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    <head><title>Osteoporosis, harmful calcification, and nerve/muscle malfunctions</title></head>
    <body>
        <h1>
            Osteoporosis, harmful calcification, and nerve/muscle malfunctions
        </h1>

        <p>
            During pregnancy, a woman's ability to retain dietary calcium and iron increases, and the baby seems to be
            susceptible to overloading. A normal baby doesn't need dietary iron for several months, as it uses the iron
            stored in its tissue, and recently it has been reported that normal fetuses and babies may have calcified
            pituitary glands. Pituitary cell death is sometimes seen with the concretions. (Groisman, et al.)
            Presumably, the calcification is resorbed as the baby grows. This is reminiscent of the "age pigment" that
            can be found in newborns, representing fetal stress from hypoxia, since that too disappears shortly after
            birth. Iron overload, age pigment, and calcification of soft tissues are so commonly associated with old
            age, that it is important to recognize that the same cluster occurs at the other extreme of (young) age, and
            that respiratory limitations characterize both of these periods of life.
        </p>
        <p>
            Calcium is probably the most popular element in physiological research, since it functions as a regulatory
            trigger in many cell processes, including cell stimulation and cell death. Its tendency to be deposited with
            iron in damaged tissue has often been mentioned. In hot weather, chickens pant to cool themselves, and this
            can lead to the production of thin egg shells. Carbonated water provides enough carbon dioxide to replace
            that lost in panting, and allows normal calcification of the shells. [Science 82, May, 1982] The deposition
            of calcium is the last phase of the "tertiary coat" of the egg, to which the oviduct glands successively add
            albumin, "egg membrane," and the shell, containing matrix proteins (including some albumin; Hincke, 1995)
            and calcium crystals. Albumin is the best understood of these layers, but it is still complex and
            mysterious; its unusual affinity for metal ions has invited comparisons with proteins of the immune system.
            It is known to be able to bind iron strongly, and this is considered to have an "immunological" function,
            preventing the invasion of organisms that depend on iron. Maria de Sousa ("Iron and the lymphomyeloid
            system: A growing knowledge," Iron in Immunity, Cancer and Inflammation, ed. by M. de Sousa and J. H. Brock,
            Wiley &amp; Sons, 1989) has argued that the oxygen delivery system and the immune system evolved together,
            recycling iron in a tightly controlled system.
        </p>
        <p>
            The role of macrophages in the massive turnover of hemoglobin, and as osteoclasts, gives us a perspective in
            which iron and calcium are handled in analogous ways. Mechnikov's view of the immune system, growing from
            his observations of the "phagocytes," similarly gave it a central role in the organism as a form-giving/
            nutrition-related process. In a family with "marble-bone disease," or osteopetrosis, it was found that their
            red blood cells lacked one form of the carbonic anhydrase enzyme, and that as a result, their body fluids
            retained abnormally high concentrations of carbon dioxide. Until these people were studied, it had been
            assumed that an excess of carbon dioxide would have the opposite effect, dissolving bones and causing
            osteoporosis or osteopenia, instead of osteopetrosis. The thyroid hormone is responsible for the carbon
            dioxide produced in respiration. Chronic hypothyroidism causes osteopenia, and in this connection, it is
            significant that women (as a result of estrogen's effects on the thyroid) are much more likely than men to
            be hypothyroid, and that, relative to men, women in general are "osteopenic," that is, they have more
            delicate skeletons than men do.
