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Retained fetal adrenal cortex in a cynomolgus macaque (Macaca fascicularis) Zaher Radi a,∗ , Mark Evans b a b
Pfizer Worldwide Research and Development, Drug Safety Research and Development, 1 Burtt Road, Andover, MA 01810, USA Pfizer Worldwide Research and Development, Drug Safety Research and Development, 10646 Science Center Drive, San Diego, CA 92121, USA
a r t i c l e
i n f o
Article history: Received 8 February 2014 Accepted 29 April 2014 Keywords: Adrenal gland Cynomolgus macaque Histopathology Retained adrenal cortex Toxicology
a b s t r a c t An incidental, bilateral, retained fetal adrenal cortex was detected in a male cynomolgus macaque (age, approximately 2.4 y) used in a 4-week toxicology study. Microscopic examination of the adrenal gland cortex zone revealed the presence of additional solid sheets and columns of cells supported by vascular capillary bed and composed of large polyhedral cells with abundant eosinophilic, slightly finely vacuolated cytoplasm that surrounded the entire circumference of the medulla. Nuclei were vesicular, round to oval with prominent small nucleoli. There was no evidence for inflammation or cellular degeneration. Based on the microscopic examination, a diagnosis of retained fetal cortex of the adrenal gland was made. This morphologic change resembles fetal cortex in human infants. To our knowledge, this case description is the first report of a cynomolgus macaque with the rare entity of retained fetal cortex, which should not be misinterpreted as a test article-related change. © 2014 Elsevier GmbH. All rights reserved.
1. Introduction Generally, by light microscopy, the adrenal gland cortex of adult mammals consists of: an outermost layer, zona glomerulosa (site of the mineralocorticoid hormone [aldosterone] production), a middle layer, zona fasciculata (site of glucocorticoid hormone [cortisol] production), and an innermost layer, zona reticularis (site of steroid sex hormones [androgens, estrogens, and progestins] production) (Rosol et al., 2001). Three functionally distinct zones are present in nonhuman primate fetal adrenal cortex: (1) fetal zone, (2) transitional zone, which is the likely site of glucocorticoid synthesis, and (3) definitive zone, which is the likely site of mineralocorticoid synthesis (Mesiano and Jaffe, 1997). The fetal zone in human adrenal gland is present as a definite structure by the fourth fetal month and continues with no morphological change up to the time of birth (Brenner, 1940). There is no evidence of any sex variation in either the size or appearance of the adrenal glands in human infants (Brenner, 1940). In human infants, the weight of the adrenal glands after birth falls to about two-thirds (Brenner, 1940; Scammon, 1926) because the fetal zone, which constitutes approximately 80% of the cortex at term, rapidly involutes after birth (Brenner, 1940; Lewis
∗ Corresponding author. Tel.: +1 978 247 3981. E-mail address: Zaher.Radi@Pfizer.com (Z. Radi).
and Pappenheimer, 1916). However, there are marked individual variations in the rate of involution of the fetal cortex (Brenner, 1940). A similar involution of the fetal zone has been reported to occur in the adrenal glands of rhesus macaques (Macaca mulatta) (Lanman, 1957; McNulty et al., 1981) and marmosets (Benirschke and Richart, 1964). No cases of either fetal cortex zone or retained fetal adrenal cortex have been reported in cynomolgus monkeys (Macaca fascicularis), the most common nonhuman primate species used in toxicology studies in safety assessment of novel pharmaceutical therapeutic agents. Here we report a case of retained fetal adrenal cortex in a cynomolgus macaque used in a toxicology study. 2. Materials and methods The affected animal, a test article-dosed animal from a mid-dose group, was a 2.4-y-old, male cynomolgus macaque (M. fascicularis) from a 4-week toxicology Good Laboratory Practice (GLP) study conducted at Pfizer Worldwide Research and Development Laboratories in Groton, CT. Pfizer facility is accredited by the Association for Assessment and Accreditation of Animal Care International (AAALAC). Macaques in this study were housed in a temperatureand humidity-monitored environment. The targeted range of temperature and relative humidity was between 18 and 29 ◦ C and 30 and 70%, respectively. An automatic lighting system provided a 12h diurnal cycle. The animals were individually housed in stainless
http://dx.doi.org/10.1016/j.etp.2014.04.006 0940-2993/© 2014 Elsevier GmbH. All rights reserved.
