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J Thyroid Res. 2013; 2013: 124538.
Published online 2013 March 20. doi:  10.1155/2013/124538
PMCID: PMC3616354

Thyroid Hormone and Wound Healing

Abstract

Although thyroid hormone is one of the most potent stimulators of growth and metabolic rate, the potential to use thyroid hormone to treat cutaneous pathology has never been subject to rigorous investigation. A number of investigators have demonstrated intriguing therapeutic potential for topical thyroid hormone. Topical T3 has accelerated wound healing and hair growth in rodents. Topical T4 has been used to treat xerosis in humans. It is clear that the use of thyroid hormone to treat cutaneous pathology may be of large consequence and merits further study. This is a review of the literature regarding thyroid hormone action on skin along with skin manifestations of thyroid disease. The paper is intended to provide a context for recent findings of direct thyroid hormone action on cutaneous cells in vitro and in vivo which may portend the use of thyroid hormone to promote wound healing.

1. Introduction

Despite early observation of cutaneous pathology associated with thyroid disease [1, 2], research on the topic remains sparse. Direct thyroid hormone action has been demonstrated on cutaneous biology including on the epidermis, dermis, and hair. In addition, autoimmune diseases with cutaneous manifestations may be associated with thyroid dysfunction (which may be autoimmune in etiology itself).

The lack of investigation into cutaneous responses to thyroid hormone might be attributed to the fact that mostcases of thyroid disease are controlled with existing medication. However, there is a slowly evolving literature that suggests that the thyroid hormone pathway is integral to cutaneous physiology and that manipulation of the thyroid hormone pathway in skin could be used to treat cutaneous disease.

The skin manifestations of hypothyroidism have been described since the 1800s. Indeed, the observation associating hypothyroidism with the skin [1] predates the classic publication associating hypothyroidism with the thyroid [2].

Thyrotoxicosis is also associated with cutaneous manifestations [3]. Although autoimmune-associated manifestations may be specific to Graves' disease, thyrotoxicosis in general may result in skin sequelae. Starting in the 1950s, there were attempts to use parenteral and topical tri-iodothyronine (T3) to treat pretibial myxedema in Graves' patients [47]. In all cases, lesions improved with topical or intralesional steroids which ended further study of thyroid hormone action. At that time, it was noted that topical thyroxine (T4) stimulated hair growth and pigmentation in cows [8].

2. Direct Thyroid Hormone Action on Skin Tissues

Thyroid hormone action on skin is mediated through the thyroid hormone receptor (TR). The three most recognized thyroid hormone binding isoforms of TR have been found in cutaneous tissues [912] although methods used do not specifically distinguish which of the three isoforms predominates.

The predominant circulating thyroid hormone is the prohormone, T4. T4 is converted to the active thyroid hormone, T3, by intracellular thyroid hormone deiodinases [13, 14]. Two of the enzymes (D1, D2) primarily activate T4 to T3. The third enzyme, D3, converts T4 to inactive reverse T3 (rT3). Investigators have showed conversion of T4 to either T3 or rT3 in cutaneous cultures, demonstrating indirectly the presence of thyroid hormone deiodinases in skin [1517]. D3 is not expressed significantly in most peripheral tissues. However, assays of enzyme activity suggest that D3 is active in goat epidermis [18], mouse epidermis [19], and human skin in vivo [20, 21]. D2 activity has been demonstrated in cultured human fibroblasts [22]. Neither D1 nor D3 has been found to be active in the dermal fibroblasts, suggesting that D3 expression may be limited to epidermis.

In addition, investigators have identified elements of the hypothalamic-pituitary-thyroid hormone axis in human skin [2325] and have determined that thyroid hormone receptors mediate skin proliferation and inflammation along with skin response to retinoids [26, 27].

2.1. Epidermal Changes

Thyroid hormone accelerates barrier formation by increasing the activity of enzymes in the cholesterol sulfate cycle, and hypothyroidism may hinder the epidermal barrier function [28, 29]. Hypothyroidism also may affect the development of the lamellar granules (Odland bodies), which are vital in the establishment of a normal stratum corneum [30]. In vitro keratinocyte studies have shown that depletion of T3 results in elevated levels of transglutaminase (involved in the formation of the cornified envelope). Further in vitro analysis has suggested that T3 depleted keratinocytes have diminished levels of plasminogen activator [31].