        </p>

        <p>
            In an experiment, rats were given a standard diet, to which had been added 1% Armour thyroid, that is, they
            were made extremely hyperthyroid. Since their diet was inadequate (later experiments showed that this amount
            of thyroid didn't cause growth retardation when liver was added to the diet) for their high metabolic rate,
            they died prematurely, in an apparently undernourished state, weighing much less than normal rats. Their
            bones, however, were larger and heavier than the bones of normal rats. A few incompetent medical "studies"
            have made people fear that "taking thyroid can cause osteoporosis." Recognizing that hypothyroid women are
            likely to have small bones and excessive cortisol production, the inadequate treatment of hypothyroidism
            with thyroxin (the thyroid-suppressive precursor material), is likely to be associated with relative
            osteoporosis, simply because it doesn't correct hypothyroidism. Similar misinterpretations have led people
            to see an association between "thyroid use" (generally thyroxin) and breast cancer--hypothyroid women are
            likely to have cancer, osteoporosis, obesity, etc., and are also likely to have been inadequately treated
            for hypothyroidism. T3, the active form of thyroid hormone, does contribute to bone formation. (For example,
            M. Alini, et al.)
        </p>
        <p>
            Around the same time (early 1940s) that the effects of thyroid on bone development were being demonstrated,
            progesterone was found to prevent age-related changes in bones, and "excessive" seeming doses of thyroid
            were found to prevent age-related joint diseases in rats.
        </p>
        <p>
            A logical course of events, building on these and subsequent discoveries, would have been to observe that
            the glucocorticoids cause a negative calcium balance, leading to osteoporosis, and that thyroid and
            progesterone oppose those hormones, protecting against osteoporosis. But the drug industry had discovered
            the profits in estrogen ("the female hormone") and the cortisone-class of drugs. Estrogen was promoted to
            prevent miscarriages, to stop girls (and boys) from growing too tall, to cure prostate and breast cancer, to
            remedy baldness, and 200 other absurdities. As all of those frauds gradually became untenable, even in the
            commercial medical culture, the estrogen industry began to concentrate on osteoporosis and femininity. Heart
            disease and Alzheimer's disease back those up.
        </p>
        <p>
            "If estrogen causes arthritis, prescribe prednisone for the inflammation. If prednisone causes osteoporosis,
            increase the dose of estrogen to retard the bone-loss. People are tough, and physiological therapies aren't
            very profitable."
        </p>
        <p>
            Fifteen years ago I noted in a newsletter that hip fractures most often occur in frail, underweight old
            women, and that heavier, more robust women seem to be able to bear more weight with less risk of fracture.
            Although I hadn't read it at the time, a 1980 article (Weiss, et al.) compared patients with a broken hip or
            arm with a control group made up of hospitalized orthopedic patients with problems other than hip or arm
            fractures. The fracture cases' weight averaged 19 pounds lighter than that of the other patients. They were
            more than 3.6 times as likely to be alcoholic or epileptic. It would be fair to describe them as a less
            robust group.
        </p>
        <p>
            Since the use of estrogen has become so common in the U.S., it is reasonable to ask whether the incidence of
            hip fractures in women over 70 has declined in recent decades. If estrogen protects against hip fractures,
            then we should see a large decrease in their incidence in the relevant population.
        </p>
        <p>
            Hip fractures, like cancer, strokes, and heart disease, are strongly associated with old age. Because of the
            baby-boom, 1945 to 1960, our population has a bulge, a disproportion in people between the ages of 35 and
            50, and those older. Increasingly, we will be exposed to publicity about the declining incidence of disease,
            fraudulently derived from the actually declining proportion of old people. For example, analyzing claims
            based on the pretense that the population bulge doesn't exist, I have seen great publicity given to studies
            that would imply that our life-expectancy is now 100 years, or more.
        </p>
        <p>
            Comparing the number of hip fractures, per 1000 75 year old women, in 1996, with the rate in 1950, we would
            have a basis for judging whether estrogen is having the effect claimed for it.
