736 lines
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736 lines
57 KiB
HTML
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<head><title>The transparency of life: Cataracts as a model of age-related disease</title></head>
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<body>
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<h1>
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The transparency of life: Cataracts as a model of age-related disease
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</h1>
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<em><p>
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Cataracts can disappear when the eye's metabolic condition is corrected. A supply of energy is essential
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to maintain the transparent structure.
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</p>
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<p>
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Lactic acid increases as carbon dioxide decreases, during a typical energy deficiency. Deficient
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thyroid, and the resulting excess of cortisol relative to pregnenolone and progesterone, define the
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energy deficiency.
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</p>
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<p>
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Increased lactate relative to CO2 in the cell alters cell pH and electrical charge, causing swelling.
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Swelling and increased water content characterize the cataract.
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</p>
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<p>
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High altitude is inversely related to cataracts, despite the known role of sunlight in causing
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cataracts; this is a strong confirmation of the protective role of carbon dioxide.
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</p></em>
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<hr />
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<p>
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In the markets around Lake Patzcuaro, they sell green transparent fish, about 6 inches long. When cooked,
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the meat is white, like ordinary fish. Most fish filets are a little translucent, but are at least cloudy,
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and usually pink by transmitted light. I don"t know how the transparent fish work, because it seems that the
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blood and the network of blood vessels needed to sustain muscle activity would diffuse the light. Anyway,
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cooking disrupts the mysteriously ordered state of water and proteins that makes them transparent, roughly
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the way egg-white loses its transparency when it is cooked. I have never heard a convincing explanation for
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the opacity of cooked egg-white, either, but anything that disrupts the original structuring of the
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protein-water interaction will destroy the transparency.
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</p>
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<p>
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Around 1970, I used a technique called nuclear magnetic resonance (NMR), which is the basis for the
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procedure known as MRI (magnetic resonance imaging), to compare the state of water in old (uterine) tissue
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and young tissue. Old tissue predictably contains less water than young tissue, but I found that the water
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in the old tissue was in a relatively free and uncontrolled state. When tissue swells and takes up water,
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more of the water is likely to be in this uncontrolled state, and this is one of the things that makes MRI
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so useful, because tumors, for example, show up vividly because of their large amount of uncontrolled
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("unbound") water. I suspect that the measurements I made on uterine tissue showed a localized effect, that
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opposed the general trend toward increased dryness with aging. In the case of cataracts, this is clearly the
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case<strong>: </strong> Most of the lens becomes drier with age, but at a certain point there is a reversal,
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and some of the tissue takes up too much water. That"s why I refer to cataracts as a model of age-related
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disease, rather than as a model of aging. In this sense, I am including them among the inflammatory diseases
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of aging--colitis, arthritis, and cancer, for example. MRI now can show developing cataracts before they are
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visible, because of increased water content in the area.
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</p>
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<p>
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The lens of the eye is a fairly dense, tough, transparent living structure, which can develop opaque areas,
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cataracts, as a result of old age, poisoning, radiation, disease, or trauma. The varieties of cataract
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relate to the causes. Most of the oxidative metabolism of the lens is in or near the epithelial layer that
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surrounds it. Old-age cataracts most often begin in this region.
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</p>
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<p>
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Although the efficient oxidative energy metabolism occurs near the surface of the lens, <strong>there is a
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constant flow of fluid through the lens,</strong>
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entering it mainly in the front and back, and leaving on its "sides" or equator (considering the front and
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back as the poles, the direction light passes through). Oxygen and nutrients are supplied to the lens by way
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of this circulation of fluid, entering mostly from the aqueous humor in front (which also supplies the
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cornea), but also from the vitreous humor behind the lens.
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</p>
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<p>
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When the flow of nutrients and energy is impaired, the organized state of the protein and water system in
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the cell is damaged, and an excess of water is taken up by the cells, as the protein content decreases. The
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loss of organization causes light to be dispersed, with a loss of transparency.
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</p>
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<p>
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The lens of the eye is usually treated as something so specialized that it is hardly considered to be part
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of our living substance, just as dentistry has tended to treat teeth as inert things to be approached
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mechanically, rather than physiologically. <strong>The lens"s circulatory system is very interesting,
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because of what it says about the nature of living substance. In the absence of blood vessels, it
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provides its own flow of nutrients.</strong> This flow is reminiscent of the flow of substances through
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the dentine channels of the teeth, through the axons of nerves (two-way transport in a very narrow channel),
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and, in some ways recalls the flow of fluids in plants, called "guttation" (drop formation), which is
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disturbing to botanists, because it is contrary to the textbook descriptions of proper physiology.
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</p>
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<p>
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<strong>The flow of material through lens cells, dentine canals, and nerve axons should allow us to gain a
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perspective in which these observable processes become a model for other biological situations</strong>
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in which "transport" occurs<strong>:</strong> Kidney, intestine, or the skin of frogs, for example, in which
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water, ions, and other solutes are moved in considerable quantities.
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</p>
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<p>
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When cells metabolize, they create gradients. In the cell, electrical, chemical, osmotic, and thermal
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gradients, for example, are constantly being produced or maintained. The whole substance of the cell is
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involved in its life processes. Because of prejudices introduced 200 years ago, the life of the cell has
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been relegated to its "membrane" (where hypothetical "membrane pumps" reside) and its nucleus. <strong>
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When the term "cell" (hollow space) came into use instead of "corpuscle" (little body), a mind-set came
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into existence that discounted the importance of most of the living material,</strong> and claimed that
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it was a mere "random solution." Random solutions don"t do much. The wonderful "membrane," under the
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direction of the nucleus (and its set of instructions), took care of everything.
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</p>
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<p>
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Whenever assimilation or excretion took place, it was explained by inventing a property possessed by the
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cell "membranes." Therefore, we have physiology textbooks that have an unfounded explanation for everything.
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Before Copernicus, planetary movements were described as arbitrary "epicycles." They didn't make sense, but
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people studied them and felt that they were important. "Membrane physiology" is the modern equivalent of the
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Ptolemaic epicycles.
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</p>
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<p>
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We know that glucose can be metabolized into pyruvic acid, which, in the presence of oxygen, can be
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metabolized into carbon dioxide. Without oxygen, pyruvic acid can be converted into lactic acid. The
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production of lactic acid tends to increase the pH inside the cell, and its excretion can lower the pH
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outside the cell.
