Candida albicans, the decline of testosterone levels, and age-related changes seen in andropause Matthew L. Cavaiola, NMD, LAc
As the baby boomer population continues to age, increasing numbers of men, especially those aged between 40 and 70 years, are experiencing symptoms of the aging process. The noticeable changes that men undergo during this phase of their lives have been coined andropause or male menopause. Symptoms that men commonly experience during andropause include fatigue, lowered libido, erectile dysfunction, loss of muscle mass, weight gain, musculoskeletal pain, prostate and urinary changes, and mood alterations like anxiety, depression, and insomnia.
Although the adrenal and thyroid glands are undoubtedly important when it comes to maintaining vitality throughout the aging process, the decline in function of testes and their main hormone product, testosterone, primarily contributes to the aforementioned symptoms. The decline in testosterone levels occurs insidiously beginning at around age 35 years and is commonly believed to decrease each year by 1% to 1.5%.
A multitude of factors can contribute to the hormonal imbalances seen in aging men. These include poor diet, lack of exercise, sleep irregularities, emotional stress, smoking, alcohol consumption, vitamin and mineral deficiencies, dyslipidemia, pharmaceutical drug use, gastrointestinal health, and environmental toxicity. Although each of these factors can certainly affect hormone levels at an individual level, it is often the cumulative effects of multiple factors over the course of a lifetime that ultimately will cause earlier cessation of testosterone production and more drastic symptoms associated with the aging process.
Candida albicans is an opportunistic pathogen that has been implicated by those in the naturopathic medical community as an etiological factor in the development of a host of chronic conditions. These diseases include fibromyalgia, chronic fatigue syndrome, autism, irritable bowel syndrome, eczema and atopic dermatitis, leaky gut syndrome, Crohn’s disease, ulcerative colitis, and celiac disease, just to name a few. The objective of this article is to elucidate whether (and if so how) C albicans is involved in the decline of testosterone levels and the age-related changes seen in andropause.
Male Sex Hormone Production
The hypothalamus synthesizes and releases gonadotropin-releasing hormone and secretes it every 90 to 120 minutes, when it binds to and causes the anterior pituitary gland to release luteinizing hormone and, to a lesser extent, follicle-stimulating hormone into the general circulation. Luteinizing hormone is taken up by Leydig cells of the testicle, which ultimately results in the secretion of androgens, including testosterone and small amounts of dihydrotestosterone (DHT), androstenedione, estradiol, estrone, pregnenolone, progesterone, 17-α-hydroxypregnenolone, and 17-α-hydroxyprogesterone.1
More than 95% of testosterone comes directly from Leydig cells in testes. Dihydrotestosterone and estrogen are secreted not only directly by Leydig cells but also by direct conversion in peripheral tissues from androgens and estrogen. About 80% of circulating concentrations of these 2 steroids is derived from peripheral conversion. These 2 hormones have been linked to many of the symptoms and concomitant illnesses associated with the aging process, including benign prostatic hypertrophy and male pattern baldness.
While circulating in the bloodstream, androgens and estrogen are in a free (unbound) state or are bound to carrier proteins like albumin and sex hormone–binding globulin (SHBG). About 38% of testosterone is bound to the carrier protein albumin, and another 60% is bound to SHBG. The remaining 2% of circulating free testosterone is not bound to serum proteins and is able to enter cells and exert its metabolic effects very rapidly. Testosterone that is bound to carrier proteins can also dissociate from these proteins and enter target cells. Therefore, the amount of free, or “bioavailable,” testosterone (free testosterone and testosterone bound to albumin) may actually be greater than just the amount of non–protein-bound hormone.
