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<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: large"
><strong>Rosacea, inflammation, and aging:</strong> <strong>The inefficiency of stress</strong
></span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><em>Rosacea, or acne rosacea, has been defined as "vascular and follicular dilation involving the
nose and contiguous portions of the cheeks . . ." that may involve persistent erythema with
hyperplasia of sebaceous glands. </em><em><strong>Stedman's Medical Dictionary 23rd
edition.</strong></em></span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Light-skinned people, especially women between the ages of 30 and 50, sometimes develop a
persistent redness of their cheeks and nose. It may begin as a tendency to flush excessively,
but the blood vessels can become chronically dilated. Similar processes occur in dark-skinned
people less frequently.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>The eyes are sometimes involved, with redness of the exposed areas (conjuctival hyperemia). New
blood vessels develop in the area, and the flow of blood through the affected tissue is greatly
increased. The tissues become thickened and fibrotic, with the multiplication of fibroblasts and
the increased deposition of collagen.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>The cornea normally receives its oxygen from the air, and its nutrients from the aqueous humor. As
rosacea of the eye develops, the blood vessels surrounding the cornea become increasingly
visible, and, especially on the inner (nasal) side of the eye, the vessels tend to enlarge and
become tortuous. Rhinophyma, or potato nose, has been described as a late development of
rosacea.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Too often, the medical reaction is to give the condition a name, and to distinguish its variants as
if they were different problems, and then to use the most direct means to eliminate the problem
they have defined.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>A typical attitude is that "Rosacea is an enigmatic disease with multiple exacerbations and
remissions, and, unfortunately, treatment is directed toward symptomatic control rather than
cure" (Randleman).</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Lasers or other radiation, caustic chemical abrasion, surgical planing and dermal shaves, and other
forms of surgery may be used to destroy the superficial blood vessels, and to reduce the
enlarged nose or other irregularities. A few decades ago, when rosacea was believed to be the
result of a local infection, antibiotics were used to treat it, and some of them, including
tetracycline, helped. It was discovered that some antibiotics have anti-inflammatory actions,
apart from their germicidal effects, and now it is very common to prescribe the chronic use of
tetracycline to suppress symptoms.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Rosacea, and the fibrotic changes associated with it (pingueculae and pterygia in the eyes,
rhinophyma of the nose, etc.), are much more than "cosmetic" issues, involving the skin and eye
surface. If the invasive proliferation of blood vessels can be prevented, it's important to do
that, because, for example, pannus/neovascularization of the cornea can seriously impair
vision. </span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>But possibly the strangest thing about the relationship of the medical profession to rosacea is
that its essential features, invasive neovascularization and fibrotic growth, are of great
interest when they occur elsewhere, and many physiological processes are known to regulate the
growth of blood vessels and fibroblasts, but nearly all the attention given to rosacea and
rhinophyma concerns control of symptoms for cosmetic effect. Rosacea is a physiological problem
that deserves consideration in the light of all that's known about physiology and developmental
biology.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>The increased incidence of rosacea after the age of 30, and the fact that it occurs most commonly
in the areas that are most exposed to sunlight (bald men sometimes develop it on the top of the
head), indicate that aging and irritation are essential causes. Stress, irritation (such as
produced by ultraviolet or ionizing radiation or free radicals), and aging are known to cause
disorganized growth of fibrous and vascular tissues in various parts of the body. The occurrence
of these processes at the surface, where the changes can be observed immediately, and without
invasive procedures, should have aroused wide interest among those who study kidney disease,
diabetes, and other degenerative diseases in which fibrosis and neovascularization play
important roles.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>A localized stress or irritation at first produces vasodilation that increases the delivery of
blood to the tissues, allowing them to compensate for the stress by producing more energy. Some
of the agents that produce vasodilation also reduce oxygen consumption (nitric oxide, for
example), helping to restore a normal oxygen tension to the tissue. Hypoxia itself (produced by
factors other than irritation) can induce vasodilation, and if prolonged sufficiently, tends to
produce neovascularization and fibrosis. </span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Sensitivity to the harmful effects of light can be increased by some drugs and by excess porphyrins
produced in the body (and by the porphyrin precursor, delta-amino levulinic acid), leading to
rosacea, so those factors should be considered, but too often alcohol (which can cause porphyrin
to increase) is blamed for rosacea and rhinophyma, without justification. There are many ways in
which poor health can increase light sensitivity. Some types of excitation produced by
metabolites (or by the failure of inhibitory metabolites) can produce vasodilation, involving
the release of nitric oxide (Cardenas, et al., 2000), setting off a series of potentially
pathological reactions, including fibrosis. The nitric oxide increases glycolysis while lowering
energy production. The excitatory metabolite glutamate, and nitric oxide, are both inhibited by
aspirin (Moro, et al., 2000).</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>When blood flow in skin affected by rosacea was measured, circulation was 3 or 4 times higher than
normal (Sibenge & Gawkrodger, 1992), and oxygen tension may be increased. An inability to
extract oxygen from the blood, or to use it to produce energy, will produce the same hyperemia
that would be produced by a lack of oxygen. These measurements suggest that mitochondrial
defects would be the best place to look for a general cause of rosacea.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>When mitochondria are damaged, active cells produce increased amounts of lactic acid, even in the
presence of adequate oxygen. Otto Warburg identified this kind of metabolism, aerobic
glycolysis, as an essential feature of cancer, and showed that it could be produced by stress,
ionizing radiation, carcinogenic toxins, and even by a simple oxygen deficiency. Other
investigators around the same time showed that lactic acid produces vasodilation (for example,
in the cornea), and more recently it has been shown to promote the development of fibrosis, and
it has been called a "phlogogen," a promoter of inflammation. </span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Riboflavin, vitamin B2, is an essential component of the mitochondrial respiratory enzymes, and it
is very easily destroyed by light (blue light and especially ultraviolet). When it is excited by
high energy light, it can spread the damage to other components of the mitochondria, including
the cytochromes and the polyunsaturated fatty acids. The other B vitamins are affected when
riboflavin's actions are disturbed.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Vitamin K is also extremely light sensitive, and it interacts closely with coenzyme Q in regulating
mitochondrial metabolism. For example, mitochondrial Complex-I, NADH-ubiquinone reductase, is
probably the most easily damaged part of the mitochondrion, and it is protected by vitamin K.
