1362-70.

Breathe-in
Experience,
Breathe-out Poetry.

Muriel Rukeyser quotes (American Writer, 1913-1980)

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157

Time Cycles

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158

The Tyranny of Time


We have become a clock driven
society, one that arranges time according
to the demands of a commercial or
industrial complex often fostered by profit
and/or leisure, rather than arranging time
so that our internal clocks are in
synchrony with the natural environment of
this clockwork Earth.
Koukkari and Sothern. Introduction to Biological Rhythms. 2006. p. 11

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159

Three rhythm domains

Circadian (20 to 28
hours)

Ultradian (< 20 hours)

Infradian (> 28 hours)

Koukkari and Sothern. Introduction to Biological Rhythms.


2006. p. 15

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160

Examples of biological rhythms

Circadian: body temperature in humans


and leaf movements of plants.
Ultradian: brain waves of humans and
twining of movements of bean shoots.
Infradian: the menstrual cycle of human
females and the annual germination of
certain seeds.

Koukkari and Sothern. Introduction to Biological Rhythms. 2006. p. 15

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161

Circadian Cycle

Organisms have to be able to extract time of day


information from dawn and dusk.
Foster & Kreitzman from Life Rhythms, 2005, p. 95.

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162

Introduction to the Circadia


In humans, like other
organisms, most
physiological and
behavioral functions are
manifested
rhythmically across
days and nights.
When a human being encounters a new day, the body
prepares itself for the new tasks ahead and boost
heart rate, blood pressure and temperature.
Journal of Circadian Rhythms 2010, 8:3

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163

Circadian Clock

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These rhythms
are the
outward
manifestation
of an internal
timing
system
generated by a
circadian clock
that is
synchronized
by the day164
night cycle.

Circadian Clock
The circadian timing
system proficiently
coordinates the
physiology of living
organisms to match
environmental or
imposed 24-hour
cycles.
Nat Rev Neurosci 2003 , 4:649-661.

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165

Circadian Clock
Circadian clocks are
endogenous and selfsustained timetracking systems that
enable organisms to
anticipate
environmental changes,
thereby adapting their
behavior and
physiology to the
appropriate time of day.
Trends Neurosci 2002 , 25:632-637.

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166

Circadian Clock
A wide range of
biological processes
are regulated by
the circadian clock
including sleep-wake
cycles, body
temperature, energy
metabolism, cell
cycle and hormone
secretion.
Annu Rev Genomics Hum Genet 2004 , 5:407-441.
Curr Top Dev Biol 2007 , 78:173-216.

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167

Master Clock
The mammalian
clock system is
hierarchical with a
master clock that
controls circadian
rhythms and resides
in the
suprachiasmatic
nucleus (SCN) of the
hypothalamus.
Journal of Circadian Rhythms 2010, 8:3

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168

Master Clock
The SCN pacemaker
consists of multiple,
autonomous single
cell circadian
oscillators, which
are synchronized to
generate a
coordinated rhythmic
output in intact
animals.
Neuron 1995 , 14:697-706.
Cell 1997 , 91:855-860.

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169

Master Clock
In mammals, the
circadian
photoreception
pathways are
distinct from those of
visual perception.
N Engl J Med 1995 , 332:6-11.
Science 1999 , 284:502-504.
Science 1999 , 284:505-507.

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170

Master Clock
Light is perceived by
a subset of
melanopsinexpressing retinal
ganglion cells, and
the photic
information is
directly conveyed to
the SCN clock
through the retinohypothalamic tract.
Nature Neurosci 2001 , 4:1165.
Science 2002 , 295:1065-1070.

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171

Retinal Melanopsin
Mutant mice lacking rods and cones (blind)
can, nevertheless, be entrained by light
dark cycles.
Koukkari and Sothern. Introduction to Biological Rhythms. 2006. p. 37

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172

SCN Environmental
Synchronizer
The suprachiasmatic
nuclei (SCN) of the
hypothalamus are
necessary for
coordination of major
aspects of circadian
rhythmicity in
mammals.
Brain Res Mol Brain Res. 2004 May 19;124(2):143-51.