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</p>
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<p>
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The decrease of carbon dioxide that generally accompanies increased lactic acid, corresponds to increased
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intracellular pH. Carbon dioxide binds to many types of protein, for example by forming carbamino groups,
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changing the protein conformation, as well as its electrical properties, such as its isoelectric point. With
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increased pH, cell proteins become more strongly ionized, tending to separate, allowing water to enter the
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spaces, in the same way a gel swells in an alkaline solution.
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</p>
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<p>
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The Bohr-Haldane effect describes the fact that hemoglobin releases oxygen in the presence of carbon
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dioxide, and releases carbon dioxide in the presence of oxygen. When oxygen is too abundant, it makes
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breathing more difficult, and one of its effects is to cause carbon dioxide to be lost rapidly. At high
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altitude, more carbon dioxide is retained, and this makes cellular respiration more efficient.
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</p>
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<p>
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The importance of carbon dioxide to cell control process, and to the structure of the cell and the structure
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of proteins in general suggested that degenerative diseases would be less common at high altitude. Wounds
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and broken bones heal faster at high altitude, but the available statistics are especially impressive in two
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of the major degenerative conditions, cancer and cataracts.
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</p>
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<p></p>
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<p>
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The two biggest studies of altitude and cataracts (involving 12,217 patients in one study, and 30,565
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lifelong residents in a national survey in Nepal) showed a negative correlation between altitude and the
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incidence of cataract. At high altitude, cataracts appeared at a later age. <strong>In Nepal, an increase of
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a few thousand feet in elevation decreased the incidence of cataracts by 2.7 times. At the same time, it
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was found that exposure to sunlight increased the incidence of cataracts, and since the intensity of
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ultraviolet radiation is increased with altitude, this makes the decreased incidence of cataracts even
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more important.</strong>
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</p>
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<p>
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All of the typical causes of cataracts, aging, poisons, and radiation, decrease the formation of carbon
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dioxide, and tend to increase the formation of lactic acid.<strong>
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Lactic acid excess is typically found in eyes with cataracts.</strong>
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</p>
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<p>
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The electrical charge on the structural proteins will tend to increase in the presence of lactic acid or the
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deficiency of carbon dioxide, and the increase of charge will tend to increase the absorption of water.
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</p>
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<p>
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The lens can survive for a considerable length of time <em>in vitro </em>
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(since it has its own circulatory system),<em> </em>
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so it has been possible to demonstrate that changes in the composition of the fluid can cause opacities to
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form, or to disappear.
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</p>
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<p>
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Oxidants, including hydrogen peroxide which occurs naturally in the aqueous humor, can cause opacities to
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form quickly, but they will also disappear quickly in a solution that restores metabolic energy. The lens
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regulates itself powerfully<strong>;</strong> for example, it will swell when put into a hypotonic solution,
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but will quickly adapt, returning to approximately its normal size.
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</p>
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<p>
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Several years ago, I saw what appeared to be oxidant-induced cataracts. Two women had a very sudden onset of
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cataracts, and I asked about their diet and supplements<strong>;</strong> it turned out that one of them had
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begun taking 500 mg of zinc daily a few months earlier, and the other had begun taking 600 mg of zinc and
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250 mg of iron, on her doctor"s recommendation, just a couple of months before the cataracts appeared.
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</p>
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<p>
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For some reason, there have been many nutritional supplements sold as cataract remedies in the form of eye
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drops. I suppose a trace of the material could diffuse through the cornea into the aqueous humor, where it
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might make a difference in the lens"s nutrient supply, but it seems more reasonable to treat the body as a
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whole, nourishing every part in a balanced way.
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</p>
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<p>
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Besides living at a high elevation or breathing extra carbon dioxide, the most certain way to increase the
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amount of carbon dioxide in the eye, and to prevent an excess of lactic acid, is to make sure that your
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thyroid function is adequate.
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</p>
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<p>
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One man who took thyroid, USP, and vitamin E told me that his cataracts had regressed, but I haven"t known
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other people who tried this.
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</p>
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<p>
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If a person already has distinct cataracts, it might be worthwhile to experiment with a relatively high
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degree of hypercapnia, for example, breathing a 5% mixture of CO2 in air.
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</p>
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<p>
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Carbon dioxide, at higher levels than are normal at sea level, has a profound effect on free radicals,
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reducing the free radical activity in the blood to approximately zero, before reaching the level that
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produces acidosis.
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</p>
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<p>
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There are several situations in which carbon dioxide affects the hydration, water content, of biological
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materials, that I think give an insight into its effects on the lens. Hydrophilic glycoproteins are involved
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in each case. These are proteins with attached chains of sugar molecules that make them associate with a
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large amount of water. In the cornea, increased carbon dioxide strongly protects against swelling. The bulk
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of the cornea is a connective tissue that is relatively simple and passive compared to the compact cellular
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structure of the lens, and it is conventional to describe the thin layers of cells on the inside and outside
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of the cornea as being responsible for the water content of the underlying substance. However, even when the
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epithelial cells are removed, it has been demonstrated that carbon dioxide is able to prevent corneal
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swelling. (M.V. Riley, et al., "The roles of bicarbonate and CO2 in transendothelial fluid movement and
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control of corneal thickness," <em>
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Invest. Ophthalmol. Vis. Sci. 36(1),</em> 103-112, 1995.)
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</p>
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<p>
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Bronchial mucous secretions are an even simpler system, so it is very interesting that carbon dioxide is
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recognized as the most powerful regulator of their behavior. (This has important implications for "cystic
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fibrosis," or mucoviscidosis.) Goodman and Gilman (page 1068, <em>
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Pharmacological Basis of Therapeutics,</em> 2nd Edition, Macmillan Co., 1956), say
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</p>
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<p>
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"Among inhalants, steam and carbon dioxide have been found to be excellent expectorants. Relative humidity
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above 85 per cent liquefies sputum, decreases its viscosity...." "Carbon dioxide is the most effective agent
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of all. It not only lowers the viscosity of tenacious sputum, thereby facilitating expectoration, but it
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decreases the volume of sputum by promoting its active resorption by bronchial mucosa." "A five to ten per
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cent concentration of carbon dioxide is adequate and well tolerated if administered at intervals." "Oxygen
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has been shown to be an antiexpectorant and has effects opposite to those of carbon"
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</p>
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<p>
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Oxygen tends to displace carbon dioxide from tissue, and is a source of free radicals.