Vitamin E, coenzyme Q, and the polyunsaturated fatty acids are also light sensitive, and they
are more susceptible to free radical damage when vitamin K is deficient.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Niacinamide, one of the B vitamins, provides energy to this mitochondrial system. Under stress and
strong excitation, cells waste niacinamide-NADH, but niacinamide itself has a sedative
antiexcitatory effect, and some of its actions resemble a hormone. Estrogen tends to interfere
with the formation of niacin from tryptophan. Tryptophan, rather than forming the sedative
niacin (pyridine carboxylic acid), can be directed toward formation of the excitatory quinolinic
acid (pyridine dicarboxylic acid) by polyunsaturated fatty acids. Excitation must be in balance
with a cell's energetic resources, and niacinamide can play multiple protective roles,
decreasing excitation, increasing energy production, and stabilizing repair systems. The state
of excitation and type of energy metabolism are crucial factors in governing cell functions and
survival.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>The polyunsaturated fatty acids, besides their interactions with estrogen and tryptophan
metabolism, promote excitation and decrease energy production in several other ways. For
example, they increase the excitatory effects of the glutamate pathways (Yu, et al., 1986;
Nishikawa, 1994), and their breakdown products inhibit mitochondrial respiration (Humphries, et
al., 1998; Picklo, et al., 1999; Lovell, et al., 2000).</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>The excess excitation that produces nitric oxide and lactic acid lowers the energy production of
vascular cells, possibly enough to lower their contractile ability (Geng, et al., 1992), causing
vasodilation. When flushing is caused by a mismatch between energy supply and energy demand,
caffeine can decrease the vasodilation (Eikvar & Kirkebøen, 1998), but when vasodilation is
caused more physiologically by carbon dioxide, caffeine doesn't have that effect (Meno, et al.,
2005). In a study in which drinking hot water or coffee was compared with drinking
room-temperature coffee or caffeine, it was found that the hot liquids caused flushing, but cool
coffee and caffeine didn't.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Caffeine increases cells' energy efficiency, and by opposing the effects of adenosine (secreted by
cells that are stressed and energy-depleted), it can inhibit vasodilation, angioneogenesis
(Merighi, et al., 2007; Ryzhov, et al., 2007), and fibrosis (Chan, et al., 2006). </span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>One nearly ubiquitous source of inappropriate excitation and energy depletion is the endotoxin,
bacterial lipopolysaccharides absorbed from the intestine (Wang and White, 1999). That this
ubiquitous toxin has a role in rosacea is suggested by the observation that intestinal
stimulation, to speed transit through the bowel, immediately relieved symptoms (Kendall, 2002).
Increased cortisol (Simon, et al., 1998) and sepsis (Levy, 2007) interfere with mitochondrial
energy production.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Simple nervous blushing or flushing is usually considered harmless, and when a person is
overheated, the reddening of the skin has the function of facilitating heat loss, to restore a
normal temperature. But even nerve-regulated flushing can involve a distinct interference with
mitochondrial respiration, and can stimulate the overgrowth of blood vessels. </span></span
></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Cancer's respiratory defect that Warburg identified, fermentation with lactic acid production even
in the presence of adequate oxygen, was the result of some kind of injury to the mitochondria.
