Ledda
/
djledda-web


			
				
					
						
						
							
							<html>
    <head><title></title></head>
    <body>
        <h1></h1>

        <p></p>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: large"
                    ><strong>Rosacea, inflammation, and aging:</strong>&nbsp;<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.&nbsp;</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.&nbsp;</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.&nbsp;</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 &amp; 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.&nbsp;</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 &amp; 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).&nbsp;</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.&nbsp;</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.&nbsp; 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 &amp; 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.&nbsp;</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
                        &amp; Jarjour, 2005: high incidence in sleep, and association with migraine).&nbsp;</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.&nbsp;</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.&nbsp;</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.&nbsp;</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.&nbsp;</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.&nbsp;</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.&nbsp;<strong>[Blood estradiol level and
                            G2-chalone content in the vaginal mucosa in rats of different ages]</strong>&nbsp;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."&nbsp;</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.&nbsp;<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.&nbsp;<strong>[Clinical contribution on riboflavin deficiency of
                            the eye.]</strong>&nbsp;[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.&nbsp;<strong>Characterization of the antinociceptive
                            and anti-inflammatory activities of riboflavin in different experimental models.</strong
                        >&nbsp;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.&nbsp;<strong>[The content of riboflavin and ascorbic acid in
                            the cornea in burns of the eye.]</strong>&nbsp;[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.&nbsp;<strong>Implication of glutamate in the expression of
                            inducible nitric oxide synthase after oxygen and glucose deprivation in rat forebrain
                            slices.</strong>&nbsp;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.&nbsp;<strong>Adenosine A(2A) receptors play a role in the
                            pathogenesis of hepatic cirrhosis.</strong>&nbsp;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.&nbsp; 2003 Nov-Dec;21(6):687-90.&nbsp;<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.&nbsp;<strong>[Receptor mediated effects of
                            adenosine and caffeine]&nbsp;</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.&nbsp;<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.&nbsp;<strong>[The effects of vitamin B2 group
                            on the corneal metabolism. I.]</strong>&nbsp;[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.&nbsp;<strong>Nicotinic acid/niacinamide and the
                            skin.</strong>&nbsp;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.&nbsp;<strong>Interferon-gamma and tumor necrosis factor synergize
                            to induce nitric oxide production and inhibit mitochondrial respiration in vascular smooth
                            muscle cells.</strong>&nbsp;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.&nbsp;<strong>Riboflavin and the cornea.</strong
                        >&nbsp;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.&nbsp;<strong>Cutaneous-mucosal
                            ariboflavinosis; rosacea of cornea and medio-facial seborrheic dermatitis.</strong
                        >&nbsp;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.&nbsp;<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>&nbsp;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.&nbsp;<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.&nbsp;<strong>Inhibition of NADH-linked mitochondrial
                            respiration by 4-hydroxy-2-nonenal.</strong>&nbsp;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&nbsp; 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.&nbsp;<strong>Contribution to the ocular manifestation
                            of riboflavin deficiency.&nbsp;</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.&nbsp;&nbsp;<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.&nbsp;</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.&nbsp;<strong>Migraine and recurrent epistaxis in
                            children.&nbsp;</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.&nbsp;<strong>Tissue-specific synthesis and oxidative
                            metabolism of estrogens.&nbsp;</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.&nbsp;<strong>Effects of estradiol-17beta on expression of mRNA
                            for seven angiogenic factors and their receptors in the endometrium of ovariectomized (OVX)