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</p>
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<p>
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One of the best-known free radical scavenging substances that has been widely used as a drug is iodide. It
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has been used to treat asthma, parasites, syphilis, cancer, Graves" disease, periodontal disease, and
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arteriosclerosis. Diseases that produce tissue overgrowth associated with inflammation--granulomas--have
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been treated with iodides, and although the iodide doesn"t necessarily kill the germ, it does help to break
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down and remove the granuloma. Leprosy and syphilis were among the diseases involving granulomas* that were
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treated in this way. In the case of tuberculosis, it has been suggested that iodides combine with
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unsaturated fatty acids which inhibit proteolytic enzymes, and thus allow for the removal of the abnormal
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tissue.
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</p>
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<p>
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In experimental animals, iodide clearly delays the appearance of cataracts. (Buchberger, et al., 199l.)
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</p>
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<p>
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Inflammation, edema, and free radical production are closely linked, and are produced by most things that
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interfere with energy production.
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</p>
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<p>
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Endotoxin, produced by bacteria, mainly in the intestine, disrupts energy production, and promotes
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maladaptive inflammation. The wide spectrum of benefit that iodide has, especially in diseases with an
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inflammatory component, suggests first that it protects tissue by blocking free radical damage, but it also
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suggests the possibility that it might specifically protect against endotoxin.
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</p>
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<p>
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There are subtler differences in transparence that probably have a variety of causes, but differences in
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water content or hydration might be involved in the lower transparency that has been seen in women's lenses.
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Estrogen, which tends to produce edema and hypotonic body fluids, also increases prolactin production.
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Prolactin is involved in water and electrolyte regulation, and it has been found to <strong>accelerate the
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development of experimental cataracts.</strong> (M. C. Ng, et al, 1987.) These hormones are associated
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with the calcification of soft tissues, and cataracts contain very high levels of calcium. (Avarachan and
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Rawal, 1987; Hightower and Reddy, 1982.)
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</p>
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<p>
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Estrogen is strongly associated with free radical processes, calcium mobilization, and acetylcholine
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release, all of which are involved in the process of excitoxicity. Alvarez, et al., (1996) have shown a
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possible involvement of acetylcholine in calcium mobilization in the lens.
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</p>
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<p>
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Serotonin is another regulatory substance strongly associated with prolactin and estrogen, and it also can
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be involved in disrupting the metabolism of the lens. This is one of the potential dangers in using
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supplemental tryptophan. (Candia, et al., 1980.)
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</p>
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<p>
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Old age commonly involves some changes in the color of tissues--loss of pigment from hair and skin, with
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appearance of new pigment (age pigment, lipofuscin), which may appear as "liver spots." But there is also a
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tendency of the toenails, fingernails, teeth, and lenses to turn yellow or brown. Some of this dark material
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seems to be age pigment, derived from unsaturated fatty acids, but other components have been identified,
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for example, tryptophan from damaged proteins. The Maillard reaction (similar to the browning that occurs in
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bread crust) has often been mentioned in relation to aging, and involves the combination of protein amino
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groups with sugars. But the browning of the lens tends to be associated with the general age related drying
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of the lens, it isn"t irregularly distributed, and it doesn"t significantly harm vision.
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</p>
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<p>
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When I first heard about the age-related browning of the lens, I thought that the experience of colors would
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be affected, so I devised a test in which the relative darkness of blue and yellow could be judged in
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comparison with a graded strip of shades of grey.
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</p>
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<p>
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After people of ages ranging from 10 to 80 had given exactly the same matches, I realized that the nervous
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system probably corrects for the "yellow filter" effect of the brown lens.
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</p>
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<p>
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The browning of tissues will be the subject of another newsletter.
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</p>
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<p>
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Among the interesting causes of cataracts<strong>: </strong>
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Tamoxifen and hypotonic fluids, sodium deficiency<strong>;</strong> toxicity of tryptophan<strong>;</strong>
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oxidants (metals, hydrogen peroxide, PUFA); diabetes, photosensitizers and sunlight<strong>; </strong>
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excess calcium, deficient magnesium. Excess cortisol. Radiation. Arachidonic and linoleic acids in other
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situations have been found to block cells' regulation of their water content. Hypothyroidism tends to
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increase the activity of serotonin, estrogen, prolactin, calcium, and the tendency of tissues to retain
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water, and to decrease the level of ATP.
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</p>
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<p>
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Among the factors that probably have a role in preventing cataracts<strong>: </strong>
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Thyroid, progesterone, pregnenolone, vitamin E, iodide, pyruvate. Increasing the carbon dioxide lowers the
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cell"s pH, and tends to resist swelling. Palmitic acid (a saturated fat that can be synthesized by our
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tissues) is normally oxidized by the lens. Calcium blockers experimentally prevent cataracts, suggesting
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that magnesium and thyroid (which also act to exclude calcium from cells) would have the same effect.
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</p>
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<p>
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Thyroid hormone is essential for maintaining adequate carbon dioxide production, for minimizing lactic acid,
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cortisol and prolactin, for regulating calcium and magnesium, for avoiding hypotonicity of the body fluids,
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and for improving the ratio of palmitic acid to linoleic acid.
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</p>
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<p>.</p>
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<p><strong> </strong></p>
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<p>
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<strong> </strong>
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<strong><h3>REFERENCES</h3></strong>
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</p>
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<p>
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"Inhibition of ionic transport and ATPase activities by serotonin analogues in the isolated toad lens,"
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Candia OA; Lanzetta PA; Alvarez LJ; Gaines W, Biochim Biophys Acta (602)2, 389-400, 1980. "Tryptamine,
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5-methyltryptamine and 5-methoxytryptamine had dual effects: 1 mM in the posterior bathing solution
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depressed the potential difference of the posterior face of the lens, which resulted in an increase in the
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translenticular potential difference and short-circuit current; 1 mM in the anterior solution (in contact
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with the lens epithelium) produced a quick and pronounced reduction of the potential difference of the
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anterior face. This resulted in a 90-100% decline of the translenticular short-circuit current. Serotonin
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and tryptamine were then tested for their effect on the ATPases of lens epithelium. Both amines inhibited
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the enzymes with tryptamine at 5 mM completely inhibiting all ATPase activity. <strong>Since tryptophan is
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transported from the aqueous humor into the lens and may be converted by lens enzymes to serotonin and
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tryptamine, these findings may have physiological implications in cataractogenesis."</strong>
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</p>
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<p>
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"Effects of Ca2+ on rabbit translens short-circuit current: evidence for a Ca2+ inhibitable K+ conductance,"
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Alvarez LJ; Candia OA; Zamudio AC, Curr Eye Res, 1996 Dec, 15:12, 1198-207. PURPOSE: To characterize the
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effects of medium Ca2+ levels on rabbit lens electrical properties. Overall, these results suggest that
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<strong>lens Ca2(+)-mobilizing agents (e.g. acetylcholine)</strong> could trigger the inhibition of
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epithelial K+ conductance(s) by the direct action of Ca2+ on K+ channels."