A cell surface receptor for SHBG has been functionally identified in several tissues, including prostate, testes, breast, and liver.2 Sex hormone–binding globulin is being recognized as an important factor in age-related changes in men, such as benign prostatic hypertrophy and andropause. Because there is an SHBG receptor on prostate cells, this allows SHBG to deliver the steroids it is carrying to the prostate cell. Although DHT has the highest affinity for SHBG of any substance, most steroids delivered to the prostate are testosterone and estrogen.3
Once testosterone leaves the circulation and enters the androgen target cell, it has the following multiple fates: (1) Testosterone may be enzymatically converted to the more potent DHT by the enzyme 5-α-reductase. Dihydrotestosterone can bind to an androgen receptor and then be translocated into the nucleus, where it can be transcribed into messenger RNA, direct new protein synthesis, and exact its androgen action in the body. (2) Testosterone may directly bind to the androgen receptor and go through a process similar to that described for DHT. (3) Testosterone may be enzymatically converted into estrogen through the action of the enzyme aromatase. Once converted into estrogen, estrogen binding to an estrogen-specific receptor leads to a similar translocation into the nucleus, with transcription, DNA, and estrogen activity in the body.1
Background on C albicans
Candida albicans is a dimorphic fungi that has been considered a normal inhabitant of the human skin, mouth, vagina, and gastrointestinal tract. Infections of this yeast, which can change shape and take the form of hyphae, occur when competing bacterial flora are eliminated by systemic antibacterial drugs or when patients are immunocompromised (due to leukemia, AIDS, chemotherapy, radiation therapy, or treatment with immunosuppressive drugs), are using systemic corticosteroids, or have other conditions recognized as risk factors for developing candidal infections, including diabetes mellitus and alcoholism.4 Many studies have demonstrated a positive connection between gastrointestinal candidiasis and recurrent vulvovaginal infections, and it is now clear that C albicans may cross the intact gastrointestinal wall and cause systemic effects in nonimmunocompromised humans.
Although there is a paucity of literature demonstrating the ability of C albicans to invade the epithelium of prostate tissue and aid in the pathogenesis of chronic prostatitis, many physicians in the naturopathic community are suggesting that C albicans is more than likely a major cause of chronic nonbacterial prostatitis. It is important to note the relative embryological similarities between the prostate in men and the vagina in women. Stemming from tissue that is endodermal in origin, both the prostate gland and the lower one-third of the vagina develop from the pelvic portion of the urogenital sinus at about 10 to 12 weeks’ gestation.5,6 Because these 2 tissues are embryologically similar, it is not surprising that opportunistic species like C albicans and other pathogens would be able to invade and colonize the prostate as easily as the vagina.
Many researchers are now linking C albicans to illnesses associated with hormonal imbalance. Candida has an estrogen-binding protein that displays high affinity for estradiol and estrone and a corticosteroid-binding protein that exhibits high affinity for corticosterone and progesterone.7 When exposed to the host hormone, direct physiological responses have been elicited. Estradiol directly stimulates dimorphic transition from the yeast to the hyphal form. Because the hyphal form is associated with tissue invasion, this may increase the virulence of C albicans. Therefore, the hormonal environment of the host may affect the growth, infectivity, and pathogenicity of this yeast.
Theoretical Basis for the Role of C albicans in Hormonal Imbalance
As of this writing, I am aware of no articles or studies that directly discuss the role that C albicans may have during the aging process seen in andropausal men. Similarly, a direct correlation between C albicans and lower testosterone levels has not been established. One research team has shown significantly lower serum testosterone levels in men with dermatophytosis due to Epidermophyton floccosum and Trichophyton rubrum compared with healthy control subjects.8
The symptoms most often seen during andropause may be in part due to the balance of the sex hormones shifting away from testosterone and toward testosterone by-products, including DHT and estrogen. During this time in a man’s life, typically both the total and free portions of testosterone levels decline. Owing to years of exposure to environmental xenoestrogens and the increased rate of aromatization of testosterone to estrogen that typically occurs with age, along with the fact that estrogen strongly increases SHBG levels by 5- to 10-fold,3 it would seem likely that there would be more estrogen bioavailable to target cells, including the prostate gland.
Aromatization of testosterone occurs throughout the body and primarily occurs in adipose tissue. Greater aromatase activity can lead to an increase in body fat mass, especially subcutaneous abdominal fat. Compounding this fact is that subcutaneous adipose tissue acts as a secretory gland, often producing and emitting excessive levels of estrogen into an aging man’s bloodstream. It is well known that abdominal fat mass may predispose a man to developing a constellation of degenerative disorders, including heart disease, diabetes, and cancer. Other symptoms of estrogen dominance, which correspond to those seen in testosterone deficiency, include abdominal weight deposition, loss of muscle mass, gynecomastia, fatigue, and emotional disturbances.
