Hair Apparent: The Components of Coat Health
Knowing how nutrition, genetics and hormones affect your canine’s hair is the first stop on the road to a remarkable coat




By Susan Thorpe-Vargas, Ph.D., and John C. Cargill, M.A., M.B.A., M.S.

In box:
This is the second half of a two-part article that looks at the physical makeup, structure and growth cycle of canine hair, and the nutritional and hormonal factors that affect good hair growth. The causes of hair loss also are discussed as well as the genetics behind coat color.

From time to time, we’ve all had to deal with the proverbial bad hair day, but for dogs, bad hair days can be more than just an embarrassment. In fact, as we discussed in the first article of this two-part series, “Cultivating A Quality Coat,” in the December 2000 issue, the condition of the coat is indicative of the general well-being of the dog and can reveal underlying health problems.

We caution that there is a lot more to the science and biology of hair than first meets the eye. Many unknowns remain, and relatively little research has been done compared to other conditions. Coat health, however, is far more important than most people realize.

In the first article, we covered the genetic, developmental, environmental and gender factors that can influence hair growth and the hair growth cycle, and we discussed the basic structure and function of the hair follicle and the hair shaft. In this article we will address factors that promote hair growth and hair loss, touch on some biochemical elements—including nutritional and hormonal influences that regulate hair growth—and discuss some genetic diseases and pathologies associated with alopecia (the loss of hair). We will conclude with a brief overview of the basic genetics of hair color in the canine. Although this second article stands alone, and some material will be reiterated from the first article, those wanting more background information might find a perusal of the first part helpful.

The Growth Stages

We will begin by going to the “root” of the issue, so to speak. The hair follicle is the only mammalian accessory structure that undergoes lifelong cyclical transformations, but how the different stages of the hair cycle are defined is a subject of some debate.

Recent research suggests that the different stages can be determined by looking at the patterns and extent of cornification of the various tissues that make up the hair follicle and hair shaft. (See Figure 1). Cornification is a process that involves the transition of viable cells known as keratinocytes into organized layers of lifeless cells, which form largely impermeable barriers, in such structures as the hair shaft or the outer layers of the skin. This transformation involves 1) replacement of nuclei and cytoplasm by fibrous proteins known as keratins; 2) the organization of the keratin proteins by filament aggregating proteins; 3) the replacement of the cell membrane (the outer layer of the cells) into a virtually insoluble layer known as the cornified envelope; and 4) the synthesis of a lipid (fat) glue that holds these cells tightly together.

Cornification first involves the formation and then organization of keratin. Keratins are a class of structural proteins that compose the major component of epithelial skin cells. Epithelial cells are rapidly dividing cells that line body cavities and represent the largest type of cell within the outer layer of the skin and hair.

Next in the process is the formation of a cornified envelope, which surrounds the keratin, and the production of intercellular lipids that strengthen the corneocyte (the combination of the cornified envelope and inner keratins) together. There are two types of hair keratins, which are distinguished by the number of cysteine residues in the protein. The newer classification procedure—type I and type II keratins—is based on their size and pH (whether they are acidic or basic).

It is well recognized that the characteristics of hair growth vary with the species, gender, age, hormonal status and overall health of the animal. The periodic nature of hair growth also depends on the site on the body on which the hair resides. Hair follicles produce hair shafts of different lengths and diameters depending on their location on the body, the age or the seasonal environment of the animal.

To illustrate, we all know that mature male dogs usually carry more coat than females, including a characteristic ruff. In a study of red deer, receptors for androgens (the male sex hormones) were found only on the hair follicles of the mane. 2 Perhaps this is what is happening in dogs. Studies involving humans and other mammals’ support the theory that hormones can influence the length and quantity of hair found at various body sites. 3 The growth cycles can be visualized in three stages.

• Anagen—This is the stage in which hair is actively growing. During anagen, the follicular epithelial cells, under the influence of the follicular papilla (which functions to initiate and direct the embryonic generation of hair follicles), first differentiate into matrix cells. Matrix cells produce the hair shaft as well as a cornified lining that surrounds the hair shaft known as the inner root sheath. The period of anagen is determined genetically for each hair type in any given species, although intrinsic and extrinsic factors including nutrition and disease can modulate the duration or the length between cycles.

• Catagen—After a period of time, hair growth slows (the catagen stage) before stopping in the next stage, telogen. Catagen occurs when the matrix cells no longer undergo mitosis.