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</p>
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<p>
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"Effects of Ca2+ on rabbit translens short-circuit current: evidence for a Ca2+ inhibitable K+ conductance,"
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Alvarez LJ; Candia OA; Zamudio AC, Curr Eye Res, 1996 Dec, 15:12, 1198-207. "PURPOSE: To characterize the
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effects of medium Ca2+ levels on rabbit lens electrical properties. Overall, these results suggest that lens
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Ca2(+)-mobilizing agents (e.g. acetylcholine) could trigger the inhibition of epithelial K+ conductance(s)
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by the direct action of Ca2+ on K+ channels."
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</p>
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<p>
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"D600 increases the resistance associated with the equatorial potassium current of the lens," Walsh SP;
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Patterson JW, Exp Eye Res, 1992 Jul, 55:1, 81-5 "This effect is similar to that produced by quinine and by a
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calcium-free medium, and is attributed to the prevention of an increase in the calcium-dependent conductance
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produced by pCMPS."
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</p>
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<p>
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"Effects of hydrogen peroxide oxidation and calcium channel blockers on the equatorial potassium current of
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the frog lens," Walsh SP; Patterson JW, Exp Eye Res, 1994 Mar, 58:3, 257-65. "Hydrogen peroxide, in
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concentrations of 10-1000 microM, produces two major changes in the current-voltage relationships associated
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with the equatorial potassium current of the lens. First, the resting and reversal potentials become more
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negative than they were prior to treatment with hydrogen peroxide and second, the membrane resistance
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related to the equatorial current is decreased. The shift in the resting and reversal potentials is in the
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opposite direction from that produced by ouabain. Based on the Nernst equation, the shift in the reversal
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potential suggests that there is an <strong>increase in the concentration of potassium in the lens. The 86Rb
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uptake and efflux are increased. These observations suggest that hydrogen peroxide stimulates the
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Na,K-pump. The decrease in membrane resistance is inhibited by 100 microM of quinine, a
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calcium-dependent potassium channel blocker, and does not decrease in a calcium-free medium. This
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suggests that the decrease in resistance may be secondary to an increase in lenticular calcium.</strong>
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These effects of hydrogen peroxide are similar to those of p-chloromercuriphenylsulfonate (pCMPS), a nearly
|
|
impermeant sulfhydryl binding agent,<strong>
|
|
and suggest that permeant hydrogen peroxide may increase calcium influx by acting on sulfhydryl groups
|
|
on the outer surface of lens membranes. Verapamil, a calcium channel blocker, is reported to prevent
|
|
cataract formation.</strong>"
|
|
</p>
|
|
<p>
|
|
"Effect of prolactin on galactose cataractogenesis," Ng MC; Tsui JY; Merola LO; Unakar NJ phthalmic Res
|
|
19:2, 82-94, 1987. "Prolactin has been known to affect the water and electrolyte balance. Because increased
|
|
lens hydration has been shown to be a common phenomenon in most, if not all types of cataracts, we have been
|
|
interested in investigating a possible role of prolactin in sugar cataract induction and progression. For
|
|
this study, we have used morphological and biochemical approaches. The prolactin delivery method involved
|
|
intraperitoneal implantation of one or more pellets in Sprague-Dawley female rats. Following implantation of
|
|
the desired number of prolactin or control (nonprolactin) pellets, animals were either fed galactose and lab
|
|
chow, or lab chow diet. Gross morphological observations of whole lenses, slit-lamp examination of lenses
|
|
and light microscopic analysis of lens sections showed that in the galactose-fed prolactin group, galactose
|
|
associated alteration progressed faster and total opacification (mature cataract development) was achieved
|
|
earlier than in the nonprolactin group. The levels of galactose and dulcitol were higher in the lenses of
|
|
galactose-fed prolactin treated rats as compared to lenses from nonprolactin (control) rats. No significant
|
|
difference in lens Na+-K+ ATPase activity between the prolactin and nonprolactin group was observed. Our
|
|
results indicate that prolactin accelerates galactose-induced cataractogenesis in rats."
|
|
</p>
|
|
<p>
|
|
"A hypothetical mechanism for toxic cataract due to oxidative damage to the lens epithelial membrane,"
|
|
Bender CJ Med Hypotheses, 1994 Nov, 43:5, 307-11 Lenticular opacities can be induced by numerous external
|
|
agents that <strong>coincide with those that catalyze oxidative damage to lipids.
|
|
</strong>One of the consequences of lipid peroxidation is that the affected membrane is rendered more
|
|
permeable to protons. A proton leak in the tight epithelium of lens <strong>would uncouple the
|
|
Na+/K(+)-ATPases that regulate the water</strong> and ionic content of the bounded tissue. Once
|
|
regulatory control of the osmotic pressure is lost, <strong>
|
|
the phase state of the</strong> cell's soluble proteins would change, <strong>
|
|
leading to refractive changes or, in extreme cases, precipitation</strong>. The same does not occur in
|
|
cornea because the stroma is an extracellular polymer blend rather than solution of soluble polymers.
|
|
Polymeric phase transitions in the cornea require that divalent cations pass the epithelial membrane, which
|
|
can occur only through the action of ionophores.
|
|
</p>
|
|
<p>
|
|
Tsubota K; Laing RA; Kenyon KR Invest Ophthalmol Vis Sci, 1987 May, 28:5, 785-9, <strong>Abnormalities in
|
|
glucose metabolism are thought to be among the main causes of cataract formation.