Because C albicans is able to penetrate the epithelial wall of the prostate gland and likely other tissues to colonize these areas, it is plausible that, with higher levels of estrogen found in these tissues, this could lead to increased estrogen binding to receptor sites on Candida and to a greater likelihood of prostate-related symptoms seen in andropause. The rise in estrogen levels and the drop in testosterone levels seen bodywide are more concentrated in the prostate gland, a major site of aromatization and conversion of testosterone into DHT. Symptoms that may result from this conversion process and that are associated with benign prostatic hypertrophy include difficulty in initiating and stopping the urine stream, dribbling, greater frequency of urination, nocturia, and the need to strain during urination.3
More research concerning testosterone levels in men with overgrowth of Candida is necessary to firmly establish a causal link. Judging from preliminary data collected from patients in my clinical practice, Candida antibody levels as measured by an IgG food intolerance panel seem to have some connection to male patients who have been experiencing symptoms of andropause and a host of other chronic illnesses for years.
These antibody levels are perhaps more indicative of past exposure to Candida and not necessarily due to current overgrowth. However, using an organic acid test, a practitioner can obtain a great snapshot of the bioterrain located in the gastrointestinal tract. This test can give clues not only about the nature of the overgrowth of Candida and other pathogenic microorganisms but also about their toxic metabolites, including oxalates. Notably, research has shown that the prostate gland is as susceptible to forming oxalate stones as other tissues that form these stones, including kidneys, bones, joints, lungs, and brain, and high oxalates and their stone formation have been linked to an overgrowth of C albicans in the gastrointestinal tract.9 Serum hormone levels, including total and free testosterone, fractionated estrogens, DHT, cortisol, dehydroepiandrosterone sulfate, and progesterone, should be measured to determine the correlation between these hormone levels and the resultant data from IgG Candida antibody or organic acid testing.
Matthew L. Cavaiola, NMD, LAc is a naturopathic medical doctor and licensed acupuncturist in Arizona. Before graduating from Southwest College of Naturopathic Medicine (SCNM), Tempe, Arizona, he received his bachelor of arts degree in biological sciences and a master of science degree in human nutrition from the University of Delaware, Newark. He became so enthralled with acupuncture while attending SCNM that he went on to earn his master of science degree in acupuncture from the Phoenix Institute of Herbal Medicine and Acupuncture, Phoenix, Arizona. Dr Cavaiola is passionate about treating many chronic conditions associated with the aging process at the Phoenix Anti-Aging Clinic. He specializes in treatment of chronic illness, hormone balancing, clinical nutrition, weight loss, and acupuncture and recently acquired a hyperbaric oxygen chamber to provide a great healing modality to his private practice. Dr Cavaiola also enjoys supervising medical students at the monthly Men’s Wellness Clinics at SCNM and is an adjunct professor at Rio Salado College, Tempe, where he teaches anatomy and physiology and introduction to human nutrition.
References
1. Greenspan FS, Gardner DG. Basic and Clinical Endocrinology. 7th ed. New York, NY: McGraw-Hill Companies; 2004.
2. Heinlein CA, Chang C. The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Mol Endocrinol. 2002;16(10):2181-2187.
3. Yarnell E. Naturopathic Urology and Men’s Health. Wenatchee, WA: Healing Mountain Publishing; 2001.
4. Birdsall TC. Gastrointestinal candidiasis: fact or fiction? Alt Med Rev. 1997;2(5):346-354.
5. Drews U, Sulak O, Schneck PA. Androgens and the development of the vagina. Biol Reprod. 2002;67:1353-1359.
6. Gillenwater JY, Grayhack JT, Howards SS, Mitchell ME. Adult and Pediatric Urology. 4th ed. Vol 2. Philadelphia, PA: Lippincott Williams & Wilkins; 2002.
7. Madani ND, Malloy PJ, Rodriguez-Pombo P, Krishnan AV, Feldman D. Candida albicans estrogen-binding protein gene encodes an oxidoreductase that is inhibited by estradiol. Proc Natl Acad Sci U S A. 1994;91(3):922-926.
8. Hashemi SJ, Sarasgani MR, Zomorodian K. A comparative study of serum androgenic hormones levels between male patients with dermatophytosis and normal subjects. Jpn J Infect Dis. 2004;57(2):60-62.