He showed that one of the injuries that could produce aerobic glycolysis was a deficiency of
riboflavin. He observed that tumors generally were anoxic, and that cancers typically appeared
in the midst of tissue that was atrophying, and suggested that the cancer cells' survival was
favored by their ability to live without oxygen. This may be relevant to the observations of
many surgeons of a small cancer embedded in the fibrous tissue of large rhinophymas that have
been removed.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>The relatively high incidence of rosacea among women (some studies indicate that it may be 3 times
as common in women as in men) isn't likely to be the result of greater sun exposure, so it's
reasonable to look for hormonal causes.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>In old age, it's well recognized that men's estrogen level rises. But the estrogen industry has
convinced women that their estrogen declines as they get older. It's common knowledge that aging
rodents often go into "persistent estrus," and that their estrogen levels generally increase
with age (Parkening, et al., 1978; Anisimov and Okulov, 1981). Several studies in women have
shown that serum estrogen levels rise from the teens into the 40s (Musey, et al., 1987;
Wilshire, et al., 1995; Santoro, et al., 1996).</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Other studies show that serum and tissue estrogen concentrations are not concordant, and that some
tissues may contain several times as much estrogen as the serum (Jefcoate, et al., 2001). Local
irritation increases tissue estrogen content.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>The antiestrogens, especially progesterone, begin declining in the 30s, so that the rising estrogen
has more effect on the tissues during those years. These are the years in which the incidence of
rosacea rises suddenly. Rosacea develops later on average in men, whose estrogen levels rise
significantly at later ages.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Estrogen's most immediate effect on cells is to alter their oxidative metabolism. It promotes the
formation of lactic acid. In the long run, it increases the nutritional requirements for the B
vitamins, as well as for other vitamins. It also increases the formation of aminolevulinic acid,
a precursor of porphyrin, and increases the risk of excess porphyrin increasing light
sensitivity. Both aminolevulinic acid and excess porphyrins are toxic to mitochondria, apart
from their photosensitizing actions. Nitric oxide, glutamate, and cortisol all tend to be
increased by estrogen.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Veins and capillaries are highly sensitive to estrogen, and women are more likely than men to have
varicose veins, spider veins, leaky capillaries, and other vascular problems besides
rosacea. Estrogen can promote angioneogenesis by a variety of mechanisms, including nitric
oxide (Johnson, et al., 2006). "Estrogens potentiate corticosteroid effects on the skin such as
striae, telangiectasiae, and rosacea dermatitis" (Zaun, 1981). Early forms of oral
contraceptives, high in estrogen, were found to increase acne rosacea more than three-fold
(Prenen & Ledoux-Corbusier, 1971).</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Lactic acid, produced under the influence of estrogen, nitric oxide, or other problems of energy
formation, besides causing vasodilation, also stimulates the growth of fibroblasts. Oxygen
deprivation, or damage to mitochondria, will increase lactic acid formation, and so it will
immediately cause vasodilation, and if the problem is prolonged, new blood vessels will grow,
and fibrous connective tissue will increase. Estrogen stimulates collagen synthesis, and it has
been associated with a variety of inflammatory and fibrotic conditions (for example, Cutolo, et
al., 2003. Payne, et al., 2006, suggest the use of the anti-estrogen, tamoxifen, to treat
rhinophyma.)</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>The cornea normally contains more riboflavin even than the retina, which has a much higher rate of
metabolism. When the cornea isn't able to get enough oxygen from the air for its needs (and if
riboflavin is deficient, its need for oxygen is increased), surrounding blood vessels at first
dilate in response to the diffusing lactic acid, to increase the blood supply to the edges of
the cornea. If the problem is prolonged, the conjuctiva becomes chronically blood-shot,
hyperemic, and larger more visible blood vessels grow, surrounding the cornea, or even invading
the cornea. Many people, especially women, experienced problems of this sort from wearing
contact lenses, especially when the lenses were made of materials very impermeable to oxygen
(Dumbleton, et al., 2006).</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Sunlight, and mechanical obstruction of the cornea, produce very localized effects, but those local
effects are more likely to be harmful when there is a systemic nutritional deficiency or excess
of estrogen. When the systemic problem is very severe, the cheeks, nose, and eyes might not be
the first tissues to experience a functional disturbance. </span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>The mitochondrial inhibition produced by the action of the parasympathetic nervous system
(occurring in simple blushing) can occur wherever those nerves act, and blood vessels in all
parts of the body are responsive to the acetylcholine secreted by those nerves. Sleep typically
involves a shift of dominance in the autonomic nervous system toward the parasympathetic nerves,
with vasodilation. Nosebleeds, especially in children, commonly occur during sleep (Jarjour
& Jarjour, 2005: high incidence in sleep, and association with migraine). </span></span
></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>A 3 year-old child who had been having an average of 3 nosebleeds every day, during a nap and at
night, for several months, also had an extreme behavior problem. He became angry and sometimes
violent when he went a little longer than normal between meals. After an oral dose of about ten
milligrams of riboflavin, he was able to sleep without having another recurrence of the
nosebleeds, and his tantrums became rare. Apparently, the nerve-regulated vasodilation produced
by sleep, combined with a riboflavin deficiency, had been enough to produce nosebleeds. The
energy deficit resulting from a systemic riboflavin deficiency had probably been causing him to
be abnormally sensitive to glycogen depletion, producing sudden anger. In another individual,
the energy problem might have taken the form of a memory problem, or of a hemorrhage in the