                            ewes.&nbsp;</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.&nbsp;<strong>Remission of rosacea induced by reduction of
                            gut transit time.</strong>&nbsp;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.&nbsp;<strong>Protection from photodamage by topical
                            application of caffeine after ultraviolet&nbsp; irradiation.</strong>&nbsp;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.&nbsp;<strong>[Fibrosis and cirrhosis in the rabbit induced by
                            diethylstilbestrol and its inhibition with progesterone].</strong>&nbsp;[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.&nbsp;<strong>Acrolein, a product of lipid
                            peroxidation, inhibits glucose and glutamate uptake in primary neuronal cultures.</strong
                        >&nbsp;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.&nbsp;<strong>Effect of caffeine on cerebral blood
                            flow response to somatosensory stimulation.</strong>&nbsp;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.&nbsp;<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.&nbsp;</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.&nbsp;<strong>Mechanisms of the neuroprotective effect
                            of aspirin after oxygen and glucose deprivation in rat forebrain slices.</strong>&nbsp;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.&nbsp;<strong>Age-related changes in the female
                            hormonal environment during reproductive life.&nbsp;</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.&nbsp;<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>&nbsp;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.&nbsp;<strong>Facilitatory effect of docosahexaenoic acid on
                            N-methyl-D-aspartate response in pyramidal neurones of rat cerebral cortex.</strong
                        >&nbsp;Nishikawa M, Kimura S, Akaike N.&nbsp;</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.&nbsp;<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.&nbsp;</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.&nbsp;<strong>4-Hydroxynonenal as a biological signal:
                            molecular basis and pathophysiological implications.</strong>&nbsp;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.&nbsp;<strong>Further evidence for the role of fibrosis in the
                            pathobiology of rhinophyma.&nbsp;</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.&nbsp;<strong>Down-regulating causes of fibrosis with
                            tamoxifen: a possible cellular/molecular approach to treat rhinophyma.</strong>&nbsp;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.&nbsp;<strong>Release of arachidonic acid by NMDA-receptor
                            activation in the rat hippocampus.</strong>&nbsp;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.&nbsp;<strong>4-Hydroxy-2(E)-nonenal inhibits CNS mitochondrial
                            respiration at multiple sites.</strong>&nbsp;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.&nbsp;<strong>Acrolein inhibits respiration in
                            isolated brain mitochondria.&nbsp;</strong>Picklo MJ, Montine TJ.</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >Arch Belg Dermatol Syphiligr. 1971 Jul-Sep;27(3):253-8.&nbsp;<strong>[Hormonal contraception and
                            dermatology]</strong>Prenen M, Ledoux-Corbusier M. PIP: A group of 150 Belgian women aged
                        17-47 taking various oral contraceptives was compared with a control group of 400 with respect
                        to incidence of cholasma and piloseborrheic disorders. While taking pills, 10% of alopecia and
                        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
                        acne 21%, and acne rosacea 1%. The pill seemed to aggravate cholasma and rosaceous acne or to
                        improve piloseborrheic symptoms, depending on whether the formulation was dominant in estrogen
                        or progestagen.</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. 2000 Nov;45(5):515-9.&nbsp;<strong>Overexpression of transforming growth factor
                            beta-2 and its receptor in rhinophyma: an alternative mechanism of pathobiology.</strong
                        >&nbsp;Pu LL, Smith PD, Payne WG, Kuhn MA, Wang X, Ko F, Robson MC. "These findings support the
                        authors' hypothesis that fibrosis may also play an important role in the pathobiology of
                        rhinophyma."</span></span></span>
        </blockquote>
        <blockquote>
            <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
                                    style="font-weight: normal"
                                >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"
                            >&nbsp;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>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >Br J Dermatol. 2001 Jul;145(1):3-9.&nbsp;<strong>Topically applied lactic acid increases
                            spontaneous secretion of vascular endothelial growth factor by human reconstructed