In tissue culture studies, T3 has been shown to directly stimulate proliferation of both epidermal keratinocytes and dermal fibroblasts [3234]. However, in vivo, skin proliferation directly stimulated by T3 may be offset by inhibiting factors dependent on the systemic T3 [33]. Clinical observations of skin in thyrotoxic patients are complicated by the fact that most cases of thyrotoxicosis are the result of Graves' disease which has an associated finding of autoimmune-mediated glycosaminoglycan deposition in the dermis [35].

2.2. Dermal Changes

The skin tends to be pale in hypothyroidism both because of the dermal mucopolysaccharides and the dermal water content. Changes in hypothyroid dermis can be seen in weeks and reversed in weeks [36, 37]. Hyaluronic acid is the major glycosaminoglycan that accumulates in myxedema [38]. In addition, lack of lymphatic drainage may explain the formation of exudates that are apparent in the myxedematous state [39]. Increased dermal carotene may appear as a yellow hue on the palms, soles, and nasolabial folds. In vitro, thyroid hormone actions on cultured skin fibroblasts include inhibiting synthesis of hyaluronic acid, fibronectin, and collagen [4042].

The net effect of thyroid hormone on dermal thickness remains the subject of debate. In the past, investigators have reported skin thinning in rats made thyrotoxic with intraperitoneal (IP) T4 [43]. There have been demonstrations both of decreased collagen production in the thyrotoxic animals and increased collagen catabolism in thyrotoxic animals [43, 44]. More recent investigations suggest increased dermal thickness in mice treated with T3, whether topically or intraperitoneally [32, 33]. There is also a report of increased dermal thickness in mice treated topically with TRIAC (a thyroid hormone analog [45]).

2.3. Hair and Nail Changes

Hale and Ebling demonstrated that intraperitoneal T4 decreased both the resting phase of the hair growth cycle (telogen) and the growth phase of the hair growth cycle (anagen). Although there was an enhanced turnover, the net hair length at any given time was not changed from that of untreated animals [46]. The time to regrowth of hair following epilation was shortened by approximately 10%.

In hypothyroidism, hair can be dry, coarse, brittle, and slow growing. Nails may be thickened, brittle, and slow growing [47]. Diffuse or partial alopecia may be observed along with loss of the lateral third of the eyebrow (madarosis). The alopecia connected to hypothyroidism may be mediated by hormone effects on the initiation as well as the duration of hair growth. There is one report of long, terminal hairs on the backs and extremities of hypothyroid children [48]. The hair disappeared following thyroid hormone replacement, but no mechanism was determined.

Clinically, the hair in thyrotoxicosis may be fine and soft. Nail changes may also occur, characterized by a concave contour and distal onycholysis (Plummer's nails). Diffuse, nonscarring alopecia may also be observed.

Like with epidermal proliferation, hair changes with thyrotoxicosis are different than what might be seen with topically administered thyroid hormone. Mice and rats treated daily for 1-2 weeks with topical T3 had increased hair counts, but mice made thyrotoxic with daily intraperitoneal T3 for 1-2 weeks had decreased hair counts [33, 44]. Thyrotoxic goats had increased mohair length but decreased fiber diameter [49]. A topical mixture including thyroxine, insulin, and growth hormone increased hair counts over a 6-month treatment period in men with androgenic alopecia [50].

The dryness of hypothyroid skin results from decreased eccrine gland secretion. The mechanism for decreased sweating is not clear although the glands are atrophic on histologic examination [51]. Hypothyroidism has been reported to be a cause of increased sweat electrolytes, requiring differentiation from cystic fibrosis [52].

Hypothyroid patients may sometimes suffer Candida folliculitis. It has been theorized that this may result from decrease sebum production relative to euthyroid persons. The hair follicles may develop a flora with fewer lipophilic organisms, which are replaced by Candida albicans [53].