|
|
</strong>
|
|
The authors have made noninvasive biochemical measurements of the lens that provide information concerning
|
|
glucose metabolism in the lens epithelium. The autofluorescence of reduced pyridine nucleotides (PN) and
|
|
oxidized flavoproteins (Fp) within the rabbit lens were noninvasively measured as a function of depth using
|
|
redox fluorometry. The peak of the autofluorescence at 440 nm (excited at 360 nm) and 540 nm <strong
|
|
>(excited at 460 nm) were determined at the lens epithelium. When 8 mM sodium pentobarbital, a known
|
|
inhibitor of mitochondrial respiration, was applied to the lens, the autofluorescence peak at 440 nm
|
|
increased and that at 540
|
|
</strong>
|
|
<strong>nm decreased. The 440 nm autofluorescence is thought to be from
|
|
</strong>
|
|
|
|
reduced pyridine nucleotides, whereas the 540 nm autofluorescence is from the oxidized flavoprotein.
|
|
Blocking lens respiration with pentobarbital caused an increase in the PN/Fp ratio by a factor of 3 within
|
|
3.5 hr after pentobarbital application."
|
|
</p>
|
|
<p>
|
|
[Use of pyrimidine bases and ATP for conservative treatment of early cataracts] Larionov LN Oftalmol Zh,
|
|
1977, 32:3, 221-2
|
|
</p>
|
|
<p>
|
|
<hr />
|
|
<strong>
|
|
high levels of L-lactate and high ratios of L-lactate in the lens/L-lactate in the aqueous</strong>. 2.
|
|
Immature cataractous lenses with anterior capsular/subcapsular opacity; intermediate levels of RTP,
|
|
intermediate values for the sums of RTP, RDP, and AMP, <strong>high L-lactate levels, and intermediate
|
|
values of the ratios of L-lactate in the lens/L-lactate in the aqueous.</strong>"
|
|
</p>
|
|
<p>
|
|
Sulochana KN; Ramakrishnan S; Vasanthi SB; Madhavan HN; Arunagiri K; Punitham R, "First report of congenital
|
|
or infantile cataract in deranged proteoglycan metabolism with released xylose," Br J Ophthalmol, 1997 Apr,
|
|
81:4, 319-23." "Of 220 children of both sexes below 12 years of age, with congenital or infantile cataract
|
|
treated in Sankara Nethralaya, Madras, India, during a period of 2 years, 145 excreted fragments of GAG
|
|
(heparan and chondroitin sulphates) in their urine. There was no such excretion among the control group of
|
|
50 children. <strong>
|
|
The same was found accumulated in the blood and lenses of affected children.</strong>
|
|
In addition, xylose was present in small amounts in the urine and blood and xylitol was present in the lens.
|
|
There was a significant elevation in the <strong>activity of beta glucuronidase in lymphocytes and
|
|
urine,</strong>
|
|
when compared with normals. All the above findings suggest deranged proteoglycan metabolism. As the urine
|
|
contained mostly GAG fragments and very little xylose, Benedict's reagent was not reduced. This ruled out
|
|
galactosaemia.CONCLUSION: An increase of <strong>beta glucuronidase activity might have caused extensive
|
|
fragmentation of GAG</strong> with resultant accumulation in the blood and lens and excretion in urine.
|
|
Small amounts of xylose may have come from xylose links between GAG and core protein of proteoglycans. Owing
|
|
to their polyanionic nature, GAG fragments in the lens might abstract sodium, and with it water, thereby
|
|
increasing the hydration of the lens. Excessive hydration and the osmotic effect of xylitol from xylose
|
|
might cause cataract. While corneal clouding has been reported in inborn acid mucopolysaccharidosis,
|
|
congenital or infantile cataract with deranged metabolism of proteoglycans (acid
|
|
mucopolysaccharide-xylose-protein complex) is reported in children for the first time."
|
|
</p>
|
|
<p>
|
|
"State of electrolytes, osmotic balance and the activity of ATPase in the lenses of selenite--induced
|
|
cataracts," Avarachan PJ; Rawal UM Indian J Ophthalmol, 1987, 35:5-6, 210-3. "Selenite-cataracts
|
|
incorporated many morphological characteristics observed in human senile catracts. Progressive elevation of
|
|
sodium, marked loss of potassium, <strong>several fold increment of calcium; considerable loss of magnesium
|
|
levels,</strong>
|
|
a dose-response reduction of total-ATPase activity <strong>and significant hydration are the important
|
|
features</strong> observed in the lens during the progressive treatment of selenite. The
|
|
sodium-potassium imbalance is found to be a secondary effect during the development of cataract and is
|
|
suggested to bring about by <strong>an abnormal accumulation of calcium ions</strong> and inactivation of
|
|
transport enzyme. The calcium activated proteases could be the promoting factor for the proteolysis and
|
|
insolubilization of lens proteins in the inducement of selenite cataract. The impact of selenite on the SH
|
|
containing ATPase anzymes could be the cause of impairment in energy metabolism, derangement of electrolytes
|
|
and osmotic imbalance which, in turn, accelerate the cortical involvement of lens opacities."
|
|
</p>
|
|
|
|
<p>
|
|
"Glucose metabolism by human cataracts in culture," Wolfe JK; Chylack LT Jr Exp Eye Res 43:2, 243-9, 1986.
|
|
"Metabolism in human senile cataracts has been studied using uniformly labeled [14C]glucose. Intracapsularly
|
|
extracted lenses were cultured in TC-199 media with a glucose concentration of 5.5 mM. Results show that
|
|
lactate production accounts for 97% of the glucose metabolized. Under these standard incubation conditions
|
|
there is negligible accumulation of alpha-glycerol phosphate, glucose-6-phosphate, and sorbitol. The rate of
|
|
lactate production was found to be relatively uniform over a range of cataract severities which were
|
|
determined from the CCRG classification. The effects of several perturbants in the medium were
|
|
measured.<strong>
|
|
An ATP concentration of 3 mM was found to inhibit lactate production."