• Telogen—Telogen often is called the “resting stage.” In some species shortly after telogen begins, the hair falls out (shedding) and is replaced by a new anagen hair. This pattern of hair growth occurs in humans and some dogs such as Poodles. In most mammals, including the canine breeds that do not require hair cuts, the telogen hair may be retained in suspended animation for long periods of time—some experts suspect years.

Hormonal Factors

You may have experienced the effects that environment and gender have on hair growth, but hair follicles also may be affected by corticosteroids (steroids produced by the adrenal cortex), which have been shown to inhibit hair follicle activity, an effect that can be linked to hair loss during stress. 4 Studies in sheep showed that the effect of steroids was dose-dependent. Plasma levels of corticosteroids below 1 µg/ml stimulated the rate of wool growth, while concentrations above 3 µg/ml caused almost complete inhibition of hair growth. 5

Changes in the amount of sunlight will affect the onset of hair growth in some species, but its effect has not yet been determined in canines. The amount of exposure to daylight determines the levels of the hormone melatonin. Melatonin has many functions. It regulates several physiological processes such as daily sleep induction, seasonal biological activities (including hair growth), aging and modulation of the immune response. In one study, exogenous melatonin induced the onset of winter hair growth in minks’ seven weeks earlier than the control group. 6 Melatonin also has been shown to protect cell membranes from hydroxyl radicals, the most damaging of free radicals. Furthermore melatonin may have a role in the onset and treatment of several dermatoses and malignancies.

Endogenous melatonin is produced by the pineal gland. Melatonin blood serum levels show a circadian rhythm (24-hour cycle) with low levels during the day rising to a maximum level during the early morning hours. The increasing duration of melatonin secretion, as the daylight period declines, depresses prolactin secretion.

Prolactin is a hormone produced by the pituitary gland that has an inverse relationship with melatonin (the higher the melatonin level, the lower the prolactin). It has several biological activities. Besides an immunoregulatory function and its effect on the growth of epithelial tissues, recent work has suggested that prolactin also might act as a neuroendocrine modulator in some type of feedback mechanism between the skin and the central nervous system. 7

One of the ways the hormone might work is to modulate cytokine release in the skin. Cytokines are small proteins in the range of 5 kilo Daltons to 20 kilo Daltons (unit used to measure the mass of large molecules) that are released by cells and have specific effects on cell-cell interaction, communication and the behavior of other cells. Cytokines are not really different from hormones, but the term often is used as convenient generic shorthand for interleukins, lymphokines and several related signaling molecules such as interferons. Tumor necrosis factor (which reduces and controls inflammation) also is considered a cytokine.

A 1996 study showed that cytokines might be involved in the regulation of normal hair growth. 8 Dose-response studies demonstrated that several interleukins and tumor necrosis factor-beta are potent inhibitors of hair follicle growth. In their role as mediators of immunity and inflammatory processes, these cytokines also may be involved in the pathogenesis of some hair diseases.

Insulin-like growth factor I, a polypeptide, may play a role in modulating the genetic effects between two types of goats because both have IGF-I receptor sites on hair follicles at different stages of the hair growth cycle. Cashmere goats, for example, show a seasonally regulated and synchronized hair growth cycle, while the Angora goat has hair that grows continuously.

In some mammalian species, such as the dog, thyroid hormone stimulates the onset of hair follicle activity. Removal of the hormone causes a delay in hair follicle growth. In Icelandic-cross goats, a thyroxin deiodinase inhibitor reduced the number of active secondary follicles. 9 Thyroxin deiodinase is an enzyme that removes iodine from T4 (thyroxine) to form T3 (triiodothyrine), the thyroid hormone that has the greatest activity on cells, including the hair follicles.

Nutritional Factors

It may be difficult to mediate the effects hormones have on your canine’s coat, but one component more easily controllable is the food your dog eats. Hair follicles are metabolically active biological structures that require both micronutrients (e.g., iron, zinc and copper) and macronutrients (e.g., proteins, carbohydrates and fats) to support growth and structural functions. Besides the metabolic role these necessary nutrients play, a sufficient intake of certain requisite minerals and vitamins is primary in maintaining a healthy coat and skin. In addition, the importance of high-quality proteins in the diet cannot be stressed enough, as they are necessary for the optimum synthesis of hair proteins.