Please cite this article in press as: Radi Z, Evans M. Retained fetal adrenal cortex in a cynomolgus macaque (Macaca fascicularis). Exp Toxicol Pathol (2014), http://dx.doi.org/10.1016/j.etp.2014.04.006
G Model ETP-50826; No. of Pages 3
ARTICLE IN PRESS Z. Radi, M. Evans / Experimental and Toxicologic Pathology xxx (2014) xxx–xxx
2
steel cages and fed daily with Purina Certified Hi-Fiber Primate Diet. Fresh drinking water was provided ad libitum to all animals. Clinical and physical examinations, body weight assessment, clinical hematology/biochemistry and urinalysis were performed periodically throughout the conduct of the study. Throughout the study, no noteworthy problems were reported in any of the monkeys on the study. At study termination, the macaque of interest was euthanatized by exsanguination after intravenous barbiturate-based anesthesia solution administration and necropsied. Multiple organs, including the adrenal glands, were collected, fixed in 10% neutral buffered formalin, routinely processed to hematoxylin and eosin (H&E) slides, and evaluated by light microscopy. 3. Results In the cynomolgus macaque we report, all of the parameters assessed during the in-life portion of the study were within normal limits. Microscopic examination of the adrenal gland cortex zone revealed that all three adult zones of glomerulosa, fascicularis, and reticularis were identified clearly. In addition, an additional layer of solid sheets and columns of cells supported by vascular capillary bed and composed of large polyhedral cells with abundant eosinophilic, slightly finely vacuolated cytoplasm that surrounded the entire circumference of the medulla was present (Fig. 1A). Nuclei were vesicular, round to oval with prominent small nucleoli (Fig. 1B). The change was bilateral and there was no evidence of inflammation or cellular degeneration. 4. Discussion In adult mammals, the outer zone of the adrenal gland, the zona glomerulosa, is composed of a thin region of columnar cells arranged in an arched pattern. This zone is also called the zona multiformis in animals because of its different patterns of arrangement of secretory cells (Rosol et al., 2001). The zona fasciculata of the adrenal gland in adult mammals is the thickest zone (approximately 70% of the cortex) and is composed of columns of secretory cells separated by prominent capillaries. The cells are polyhedral and have many intracellular lipid droplets (Rosol et al., 2001). The zona reticularis is composed of polyhedral cells, whose arrangement is less linear and more as round nests or clumps of cells. The maintenance of fetal conformation of the adrenal glands depends on a functioning fetal pituitary gland. Adrenocorticotopic hormone (ACTH) is secreted by the pituitary gland. Cells of zona fasciculata secrete cortisol under ACTH regulation (Rosol et al., 2001). During gestation in humans and nonhuman primates, there is a specialized fetal adrenal cortex (Brenner, 1940; Lewis and Pappenheimer, 1916; McNulty et al., 1981). This fetal cortex is composed of large polyhedral cells that produce abundant cortisol and estrogen precursors which are important for normal development of the fetus. The cells of the fetal cortex are produced in the outer cortex and migrate medially, where they undergo hypertrophy and eventually apoptosis (McNulty et al., 1981). After birth, there is rapid regression, apoptosis, and lysis of the fetal cortex with dilatation of cortical capillaries and replacement by the typical three cortical zones of the adrenal glands (Rosol et al., 2001). The fetal zone is present until birth in rhesus macaque (M. mulatta) and it disappears slowly after birth (McNulty et al., 1981). No cases of retained fetal adrenal cortex have been reported in cynomolgus or rhesus monkeys. It is important to distinguish the physiological replacement of the fetal cortex with the definitive postnatal adrenal cortex or the retention of fetal adrenal cortex from a test article-related change in toxicity studies.
Fig. 1. Histologic appearnce of the retained fetal adrenal cortex in a cynomolgus macaque (Macaca fascicularis). (A) All three adult zones of glomerulosa (z. G), fascicularis (z. F), and reticularis (z. R) are identified clearly. Note the presence of an additional zone of fetal adrenal cortex (F. z) composed of solid sheets and columns of cells surrounding the entire circumference of the medulla [MD] (arrows). (B) Zone of fetal adrenal cortex is supported by vascular capillary bed and composed of large polyhedral cells with abundant eosinophilic, slightly finely vacuolated cytoplasm. Nuclei were vesicular, round to oval with prominent small nucleoli. Magnification, 2× (A) and 40× (B).