|
|
</strong>
|
|
</p>
|
|
<p>
|
|
M. V. Riley, et al., "The roles of bicarbonate and CO2 in transendothelial fluid movement and control of
|
|
corneal thickness," Invest. Ophthalmol. Vis. Sci. 36(1), 103-112, 1995. <strong>"The equilibrium thickness
|
|
of deepithelialized corneas swollen with HCO-/CO2 on both surfaces was 35 microns less than that of
|
|
corneas swollen in HPO4-." "Normal corneal thickness can be maintained in vitro only in media that
|
|
contain HCO3- at concentrations of more than 20 mM."</strong>
|
|
</p>
|
|
|
|
<p>
|
|
"The effect of X-irradiation on the sodium-potassium-activated adenosine triphosphatase (Na-K-ATPase)
|
|
activity in the epithelium of the rat lens. A histochemical and biochemical study," Palva M Acta Ophthalmol
|
|
(Copenh), 1978 Jun, 56:3, 431-8. "The epithelial Na-K-ATPase activity of the rat lens was studied after
|
|
X-irradiation at intervals of three to ninety days. The enzyme was demonstrated histochemically by light
|
|
microscopy and it was measured biochemically by a fluorometric method. Neither histochemical nor biochemical
|
|
changes of Na-K-ATPase content of the lens epithelium were observed during the development of cataract. In
|
|
whole-mount preparations the enzyme activity was localized in the cell membranes. However, one month after
|
|
radiation a few peripheral cells had in addition a precipitated over the whole cell. <strong>The unaltered
|
|
Na-K-ATPase</strong>
|
|
<strong>
|
|
content in the epithelium</strong> suggests that the hydration of the lens after X-irradiation is
|
|
primarily caused by <strong>changes in the passive permeability properties of the cell membranes and not by
|
|
a decreased capacity of the activity cation pump."
|
|
</strong>
|
|
</p>
|
|
<p>
|
|
McNamara NA; Polse KA; Bonanno JA<strong> "Stromal acidosis modulates corneal swelling." </strong>
|
|
|
|
Invest Ophthalmol Vis Sci, 1994 Mar, 35:3, 846-50 "PURPOSE. Studies have shown that stromal acidosis reduces
|
|
the rate of corneal thickness recovery after induced edema, providing the first human in vivo evidence that
|
|
corneal pH can influence corneal hydration control. This finding raises the question of the possible effect
|
|
that pH may have on induced corneal swelling. To explore this question, the corneal swelling response to
|
|
hypoxia was measured while stromal pH was controlled. METHODS. Corneal edema and stromal acidosis was
|
|
induced in ten subjects by passing a mixture of nitrogen and carbon dioxide gas across the eyes through
|
|
tight-fitting goggles. <strong>One eye of each subject received 100% N2, whereas the contralateral eye
|
|
received a mixture of 95% N2 and 5% CO2. Exposures of 95% N2 + 5% CO2 lower pH on average to 7.16 versus
|
|
7.34 for 100% N2 alone.</strong> Before and after 2.5 hours of gas exposure, central corneal thickness
|
|
(CCT) was measured. RESULTS. <strong>Eyes exposed to the lower pH environment (eg, N2 + CO2) developed less
|
|
change in CCT</strong> compared to the eyes receiving N2 alone. Overall increase in CCT was 29.9 +/- 5.3
|
|
microns for eyes exposed to the 95% N2 + 5% CO2 gas mixture, versus 37.1 +/- 4.8 microns for 100% N2 <strong
|
|
>eyes (P < 0.0001). CONCLUSIONS. The corneal swelling response to hypoxia can be reduced by lowering
|
|
stromal pH. Because changes in corneal pH alone have not been found to alter steady-state CCT, it is
|
|
proposed that pH
|
|
</strong>
|
|
exerts its effect only under non-steady-state conditions (ie, corneal swelling and deswelling). This
|
|
suggests that acidosis may produce changes in the <strong>rate of lactate metabolism</strong> or alter
|
|
endothelial hydraulic conductivity."
|
|
</p>
|
|
|
|
<p>
|
|
Buchberger W; Winkler R; Moser M; Rieger G, "Influence of iodide on cataractogenesis in Emory mice,"
|
|
Ophthalmic Res, 1991, 23:6, 303-8. Cataract development was studied in two groups of Emory mice by
|
|
periodical biomicroscopic examinations (beginning at 5 weeks of age) and by a final evaluation of
|
|
water-soluble SH groups in the lenses. The experimental group was given 256 micrograms iodide/kg body weight
|
|
with the drinking water throughout the study. The untreated control group received tap water. <strong>Iodide
|
|
treatment induced a delay of cataract formation...."</strong> "A still significant difference in the
|
|
degree of cataract was also found between the two groups at week 47 of age. No difference was found in the
|
|
content of water-soluble SH groups. The results are discussed in relation <strong>to the known antioxidant
|
|
and .OH-scavenging effect of iodide and to the oxidative changes in the lens occurring during
|
|
progression of cataract development.</strong>"
|
|
</p>
|
|
<p>
|
|
"[The chemical nature of the fluorescing products accumulating in the lipids of the crystalline lenses of
|
|
mice with hereditary cataract]," Shvedova AA; Platonov ES; Polianskii NB; Babizhaev MA; Kagan VE Biull Eksp
|
|
Biol Med, 1987 Mar, 103:3, 301-4.<strong>
|
|
"The content of diene conjugates (lipid hydroperoxides) was shown to be significantly higher in lipids
|
|
extracted from the lenses of mice with hereditary cataract than in the controls. The same holds true for
|
|
characteristics of fluorescence of the end-product of lipid peroxidation."</strong> "It was established
|
|
that high-molecular weight fluorescent fractions corresponded to lipid components of <strong>
|
|
lipofuscin-like pigments.</strong> NMR and mass spectrometry of low-molecular weight fractions suggested
|
|
that they contained predominantly products of free radical oxidation of <strong>long chain polyunsaturated
|
|
fatty acids (C22:6). "</strong>
|
|
</p>
|
|
<p>
|
|
"Formation of N'-formylkynurenine in proteins from lens and other sources by exposure to sunlight," Pirie A
|
|
Biochem J, 1971 Nov, 125:1, 203-8.
|
|
</p>
|
|
<p>
|
|
"Lipid fluorophores of the human crystalline lens with cataract." Babizhayev MA Graefes Arch Clin Exp
|
|
Ophthalmol, 1989, 227:4, 384-91 "It has been established that the development of cataract is accompanied by
|
|
the formation of various fluorophores in the lipid fraction of the lens. These lipid-fluorescing products
|
|
have been separated chromatographically according to polarity and molecular weight. It is shown that the
|
|
initial stages of the development of cataract are characterized by the appearance of lipid fluorophores in
|
|
the near ultraviolet and violet regions of the spectrum <strong>(excitation maximum 302-330 nm, emission
|
|
maximum 411 nm) with low</strong> polarity and a small molecular weight; the maturing of the cataract
|
|
is<strong>
|
|
characterized by an increase in the intensity of the long-wave fluorescence of the lipids in the
|
|
blue-green region (430-480 nm) and by the formation of
|
|
</strong>
|
|
|
|
polymeric high-molecular-weight fluorescing lipid products with high polarity. It has been demonstrated that
|
|
the appearance of lipid fluorophores in the <strong>crystalline lens is associated with the free radical
|
|
oxidative modification of the phospholipids and fatty acids in cataract."