Poor nutrition, often contiguous with illness or generalized disease states, will shorten the hair growth cycle considerably. Severe illness or stress may cause many hair follicles to enter the dormant phase early. Disease also may lead to the faulty formation of the hair cuticle. This probably would require a really poor diet as well, and it would be inhumane to test this experimentally. Damage to the cuticle results in a dull, lusterless coat. Good nutrition, however, will not compensate for genetic shortcomings.

The take-home message here is that a lack of proper nutrition will result in poor coat quality, but good nutrition will not overcome a genetically determined defect. The following nutritional components, however, play particular roles in skin and coat health.

• Sulfur amino acids—An adequate supply of the two sulfur-containing amino acids, methionine and cysteine, especially is significant along with the co-factor pyridoxine, which is necessary for the conversion of methionine to cysteine. Cysteine is the major amino acid of the structural protein keratin, and cysteine’s ability to cross-link is necessary for the tensile strength of the hair. Both folic acid and methylated cyanocobalamin (a homologue of vitamin B6) play an important role in the conversion of homocysteine (an intermediate cysteine structure) to methionine.

• Pantothenic acid—This acid is a constituent of co-enzyme A, which plays a role in protein and fatty acid synthesis. In humans, protein malnutrition shrinks the diameter of the hair shaft and reduces the number of anagen hair follicles. An inadequate supply of pantothenic acid has been shown to cause hair loss in dogs and rats. 10

• Vitamin C—Vitamin C is manufactured by the dog (as opposed to humans, who cannot manufacture their own vitamin C and must have an exogenous source through diet) and is necessary for the cross-linking of hydroxyproline, which is the most common amino acid in collagen.

• Magnesium—Certain minerals are required in all metabolically active cells. More specifically, the synthesis and breakdown of DNA require magnesium. It also is needed by the kinase enzymes responsible for phosphate transfer reactions (a major component of secondary messenger signal transduction). These enzymes are metal-activated; the magnesium provides an electrostatic shield between phosphate groups so that they don’t repel each other. Signal transduction is a cascade of processes by which an extracellular signal (typically a hormone or neurotransmitter) interacts with a receptor at the cell surface. This causes a change in the level (concentration) of a second messenger such as calcium and ultimately effects a change in the cells’ functioning. Two examples of this would be triggering glucose uptake or initiating cell division.

• Calcium—Intracellular calcium plays an important part in the regulation of proliferation and differentiation of keratinocytes. 11 Calcium also may mediate their response to epidermal growth factor.

• Potassium (K+)—Potassium deficiencies cause hair loss in the rat and poor coats in mice. 12 The opening of K+ channels on hair follicles may be a hair growth-regulating mechanism. Tiny pores in the cell membrane control the flow of ions in and out of cells. These ion “gates” or “channels” open and close depending on the cell’s overall electrostatic charge, either negative or positive. The ion flow is responsible for processes such as nerve conduction and muscle contraction and recently has been implicated in “turning on” hair follicle growth.

• Manganese—Manganese is involved in activating the enzymes responsible for adding sugar moieties (moieties are functional groups that are transferred intact from one molecule to another) to proteins to form the glycoproteins found in chondroitin and collagen, which support the dermal portions of the hair follicles.

• Selenium and copper—These are two important micronutrients. Selenium plays an active role in the enzyme thyroxin deiodinase previously mentioned. Copper is required for the cross-linking necessary for the structural integrity of collagen and is involved in the production of melanin—the pigment cells—by way of the enzyme tyrosinase.

• Zinc—Zinc is an essential component of many enzymes with important roles in such processes as gene expression and the metabolism of proteins, fats and carbohydrates. Zinc-responsive dermatosis is seen in many types of dogs, especially the Arctic breeds. 13

When figuring a diet for your dog, remember what that you aren’t feeding may be important, too. You can’t create a good coat in the normal dog with “ultra” nutrition, but you sure can mess up a good coat if you don’t have a complete and balanced diet for that individual dog, whether commercial, homebrew or raw food. This includes both macro- and micronutrients, i.e., the whole shebang. If there is a genetic fault or current medical condition, such as zinc dermatosis, diets are available to ameliorate that fault.

Hair Loss

No matter what the underlying cause, be it nutrition, illness or other, disruption of the hair cycle results in poor coat quality or excessive loss or thinning of the hair. A healthy, gleaming coat reflects the genetic, nutritional and overall health status of our dogs. A poor coat indicates the opposite. Several diseases can cause hair loss (alopecia). Some of these maladies listed below:

• Diseases of the hair follicle—Follicular dysplasias result in a reduced quantity and/or quality of structural proteins and fat-building blocks of the hair shaft and are seen during the anagen portion of the hair cycle. Although most dysplasias are associated with hair loss, any change in hair texture, body or length of hair can be considered a dysplasia. Follicular dysplasias are not curable, but therapeutic treatments are available.