Similar to what happens in human babies during the first weeks of postnatal life, rhesus macaque adrenal glands weight decrease (McNulty et al., 1981). Thus, one can translate for a similar adrenal glands changes phenomenon from rhesus to cynomolgus macaques. Although the human adrenal fetal zone is commonly believed to go through a rapid collapse with necrosis and hemorrhage, no such dramatic event occurs in rhesus macaque adrenal glands (McNulty et al., 1981). Instead, the rhesus macaque fetal zone undergoes a gradual remodeling to adult conformation over a period of months, or perhaps longer (McNulty et al., 1981). This remodeling is characterized first by the appearance of a band of small cells with little cytoplasm in the outer fetal zone, at or shortly before parturition. As the infant ages, this “dense band” is found progressively closer to the medulla. As the band appears to move centrally, mature zona fasciculata becomes recognizable outside it, while a shrinking fetal zone persists inside it. These remaining cells of the fetal zone are smaller and have less vacuolated cytoplasm than fetal-zone cells at birth, but are not necrotic. At 6 months, a central rim of fetal zone is still present (McNulty et al., 1981). The ultimate fate of the dense band is not known.
Please cite this article in press as: Radi Z, Evans M. Retained fetal adrenal cortex in a cynomolgus macaque (Macaca fascicularis). Exp Toxicol Pathol (2014), http://dx.doi.org/10.1016/j.etp.2014.04.006
G Model ETP-50826; No. of Pages 3
ARTICLE IN PRESS Z. Radi, M. Evans / Experimental and Toxicologic Pathology xxx (2014) xxx–xxx
Sucheston and Cannon (1968) did not see involution of the human fetal adrenal cortex with hemorrhage and cell loss, but rather a slow regression of the fetal zone throughout the first year. During this time, they saw little mitosis or signs of cell death, and suggested that the final structure of the adrenal cortex is slowly achieved by proliferation of the definitive cortex and a transformational process whereby fetal zone cells mature into the zona fasciculata. The exact trigger for the initiation of maturation in rhesus macaque fetal cortex remains unknown. The following hypotheses have been proposed: (1) decreasing sensitivity of the fetal cortical cells to ACTH, (2) declining release of ACTH by the late-fetal and infant pituitary, (3) withdrawal of placental adrenotropic factors or ACTH-related peptides from the fetal pituitary, and (4) withdrawal of factors inhibiting cortical maturation (McNulty et al., 1981).
3
References Benirschke K, Richart R. Observations on the fetal adrenals of marmoset monkeys. Endocrinology 1964;74:382–7. Brenner MC. Studies on the involution of the fetal cortex of the adrenal glands. Am J Pathol 1940;16:787–98. Lanman JT. The adrenal fetal zone: its occurrence in primates and a possible relationship to chorionic gonadotropin. Endocrinology 1957;61:684–91. Lewis RW, Pappenheimer AM. A study of the involutional changes which occur in the adrenal cortex during infancy. J Med Res 1916;34:81–3. McNulty WP, Novy MJ, Walsh SW. Fetal and postnatal development of the adrenal glands in Macaca mulatta. Biol Reprod 1981;25:1079–89. Mesiano S, Jaffe RB. Developmental and functional biology of the primate fetal adrenal cortex. Endocr Rev 1997;18:378–403. Rosol TJ, Yarrington JT, Latendresse J, Capen CC. Adrenal gland: structure, function, and mechanisms of toxicity. Toxicol Pathol 2001;29:41–8. Scammon RE. The prenatal growth and natal involution of the human suprarenal gland. Proc Soc Exp Biol Med 1926;26:809–11. Sucheston ME, Cannon MS. Development of zonular patterns in the human adrenal gland. J Morphol 1968;126:477–91.
Please cite this article in press as: Radi Z, Evans M. Retained fetal adrenal cortex in a cynomolgus macaque (Macaca fascicularis). Exp Toxicol Pathol (2014), http://dx.doi.org/10.1016/j.etp.2014.04.006
ARTICLE IN PRESS
ETP-50826; No. of Pages 3
Experimental and Toxicologic Pathology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Experimental and Toxicologic Pathology journal homepage: www.elsevier.de/etp
Retained fetal adrenal cortex in a cynomolgus macaque (Macaca fascicularis) Zaher Radi a,∗ , Mark Evans b a b
Pfizer Worldwide Research and Development, Drug Safety Research and Development, 1 Burtt Road, Andover, MA 01810, USA Pfizer Worldwide Research and Development, Drug Safety Research and Development, 10646 Science Center Drive, San Diego, CA 92121, USA
a r t i c l e
i n f o
Article history: Received 8 February 2014 Accepted 29 April 2014 Keywords: Adrenal gland Cynomolgus macaque Histopathology Retained adrenal cortex Toxicology
a b s t r a c t An incidental, bilateral, retained fetal adrenal cortex was detected in a male cynomolgus macaque (age, approximately 2.4 y) used in a 4-week toxicology study. Microscopic examination of the adrenal gland cortex zone revealed the presence of additional solid sheets and columns of cells supported by vascular capillary bed and composed of large polyhedral cells with abundant eosinophilic, slightly finely vacuolated cytoplasm that surrounded the entire circumference of the medulla. Nuclei were vesicular, round to oval with prominent small nucleoli. There was no evidence for inflammation or cellular degeneration. Based on the microscopic examination, a diagnosis of retained fetal cortex of the adrenal gland was made. This morphologic change resembles fetal cortex in human infants. To our knowledge, this case description is the first report of a cynomolgus macaque with the rare entity of retained fetal cortex, which should not be misinterpreted as a test article-related change. © 2014 Elsevier GmbH. All rights reserved.