9. Narayan S, Mongha R, Kundu AK. Gross calcification within the prostate gland and its significance and treatment. Indian J Surg. 2008;70(4):203-204
As the baby boomer population continues to age, increasing numbers of men, especially those aged between 40 and 70 years, are experiencing symptoms of the aging process. The noticeable changes that men undergo during this phase of their lives have been coined andropause or male menopause. Symptoms that men commonly experience during andropause include fatigue, lowered libido, erectile dysfunction, loss of muscle mass, weight gain, musculoskeletal pain, prostate and urinary changes, and mood alterations like anxiety, depression, and insomnia.
Although the adrenal and thyroid glands are undoubtedly important when it comes to maintaining vitality throughout the aging process, the decline in function of testes and their main hormone product, testosterone, primarily contributes to the aforementioned symptoms. The decline in testosterone levels occurs insidiously beginning at around age 35 years and is commonly believed to decrease each year by 1% to 1.5%.
A multitude of factors can contribute to the hormonal imbalances seen in aging men. These include poor diet, lack of exercise, sleep irregularities, emotional stress, smoking, alcohol consumption, vitamin and mineral deficiencies, dyslipidemia, pharmaceutical drug use, gastrointestinal health, and environmental toxicity. Although each of these factors can certainly affect hormone levels at an individual level, it is often the cumulative effects of multiple factors over the course of a lifetime that ultimately will cause earlier cessation of testosterone production and more drastic symptoms associated with the aging process.
Candida albicans is an opportunistic pathogen that has been implicated by those in the naturopathic medical community as an etiological factor in the development of a host of chronic conditions. These diseases include fibromyalgia, chronic fatigue syndrome, autism, irritable bowel syndrome, eczema and atopic dermatitis, leaky gut syndrome, Crohn’s disease, ulcerative colitis, and celiac disease, just to name a few. The objective of this article is to elucidate whether (and if so how) C albicans is involved in the decline of testosterone levels and the age-related changes seen in andropause.
Male Sex Hormone Production
The hypothalamus synthesizes and releases gonadotropin-releasing hormone and secretes it every 90 to 120 minutes, when it binds to and causes the anterior pituitary gland to release luteinizing hormone and, to a lesser extent, follicle-stimulating hormone into the general circulation. Luteinizing hormone is taken up by Leydig cells of the testicle, which ultimately results in the secretion of androgens, including testosterone and small amounts of dihydrotestosterone (DHT), androstenedione, estradiol, estrone, pregnenolone, progesterone, 17-α-hydroxypregnenolone, and 17-α-hydroxyprogesterone.1
More than 95% of testosterone comes directly from Leydig cells in testes. Dihydrotestosterone and estrogen are secreted not only directly by Leydig cells but also by direct conversion in peripheral tissues from androgens and estrogen. About 80% of circulating concentrations of these 2 steroids is derived from peripheral conversion. These 2 hormones have been linked to many of the symptoms and concomitant illnesses associated with the aging process, including benign prostatic hypertrophy and male pattern baldness.
While circulating in the bloodstream, androgens and estrogen are in a free (unbound) state or are bound to carrier proteins like albumin and sex hormone–binding globulin (SHBG). About 38% of testosterone is bound to the carrier protein albumin, and another 60% is bound to SHBG. The remaining 2% of circulating free testosterone is not bound to serum proteins and is able to enter cells and exert its metabolic effects very rapidly. Testosterone that is bound to carrier proteins can also dissociate from these proteins and enter target cells. Therefore, the amount of free, or “bioavailable,” testosterone (free testosterone and testosterone bound to albumin) may actually be greater than just the amount of non–protein-bound hormone.