Most follicular dysplasias are present at or soon after birth. One example of a follicular dysplasia is the ectodermal defect that gives the Chinese Crested its appearance. Thus, a genetic defect actually has become a characteristic of the breed.

Other types of follicular dysplasias are “acquired” in that the change in hair texture, body or length occurs once the animal matures. Such diseases include poisoning by a toxin, such as thallium, or when the hair follicle is attacked by the body’s own lymphocytes, as can be seen in the disease alopecia areata. Sometimes melanocyte/matrix cell disruptions result in hair loss and malformed hairs. A fairly common example is the “color mutant” (dilution) alopecia that occurs in some pubescent or young adult dogs. Another color mutant alopecia, “black/dark hair follicular dysplasia,” is seen in some 3- to 6-week-old dogs.

• Hair cycle abnormalities and follicular atrophies—An abnormal hair cycle, especially one resulting in anagen inhibition or one that induces catagen or prolongs telogen, often will result in hairlessness. This is the most common cause of hair loss in the dog. As a rule, 50 percent of the secondary hairs will be lost before the hair loss is recognized, whereas loss of 30 percent of only primary hairs is needed before hair loss is noted. Hair cycle abnormalities may be caused by primary endocrinopathies such as hyperadrenocorticism or by other anomalies associated with the over- or under-production of essential factors. Treatment depends on the underlying cause; hyperadrenocorticism, for instance, would require hormonal therapy.

• Traumatic hair loss—Hair loss due to plucking of the hair shaft or scratching in response to intense pruritus is one of the most common causes of alopecia in dogs. Trauma usually results in starting new hair growth; i.e., it initiates anagen.

Scarring alopecias—A scarring alopecia can result from an inflammatory reaction associated with a furunculosis (a localized staphylococcus infection originating deep in the hair follicle) following a bacterial of dermatophytic pyoderma (fungal infection). Hair loss also can occur as a result of chemical, electric, heat and radiation burns where the hair follicle actually is destroyed. Cutaneous vasculitis (a temporary inflammatory disease that damages blood vessels and results in a lack of blood flow to the skin) has been recognized as an idiosyncratic reaction to the killed rabies vaccine. Various forms of lupus erythematosus (characterized by cutaneous skin lesions), dermatomyositis (an inflammation primarily of the muscles but which also produces a severe skin rash) and lichen planopilaris (a rare, patchy alopecia with follicular hyperkeratinosis) all can cause fibrosis and glassy membrane collapse of the hair follicle with scarring. Often this hair loss is permanent.

Self-inflicted, infective traumas also may cause hair loss but can be prevented by promptly treating infections with antibiotics, using special collars that keep dogs from scratching and biting themselves and treating psychoses that can instigate self-trauma.

Accounting For Color

Hair loss obviously is of important interest to many fanciers, but another component of the coat—color—at times can be equally on the enthusiast’s mind. One of the great mysteries of dogdom is color genetics, a topic that occupies many hours of discussion in the fancy. What follows is a bare bones discussion of canine color genetics.

Hair pigment cells are called melanocytes, and they are derived from the same cells that arise from the neural crest (a group of migrating embryonic cells) early in embryonic development. There are two primary mammalian pigments. One, eumelanin, the most abundant type, is black but in some breeds can vary from brown or blue-gray. The second pigment, pheomelanin, contains sulfur and varies from pale cream through shades of yellow, tan and red to mahogany.

The enzyme tyrosinase controls the production of melanin. In an albino, this enzyme is not produced; therefore, pigment cannot be made. A simplistic way of looking at the color genes is to break them up into those that control the color, those that determine the pattern of that color, and those that modify either or both. The latter type often controls when and where other genes are turned on or off. The following is a brief rundown of the color genes:

• E (extension) gene and B (black) gene are color determinant genes. The B gene sets the type of dark pigment, and the E gene determines the degree to which the B gene is expressed.
• A (agouti) gene determines the pattern of eumelanin and pheomelanin.
(The A and E alleles control the appearance of the black and yellow pigment in the coat of most breeds)
• S (white spotting) gene controls the coverage of both types of melanin.
• C (albino series) genes dilute the light pigment.
• D (dilution) gene dilutes the dark pigment.
• M (merle) gene mottles the dark pigment.
• T (ticking) gene ticks the dark pigment.