3. Potential Use of Thyroid Hormone in the Treatment of Cutaneous Pathology

Knowledge of cutaneous manifestations of thyrotoxicosis does not predict the direct effects of T3 on skin in vivo. T3 effects on skin depend on route of delivery. Because epidermis expresses the inactivating type 3 deiodinase [19], thyroid hormone action on epidermis in systemic thyrotoxicosis is less than might be predicted. In contrast to the findings with systemic thyrotoxicosis, topical T3 bypasses the inactivating type 3 deiodinase and stimulates epidermal proliferation, dermal thickening, and hair growth [32, 33]. Topical application of TRIAC (tri-iodothyroacetic acid), the thyroid hormone analog, thickens skin by stimulating production of collagen [45]. Further, topical TRIAC has been shown to reverse the dermal atrophy associated with corticosteroids.

The importance of thyroid hormone in wound healing had been debated historically. In 1973 and 1974, Mehregan and Zamick reported that oral T3 accelerated the rate of wound healing in euthyroid rats and improved the quality of the wounds [54, 55]. Scars were smoother in T3-treated animals. Lennox and Johnston reported accelerated wound healing and increased tensile strength when rats were given supraphysiologic doses of T4 [56]. Pirk et al. reported no change in wound healing with 1.3 μg/100 mg body weight intraperitoneal T4 in hamsters but increased rate of fracture repair [57]. Ashton and Dekel also reported increased fracture repair rate in mice given 20 μg/100 mg body weight subcutaneous T4 [58]. In small series, there are reports that hypothyroid patients required thyroid hormone to achieve healing of radiation-induced neck fistulae [59, 60]. Conversely, Cannon [61] reported that hypothyroidism did not diminish wound strength in pigs, and Ladenson et al. [62] did not detect wound healing deficits in hypothyroid humans.

In contrast, most recent data suggest that topical thyroid hormone may accelerate wound healing rate. Topical application of supraphysiological doses of T3 accelerated wound healing in normal mice and rats [6365]. A human wound healing formulation has been described that requires T4 in addition to growth hormone and insulin [66].

While direct thyroid hormone action has been demonstrated on cutaneous cell biology, much more study remains to be done. There is a slowly evolving literature to suggest an important role for thyroid hormone in cutaneous wound repair that could be harnessed as a pharmaceutical.

Conflict of Interests

The author has no conflict of interests relating to this paper.