1. Introduction Generally, by light microscopy, the adrenal gland cortex of adult mammals consists of: an outermost layer, zona glomerulosa (site of the mineralocorticoid hormone [aldosterone] production), a middle layer, zona fasciculata (site of glucocorticoid hormone [cortisol] production), and an innermost layer, zona reticularis (site of steroid sex hormones [androgens, estrogens, and progestins] production) (Rosol et al., 2001). Three functionally distinct zones are present in nonhuman primate fetal adrenal cortex: (1) fetal zone, (2) transitional zone, which is the likely site of glucocorticoid synthesis, and (3) definitive zone, which is the likely site of mineralocorticoid synthesis (Mesiano and Jaffe, 1997). The fetal zone in human adrenal gland is present as a definite structure by the fourth fetal month and continues with no morphological change up to the time of birth (Brenner, 1940). There is no evidence of any sex variation in either the size or appearance of the adrenal glands in human infants (Brenner, 1940). In human infants, the weight of the adrenal glands after birth falls to about two-thirds (Brenner, 1940; Scammon, 1926) because the fetal zone, which constitutes approximately 80% of the cortex at term, rapidly involutes after birth (Brenner, 1940; Lewis
∗ Corresponding author. Tel.: +1 978 247 3981. E-mail address: Zaher.Radi@Pfizer.com (Z. Radi).
and Pappenheimer, 1916). However, there are marked individual variations in the rate of involution of the fetal cortex (Brenner, 1940). A similar involution of the fetal zone has been reported to occur in the adrenal glands of rhesus macaques (Macaca mulatta) (Lanman, 1957; McNulty et al., 1981) and marmosets (Benirschke and Richart, 1964). No cases of either fetal cortex zone or retained fetal adrenal cortex have been reported in cynomolgus monkeys (Macaca fascicularis), the most common nonhuman primate species used in toxicology studies in safety assessment of novel pharmaceutical therapeutic agents. Here we report a case of retained fetal adrenal cortex in a cynomolgus macaque used in a toxicology study. 2. Materials and methods The affected animal, a test article-dosed animal from a mid-dose group, was a 2.4-y-old, male cynomolgus macaque (M. fascicularis) from a 4-week toxicology Good Laboratory Practice (GLP) study conducted at Pfizer Worldwide Research and Development Laboratories in Groton, CT. Pfizer facility is accredited by the Association for Assessment and Accreditation of Animal Care International (AAALAC). Macaques in this study were housed in a temperatureand humidity-monitored environment. The targeted range of temperature and relative humidity was between 18 and 29 ◦ C and 30 and 70%, respectively. An automatic lighting system provided a 12h diurnal cycle. The animals were individually housed in stainless
http://dx.doi.org/10.1016/j.etp.2014.04.006 0940-2993/© 2014 Elsevier GmbH. All rights reserved.