In summary, the B genes determine dark color. The series of E, A, S, D, T and some other genes not addressed herein determine the expression of the pigment in terms of coverage, location, pattern and depth of color. This topic soon becomes cloudy, so we will quickly leave this subject with the proviso that,“there be dragons there”.

For those of you with an avid interest in this subject, we refer you to two excellent sites:

• “Animal Genetics” by Sue Ann Bowling, Ph.D., http://www.bowlingsite.mcf.com/Genetics/Genetics.html ; and

• “Canine Coat Color” by Bonnie Dalzell, M.A.,
http://www.borzois.com/coatcolor/coat.color.html

* * * * *
We have, in two sequential articles, laid out the basics of hair structure, the underlying genetics of hair growth and the cyclic nature of that growth. We also have stressed the importance of hair as an overall indicator of health and the part good nutrition plays in maintaining that health.

Because so little is known about the underlying physiology of hair, we have been able to share with you only just a part of the picture. We do hope, however, that we have conveyed there is more to hair growth and holding coat than when we first encountered the subject.

The authors also would like to thank Dr. Robert Dunstan for allowing us to see unpublished papers and for his time and energy in correcting any errors or misperceptions. We also urge that you cooperate with his study by providing hair samples of your respective breeds (see the sidebar for details). There still is much to learn.

Susan Thorpe-Vargas has a doctorate in immunology and has an extensive chemistry and lab background. She has been involved in numerous Environmental Protection Agency cleanup sites. Susan also raises and shows Samoyeds. She may be reached by e-mail at docvite@aol.com .

John Cargill, retired Officer of Marines, statistician and science writer, grew up with Airedale Terriers and American Foxhounds but now lives in Smyrna, N.C., with his 5-year-old male Akita, Ch. Kimdamar’s Jambalaya Jazz (call name “JJ”). He may be reached by e-mail at cargilljc@aol.com .

Susan and John won the Dog Writers Association of America’s Maxwell Medallion and the IAMSÆ Eukanuba Canine Health Award for their series of articles on canine genetics that appeared in DOG WORLD. This year they won the Eukanuba award again for a recent DOG WORLD article on acupuncture, and they were awarded another Maxwell Medallion for their DOG World series on the geriatric dog.

Sidebar:

Comprehending Coat Differences

The Comparative Dermatology Laboratory at Texas A&M University is embarking on an ambitious study funded by the American Kennel Club Canine Health Foundation to define by picture and measurement the features that distinguish the different coat types of the most common canine breeds recognized by the AKC. The importance of this study is clear when one considers that it is not known how the coat of a Whippet differs from a Beagle or what makes the coat of one dog better than another. In addition, defining “normal” in terms of number and diameter of hairs/unit area can be used to assess the severity of diseases with hair loss. This knowledge may allow veterinarians to make a definitive diagnosis of some diseases without the need for biopsy.

The dermatology lab proposes to study the coat of these canine breeds using the following three methods never used before to evaluate the canine hair coat: 1) Analysis of dermscope images. The dermscope is a portable scanning microscope that enables researchers to take a closer look at the canine hair coat. 2) The use of an Optical Fibre Diameter Analysis unit to define the curvature and diameter of different canine breeds’ hair. Preliminary work with this unit suggests each breed may have its own unique diameter/curvature fingerprint. Based on a small number of dogs, researchers have been able to distinguish diameter/curvature differences between Miniature and Standard Poodles. 3) The use of histologic sections to define the relationship between the guard and undercoat hairs and to correlate these findings with the dermscope evaluation. The goal is to ultimately publish these findings in a text that hopefully will be a standard reference used by breeders and veterinarians.

For Phase 1, samples from dogs that are representative of the 40 most common breeds recognized by the AKC are needed. In Phase 2 the remaining breeds will be looked at. In order to perform this study, the researchers believe it would be best to use show-quality dogs between 4 and 7 years old that have completed their careers in the ring and do not have to be maintained in a show coat. Dogs are preferred, but bitches are acceptable. From these animals 2mm to 6mm punch biopsies (skin samples) from the dorsal-lumbar area (the top of the pelvis) are needed as well as clipped hair. Researchers would like to get samples from six dogs per breed. Representative samples from coat variations within a breed (for example, the Dachshund with its short-, long- and wire-coated forms, etc.) are needed as well.