        </p>
        <p>
            The x-ray data seem to convince many people estrogen is improving bone health, by comparing measurements in
            the same person before and after treatment. Does estrogen cause water retention? Yes. Does tissue water
            content increase measured bone density? Yes. Are patients informed that their "bone scans" don't have a
            scientific basis? No. The calcification of soft tissues under the influence of estrogen must also be taken
            into account in interpreting x-ray evidence. (Hoshino, 1996) Granted that woman who are overweight have
            fewer hip fractures (and more cancer and diabetes), what factors are involved? Insulin is the main factor
            promoting fat storage, and it is anabolic for bone. (Rude and Singer, "Hormonal modifiers of mineral
            metabolism.") The greatest decrease in bone mass resulting from insulin deficiency was seen in white
            females, and after five years of insulin treatment, there was a lower incidence of decreased bone mass
            (Rosenbloom, et al., 1977). McNair, et al. (1978 and 1979) found that the loss of bone mass coincided with
            the onset of clinical diabetes. Since excess cortisol can cause both high blood sugar and bone loss, when
            diabetes is defined on the basis of high blood sugar, it will often involve high blood sugar caused by
            excess cortisol, and there will be calcium loss. Elsewhere, I have pointed out some of the similarities
            between menopause and Cushing's syndrome; a deficiency of thyroid and progesterone can account for many of
            these changes. Nencioni and Polvani have observed the onset of progesterone deficiency coinciding with bone
            loss, and have emphasized the importance of progesterone's antagonism to cortisol.
        </p>

        <p>
            Johnston (1979) found that progesterone (but not estrone, estradiol, testosterone, or androstenedione) was
            significantly lower in those losing bone mass most rapidly.
        </p>
        <p>
            Around the age of 50, when bone loss is increasing, progesterone and thyroid are likely to be deficient, and
            cortisol and prolactin are likely to be increased. Prolactin contributes directly to bone loss, and is
            likely to be one of the factors that contributes to decreased progesterone production.
        </p>
        <p>
            Estrogen tends to cause increased secretion of prolactin and the glucocorticoids, which cause bone loss, but
            it also promotes insulin secretion, which tends to prevent bone loss. All of these factors are associated
            with increased cancer risk.
        </p>
        <p>
            Thyroid and progesterone, unlike estrogen, stimulate bone-building, and are associated with a decreased risk
            of cancer. It seems sensible to use thyroid and progesterone for their general anti-degenerative effects,
            protecting the bones, joints, brain, immune system, heart, blood vessels, breasts, etc.
        </p>
        <p>
            But the issue of calcification/decalcification is so general, we mustn't lose interest just because the
            practical problem of osteoporosis is approaching solution.
        </p>

        <p>
            For example, healthy high energy metabolism requires the exclusion of most calcium from cells, and when
            calcium enters the stimulated or deenergized cell, it is likely to trigger a series of reactions that lower
            energy production, interfering with oxidative metabolism. During aging, both calcium and iron tend to
            accumulate and they both seem to have an affinity for similar locations, and they both tend to displace
            copper. (Compare K. Sato, et al., on the calcification of copper-containing paints.) Elastin is a protein,
            the units of which are probably bound together by copper atoms. In old age, elastin is one of the first
            substances to calcify, for example in the elastic layers of arteries, causing them to lose elasticity, and
            to harden into almost bone-like tubes. In the heart and kidneys, the mitochondria (rich in copper-enzymes)
            are often the location showing the earliest calcification, for example when magnesium is deficient.
        </p>
        <p>
            Obviously, certain proteins have higher than average affinity for copper, iron, and calcium. For example,
            egg-white's unusual behavior with copper can be seen if you make a meringue in a copper pan--the froth is
            unusually firm. My guess is that copper atoms bind the protein molecules into relatively elastic systems. In
            many systems, calcium forms the link between adhesive proteins.