A cell surface receptor for SHBG has been functionally identified in several tissues, including prostate, testes, breast, and liver.2 Sex hormone–binding globulin is being recognized as an important factor in age-related changes in men, such as benign prostatic hypertrophy and andropause. Because there is an SHBG receptor on prostate cells, this allows SHBG to deliver the steroids it is carrying to the prostate cell. Although DHT has the highest affinity for SHBG of any substance, most steroids delivered to the prostate are testosterone and estrogen.3
Once testosterone leaves the circulation and enters the androgen target cell, it has the following multiple fates: (1) Testosterone may be enzymatically converted to the more potent DHT by the enzyme 5-α-reductase. Dihydrotestosterone can bind to an androgen receptor and then be translocated into the nucleus, where it can be transcribed into messenger RNA, direct new protein synthesis, and exact its androgen action in the body. (2) Testosterone may directly bind to the androgen receptor and go through a process similar to that described for DHT. (3) Testosterone may be enzymatically converted into estrogen through the action of the enzyme aromatase. Once converted into estrogen, estrogen binding to an estrogen-specific receptor leads to a similar translocation into the nucleus, with transcription, DNA, and estrogen activity in the body.1
Background on C albicans
Candida albicans is a dimorphic fungi that has been considered a normal inhabitant of the human skin, mouth, vagina, and gastrointestinal tract. Infections of this yeast, which can change shape and take the form of hyphae, occur when competing bacterial flora are eliminated by systemic antibacterial drugs or when patients are immunocompromised (due to leukemia, AIDS, chemotherapy, radiation therapy, or treatment with immunosuppressive drugs), are using systemic corticosteroids, or have other conditions recognized as risk factors for developing candidal infections, including diabetes mellitus and alcoholism.4 Many studies have demonstrated a positive connection between gastrointestinal candidiasis and recurrent vulvovaginal infections, and it is now clear that C albicans may cross the intact gastrointestinal wall and cause systemic effects in nonimmunocompromised humans.
Although there is a paucity of literature demonstrating the ability of C albicans to invade the epithelium of prostate tissue and aid in the pathogenesis of chronic prostatitis, many physicians in the naturopathic community are suggesting that C albicans is more than likely a major cause of chronic nonbacterial prostatitis. It is important to note the relative embryological similarities between the prostate in men and the vagina in women. Stemming from tissue that is endodermal in origin, both the prostate gland and the lower one-third of the vagina develop from the pelvic portion of the urogenital sinus at about 10 to 12 weeks’ gestation.5,6 Because these 2 tissues are embryologically similar, it is not surprising that opportunistic species like C albicans and other pathogens would be able to invade and colonize the prostate as easily as the vagina.
Many researchers are now linking C albicans to illnesses associated with hormonal imbalance. Candida has an estrogen-binding protein that displays high affinity for estradiol and estrone and a corticosteroid-binding protein that exhibits high affinity for corticosterone and progesterone.7 When exposed to the host hormone, direct physiological responses have been elicited. Estradiol directly stimulates dimorphic transition from the yeast to the hyphal form. Because the hyphal form is associated with tissue invasion, this may increase the virulence of C albicans. Therefore, the hormonal environment of the host may affect the growth, infectivity, and pathogenicity of this yeast.
Theoretical Basis for the Role of C albicans in Hormonal Imbalance
As of this writing, I am aware of no articles or studies that directly discuss the role that C albicans may have during the aging process seen in andropausal men. Similarly, a direct correlation between C albicans and lower testosterone levels has not been established. One research team has shown significantly lower serum testosterone levels in men with dermatophytosis due to Epidermophyton floccosum and Trichophyton rubrum compared with healthy control subjects.8
The symptoms most often seen during andropause may be in part due to the balance of the sex hormones shifting away from testosterone and toward testosterone by-products, including DHT and estrogen. During this time in a man’s life, typically both the total and free portions of testosterone levels decline. Owing to years of exposure to environmental xenoestrogens and the increased rate of aromatization of testosterone to estrogen that typically occurs with age, along with the fact that estrogen strongly increases SHBG levels by 5- to 10-fold,3 it would seem likely that there would be more estrogen bioavailable to target cells, including the prostate gland.
Aromatization of testosterone occurs throughout the body and primarily occurs in adipose tissue. Greater aromatase activity can lead to an increase in body fat mass, especially subcutaneous abdominal fat. Compounding this fact is that subcutaneous adipose tissue acts as a secretory gland, often producing and emitting excessive levels of estrogen into an aging man’s bloodstream. It is well known that abdominal fat mass may predispose a man to developing a constellation of degenerative disorders, including heart disease, diabetes, and cancer. Other symptoms of estrogen dominance, which correspond to those seen in testosterone deficiency, include abdominal weight deposition, loss of muscle mass, gynecomastia, fatigue, and emotional disturbances.