References

1. Ord WM. On myxoedema, term proposed to be applied to an essential condition in the “cretinoid” affection occasionally observed in middle-aged women. Medico-Chirurgical Transactions. 1878;61:57–78. [PMC free article] [PubMed]
2. Horsley V. The thyroid gland: its relation to the pathology of myxoedema and cretinism, to the question of surgical treatment of goitre, an to the general nutrition of the body. British Medical Journal. 1885;1:111–115. [PMC free article] [PubMed]
3. Abulkadir J, Besrat A, Abraham G, et al. Thyrotoxicosis in Ethiopian patients-a prospective study. Transactions of the Royal society of Tropical Medicine and Hygiene. 1982;76:500–502. [PubMed]
4. Warthin TA, Boshell BB. Pretibial myxedema; treated with local injection of triiodothyronine. American Medical Association Archives of Internal Medicine. 1957;100(2):319–321. [PubMed]
5. Gabrilove JL, Alavarez AS, Churg J. Generalized and localized (pretibial) myxedema: effect of thyroid analogues and adrenal glucocorticoids. The Journal of Clinical Endocrinology and Metabolism. 1960;20:825–832. [PubMed]
6. Gimlette TMD. Pretibial myxoedema. British Medical Journal. 1960;2(5195):348–351. [PMC free article] [PubMed]
7. Cohen BD, Benua RS, Rawson RW. Localized myxedema involving the upper extremities. Archives of Internal Medicine. 1963;111:641–646. [PubMed]
8. Berman A. Peripheral effects of L-thyroxine on hair growth and coloration in cattle. Journal of Endocrinology. 1960;20:288–292.
9. Ahsan MK, Urano Y, Kato S, Oura H, Arase S. Immunohistochemical localization of thyroid hormone nuclear receptors in human hair follicles and in vitro effect of L-triiodothyronine on cultured cells of hair follicles and skin. Journal of Medical Investigation. 1998;44(3-4):179–184. [PubMed]
10. Torma H, Rollman O, Vahlquist A. Detection of mRNA transcripts for retinoic acid, vitamin D3, and thyroid hormone (c-erb-A) nuclear receptors in human skin using reverse transcription and polymerase chain reaction. Acta Dermato-Venereologica. 1993;73(2):102–107. [PubMed]
11. Billoni N, Buan B, Gautier B, Gaillard O, Mahé YF, Bernard BA. Thyroid hormone receptor β1 is expressed in the human hair follicle. British Journal of Dermatology. 2000;142(4):645–652. [PubMed]
12. Törmä H, Karlsson T, Michaëlsson G, Rollman O, Vahlquist A. Decreased mRNA levels of retinoic acid receptor α, retinoid X receptor α and thyroid hormone receptor α in lesional psoriatic skin. Acta Dermato-Venereologica. 2000;80(1):4–9. [PubMed]
13. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocrine Reviews. 2002;23(1):38–89. [PubMed]
14. Bianco AC, Kim BW. Deiodinases: implications of the local control of thyroid hormone action. The Journal of Clinical Investigation. 2006;116(10):2571–2579. [PMC free article] [PubMed]
15. Refetoff S, Matalon R, Bigazzi M. Metabolism of L-thyroxine (T4) and L-triiodothyronine (T3) by human fibroblasts in tissue culture: evidence for cellular binding proteins and conversion of T4 to T3. Endocrinology. 1972;91(4):934–947. [PubMed]
16. Huang TS, Chopra IJ, Beredo A, Solomon DH, Chua Teco GN. Skin is an active site for the inner ring monodeiodination of thyroxine to 3,3′,5′-triiodothyronine. Endocrinology. 1985;117(5):2106–2113. [PubMed]
17. Kaplan MM, Pan C, Gordon PR, Lee JK, Gilchrest BA. Human epidermal keratinocytes in culture convert thyroxine to 3,5,3′-triiodothyronine by type II iodothyronine deiodination: a novel endocrine function of the skin. Journal of Clinical Endocrinology and Metabolism. 1988;66(4):815–822. [PubMed]
18. Villar D, Nicol F, Arthur JR, et al. Type II and type III monodeiodinase activities in the skin of untreated and propylthiouracil-treated cashmere goats. Research in Veterinary Science. 2000;68(2):119–123. [PubMed]
19. Huang MP, Rodgers KA, O’Mara R, et al. The thyroid hormone degrading type 3 deiodinase is the primary deiodinase active in murine epidermis. Thyroid. 2011;21:1263–1268. [PubMed]
20. Schröder-Van Der Elst JP, Van Der Heide D, De Escobar GM, Obregón MJ. Iodothyronine deiodinase activities in fetal rat tissues at several levels of iodine deficiency: a role for the skin in 3,5,3′-triiodothyronine economy? Endocrinology. 1998;139(5):2229–2234. [PubMed]