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173

Master Clock

This photic entrainment corrects the phase of


the SCN oscillator every day to ensure
synchronization of circadian with geophysical
time.

Journal of Circadian Rhythms 2010, 8:3

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174

The Master Clock


To coordinate timeappropriate
metabolic responses
in peripheral tissues,
the rhythm of SCN
(suprachiasmatic
nuclei) neuronal
activity must be
entrained by the
daily environmental
cycle.
Ann Acad Med Singapore. 2008 Aug;37(8):662-8. Review.

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175

Master Clock
In general terms, the
period of the clock
is genetically
determined,
whereas its phase is
heavily influenced
by environmental
zeitgebers (cues or
stimuli) such as light.
Journal of Circadian Rhythms 2010, 8:3

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176

Zeitgeber
The major zeitgeber
(time-giver) is light
intensity.

Ann Acad Med Singapore.

2008 Aug;37(8):662-8. Review

Other zeitgegers
include food,
temperature,
exercise, social
interaction and odor.
The zeitgeber uses the neuroendocrine system
to entrain slave oscillators.
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177

Slave Oscillators
A major finding in the
field of circadian
rhythms in recent years
is that the SCN is not
the only circadian clock
in the organism.
Indeed, most tissues
including extra-SCN
brain regions and
peripheral organs bear
circadian oscillators.
J Biol Rhythms 2003 , 18:250-260.

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178

Slave Oscillators
The SCN
synchronizes
peripheral
clocks in organs
so that a coherent
rhythm is
orchestrated at
the organismal
level to ensure
temporally
coordinated
physiology.
J Biol Rhythms 2001 , 16:196-204.
Cell Tissue Res 2002 , 309:109-118
Eur J Neurosci 1999 , 11:1535-1544.

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179

Molecular Mechanism
of the Circadian Clock
The molecular
clockwork is composed
of a network of
transcriptionaltranslational
feedback loops that
drive rhythmic, ~24hour expression
patterns of core clock
components.
Science 2000 , 288:1013-1019.

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180

The Endogenous Clock


The clock consists of
interacting
molecules whose
levels repeatedly
fluctuate every 24
hours.
A time point is
specified by the
concentrations of
these molecules in
the nucleus and
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cytoplasm.

181

Molecular Mechanism
of the Circadian Clock
Core clock
components are
genes whose
protein products
are necessary for
the generation and
regulation of
circadian rhythms
within individual cells
throughout the
organism.
J Biol Rhythms 2004 , 19:339-347.

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182

Circadian Clock and Cell Cycle


The circadian
clock controls
the
expression of
cell cyclerelated
genes.

Circadian
Clock Genes

Science 2003 , 302:255-259.

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183

Clock-Cancer Connection
Exposure to light-atnight, including
disturbance of the
circadian rhythm,
possibly mediated
via the melatonin
synthesis and
clock genes, has
been suggested as a
contributing cause of
breast cancer.
Journal of Circadian Rhythms 2010, 8:3

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185

Breathe-in
Experience,
Breathe-out Poetry.

Muriel Rukeyser quotes (American Writer, 1913-1980)

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186

How do you keep 50 Trillion


cells Happy, Healthy and Under
Control?

Entrainmen
t
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187

Entrainment
In chronobiology,
entrainment of a
circadian system is
the alignment of
its own period and
phase to the period
and phase of an
external rhythm.
http://en.wikipedia.org/wiki/Entrainment_(chronobiology)

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188

Chronobiologic Function
In animals,
circulating levels of
the hormone
melatonin vary in
a daily cycle,
thereby allowing the
entrainment of the
circadian rhythms of
several biological
functions.
Int. J. Clin. Pract. 2007; 61 (5): 83545.

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190

The Survival Advantage


The synchrony
achieved between
an organisms
metabolism and
its environment
confers a survival
advantage.
Ann Acad Med Singapore. 2008 Aug;37(8):662-8.
Review.