Because C albicans is able to penetrate the epithelial wall of the prostate gland and likely other tissues to colonize these areas, it is plausible that, with higher levels of estrogen found in these tissues, this could lead to increased estrogen binding to receptor sites on Candida and to a greater likelihood of prostate-related symptoms seen in andropause. The rise in estrogen levels and the drop in testosterone levels seen bodywide are more concentrated in the prostate gland, a major site of aromatization and conversion of testosterone into DHT. Symptoms that may result from this conversion process and that are associated with benign prostatic hypertrophy include difficulty in initiating and stopping the urine stream, dribbling, greater frequency of urination, nocturia, and the need to strain during urination.3
More research concerning testosterone levels in men with overgrowth of Candida is necessary to firmly establish a causal link. Judging from preliminary data collected from patients in my clinical practice, Candida antibody levels as measured by an IgG food intolerance panel seem to have some connection to male patients who have been experiencing symptoms of andropause and a host of other chronic illnesses for years.
These antibody levels are perhaps more indicative of past exposure to Candida and not necessarily due to current overgrowth. However, using an organic acid test, a practitioner can obtain a great snapshot of the bioterrain located in the gastrointestinal tract. This test can give clues not only about the nature of the overgrowth of Candida and other pathogenic microorganisms but also about their toxic metabolites, including oxalates. Notably, research has shown that the prostate gland is as susceptible to forming oxalate stones as other tissues that form these stones, including kidneys, bones, joints, lungs, and brain, and high oxalates and their stone formation have been linked to an overgrowth of C albicans in the gastrointestinal tract.9 Serum hormone levels, including total and free testosterone, fractionated estrogens, DHT, cortisol, dehydroepiandrosterone sulfate, and progesterone, should be measured to determine the correlation between these hormone levels and the resultant data from IgG Candida antibody or organic acid testing.
Matthew L. Cavaiola, NMD, LAc is a naturopathic medical doctor and licensed acupuncturist in Arizona. Before graduating from Southwest College of Naturopathic Medicine (SCNM), Tempe, Arizona, he received his bachelor of arts degree in biological sciences and a master of science degree in human nutrition from the University of Delaware, Newark. He became so enthralled with acupuncture while attending SCNM that he went on to earn his master of science degree in acupuncture from the Phoenix Institute of Herbal Medicine and Acupuncture, Phoenix, Arizona. Dr Cavaiola is passionate about treating many chronic conditions associated with the aging process at the Phoenix Anti-Aging Clinic. He specializes in treatment of chronic illness, hormone balancing, clinical nutrition, weight loss, and acupuncture and recently acquired a hyperbaric oxygen chamber to provide a great healing modality to his private practice. Dr Cavaiola also enjoys supervising medical students at the monthly Men’s Wellness Clinics at SCNM and is an adjunct professor at Rio Salado College, Tempe, where he teaches anatomy and physiology and introduction to human nutrition.References
1. Greenspan FS, Gardner DG. Basic and Clinical Endocrinology. 7th ed. New York, NY: McGraw-Hill Companies; 2004.
2. Heinlein CA, Chang C. The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Mol Endocrinol. 2002;16(10):2181-2187.
3. Yarnell E. Naturopathic Urology and Men’s Health. Wenatchee, WA: Healing Mountain Publishing; 2001.
4. Birdsall TC. Gastrointestinal candidiasis: fact or fiction? Alt Med Rev. 1997;2(5):346-354.
5. Drews U, Sulak O, Schneck PA. Androgens and the development of the vagina. Biol Reprod. 2002;67:1353-1359.
6. Gillenwater JY, Grayhack JT, Howards SS, Mitchell ME. Adult and Pediatric Urology. 4th ed. Vol 2. Philadelphia, PA: Lippincott Williams & Wilkins; 2002.
7. Madani ND, Malloy PJ, Rodriguez-Pombo P, Krishnan AV, Feldman D. Candida albicans estrogen-binding protein gene encodes an oxidoreductase that is inhibited by estradiol. Proc Natl Acad Sci U S A. 1994;91(3):922-926.
8. Hashemi SJ, Sarasgani MR, Zomorodian K. A comparative study of serum androgenic hormones levels between male patients with dermatophytosis and normal subjects. Jpn J Infect Dis. 2004;57(2):60-62.
9. Narayan S, Mongha R, Kundu AK. Gross calcification within the prostate gland and its significance and treatment. Indian J Surg. 2008;70(4):203-204
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