brain or other essential organ.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>A 37 year old slightly alcoholic man with a bright red nose and cheeks was an amateur fiction
writer, but he was having trouble with his memory for words, and for everyday events. Even
conversationally, he had to struggle for relatively familiar words. On the suggestion that
riboflavin might help his memory, by allowing his brain cells to use oxygen more efficiently, he
had his doctor give him an intravenous injection of B vitamins. When I saw him the next day, his
conversation was perfectly fluent, and he obviously had easy access to a good vocabulary. Just
as noticeable was the normal color of his nose and cheeks. For a week, he had a daily injection
of the B vitamins, and his nose color and vocabulary stayed normal. But on the weekend, after
not having the shots for two days, his nose and cheeks were again maraschino cherry red, and his
speech was halting, as he struggled for words. He forgot the whole episode, and neglected to
return to the doctor for more of the vitamin injections. Ten years later, he had developed a
medium-sized potato nose, and had his heart valves replaced. </span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>His vitamin requirements were apparently abnormally high. At first, the problems resulting from
damaged mitochondria seem mostly functional (flushing, mood, memory problems, etc.) and
variable, but chronically disturbed functions lead to structural, anatomical changes, as
prolonged stimulation alters tissue maintenance and growth.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Abram Hoffer, who had been treating schizophrenia and senile dementia with niacin, accidentally
discovered that it cured his bleeding gums. That led to its use to treat heart disease.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>The "orthomolecular" ideas of Hoffer and Linus Pauling were developed in a context of biochemistry
governed by genetics, molecular biology, in which the goal was to provide a chemical that was
lacking because of a genetic defect in metabolism. Their idea of using nutrients as drugs has
led to many unphysiological practices, in which an isolated nutrient is supposed to have a
drug-like action, and if in isolation it doesn't act like a drug, then it should be used only
according to the normal genetically determined nutritional requirement.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>But in reality, nutritional requirements are strongly influenced by history and present
circumstances. For example, when corneal mitochondria have been damaged by riboflavin
deficiency, they have been found to subsequently require more than the normal amount of the
vitamin to function properly. And the presence of a certain amount of one nutrient often
increases or decreases the amount of other nutrients needed.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>When the interactions among energy expenditure and energy production, and cellular activation and
cellular inhibition, are taken into account, then it's clear that any particular problem is
likely to have many causes and many factors that could contribute to a cure.</span></span></span
>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Lactate, glutamate, ammonium, nitric oxide, quinolinate, estrogen, histamine, aminolevulinate,
porphyrin, ultraviolet light, polyunsaturated fatty acids and endotoxin contribute to excitatory
and excitotoxic processes, vasodilation, angioneogenesis, and fibrosis. </span></span
></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Carbon dioxide, glycine, GABA, saturated fatty acids (for example, Nanji, et al., 1997), vitamin K,
coenzyme Q10, niacinamide, magnesium, red light, thyroid hormone, progesterone, testosterone,
and pregnenolone are factors that can be increased to protect against inappropriate cellular
excitation.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>All of the nutritional factors that participate in mitochondrial respiration contribute to
maintaining a balance between excessive excitation and protective inhibition. Riboflavin,
coenzyme Q10, vitamin K, niacinamide, thiamine, and selenium are the nutrients that most
directly relate to mitochondrial energy production. </span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Coffee is often avoided by people with rosacea, but it is a very good source of niacin and
magnesium, and caffeine has some of the same cell-protective functions as niacinamide.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>People suffering from rosacea have been found to be more likely than average to have suffered from
styes in childhood, to have varicose veins and spider veins, and to suffer from migraines and
depression. </span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Hypothyroidism has been identified as a factor in all of those. Good thyroid function is necessary
for resistance to bacterial infection, for regulation of blood sugar, neurotransmitters, and
hormones related to mood, and for the formation of progesterone. Progesterone regulates smooth
muscle tone, including the walls of veins, so that a deficiency allows veins to enlarge. It also
prevents overgrowth of fibrotic tissue, and in some contexts may inhibit angioneogenesis.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>GABA itself tends to raise body temperature (Ishiwata, et al., 2005), by controlling vasodilation,
and the factors such as progesterone which protect mitochondrial energy production are also
thermogenic, supporting the GABA system. Flushing, both by directly causing heat loss and by
reducing mitochondrial energy production, tends to lower body temperature.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>The sun-damaged areas in rosacea can be directly provided with some of the protective factors by
applying them topically. In the same way that topical lactate can cause vasodilation and
disturbed energy metabolism (Rendl, et al., 2001), topical niacinamide, progesterone, vitamin K,
and coenzyme Q10 can improve the metabolism and function of the local tissues. Riboflavin can
probably be useful when applied topically, but because of its extreme sensitivity to light, it
should usually be used only internally, unless the treated skin is covered to prevent exposure
to light. Topically applied caffeine, even after sun exposure, can reduce local tissue damage
(Koo, et al., 2007). Aspirin and saturated fats can also be protective when applied
topically.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Some of the benefit from antibiotics probably results from the reduced endotoxin stress when
intestinal bacteria are suppressed. However, antibiotics can kill the intestinal bacteria that
produce vitamin K, so it's important to include that in the diet when antibiotics are