        </p>
        <p>
            In brain degeneration, the regions that sometimes accumulate aluminum, will accumulate other metals instead,
            if they predominate in the environment; calcium is found in this part of the brain in some of the Pacific
            regions studied by Gajdusek. Certain cells in the brain used to be called "metalophils," because they could
            be stained intensely with silver and other metals; I suppose these are part of the immune system, handling
            iron as described by Maria de Sousa. Macrophages have been proposed as an important factor in producing
            atherosclerotic plaques (Carpenter, et al.). There is evidence that they (and not smooth muscle cells) are
            the characteristic foam cells, and their conversion of polyunsaturated oils into age pigment accounts for
            the depletion of those fats in the plaques. The same evidence could be interpreted as a defensive reaction,
            binding iron and destroying unsaturated fatty acids, and by this detoxifying action, possibly protecting
            against calcification and destruction of elastin. (This isn't the first suggestion that atherosclerosis
            might represent a protective process; see S. M. Plotnikov, et al., 1994.)
        </p>
        <p>
            Since carbon dioxide and bicarbonate are formed in the mitochondria, it is reasonable to suppose that the
            steady outward flow of the bicarbonate anion would facilitate the elimination of calcium from the
            mitochondria. Since damaged mitochondria are known to start the process of pathological calcification in the
            heart and kidneys, it probably occurs in other tissues that are respiratorily stressed. And if healthy
            respiration, producing carbon dioxide, is needed to keep calcium outside the cell, an efficient defense
            system could also facilitate the deposition of calcium in suitable places--depending on specific protein
            binding. The over-grown bones in the hyperthyroid rats and the women with osteopetrosis suggest that an
            abundance of carbon dioxide facilitates bone formation. Since no ordinary inorganic process of
            precipitation/crystallization has been identified that could account for this, we should consider the
            possibility that the protein matrix is regulated in a way that promotes (or resists) calcification. The
            affinity of carbon dioxide for the amine groups on proteins (as in the formation of carbamino hemoglobin,
            which changes the shape of the protein) could change the affinity of collagen or other proteins for calcium.
            Normally, ATP is considered to be the most important substance governing such changes of protein
            conformation or binding properties, but ordinarily, ATP and CO2 are closely associated, because both are
            produced in respiration. Gilbert Ling has suggested that hormones such as progesterone also act as cardinal
            adsorbants, regulating the affinity of proteins for salts and other molecules.
        </p>
        <p>
            Cells have many proteins with variable affinity for calcium; for example in muscle, a system called the
            endoplasmic reticulum, releases and then sequesters calcium to control contraction and relaxation. (This
            calcium-binding system is backed up by--and is spatially in close association with--that of the
            mitochondrion.) Ion-exchange resins can be chemically modified to change their affinity for specific ions,
            and molecules capable of reacting strongly with proteins can change the affinities of the proteins for
            minerals. What evidence is there that carbon dioxide could influence calcium binding? The earliest
            deposition of crystals on implanted material is calcium carbonate. (J. Vuola, et al, 1996.) In newly formed
            bone, the phosphate content is low, and increases with maturity. While mature bone has an apatite-like ratio
            of calcium and phosphate, newly calcified bone is very deficient in phosphate (according to Dallemagne, the
            initial calcium to phosphorus ratio is 1.29, and it increases to 2.20.) (G. Bourne, 1972; Dallemagne.)
        </p>
        <p>
            The carbonate content of bone is often ignored, but in newly formed bone, it is probably the pioneer.
            Normally, "nucleation" of crystals is thought of as a physical event in a supersaturated solution, but the
            chemical interaction between carbon dioxide and amino groups (amino acids, protein, or ammonia, for example)
            removes the carbon dioxide from solution, and the carbamino acid formed becomes a bound anion with which
            calcium can form a salt. With normal physiological buffering, the divalent calcium (Ca2+) should form a link
            between the monovalent carbamino acid and another anion. Linking with carbonate (CO32-), one valence would
            be free to continue the salt-chain. This sort of chemistry is compatible with the known conditions of bone
            formation.