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191

The Natural Day v 24/7


Prior to the early 1900s, the selective
advantage to humans to synchronize
their activities with the daily and yearly
motion of our planet was very evident.
Night was partitioned for rest and sleep,
while daylight with a span for activity and
movement.
People had little else to do at night but
sleep.
Koukkari and Sothern. Introduction to Biological Rhythms. 2006. p. 377

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192

Time Schedules
Regardless of
whatever schedules
society imposes or
we impose, we are
born with a
temporal system of
rhythms as part of
our genetic structure.
Koukkari and Sothern. Introduction to Biological Rhythms.
2006. p. 378

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193

Time schedules
Depending upon the
circumstances there
may be harmony or
discord between our
internal rhythms and
the external clocks of
our society.
Koukkari and Sothern. Introduction to Biological Rhythms.
2006. p. 379

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194

Artificial Rhythms
Life moves in
synchrony to the
beat of clocks and
calendars, some
outside the body and
some within the very
cells of all living
things.
Koukkari and Sothern. Introduction to Biological Rhythms.
2006. p. 1

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195

Watches, Clocks,
Calendars and Schedules
These independent
devices may be either
in or out of phase with
the biological clocks and
rhythms of our body,
which over millions of
years, have adapted to
the motions of our
planet with its
environmental cues as
to when an activity
should best occur.
Koukkari and Sothern. Introduction to Biological Rhythms.
2006. p. 376

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196

Circannual Cycle

Light can
be used to
calculate
the time of
year.
Foster & Kreitzman from Life Rhythms,
2005, p. 84.

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197

Cultura Mata
Today, the trends in
urbanization and
the utilization of
electrical power
and rapid
transportation shield
most of us from
witnessing much of
the seasonal
biological diversity
found in nature.
Koukkari and Sothern. Introduction to Biological Rhythms.
2006. p. 107
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198

Addaptaion to Light
Availability
Native plants and
animals have become
adapted to the
seasons of their
environment by
responding to the
changes in the lengths
of daylight and night
in preparation for
climactic changes that
are to come.
Koukkari and Sothern. Introduction to Biological Rhythms.
2006. p. 109
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199

Photoperiodism
These responses,
which are associated
with the seasons of
the year, involve a
physiological process
known as
photoperiodism.
Koukkari and Sothern. Introduction to Biological Rhythms.
2006. p. 109

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200

Light as Environmental Signal


Visible light exposure modulates pituitary and pineal
gland changes.
Melatonin,
norepinephrine,
and acetylcholine
decrease with
light activation,
whereas cortisol,
serotonin, GABA,
and dopamine
levels increase.
Ann N Y Acad Sci. 2000;917:435-45.

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201

[With light activiation]


... cortisol, serotonin,
GABA, and dopamine
levels increase.

Ann N Y Acad Sci. 2000;917:435-45.

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202

Dopamine: Helping Males


Copulate for at least 200
Million Years

Brain dopamine
systems are implicated
in a variety of
behavioral responses
and clinical syndromes,
including sex, drug
addiction, feeding,
satiety, sleep,
wakefulness, arousal,
attention, reward,
decision-making,
depression, anxiety,
psychosis, and
www.drbonci.com
movement disorders. 203

Dopamine: Modulator
of Food Seeking.
The dopamine
projection to the
nucleus accumbens
has been implicated in
behaviors directed
toward the
acquisition and
consumption of
natural rewards.
J Neurosci. 2004 Feb 11;24(6):1265-71.

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204

Dopamine and Reward


Dopamine is
closely
associated with
reward-seeking
behaviors, such
as consumption
and addiction.
Nature. 2009 Jun 11;459(7248):837-41.

Addiction depends
on Speed of Reward.

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205

Reduced Motivation
In humans, drugs that reduce dopamine
activity (neuroleptics, e.g. antipsychotics:
clozapine, haldol) have been shown to
reduce motivation, cause anhedonia
(inability to experience pleasure), and longterm use has been associated with the
irreversible movement disorder, tardive
dyskinesia.
Pharmacopsychiatry. 2003 Nov;36 Suppl 3:S181-90.