21. Santini F, Vitti P, Chiovato L, et al. Role for inner ring deiodination preventing transcutaneous passage of thyroxine. Journal of Clinical Endocrinology and Metabolism. 2003;88(6):2825–2830. [PubMed]
22. Dumitrescu AM, Liao XH, Abdullah MSY, et al. Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Nature Genetics. 2005;37(11):1247–1252. [PubMed]
23. Slominski A, Wortsman J, Kohn L, et al. Expression of hypothalamic-pituitary-thyroid axis related genes in the human skin. Journal of Investigative Dermatology. 2002;119(6):1449–1455. [PMC free article] [PubMed]
24. Bodó E, Kany B, Gáspár E, et al. Thyroid-stimulating hormone, a novel, locally produced modulator of human epidermal functions, is regulated by thyrotropin-releasing hormone and thyroid hormones. Endocrinology. 2010;151(4):1633–1642. [PubMed]
25. Paus R. Exploring the “thyroid-skin connection” : concepts, questions, and clinical relevance. Journal of Investigative Dermatology. 2010;130:93–101. [PubMed]
26. Contreras-Jurado C, García-Serrano L, Gómez-Ferrería M, Costa C, Paramio JM, Aranda A. The thyroid hormone receptors as modulators of skin proliferation and inflammation. The Journal of Biological Chemistry. 2011;286(27):24079–24088. [PubMed]
27. Garcia-Serrano L, Gomez-Ferreria MA, Contrera-Jurado C, Segrelles C, Paramio JM, Aranda A. The thyroid hormone receptors modulate the skin response to retinoids. PLoS ONE. 2011;6e23825 [PMC free article] [PubMed]
28. Rosenberg RM, Isseroff RR, Ziboh VA, Huntley AC. Abnormal lipogenesis in thyroid hormone-deficient epidermis. Journal of Investigative Dermatology. 1986;86(3):244–248. [PubMed]
29. Hanley K, Jiang Y, Katagiri C, Feingold KR, Williams ML. Epidermal steroid sulfatase and cholesterol sulfotransferase are regulated during late gestation in the fetal rat. Journal of Investigative Dermatology. 1997;108(6):871–875. [PubMed]
30. Hanley K, Devaskar UP, Hicks SJ, et al. Hypothyroidism delays fetal stratum corneum development in mice. Pediatric Research. 1997;42(5):610–614. [PubMed]
31. Isseroff RR, Chun KT, Rosenberg RM. Triiodothyronine alters the cornification of cultured human keratinocytes. British Journal of Dermatology. 1989;120(4):503–510. [PubMed]
32. Safer JD, Fraser LM, Ray S, Holick MF. Topical triiodothyronine stimulates epidermal proliferation, dermal thickening, and hair growth in mice and rats. Thyroid. 2001;11(8):717–724. [PubMed]
33. Safer JD, Crawford TM, Fraser LM, et al. Thyroid hormone action on skin: diverging effects of topical versus intraperitoneal administration. Thyroid. 2003;13(2):159–165. [PubMed]
34. Holt PJA. In vitro responses of the epidermis to triiodothyronine. Journal of Investigative Dermatology. 1978;71(3):202–204. [PubMed]
35. Holt PJA, Marks R. The epidermal response to change in thyroid status. Journal of Investigative Dermatology. 1977;68(5):299–301. [PubMed]
36. Reuter MJ. Histopathology of the skin in myxedema. Archives of Dermatology and Syphilology. 1931;24:55–71.
37. Gabrilove JL, Ludwig AW. The histogenesis of myxedema. The Journal of Clinical Endocrinology and Metabolism. 1957;17(8):925–932. [PubMed]
38. Smith TJ, Bahn RS, Gorman CA. Connective tissue, glycosaminoglycans, and diseases of the thyroid. Endocrine Reviews. 1989;10(3):366–391. [PubMed]
39. Parving HH, Hansen JM, Nielsen SL. Mechanisms of edema formation in myxedema—increased protein extravasation and relatively slow lymphatic drainage. The New England Journal of Medicine. 1979;301(9):460–465. [PubMed]
40. Smith TJ, Murata Y, Horwitz AL, Philipson L, Refetoff S. Regulation of glycosaminoglycan synthesis by thyroid hormone in vitro. The Journal of Clinical Investigation. 1982;70(5):1066–1073. [PMC free article] [PubMed]
41. Murata Y, Ceccarelli P, Refetoff S, Horwitz AL, Matsui N. Thyroid hormone inhibits fibronectin synthesis by cultured human skin fibroblasts. Journal of Clinical Endocrinology and Metabolism. 1987;64(2):334–339. [PubMed]
42. De Rycker C, Vandalem JL, Hennen G. Effects of 3,5,3′-triiodothyronine on collagen synthesis by cultured human skin fibroblasts. FEBS Letters. 1984;174(1):34–37. [PubMed]
43. Fink CW, Ferguson JL, Smiley JD. Effect of hyperthyroidism and hypothyroidism on collagen metabolism. The Journal of Laboratory and Clinical Medicine. 1967;69(6):950–959. [PubMed]