        </p>
        <p>
            Klein, et al. (1996), think of uncoupled oxidative phosphorylation in terms of "subtle thermogenesis," which
            isn't demonstrated in their experiment, but their experiment actually suggests that stimulated production of
            carbon dioxide is the factor that stimulates calcification. Their experiment seems to be the in vitro
            equivalent of the various observations mentioned above. DHEA, which powerfully stimulates bone formation, is
            (like thyroid and progesterone) thermogenic, but in these cases, the relevant event is probably the
            stimulation of respiration, not the heat production. In pigs (Landrace strain) susceptible to malignant
            hyperthermia, there is slow removal of calcium from the contractile apparatus of their muscles. Recent
            evidence shows that an extramitochondrial NADH-oxidase is functioning. This indicates that carbon dioxide
            production is limited. I think this is responsible for the cells' sluggishness in expelling calcium.
        </p>

        <p>
            Stress-susceptible pigs show abnormalities of muscle metabolism (e.g., high lactate formation) that are
            consistent with hypothyroidism. (T. E. Nelson, et al., "Porcine malignant hyperthermia: Observations on the
            occurrence of pale, soft, exudative musculature among susceptible pigs," Am. J. Vet. Res. 35, 347-350, 1974;
            M. D. Judge, et al., "Adrenal and thyroid function in stress-susceptible pigs (Sus domesticus)," Am. J.
            Physiol. 214(1), 146-151, 1968.)
        </p>
        <p>
            Malignant hyperthermia during surgery is usually blamed on genetic susceptibility and sensitivity to
            anesthetics. (R. D. Wilson, et al., "Malignant hyperpyrexia with anesthesia," JAMA 202, 183-186, 1967; B.A
            Britt and W. Kalow, "Malignant hyperthermia: aetiology unknown," Canad. Anaesth. Soc. J. 17, 316-330, 1970.)
            Hypertonicity of muscles, various degrees of myopathy and rigidity, and uncoupling of oxidative
            phosphorylation occur in these people, as in pigs. Lactic acidosis suggests that mitochondrial respiration
            is defective in the people, as in the pigs. Besides the sensitivity to anesthetics, the muscles of these
            people are abnormally sensitive to caffeine and elevated extracellular potassium. During surgery, artificial
            ventilation, combined with stress, toxic anesthetics, and any extramitochondrial oxidation that might be
            occurring (such as NADH-oxidase, which produces no CO2), make relative hyperventilation a plausible
            explanation for the development of hyperthermia. Hyperventilation can cause muscle contraction. Panting
            causes a tendency for fingers and toes to cramp. Free intracellular calcium is the trigger for muscle
            contraction (and magnesium is an important factor in relaxation.) Capillary tone, similarly, is increased by
            hyperventilation, and relaxed by carbon dioxide. The muscle-relaxing effect of carbon dioxide shows that the
            binding of intracellular calcium is promoted by carbon dioxide, as well as by ATP. The binding of calcium in
            a way that makes it unable to interfere with cellular metabolism is, in a sense, a variant of simple
            extrusion of calcium, and the binding of calcium to extracellular materials. A relaxed muscle and a strong
            bone are characterized by bound calcium.
        </p>
        <p>
            Activation of the sympathetic nervous system promotes hyperventilation. This means that hypothyroidism, with
            high adrenalin (resulting from a tendency toward hypoglycemia because of inefficient use of glucose and
            oxygen), predisposes to hyperventilation.
        </p>
        <p>
            Muscle stiffness, muscle soreness and weakness, and osteoporosis all seem to be consequences of inadequate
            respiration, allowing lactic acid to be produced instead of carbon dioxide. Insomnia, hyperactivity,
            anxiety, and many chronic brain conditions also show evidence of defective respiration, for example, either
            slow consumption of glucose or the formation of lactic acid, both of which are common consequences of low
            thyroid function. Several studies (e.g., Jacono and Robertson, 1987) suggest that abnormal calcium
            regulation is involved in epilepsy. The combination of supplements of thyroid (emphasizing T3), magnesium,
            progesterone and pregnenolone can usually restore normal respiration, and it seems clear that this should
            normalize calcium metabolism, decreasing the calcification of soft tissues, increasing the calcification of
            bones, and improving the efficiency of muscles and nerves. (Magnesium, like carbonate, is a component of
            newly formed bone.) The avoidance of polyunsaturated vegetable oils is important for protecting respiration;
            some of the prostaglandins they produce have been implicated in osteoporosis, but more generally, they
            antagonize thyroid function and they can interfere with calcium control. The presence of the "Mead acid"
            (the omega-9 unsaturated fat our enzymes synthesize) in cartilage suggests a new line of investigation
            regarding the bone-toxicity of the polyunsaturated dietary oils.