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206

Light Exposure Increases


Cortisol
[B]right light
increased cortisol
levels and body
temperature and
improved alertness
significantly.
Pak J Biol Sci. 2010 May 1;13(9):431-6.

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207

Cortisol Hunger
In binge eating
disorder, there is an
hyperactive HPA
axis related to
abdominal obesity
that persists even
after treatment,
suggesting that
cortisol might be
a primary factor
in the disorder.
Ann N Y Acad Sci. 2004 Dec;1032:202-7.

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208

Light, Hyperglycemia &


Obesity
Disrupted light-dark
cycle induces
obesity with
hyperglycemia in
genetically intact
animals.
Neuro Endocrinol Lett. 2009;30(4):458-61.

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209

Light & Insulin Resistance


Circadian
misalignment
may lead to
central and
peripheral
deleterious
consequences,
such as memory
deficit and
insulin
resistance.
www.drbonci.com

Front Neuroendocrinol. 1993 Oct;14(4):303210


47.

Sleep and Glucose Metabolism


Under normal
conditions, glucose
tolerance is
modulated by
circadian
rhythmicity and
sleep, two central
nervous system
processes which may
be influenced by
melatonin.
Therapie. 1998 Sep-Oct;53(5):467-72.

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211

Cancer & Obesity

Cancers linked to
obesity among
women comprise
approximately 51%
of all new cancers.

Among men, cancers


linked to obesity
comprise
approximately 14%
of new cancers.
http://www.obesity.org/information/cancer_obesity.asp

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212

Sleep Loss & Obesity


Cross-sectional and
longitudinal
epidemiological
studies have shown
associations between
short sleep
duration and
obesity, diabetes and
hypertension.
Obes Rev. 2009 Nov;10 Suppl 2:37-45.

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213

Sleep Loss & Obesity


Accumulating
evidence from both
epidemiologic
studies and wellcontrolled laboratory
studies indicates that
chronic partial
sleep loss may
increase the risk of
obesity and weight
gain.
Endocr Dev. 2010;17:11-21.

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214

Neuroendocrine Dysfunction &


Sleep
Epidemiologic studies in adults and children
and laboratory studies in young adults
indicate that sleep restriction results in
metabolic and endocrine alterations,
including decreased glucose tolerance,
decreased insulin sensitivity, increased
evening concentrations of cortisol,
increased levels of ghrelin, decreased levels
of leptin and increased hunger and
appetite.
Endocr Dev. 2010;17:11-21.

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215

Insulin Resistance & Sleep Interruption


Fragmentation of
sleep across all
stages is associated
with a decrease in
insulin sensitivity.
Chest. 2010 Jan;137(1):95-101.

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216

Insulin Resistance & Cancer


[H]yperinsulinemia is
an independent
risk factor for
breast cancer and
may have a
substantial role in
explaining the
obesity-breast cancer
relationship.
J Natl Cancer Inst. 2009 Jan 7;101(1):48-60.

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217

Insulin Resistance & Sleep Interruption


Increases in
sympathetic
nervous system
and
adrenocortical
activity likely
mediate the
adverse metabolic
effects of poor
sleep quality.
Chest. 2010 Jan;137(1):95-101.

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218

Poor Sleep Hygiene


Compared to a few
decades ago, adults,
as well as children,
sleep less.
Sleeping as little as
possible is often seen
as an admirable
behavior in
contemporary
society.
Endocr Dev. 2010;17:11-21.

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219

Light pollution
The prevalent trend in human society to use
artificial light has reached ruinous
levels throughout much of the world such
that nocturnal sky brightness has increased
many fold from natural conditions.
Illuminating the night and thereby
extending the daylong past sunset is an
ever increasing dilemma.
Koukkari and Sothern. Introduction to Biological Rhythms. 2006. p. 408

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220

Light Pollution & Health


Ill-timed artificial
lighting and the lack
of sunlight may
cause circadian
disruption that can
lead to health
problems.
Koukkari and Sothern. Introduction to Biological Rhythms.
2006. p. 408

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221

Effects on Clinical Health


Light thus has the
ability to act like a
drug and, as such,
has become a public
health issue in the
industrialized world
.