|
|
</strong>
|
|
</p>
|
|
<p>
|
|
"Incidence of cataracts in the mobile eye hospitals of Nepal," Brandt F; Malla OK; Pradhan YM; Prasad LN;
|
|
Rai NC; Pokharel RP; Lakhe S, Graefes Arch Clin Exp Ophthalmol, 1982, 218:1, 25-7 The incidence of cataract
|
|
in Nepal was determined from data collected in 14 mobile eye hospitals (called 'eye camps'). Of a total of
|
|
<strong>12,217</strong> patients examined in the out-patient department (OPD), cataract surgery was
|
|
performed on 2,163. The percentage of cataract patients in the OPD was <strong>less in the mountains (13.8%)
|
|
than in the Tarai plains (19.8%).</strong>
|
|
In the inhabitants of the mountains, the majority of whom belong to the Tibeto-Birman race, <strong
|
|
>cataracts appeared at a significantly later age in both males and females compared to the people of the
|
|
plains, who are mostly Indo-Aryan.</strong> Cataracts were discovered in both groups at a younger age in
|
|
women than in men."
|
|
</p>
|
|
|
|
<p>
|
|
"Associations among cataract prevalence, sunlight hours, and altitude in the Himalayas." Brilliant LB;
|
|
Grasset NC; Pokhrel RP; Kolstad A; Lepkowski JM; Brilliant GE; Hawks WN; Pararajasegaram R., Am J Epidemiol
|
|
118:2, 250-64 1983. "The relationship between cataract prevalence, altitude, and sunlight hours was
|
|
investigated in a <strong>large national probability sample survey of 105 sites</strong> in the Himalayan
|
|
kingdom of Nepal, December 1980 through April 1981. Cataract of senile or unknown etiology was diagnosed by
|
|
ophthalmologists in 873 of <strong>30,565</strong>
|
|
<strong>full-time life-long residents</strong> of survey sites. Simultaneously, the altitude of sites was
|
|
measured using a standard mountain altimeter. Seasonally adjusted average daily duration of sunlight
|
|
exposure for each site was calculated by a method which took into account latitude and obstructions along
|
|
the skyline. Age- and sex-standardized <strong>cataract prevalence was 2.7 times higher in sites at an
|
|
altitude of 185 meters or less than in sites over 1000 meters. Cataract prevalence was negatively
|
|
correlated with altitude</strong>
|
|
<hr />
|
|
</p>
|
|
<p>
|
|
<strong>"The untenability of the sunlight hypothesis of cataractogenesis</strong>," Harding JJ Doc
|
|
Ophthalmol 88:3-4, 345-9, 1994-95. "The excess prevalence of cataract in <strong>third world countries led
|
|
early this century to the hypothesis that sunlight causes cataract. The hypothesis, which ignored
|
|
differences in diet, culture, poverty and prevalence of other diseases</strong> such as diarrhoea,
|
|
received little support until about thirty years ago when biochemical studies were set up to explore the
|
|
browning of lens proteins, which is a common feature of cataract on the Indian subcontinent. Initially these
|
|
studies were encouraging in that exposure to sunlight caused some changes seen in cataractous lenses, but
|
|
eventually the hypothesis was rejected because the first change in the laboratory was the destruction of
|
|
tryptophan, <strong>but this was not found in brown cataract lenses.</strong> A brown nuclear cataract could
|
|
not be produced artificially in the laboratory using sunlight or UV exposure. Exposure of laboratory animals
|
|
has produced lens opacities, but in most experiments the doses required have also caused keratitis,
|
|
conjunctivitis, iritis and inflammation. The cornea seems more sensitive than the lens, which is not
|
|
surprising, as it gets the first chance to absorb damaging UV. The biochemical rejection of the hypothesis
|
|
coincided with the re-start of the epidemiological studies. Most of these are simply latitude studies and
|
|
are no more than a repeat of what was available sixty years ago. They do not help to find a cause. <strong
|
|
>Two studies showed that cataract was less common at higher altitude in the Himalayas, but unfortunately led
|
|
to opposing conclusions</strong>. On the basis of common knowledge that UV exposure was greater at
|
|
higher altitude, the first altitude study led to the rejection of the sunlight hypothesis."
|
|
</p>
|
|
<p>
|
|
"Anticataract action of vitamin E: its estimation using an in vitro steroid cataract model," Ohta Y; Okada
|
|
H; Majima Y; Ishiguro I Ophthalmic Res, 1996, 28 Suppl 2:, 16-25 "The aim of this study was to estimate the
|
|
anticataract action of vitamin E using an in vitro methylprednisolone (MP)-induced cataract model. The same
|
|
severity of early cortical cataract was induced in lenses isolated from male Wistar rats aged 6 weeks by
|
|
incubation with MP (1.5 mg/ml) in TC-199 medium. The cataractous lenses showed slight increases in lipid
|
|
peroxide (LPO) content and Na+/K+ ratio and slight decreases in reduced glutathione (GSH) content and
|
|
glyceraldehyde-3-phosphate dehydrogenase (GAP-DH), a sensitive index of oxidative stress, and
|
|
Na+,K(+)-ATPase activities. When the cataractous lenses were further incubated in TC-199 medium with and
|
|
without vitamin E (250 micrograms/ml) for 48 h, the progression of cataract was prevented in the vitamin
|
|
E-treated lenses, but not in the vitamin E-untreated lenses. The vitamin E-untreated lenses showed a
|
|
decrease in vitamin E content and an increase in water content in addition to further increases in LPO
|
|
content and Na+/K+ ratio and further decreases in GSH content and GAP-DH and Na+,K(+)-ATPase activities. In
|
|
contrast, the changes of these components and enzymes except for GSH were attenuated in the vitamin
|
|
E-treated lenses. From these results, it can be estimated that vitamin E prevents in vitro cataractogenesis
|
|
in rat lenses treated with MP by protecting the lenses against oxidative damage and loss of membrane
|
|
function. "
|
|
</p>
|
|
<p>
|
|
"Prevention of oxidative damage to rat lens by pyruvate in vitro: possible attenuation in vivo," Varma SD;
|
|
Ramachandran S; Devamanoharan PS; Morris SM; Ali AH,.Curr Eye Res, 1995 Aug, 14:8, 643-9 "Studies have been
|
|
conducted to assess the possible preventive effect of pyruvate against lens protein oxidation and consequent
|
|
denaturation and insolubilization. Rat lens organ culture system was used for these studies. The content of
|
|
water insoluble proteins (urea soluble) increased if the lenses were cultured in medium containing hydrogen
|
|
peroxide. Incorporation of pyruvate in the medium prevented such insolubilization. The insolubilization was
|
|
associated primarily with loss of gamma crystallin fraction of the soluble proteins. PAGE analysis
|
|
demonstrated that insolubilization is related to -S-S- bond formation which was preventable by pyruvate.