used.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Some fibers, such as raw carrots, that are effective for lowering endotoxin absorption also contain
natural antibiotics, so regular use of carrots should be balanced by occasional supplementation
with vitamin K, or by occasionally eating liver or broccoli.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Abram Hoffer's research was instrumental in getting niacin recognized as a heart protective drug,
but nearly everyone who prescribes it does so to lower blood lipids. That wasn't Hoffer's
understanding of its function. He thought it acted directly on blood vessels to protect their
integrity. During his studies of its effects on heart disease, he saw that it also lowered
cancer mortality, and so began treating cancer patients with it, with considerable success, but
there was no medical cliché that could allow the profession to follow in that
direction. </span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>The arguments I have outlined for considering rosacea to be essentially a problem of metabolic
energy, and the mechanisms that I mention for restoring mitochondrial functions, might seem more
complex than Hoffer's orthomolecular views. However, this approach is actually much simpler
conceptually than any of the ideologies of drug treatment. It simply points out that certain
excitatory factors can interfere with energy production, and that there are opposing
"inhibitory" factors that can restore energy efficiency. Sometimes, using just one or two of the
factors can be curative.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Because mitochondrial respiration is very similar in every kind of tissue, a physiological view of
rosacea could incline us toward considering the effects of these metabolic factors in other
organs during stress and aging--what would the analogous condition of rosacea and rhinophyma be
in the brain, heart, liver, or kidney?</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><strong><h3>REFERENCES</h3></strong></span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Probl Endokrinol (Mosk), 1981 Mar-Apr, 27:2, 48-52. <strong>[Blood estradiol level and
G2-chalone content in the vaginal mucosa in rats of different ages]</strong> Anisimov
VN; Okulov VB "17 beta-Estradiol level was higher in the blood serum of rats aged 14 to 16
months with regular estral cycles during all the phases as compared to that in 3- to 4-month-old
female rats." </span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Invest Ophthalmol Vis Sci. 1991 Jun;32(7):1981-5. <strong>Analysis of flavins in ocular
tissues of the rabbit</strong>. Batey DW, Eckhert CD. Riboflavin is the precursor of flavin
mononucleotide (FMN) and flavin adenine dinucleotide (FAD), coenzymes required for the activity
of flavoenzymes involved in the transfer of electrons in oxidation-reduction reactions. Flavins
are light sensitive and rapidly degrade when exposed to light in the near ultraviolet and
visible wavelengths. Some of the byproducts of flavin photodegradation are toxic. A quantitative
survey of flavins in rabbit ocular tissues is reported. Adult male Dutch-Belt Rabbits were fed
purified diets containing 3, 30, or 300 mg riboflavin/kg for 1 month. A method of aqueous
extraction and high-performance liquid chromatography with fluorescence detection was used to
measure riboflavin, FMN, and FAD in cornea, lens cortex, lens nucleus, retina, and blood. The
retina contained the highest flavin concentration. In all tissues, the primary flavin was FAD
followed by FMN and riboflavin. The highest concentration of riboflavin occurred in the cornea
followed by the retina, lens cortex, and lens nucleus. A trend toward increasing concentrations
of riboflavin occurred in the retina and blood in response to excess dietary riboflavin, but the
concentration changes were not statistically significant. The highest concentration of FAD and
FMN occurred in the retina followed by the cornea and the lens cortex and nucleus. The relative
contribution of riboflavin, FMN, and FAD to the total flavin pool was markedly different in the
various tissues of the eye. The proportion of tissue flavins present as riboflavin decreased
from anterior to posterior. It was highest in the cornea followed by lens and retina. The
pattern of distribution for FMN was: cornea greater than retina greater than lens cortex and
nucleus.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Boll Ocul. 1955 Mar;34(3):157-70. <strong>[Clinical contribution on riboflavin deficiency of
the eye.]</strong> [Article in Italian] Bellomio S.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Eur J Pharmacol. 2006 Oct 10;547(1-3):184-91. <strong>Characterization of the antinociceptive
and anti-inflammatory activities of riboflavin in different experimental models.</strong
> Bertollo CM, Oliveira AC, Rocha LT, Costa KA, Nascimento EB Jr, Coelho MM.</span></span
></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Vestn Oftalmol. 1961 Nov-Dec;74:48-53. <strong>[The content of riboflavin and ascorbic acid in
the cornea in burns of the eye.]</strong> [Article in Russian] Blinova LI, Tsypin LM,
Sheinberg AI.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>J Neurochem. 2000 May;74(5):2041-8. <strong>Implication of glutamate in the expression of
inducible nitric oxide synthase after oxygen and glucose deprivation in rat forebrain
slices.</strong> Cardenas A, Moro MA, Hurtado O, Leza JC, Lorenzo P, Castrillo A,
Bodelon OG, Bosca L, Lizasoain I.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Br J Pharmacol. 2006 Aug;148(8):1144-55. <strong>Adenosine A(2A) receptors play a role in the
pathogenesis of hepatic cirrhosis.</strong> Chan ES, Montesinos MC, Fernandez P, Desai
A, Delano DL, Yee H, Reiss AB, Pillinger MH, Chen JF, Schwarzschild MA, Friedman SL, Cronstein
BN.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Clin Exp Rheumatol. 2003 Nov-Dec;21(6):687-90. <strong>New roles for estrogens in
rheumatoid arthritis.</strong>Cutolo M, Capellino S, Montagna P, Villaggio B, Sulli A,
Seriolo B, Straub RH. Sex hormones appear to play an important role as modulators of autoimmune
disease onset/perpetuation. Steroid hormones are implicated in the immune response, with
estrogens as enhancers at least of humoral immunity, and androgens and progesterone (and
glucocorticoids) as natural immune suppressors. Serum levels of estrogens have been found to be
normal in rheumatoid arthritis (RA) patients. Synovial fluid levels (SF) of proinflammatory
estrogens relative to androgens are significantly elevated in both male and female RA patients
as compared to controls, which is most probably due to an increase in local aromatase activity.