Koukkari and Sothern. Introduction to Biological Rhythms.


2006. p. 408

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222

Effects on Clinical Health


Areas possibly affected
by changes in
melatonin production
include endocrine
functions associated
with puberty,
psychiatric illness,
stress related
disorders, immune
responses, and
carcinogenesis.
Koukkari and Sothern. Introduction to Biological Rhythms.
2006. p. 408

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223

Breathe-in
Experience,
Breathe-out Poetry.

Muriel Rukeyser quotes (American Writer, 1913-1980)

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224

Mammalian Hibernation: A Naturally


Reversible Model for Insulin Resistance in
Man?
Fat deposition occurs
on a circannual basis.
It is entrained by the
length of daylight,
with peak fat deposition
occurring as days
shorten in the autumn.
Diab Vasc Dis Res. 2008 Jun;5(2):76-81.

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225

Mammalian Hibernation: A Naturally


Reversible Model for Insulin Resistance in
Man?
The circannual cycle of
hibernation exhibits
similarities and
differences between the
obligatory, yet
reversible, natural
obesity and
accompanying insulin
resistance of natural
hibernation, and the
pandemic of human
obesity and metabolic
syndrome.
Diab Vasc Dis Res. 2008 Jun;5(2):76-81.

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226

Prehibernation Insulin
Resistance
The bats showed high
circulating blood
glucose levels and
impaired glucose
tolerance during the
period of fat deposition
suggesting insulin
resistance condition
which improves after
winter when most of
the fat has been utilized
as a metabolic fuel.
Comp Biochem Physiol A Mol Integr Physiol. 2010
Mar;155(3):392-400.

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227

Sleep Normalizes Physiology


The high circulating
melatonin levels during the
period of maximum body fat
at the beginning of winter
prepare the bats for winter
dormancy by modulating
the glucose homeostasis
through affecting blood
glucose levels, muscle and
liver glycogen stores, insulin
receptor and glucose
transporter 4 (GLUT 4)
expression.
Comp Biochem Physiol A Mol Integr Physiol. 2010
Mar;155(3):392-400.

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228

Insulin Resistance
in Mammalian Hibernators
Mammals that undergo
winter hibernation
prepare by dramatically
increasing food intake
and consequently, body
fat stores during the
summer and early
autumn.
FASEB Journal. 2007;21:964.2

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229

Insulin Resistance
in Mammalian Hibernators
Several species nearly double their body mass
in the form of fat.
FASEB Journal. 2007;21:964.2

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230

Insulin Resistance
in Mammalian Hibernators

Elevated serum glucose has an antifreeze


effect. ~TS Wiley, et. al.
www.drbonci.com

The consequence
of this significant
increase in fat
mass has been
shown to be
hyperinsulinemia,
peripheral
insulin
resistance, and
elevated serum
glucose levels in
all species
investigated thus
231
far.

Hibernation Disease/
Endless Summer
The diseases that we
know to correlate with
obesityhigh blood
pressure, heart disease,
diabetes, cancer, and
depressionare all
really the result of a
vestigial hibernation
instinct brought on by
too much artificial light.
Lights Out: Sleep, Sugar, and Survival (T. S. Wiley) Loc.
2041-47

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232

Hibernation Disease/
Endless Summer
Mammal studies concur
that once you start the
hibernation preparation
cycle, hyperlipidemia
(high cholesterol), high
blood pressure, and
insulin resistance (leading
to obesity) are normal
states that resolve
themselves with the
extended sleep that
follows in nature.
Lights Out: Sleep, Sugar, and Survival (T. S. Wiley) Loc. 204147

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233

Entrain Yourself
1.Entrain yourself to
the planetary
cycles of light-dark
and the seasonal
shifts to
experience better
health.
2.Live in the cyclical
tide of
cholecalciferol and
melatonin.
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234

A Special Thank You!


The entire MSCA DII
Membership
Dr. Russell Matthias
Dr. Ron Manfredi
Dr. Doran Nicholson
I am honored by your
friendship.

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235