|
|
Since pyruvate is a normal tissue metabolite the findings are considered pathophysiologically significant
|
|
against cataract formation. This was apparent by the <strong>prevention of selenite cataract in vivo by
|
|
intraperitoneal administration of pyruvate.</strong>"
|
|
</p>
|
|
|
|
<p>
|
|
"Glucocorticoid-induced cataract in chick embryo monitored by Raman spectroscopy," Mizuno A; Nishigori H;
|
|
Iwatsuru M Invest Ophthalmol Vis Sci, 30:1, 132-7, 1989. "Glucocorticoid-induced cataract lens in chick
|
|
embryo was monitored by laser Raman spectroscopy. The lens opacity that appeared in chick embryo is a
|
|
reversible one. Raman spectra show no significant change in the relative content of water or secondary
|
|
structure of the proteins upon lens opacification. The intensity ratios of tyrosine doublet bands in Raman
|
|
spectra between clear and opaque lens portions are changes. <strong>
|
|
This change is reversible,
|
|
</strong>and <strong>is interpreted as a protein-water phase separation that occurred during lens
|
|
opacification</strong>."
|
|
</p>
|
|
<p>
|
|
"[NMR study of the state of water in the human lens during cataract development]" Babizhaev MA; Deev AI;
|
|
Nikolaev GM, Biofizika 30:4, 671-4,1985. "Water proton spin-spin relaxation times (T2) and the content of
|
|
bound, "non-freezable" at -9 degrees C water in both normal human lenses and human lenses of different
|
|
stages of cataract progression (cataracta incipiens, nondum matura, mature hypermatura) were measured by NMR
|
|
spin echoes method. By the stage of cataracta nondum matura, increase of bound water content and
|
|
simultaneous, almost half decrease of the relaxation time (T2), were observed. However, on the following
|
|
stages of cataract evaluation (almost mature, mature cataracts) <strong>a gradual decrease of bound water
|
|
content is noted,
|
|
</strong>but only for the mature cataract stage the water content significantly differs from that of the
|
|
normal one. On the stage of hypermature cataract the presence of two unexchanged with each other fractions
|
|
of water is found. The obtained data are <strong>explained by lens protein reconstructions during the
|
|
cataract progression.</strong>"
|
|
</p>
|
|
<p>
|
|
Hightower KR; Reddy VN "Ca++-induced cataract." Invest Ophthalmol Vis Sci, 1982 Feb, 22:2, 263-7 "Cataracts
|
|
in cultured rabbit lenses were produced by elevation of internal calcium. Experimental procedures were
|
|
successful in increasing levels of total and bound Ca++, often without significant changes in sodium,
|
|
potassium, or water content. Although the excess in calcium was predominantly associated with water-soluble
|
|
proteins and was freely diffusible, a significant amount was bound to membranes and cytosol water-insoluble
|
|
proteins. Thus, in lenses with a 10-fold increase in total Ca++, the bound Ca++ increased twofold, nearly
|
|
35% of which remained fixed to water-insoluble and membrane proteins after exhaustive (72 hr) dialysis. In
|
|
contrast, over 95% of the Ca++ in water-soluble protein fractions was removed by dialysis."
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|
</p>
|
|
<p>
|
|
[Use of pyrimidine bases and ATP for conservative treatment of early cataracts] Larionov LN Oftalmol Zh,
|
|
1977, 32:3, 221-2.
|
|
</p>
|
|
<p>
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|
"Noninvasive measurements of pyridine nucleotide and flavoprotein in the lens," Tsubota K; Laing RA; Kenyon
|
|
KR Invest Ophthalmol Vis Sci 28:5, 785-9, 1987. "<strong>Abnormalities in glucose metabolism are thought to
|
|
be among the main causes of cataract formation.
|
|
</strong>
|
|
The authors have made noninvasive biochemical measurements of the lens that provide information concerning
|
|
glucose metabolism in the lens epithelium. The autofluorescence of reduced pyridine nucleotides (PN) and
|
|
oxidized flavoproteins (Fp) within the rabbit lens were noninvasively measured as a function of depth using
|
|
redox fluorometry. The peak of the autofluorescence at 440 nm (excited at 360 nm) and 540 nm <strong
|
|
>(excited at 460 nm) were determined at the lens epithelium. When 8 mM sodium pentobarbital, a known
|
|
inhibitor of mitochondrial respiration, was applied to the lens, the autofluorescence peak at 440 nm
|
|
increased and that at 540 nm decreased. The 440 nm autofluorescence is thought to be from
|
|
</strong>
|
|
|
|
reduced pyridine nucleotides, whereas the 540 nm autofluorescence is from the oxidized flavoprotein.
|
|
Blocking lens respiration with pentobarbital caused an increase in the PN/Fp ratio by a factor of 3 within
|
|
3.5 hr after pentobarbital application."
|
|
</p>
|
|
<p>
|
|
<hr />
|
|
<strong>
|
|
high levels of L-lactate and high ratios of L-lactate in the lens/L-lactate in the aqueous</strong>. 2.
|
|
Immature cataractous lenses with anterior capsular/subcapsular opacity; intermediate levels of RTP,
|
|
intermediate values for the sums of RTP, RDP, and AMP, <strong>high L-lactate levels, and intermediate
|
|
values of the ratios of L-lactate in the lens/L-lactate in the aqueous."</strong>
|
|
</p>
|
|
<p>
|
|
"Lipid fluorophores of the human crystalline lens with cataract," Babizhayev MA Graefes Arch Clin Exp
|
|
Ophthalmol, 1989, 227:4, 384-91. [Initial stages of cataracts are characterized by the fluorescence of the
|
|
products of fatty acid free radical oxidation.]
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</p>
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<p>© Ray Peat 2006. All Rights Reserved. www.RayPeat.com</p>
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