Thus, available steroid pre-hormones are rapidly converted to proinflammatory estrogens in the
synovial tissue in the presence of inflammatory cytokines (i.e. TNF alpha, IL-1, IL-6). The
increased estrogen concentrations observed in RA SF of both sexes are characterized mainly by
the hydroxylated forms, in particular 16 alpha-hydroxyestrone, showing a mitogenic stimulating
role. Indeed, recent studies by us indicate that 17-beta estradiol (E2) clearly enhanced the
expression of markers of cell growth and proliferation, whereas testosterone (T) induced an
increase in markers indicating DNA damage and apoptosis. In particular, our data further shows
that the enhancing role of estrogens on the immune/inflammatory response is exerted by
activating the NFkB complex. In conclusion, locally increased estrogens may exert activating
effects on synovial cell proliferation, including macrophages and fibroblasts, suggesting new
roles for estrogens in RA.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Tidsskr Nor Laegeforen. 1998 Mar 30;118(9):1390-5. <strong>[Receptor mediated effects of
adenosine and caffeine] </strong>[Article in Norwegian] Eikvar L, Kirkebøen KA.
"Adenosine consists of one ribose and one purine moiety and binds to specific receptors on cell
membranes. The receptors are coupled to G-proteins and additionally to various effector-systems.
When a mismatch occurs between energy supply and energy demand, adenosine is produced by the
catabolism of adenosine triphosphate. The metabolism of an organ is thereby coupled to the local
blood supply (metabolic vasodilation)."</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Arch Dermatol. 1988 Jan;124(1):72-9. <strong>Health effects of sunlight exposure in the United
States. Results from the first National Health and Nutrition Examination Survey,
1971-1974.</strong><hr /></span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Nippon Ganka Gakkai Zasshi. 1961 Dec 10;65:2439-44. <strong>[The effects of vitamin B2 group
on the corneal metabolism. I.]</strong> [Article in Japanese] Funatsu H, Motegi
T.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>J Cosmet Dermatol. 2004 Apr;3(2):88-93. <strong>Nicotinic acid/niacinamide and the
skin.</strong> Gehring W.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Circ Res. 1992 Nov;71(5):1268-76. <strong>Interferon-gamma and tumor necrosis factor synergize
to induce nitric oxide production and inhibit mitochondrial respiration in vascular smooth
muscle cells.</strong> Geng Y, Hansson GK, Holme E. "Nitric oxide (NO) is an important
signal substance in cell-cell communication and can induce relaxation of blood vessels by
activating guanylate cyclase in smooth muscle cells (SMCs)." "It was recently shown that SMCs
may themselves produce NO or an NO-related compound. We have studied NO production and its
effects on energy metabolism in cultured rat aortic smooth muscle cells. It was observed that
the cytokines, interferon-gamma and tumor necrosis factor-alpha, synergistically induced an
arginine-dependent production of NO in these cells. This was associated with an inhibition of
complex I (NADH: ubiquinone oxidoreductase) and complex II (succinate: ubiquinone
oxidoreductase) activities of the mitochondrial respiratory chain, suggesting that NO blocks
mitochondrial respiration in these cells. Lactate accumulated in the media of the cells,
implying an increased anaerobic glycolysis, but there was no reduction of viability. An
NO-dependent inhibition of mitochondrial respiration and a switch to anaerobic glycolysis would
reduce energy production of the SMCs. This would in turn reduce the contractile capacity of the
cell and might represent another NO-dependent vasodilatory mechanism."</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Q Bull Northwest Univ Med Sch. 1952;26(2):120-3. <strong>Riboflavin and the cornea.</strong
> Gordon OE.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Bull Soc Fr Dermatol Syphiligr. 1950 May-Jun;57(3):277-80. <strong>Cutaneous-mucosal
ariboflavinosis; rosacea of cornea and medio-facial seborrheic dermatitis.</strong
> Gougerot H, Grupper C, Plas G.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Br J Dermatol. 2005 Dec;153(6):1176-81. <strong>Comorbidity of rosacea and depression: an
analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory
Care Survey--Outpatient Department data collected by the U.S. National Center for Health
Statistics from 1995 to 2002.</strong> Gupta MA, Gupta AK, Chen SJ, Johnson AM.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Biochemistry. 1998 Nov 10;37(45):15835-41. <strong>Selective inactivation of
alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase: reaction of lipoic acid with
4-hydroxy-2-nonenal.</strong>Humphries KM, Szweda LI. "Previous research has established
that 4-hydroxy-2-nonenal (HNE), a highly toxic product of lipid peroxidation, is a potent
inhibitor of mitochondrial respiration. HNE exerts its effects on respiration by inhibiting
alpha-ketoglutarate dehydrogenase (KGDH). Because of the central role of KGDH in metabolism and
emerging evidence that free radicals contribute to mitochondrial dysfunction associated with
numerous diseases, it is of great interest to further characterize the mechanism of inhibition."