        </p>
        <p><h3>REFERENCES</h3></p>
        <p>
            G. R. Sauer, et al., "A facilitating role for carbonic anhydrase activity in matrix vesicle mineralization,"
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            dioxide or bicarbonate concentration on the resorptive action of rat osteoclasts," J. Bone and Mineral Res.
            9(3), 375-379, 1994. (...resorption was almost abolished in the presence of 2.5% CO2 at pH 7.61 but
            increased in a stepwise manner up to 1.3 pits per osteoclast when dentin slices were cultured with 10% CO2
            at pH 6.97.")
        </p>

        <p>
            D. A. Bushinsky, et al., "Acidosis and bone," Min. &amp; Electrolyte Metab. 20(1-2), 40-52, 1994. ("During
            acute respiratory acidosis there is no measurable influx of protons in bone and during chronic studies there
            is no measurable calcium efflux.")
        </p>
        <p>
            D. A. Bushinsky, et al., "Decreased bone carbonate content in response to metabolic but not respiratory
            acidosis," Amer. J. Physiol. 265(4, part 2), F530-F536, 1993. ("...elevated pCO2 doesn't allow bone
            carbonate dissolution despite reduced pH.")
        </p>
        <p>
            J. Vuola, et al., "Bone marrow induced osteogenesis in hydroxyapatite and calcium carbonate implants,"
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            calcified skeletons at precambrian-cambrian transition," Proc. Nat. Acad. Sci. U.S. 93(4), 1554-1559, 1996.
        </p>
        <p>
            M. J. Dallemagne, Acta Physiother. Rheumatol. Belg.3, 77, 1947; Nature (London) 161, 115, 1948; Annu. Rev.
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        </p>
        <p>
            G. H. Bourne, ed., The Biochemistry and Physiology of Bone; Physiology and Pathology, Academic Press, 1972.
        </p>
        <p>
            J. A. Schlechte, et al., "Bone density in amenorrheic women with and without hyperprolactinemia," J. Clin.
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        </p>
        <p>
            C. C. Johnston, et al., "Age-related bone loss," pages 91-100 in U. S. Barrel, editor, Osteoporosis II,
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            beta-estradiol, or retinoic acid...." D-3 and glucocorticoids "may regulate osteogenesis from the bone
            marrow but a similar role for estrogen is not supported.") P. W. Stacpoole, "Lactic acidosis and other
            mitochondrial disorders," Metabolism 46(3), 306-321, 1997.
        </p>
        <p>
            L. M. Banks, et al., "Effect of degenerative spinal and aortic calcification on bone density measurements in
            post-menopausal women: Links betwwen osteoporosis and cardiovascular disease?" Eur. J. of Clin.
            Investigation 24(12), 813-817, 1994. ("Women with spinal degenerative calcification had higher spine bone
            density when measured by dual photon absorptionmetry compared to those without calcification." "Women with
            aortic calcification had significantly lower quantitative computer tomography and proximal femur bone
            density compared to those without calcification."
        </p>
        <p>
            S. E. Wendelaar Bonga and G. Flik, "Prolactin and calcium metabolism in a teleost fish, Sarotherodon
            mossambicus," Gen. Compar. Endocrinol. 46, 21-26, 1982.
        </p>

        <p>
            U.S. Barzel, "The skeleton as an ion exchange system: Implications for the role of acid-base imbalance in
            the genesis of osteoporosis," J. of Bone and Mineral Res. 10(10), 1431-1436, 1995.