44. Kivirikko KI, Laitinen O, Aer J, Halme J. Metabolism of collagen in experimental hyperthyroidism and hypothyroidism in the rat. Endocrinology. 1967;80(6):1051–1061. [PubMed]
45. Faergemann J, Särnhult T, Hedner E, et al. Dose-response effects of tri-iodothyroacetic acid (Triac) and other thyroid hormone analogues on glucocorticoid-induced skin atrophy in the haired mouse. Acta Dermato-Venereologica. 2002;82(3):179–183. [PubMed]
46. Hale PA, Ebling FJ. The effect of a single epilation on successive hair eruptions in normal and hormone-treated rats. Journal of Experimental Zoology. 1979;207(1):49–71. [PubMed]
47. Mullin GE, Eastern JS. Cutaneous signs of thyroid disease. American Family Physician. 1986;34(4):93–98. [PubMed]
48. Perloff WH. Hirsutism; a manifestation of juvenile hypothyroidism. Journal of the American Medical Association. 1955;157(8):651–652. [PubMed]
49. Puchala R, Prieto I, Banskalieva V, Goetsch AL, Lachica M, Sahlu T. Effects of bovine somatotropin and thyroid hormone status on hormone levels, body weight gain, and mohair fiber growth of Angora goats. Journal of Animal Science. 2001;79(11):2913–2919. [PubMed]
50. Lindenbaum ES, Feitelberg AL, Tendler M, et al. Pilot study of a novel treatment for androgenetic alopecia using enriched cell culture medium: clinical trials. Dermatology Online Journal. 2003;9, article 4 [PubMed]
51. Means MA, Dobson RL. Cytological changes in the sweat gland in hypothyroidism. Journal of the American Medical Association. 1963;186:113–115. [PubMed]
52. Squires L, Dolan TF. Abnormal sweat chloride in auto-immune hypothyroidism. Clinical Pediatrics. 1989;28(11):535–536. [PubMed]
53. Dekio S, Imaoka C, Jidoi J. Candida folliculitis associated with hypothyroidism. British Journal of Dermatology. 1987;117(5):663–664. [PubMed]
54. Zamick P, Mehregan AH. Effect of 1-tri-iodothyronine on marginal scars of skin grafted burns in rats. Plastic and Reconstructive Surgery. 1973;51(1):71–75. [PubMed]
55. Mehregan AH, Zamick P. The effect of triiodothyronine in healing of deep dermal burns and marginal scars of skin grafts. A histologic study. Journal of Cutaneous Pathology. 1974;1(3):113–116. [PubMed]
56. Lennox J, Johnston ID. The effect of thyroid status on nitrogen balance and the rate of wound healing after injury in rats. British Journal of Surgery. 1973;60(4):p. 309. [PubMed]
57. Pirk FW, El-Attar TM, Roth GD. Effect of analogues of steroid and thyroxine hormones on wound healing in hamsters. Journal of Periodontal Research. 1974;9(5):290–297. [PubMed]
58. Ashton IK, Dekel S. Fracture repair in the snell dwarf mouse. British Journal of Experimental Pathology. 1983;64(5):479–486. [PubMed]
59. Alexander MMV, Zajtchuk JT, Henderson RL. Hypothyroidism and wound healing. Occurrence after head and neck radiation and surgery. Archives of Otolaryngology. 1982;108(5):289–291. [PubMed]
60. Talmi YP, Finkelstein Y, Zohar Y. Pharyngeal fistulas in postoperative hypothyroid patients. Annals of Otology, Rhinology & Laryngology. 1989;98(4):267–268. [PubMed]
61. Cannon CR. Hypothyroidism in head and neck cancer patients: experimental and clinical observations. Laryngoscope. 1994;104(11):1–21. [PubMed]
62. Ladenson PW, Levin AA, Ridgway EC, Daniels GH. Complications of surgery in hypothyroid patients. American Journal of Medicine. 1984;77(2):261–266. [PubMed]
63. Safer JD, Crawford TM, Holick MF. Topical thyroid hormone accelerates wound healing in mice. Endocrinology. 2005;146(10):4425–4430. [PubMed]
64. Tarameshloo M, Norouzian M, Zarein-Dolob S, Dadpay M, Gazor R. A comparative study of the effects of topical application of Aloe vera, thyroid hormone and silver sulfadiazine on skin wounds in Wistar rats. Laboratory Animal Research. 2012;28:17–21. [PMC free article] [PubMed]
65. Kassem R, Liberty Z, Babaev M, Trau H, Cohen O. Harnessing the skin-thyroid connection for wound healing: a prospective controlled trial in guinea pigs. Clinical and Experimental Dermatology. 2012;37:850–856. [PubMed]
66. Lindenbaum ES, Shai YH, Ullmann Y, et al. Stimulated healing of recalcitrant wounds by topical application of enriched cell culture medium: a clinical report. Plastic and Reconstructive Surgery. 2001;108(1):104–113. [PubMed]

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