"These results therefore identify a potential mechanism whereby free radical production and
subsequent lipid peroxidation lead to specific modification of KGDH and PDH and inhibition of
NADH-linked mitochondrial respiration."</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Biochemistry. 1998 Jan 13;37(2):552-7. <strong>Inhibition of NADH-linked mitochondrial
respiration by 4-hydroxy-2-nonenal.</strong> Humphries KM, Yoo Y, Szweda LI. During the
progression of certain degenerative conditions, including myocardial ischemia-reperfusion
injury, mitochondria are a source of increased free-radical generation and exhibit declines in
respiratory function(s). It has therefore been suggested that oxidative damage to mitochondrial
components plays a critical role in the pathology of these processes. Polyunsaturated fatty
acids of membrane lipids are prime molecular targets of free-radical damage. A major product of
lipid peroxidation, 4-hydroxy-2-nonenal (HNE), is highly cytotoxic and can readily react with
and damage protein. In this study, the effects of HNE on intact cardiac mitochondria were
investigated to gain insight into potential mechanisms by which free radicals mediate
mitochondrial dysfunction. Exposure of mitochondria to micromolar concentrations of HNE caused
rapid declines in NADH-linked but not succinate-linked state 3 and uncoupled respiration. The
activity of complex I was unaffected by HNE under the conditions of our experiments. Loss of
respiratory activity reflected the inability of HNE-treated mitochondria to meet NADH
demand during maximum rates of O2 consumption. HNE exerted its effects on intact mitochondria by
inactivating alpha-ketoglutarate dehydrogenase. These results therefore identify a potentially
important mechanism by which free radicals bring about declines in mitochondrial
respiration.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Tohoku J Exp Med. 1954 Dec 25;61(1):93-104. <strong>Contribution to the ocular manifestation
of riboflavin deficiency. </strong>Irinoda K, Sato S.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Brain Res. 2005 Jun 28;1048(1-2):32-40. <strong>Changes of body temperature and
thermoregulatory responses of freely moving rats during GABAergic pharmacological
stimulation to the preoptic area and anterior hypothalamus in several ambient
temperatures. </strong>Ishiwata T, Saito T, Hasegawa H, Yazawa T, Kotani Y, Otokawa M,
Aihara Y.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Pediatr Neurol. 2005 Aug;33(2):94-7. <strong>Migraine and recurrent epistaxis in
children. </strong>Jarjour IT, Jarjour LK.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>J Natl Cancer Inst Monogr 2000;(27):95-112. <strong>Tissue-specific synthesis and oxidative
metabolism of estrogens. </strong>Jefcoate CR, Liehr JG, Santen RJ, Sutter TR, Yager
JD, Yue W, Santner SJ, Tekmal R, Demers L, Pauley R, Naftolin F, Mor G, Berstein L "However,
breast cancer tissue E2 levels are 10-fold to 50-fold higher in postmenopausal women than
predicted from plasma levels."</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Endocrine. 2006 Dec;30(3):333-42. <strong>Effects of estradiol-17beta on expression of mRNA
for seven angiogenic factors and their receptors in the endometrium of ovariectomized (OVX)
ewes. </strong>Johnson ML, Grazul-Bilska AT, Redmer DA, Reynolds LP.</span></span
></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Clin Exp Dermatol. 2004 May;29(3):297-9. <strong>Remission of rosacea induced by reduction of
gut transit time.</strong> Kendall SN. Rosacea is a chronic disorder characterized by
hypersensitivity of the facial vasculature, presenting with intense flushing eventually leading
to chronic erythema and telangiectasia. Although the precise aetiology of rosacea is not known,
numerous associations with inflammatory gastrointestinal tract disorders have been reported.
Furthermore, substance P-immunoreactive neurones occur in considerably greater numbers in tissue
surrounding affected blood vessels suggesting involvement of neurogenic inflammation and
moreover plasma kallikrein-kinin activation is consistently found in patients. In this report, a
patient without digestive tract disease is described, who experienced complete remission of
rosacea symptoms following ingestion of a material intended to sweep through the digestive tract
and reduce transit time below 30 h. It is possible that intestinal bacteria are capable of
plasma kallikrein-kinin activation and that flushing symptoms and the development of other
characteristic features of rosacea result from frequent episodes of neurogenic inflammation
caused by bradykinin-induced hypersensitization of facial afferent neurones. The possible
relevance of this hypothesis to other conditions featuring afferent hypersensitivity, such as
fibromyalgia, is considered.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Br J Dermatol. 2007 May;156(5):957-64. <strong>Protection from photodamage by topical
application of caffeine after ultraviolet irradiation.</strong> Koo SW, Hirakawa
S, Fujii S, Kawasumi M, Nghiem P.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Medicina (B Aires) 1985;45(2):110-6. <strong>[Fibrosis and cirrhosis in the rabbit induced by
diethylstilbestrol and its inhibition with progesterone].</strong> [Article in Spanish]
Lanari A, de Kremer GH.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Free Radic Biol Med. 2000 Oct 15;29(8):714-20. <strong>Acrolein, a product of lipid
peroxidation, inhibits glucose and glutamate uptake in primary neuronal cultures.</strong