        </p>
        <p>
            P. Schneider and C. Reiners, Letter, JAMA 277(1), 23, Jan. 1, 1997. Dual-energy x-ray absorptiometry for
            bone density can lead to false conclusions about bone mineral content, because of alterations in tissue fat
            or water content. "The influence of fat distribution on bone mass measurements with DEXA can be of
            considerable magnitude and ranges up to 10% error per 2 cm of fat."
        </p>
        <p>
            J. Pearson, et al, Osteoporosis 5, 174-184, 1995 J. Dequeker, et al, "Dual X-ray
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            important to select appropriate reference data in clinical and epidemiological studies.") T.M. Hangartner
            and C. C. Johnston, "Influence of fat on bone measurements with dual-energy absorptionmetry," Bone Miner 9,
            71-81, 1990. R. Valkema, et al., "Limited precision of lumbar spine dual photon absorptiometry by variations
            in the soft-tissue background," J. Nucl. Med. 31, 1774-1781, 1990.
        </p>

        <p>
            M. Silberberg and R. Silberberg, Arch. Path. 31(1), 85-92, 1941. (Progesterone counteracts aging of bone in
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            of old-age changes in the joints of normal mice.) G. Coryn, "Recherche experimentale sur l'influence des
            glands endocrines sur l'histologie du cartilage de conjugaison," Annales d'anatomie pathol. 16, 27, 1939.
        </p>
        <p>
            O. Rahn, "Protozoa need carbon dioxide for growth," Growth 5, 197-199, 1941. "On page 113 of this volume,
            the statement of Valley and Rettger that all bacteria need carbon dioxide for growth had been shown to apply
            to young as well as old cells." "...it is possible...to remove it as rapidly as it is produced, and under
            these circumstances, bacteria cannot multiply." K. L. H. Carpenter, et al., "Production of ceroid and
            oxidised lipids by macrophages in vitro," Lipofuscin--1987: State of the Art, I. Zs.-Nagy, editor, pp.
            245-268, 1988.
        </p>

        <p>
            A. Schlemmer, et al., "Posture, age, menopause, and osteopenia do not influence the circadian variation in
            the urinary excretion of pyridinium crosslinks," J. Bone Miner. Res. 9(12), 1883-1888, 1994. N. S. Weiss, et
            al., "Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen,:" N.
            Engl. J. Med. 303, 1195-1198, 1980.
        </p>
        <p>
            S. M. Plotnikov, et al., "Anxiety, atherogenesis, and antioxidant protection: Clinico-pathogenetic
            relationships," Bull. Exp. Biol. &amp; Medicine 117(2), 221, 1994.
        </p>
        <p>
            G. M. Groisman, et al., "Calcified concretions in the anterior pituitary gland of the fetus and the newborn:
            A light and electron microscopic study," Human Pathology 27(11), 1139-1143, 1996. (...calcified concretions
            represent a normal finding in the anterior pituitary gland of fetuses and young infants.")
        </p>

        <p>
            K. S. G. Jie. "Vitamin K status and bone mass in women with and without aortic atherosclerosis: A
            population-based study," Calc. Tiss. Intern. 59(5), 352-356, 1996. ("The finding that in atherosclerotic
            women vitamin K status is associated with bone mass supports our hypothesis that vitamin K status affects
            the mineralization processes in both bone and in atherosclerotic plaques."
        </p>
        <p>
            B. Y. Klein, et al., "Cell-mediated mineralization in culture at low temperature associated with subtle
            thermogenic response," J. of Cellular Biochemistry 63(2), 229-238, 1996. "...cell-mediated mineralization is
            preceded by characteristics of anaerobic and low efficiency energy metabolism." "Modulation of mitochondrial
            membrane potential and energy metabolism could be linked to regulation of mineralization by the uncoupling
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