Money is available to defray the cost of obtaining samples. In the next several months individual breed clubs will be contacted about this study and asked for assistance. If you have questions, please contact Dr. Robert W. Dunstan, D.V.M., M.S., The Comparative Dermatology Laboratory, Texas A&M University, College of Veterinary Medicine, College Station, Texas 77843; (979) 845-2651; e-mail: rdunstan@cvm.tamu.edu.

photo caption for sidebar:

Breed-related differences in the hair coat of a Siberian Husky (A,B) and a Miniature Poodle (C,D) as assessed using the dermscope (A,C) and horizontal sectioning of a skin biopsy (B,D). In these pictures it can be seen how the dermscope mimics the histologic sections. Note that the Husky has a much denser coat with a greater difference in diameters between guard hairs (the largest hair shafts) and the undercoat than the Miniature Poodle. Eventually it is hoped that these techniques and others can be applied to define hair growth in different canine breeds. Courtesy of professor robert dunstan, Ph.D., Texas A&M University

References
1. K.M. Credille, C.J. Lupton, R.A. Kennis, R.L. Maier, J. Dziezyc, S. Castle, G.A. Reinhart, G.M. Davenport, and R.W. Dunstan, “The Role of Nutrition on the Canine Hair Follicle: A Preliminary Report,” in G.A. Reinhart and D.P. Carey (eds)., Recent Advances in Canine and Feline Nutrition, Vol. III, Orange Frazer Press, Wilmington, Ohio, 2000, pp. 37-54.
2. V.A Randall, M.J. Thornton, A.G. Messenger, N.A. Hibberts, A.S. Loudon, and B.R. Brinklow, “Hormones and Hair Growth: Variations in Androgen Receptor Content of Dermal Papilla Cells Cultured from Human and Red Deer (Cervus elaphus) Hair Follicles,” Journal of Investigative Dermatology, Vol. 101, July 1993, pp. 114S-120S.
3. F.J.G. Ebling, P.A. Hale, and V.A. Randall, “Hormone and Hair Growth,” in L.A. Goldsmith (ed.), Physiology, Biochemistry and Molecular Biology of the Skin, Oxford University Press, New York, 1991, pp. 660-696.
4. Ibid.
5. R.E. Chapman and J.M. Bassett, “The Effects of Prolonged Administration of Cortisol on the Skin of Sheep on Different Planes of Nutrition,” Journal of Endocrinology, Vol. 48, No. 4, December 1970, pp. 649-663.
6. B. Johnston and J. Rose, “Role of Prolactin in Regulating the Onset of Winter Fur Growth in Mink (Mustela vison): A Reconsideration,” Journal of Experimental Zoology, Vol. 284, No. 4, September 1, 1991, pp. 437-444.
7. C. Sandoval, M.E. Fonseca, and R. Ochoa, “The Transcendence of Prolactin and Its Relation to the Immune Response,” Ginecologia y Obstetricia de Mexico, Vol. 65, No. 4, April 1997, pp. 148-151.
8. J.J. Bond, P.C. Wynn, and G. Moore, “Effects of Epidermal Growth Factor and Transforming Growth Factor Alpha on the Function of Wool Follicles in Culture,” Archives of Dermatology, Vol. 288, No. 7, pp. 373-382.
9. Hugh Galbraith, "Nutritional and Hormonal Regulation of Hair Follicle Growth and Development," Proceedings of the Nutrition Society, Vol. 57, 1998, pp. 195-205.
10. E.L. Sherertz and L.A. Goldsmith, “Nutritional Influence on the Skin,” in L.A. Goldsmith (ed.), Physiology, Biochemistry and Molecular Biology of the Skin, Oxford University Press, New York, 1991, pp. 1315-1328.
11. S.L. Karvonen, T. Korkiamaki, H. Yla-Outinen, et al., “Psoriasis and Altered Calcium Metabolism: Downregulated Capacitive Calcium Influx and Defective Calcium-Mediated Cell Signaling in Cultured Psoriatic Keratinocytes,” Journal of Investigative Dermatology, Vol. 114, No. 4, April 2000, pp. 693-700.
12. Galbraith.
13. S. Colombini and R.W. Dunstan, “Zinc-Responsive Dermatosis in Northern-Breed Dogs: 17 Cases (1990-1996),” Journal of the American Veterinary Medical Association, Vol. 211, No. 4, August 15, 1997, pp. 451-453.