                            epidermis.</strong>&nbsp;Rendl M, Mayer C, Weninger W, Tschachler E.</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >Nature. 1969 Aug 2;223(5205):516-7.&nbsp;<strong>Diminished responsiveness to thyroid hormone in
                            riboflavin-deficient rats.</strong>&nbsp;Rivlin RS, Wolf G.</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >J Pharmacol Exp Ther. 2007 Feb;320(2):565-72.&nbsp;<strong>Role of adenosine receptors in the
                            regulation of angiogenic factors and neovascularization in hypoxia.&nbsp;</strong>Ryzhov S,
                        McCaleb JL, Goldstein AE, Biaggioni I, Feoktistov I.</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >J Clin Endocrinol Metab 1996 Apr;81(4):1495-501,&nbsp;<strong>Characterization of reproductive
                            hormonal dynamics in the perimenopause.&nbsp;</strong><hr /></span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >J Am Acad Dermatol. 1992 Apr;26(4):590-3.&nbsp;<strong>Rosacea: a study of clinical patterns, blood
                            flow, and the role of Demodex folliculorum.</strong>&nbsp;Sibenge S, Gawkrodger DJ.</span
                    ></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >Cesk Oftalmol. 1951;7(1):37-42.&nbsp;<strong>[Effect of vitamin B1 and B2 on diseases of the
                            cornea.]</strong>&nbsp;Simkova M.</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >FEBS Lett. 1998 Sep 11;435(1):25-8.&nbsp;<strong>Glucocorticoids decrease cytochrome c oxidase
                            activity of isolated rat kidney mitochondria.</strong>&nbsp;Simon N, Jolliet P, Morin C,
                        Zini R, Urien S, Tillement JP. "The importance of mitochondria is rising as a target in
                        pathologic processes such as ischemia." "A regulation of cytochrome c oxidase activity by
                        glucocorticoids will be of particular interest in pathology involving metabolic insult."</span
                    ></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >Am J Ophthalmol. 1950 Jul;33(7):1127-36.&nbsp;<strong>The ocular manifestations of riboflavin
                            deficiency.</strong>&nbsp;Stern JJ.</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >Arch Ophthal. 1949 Oct;42(4):438-42.&nbsp;<strong>Conditioned corneal vascularity in riboflavin
                            deficiency; report of a case.</strong>&nbsp;Stern HJ.</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >Nippon Ganka Kiyo. 1962 Nov;13:489-94.&nbsp;<strong>[Variations of total vitamin B2 content in the
                            cornea, iris and ciliary body and the blood of rabbits in stress. (A preliminary
                            report)]</strong>&nbsp;[Article in Japanese] Taketani T.</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >Free Radic Res. 1996 Jun;24(6):421-7.&nbsp;<strong>The effect of the lipid peroxidation product
                            4-hydroxynonenal and of its metabolite 4-hydroxynonenoic acid on respiration of rat kidney
                            cortex mitochondria.</strong>&nbsp;Ullrich O, Henke W, Grune T, Siems WG.&nbsp;</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 Feb;72(2):652-60.&nbsp;<strong>The bacterial endotoxin lipopolysaccharide causes
                            rapid inappropriate excitation in rat cortex.&nbsp;</strong>Wang YS, White TD.</span></span
                ></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >Ophthalmologica. 1955 Jun;129(6):389-95.&nbsp;<strong>[Corneal changes in riboflavin-deficient
                            rats.]&nbsp;</strong>[Article in German] Wiesinger H, Kaunitz H, Slanetz CA.</span></span
                ></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >Arzneimittelforschung 1968 Dec;18(12): 1525-9.&nbsp;<strong>On the phlogogenic properties of lactic
                            acid in animal experiments.</strong>&nbsp;Wilhelmi G, Gdynia R.</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >Ann Intern Med 1981 Oct;95(4):468-76.&nbsp;<strong>Flushing reactions: consequences and
                            mechanisms.</strong>&nbsp;Wilkin JK</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >J Clin Endocrinol Metab 1995 Feb;80(2):608-613.&nbsp;<strong>Diminished function of the
                            somatotropic axis in older reproductive-aged women.</strong><hr /></span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >J Neurochem 1986 Oct;47(4):1181-9.&nbsp;<strong>Effects of arachidonic acid on glutamate and
                            gamma-aminobutyric acid uptake in primary cultures of rat cerebral cortical astrocytes and
                            neurons.&nbsp;</strong>Yu AC, Chan PH, Fishman RA.</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: xx-medium"
                    >Med Monatsschr Pharm. 1981 Jun;4(6):161-5.&nbsp;<strong>[Skin changes from taking hormonal
                            contraceptives]</strong>[Article in German] Zaun H. PIP: Hormonal contraceptives can induce
                        changes in the skin and its appendages. "Estrogens potentiate corticosteroid effects on the skin
                        such as striae, telangiectasiae, and rosacea dermatitis."</span></span></span>
        </blockquote>
        <p>&nbsp;</p>

        © Ray Peat Ph.D. 2013. All Rights Reserved. www.RayPeat.com
    </body>
</html>