> Lovell MA, Xie C, Markesbery WR.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>J Cereb Blood Flow Metab. 2005 Jun;25(6):775-84. <strong>Effect of caffeine on cerebral blood
flow response to somatosensory stimulation.</strong> Meno JR, Nguyen TS, Jensen EM,
Alexander West G, Groysman L, Kung DK, Ngai AC, Britz GW, Winn HR. "Hypercarbic vasodilatation
was unaffected by either caffeine or theophylline."</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Mol Pharmacol. 2007 Aug;72(2):395-406. <strong>Caffeine inhibits adenosine-induced
accumulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and
interleukin-8 expression in hypoxic human colon cancer cells. </strong>Merighi S,
Benini A, Mirandola P, Gessi S, Varani K, Simioni C, Leung E, Maclennan S, Baraldi PG, Borea
PA.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Neuropharmacology. 2000 Apr 27;39(7):1309-18. <strong>Mechanisms of the neuroprotective effect
of aspirin after oxygen and glucose deprivation in rat forebrain slices.</strong> Moro
MA, De Alba J, Cardenas A, De Cristobal J, Leza JC, Lizasoain I, Diaz-Guerra MJ, Bosca L,
Lorenzo P.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Am J Obstet Gynecol 1987 Aug;157(2):312-317. <strong>Age-related changes in the female
hormonal environment during reproductive life. </strong>Musey VC, Collins DC, Musey PI,
Martino-Saltzman D, Preedy JR "We found that increased age during reproductive life is
accompanied by a significant rise in both basal and stimulated serum follicle-stimulating
hormone levels. This was accompanied by an increase in the serum level of estradiol-17 beta and
the urine levels of estradiol-17 beta and 17 beta-estradiol-17-glucosiduronate." "Serum levels
of dehydroepiandrosterone and dehydroepiandrosterone sulfate decreased with age, but serum
testosterone was unchanged."</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Hepatology. 1997 Dec;26(6):1538-45. <strong>Dietary saturated fatty acids down-regulate
cyclooxygenase-2 and tumor necrosis factor alfa and reverse fibrosis in alcohol-induced
liver disease in the rat.</strong> Nanji AA, Zakim D, Rahemtulla A, Daly T, Miao L,
Zhao S, Khwaja S, Tahan SR, Dannenberg AJ.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>J Physiol. 1994 Feb 15;475(1):83-93. <strong>Facilitatory effect of docosahexaenoic acid on
N-methyl-D-aspartate response in pyramidal neurones of rat cerebral cortex.</strong
> Nishikawa M, Kimura S, Akaike N. </span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>J Gerontol, 1978 Mar, 33:2, 191-6. <strong>Circulating plasma levels of pregnenolone,
progesterone, estrogen, luteinizing hormone, and follicle stimulating hormone in young and
aged C57BL/6 mice during various stages of pregnancy. </strong>Parkening TA; Lau IF;
Saksena SK; Chang MC.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Antioxid Redox Signal. 1999 Fall;1(3):255-84. <strong>4-Hydroxynonenal as a biological signal:
molecular basis and pathophysiological implications.</strong> Parola M, Bellomo G,
Robino G, Barrera G, Dianzani MU.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Ann Plast Surg. 2002 Jun;48(6):641-5. <strong>Further evidence for the role of fibrosis in the
pathobiology of rhinophyma. </strong>Payne WG, Wang X, Walusimbi M, Ko F, Wright TE,
Robson MC.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Ann Plast Surg. 2006 Mar;56(3):301-5. <strong>Down-regulating causes of fibrosis with
tamoxifen: a possible cellular/molecular approach to treat rhinophyma.</strong> Payne
WG, Ko F, Anspaugh S, Wheeler CK, Wright TE, Robson MC.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Neurochem Res. 1991 Sep;16(9):983-9. <strong>Release of arachidonic acid by NMDA-receptor
activation in the rat hippocampus.</strong> Pellerin L, Wolfe LS.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>J Neurochem. 1999 Apr;72(4):1617-24. <strong>4-Hydroxy-2(E)-nonenal inhibits CNS mitochondrial
respiration at multiple sites.</strong> Picklo MJ, Amarnath V, McIntyre JO, Graham DG,
Montine TJ.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
>Biochim Biophys Acta. 2001 Feb 14;1535(2):145-52. <strong>Acrolein inhibits respiration in
isolated brain mitochondria. </strong>Picklo MJ, Montine TJ.</span></span></span>
</blockquote>
<blockquote>
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5.3% of juvenile acne cases were improved, but the following symptoms appeared: hypertrichosis
in 4%, alopecia in 14.6, juvenile acne in 16.6%, and rosaceous acne in 3.3%. The incidence of
these symptoms in the controls was cholasma .75%, hypertrichosis 5.25%, alopecia 11.5%, juvenile
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<a href="http://www.emedicine.com/oph/topic115.htm" target="_blank"><span style="color: #1155cc"><span
style="font-family: georgia, times, serif"
><span style="font-size: xx-medium"><span style="font-style: normal"><span
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>www.emedicine.com/oph/topic115.htm</span></span></span></span></span></a>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: xx-medium"
><span style="font-style: normal"><span style="font-weight: normal"
> Last Updated: May 14, 2007. Author: J Bradley Randleman, MD, Assistant Professor,
Department of Ophthalmology, Cornea, External Disease, and Refractive Surgery Section,
Emory University School of Medicine</span></span></span></span></span>
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</blockquote>
<p> </p>
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