Please cite this article in press as: Radi Z, Evans M. Retained fetal adrenal cortex in a cynomolgus macaque (Macaca fascicularis). Exp Toxicol Pathol (2014), http://dx.doi.org/10.1016/j.etp.2014.04.006
G Model ETP-50826; No. of Pages 3
ARTICLE IN PRESS Z. Radi, M. Evans / Experimental and Toxicologic Pathology xxx (2014) xxx–xxx
2
steel cages and fed daily with Purina Certified Hi-Fiber Primate Diet. Fresh drinking water was provided ad libitum to all animals. Clinical and physical examinations, body weight assessment, clinical hematology/biochemistry and urinalysis were performed periodically throughout the conduct of the study. Throughout the study, no noteworthy problems were reported in any of the monkeys on the study. At study termination, the macaque of interest was euthanatized by exsanguination after intravenous barbiturate-based anesthesia solution administration and necropsied. Multiple organs, including the adrenal glands, were collected, fixed in 10% neutral buffered formalin, routinely processed to hematoxylin and eosin (H&E) slides, and evaluated by light microscopy. 3. Results In the cynomolgus macaque we report, all of the parameters assessed during the in-life portion of the study were within normal limits. Microscopic examination of the adrenal gland cortex zone revealed that all three adult zones of glomerulosa, fascicularis, and reticularis were identified clearly. In addition, an additional layer of solid sheets and columns of cells supported by vascular capillary bed and composed of large polyhedral cells with abundant eosinophilic, slightly finely vacuolated cytoplasm that surrounded the entire circumference of the medulla was present (Fig. 1A). Nuclei were vesicular, round to oval with prominent small nucleoli (Fig. 1B). The change was bilateral and there was no evidence of inflammation or cellular degeneration. 4. Discussion In adult mammals, the outer zone of the adrenal gland, the zona glomerulosa, is composed of a thin region of columnar cells arranged in an arched pattern. This zone is also called the zona multiformis in animals because of its different patterns of arrangement of secretory cells (Rosol et al., 2001). The zona fasciculata of the adrenal gland in adult mammals is the thickest zone (approximately 70% of the cortex) and is composed of columns of secretory cells separated by prominent capillaries. The cells are polyhedral and have many intracellular lipid droplets (Rosol et al., 2001). The zona reticularis is composed of polyhedral cells, whose arrangement is less linear and more as round nests or clumps of cells. The maintenance of fetal conformation of the adrenal glands depends on a functioning fetal pituitary gland. Adrenocorticotopic hormone (ACTH) is secreted by the pituitary gland. Cells of zona fasciculata secrete cortisol under ACTH regulation (Rosol et al., 2001). During gestation in humans and nonhuman primates, there is a specialized fetal adrenal cortex (Brenner, 1940; Lewis and Pappenheimer, 1916; McNulty et al., 1981). This fetal cortex is composed of large polyhedral cells that produce abundant cortisol and estrogen precursors which are important for normal development of the fetus. The cells of the fetal cortex are produced in the outer cortex and migrate medially, where they undergo hypertrophy and eventually apoptosis (McNulty et al., 1981). After birth, there is rapid regression, apoptosis, and lysis of the fetal cortex with dilatation of cortical capillaries and replacement by the typical three cortical zones of the adrenal glands (Rosol et al., 2001). The fetal zone is present until birth in rhesus macaque (M. mulatta) and it disappears slowly after birth (McNulty et al., 1981). No cases of retained fetal adrenal cortex have been reported in cynomolgus or rhesus monkeys. It is important to distinguish the physiological replacement of the fetal cortex with the definitive postnatal adrenal cortex or the retention of fetal adrenal cortex from a test article-related change in toxicity studies.
Fig. 1. Histologic appearnce of the retained fetal adrenal cortex in a cynomolgus macaque (Macaca fascicularis). (A) All three adult zones of glomerulosa (z. G), fascicularis (z. F), and reticularis (z. R) are identified clearly. Note the presence of an additional zone of fetal adrenal cortex (F. z) composed of solid sheets and columns of cells surrounding the entire circumference of the medulla [MD] (arrows). (B) Zone of fetal adrenal cortex is supported by vascular capillary bed and composed of large polyhedral cells with abundant eosinophilic, slightly finely vacuolated cytoplasm. Nuclei were vesicular, round to oval with prominent small nucleoli. Magnification, 2× (A) and 40× (B).
Similar to what happens in human babies during the first weeks of postnatal life, rhesus macaque adrenal glands weight decrease (McNulty et al., 1981). Thus, one can translate for a similar adrenal glands changes phenomenon from rhesus to cynomolgus macaques. Although the human adrenal fetal zone is commonly believed to go through a rapid collapse with necrosis and hemorrhage, no such dramatic event occurs in rhesus macaque adrenal glands (McNulty et al., 1981). Instead, the rhesus macaque fetal zone undergoes a gradual remodeling to adult conformation over a period of months, or perhaps longer (McNulty et al., 1981). This remodeling is characterized first by the appearance of a band of small cells with little cytoplasm in the outer fetal zone, at or shortly before parturition. As the infant ages, this “dense band” is found progressively closer to the medulla. As the band appears to move centrally, mature zona fasciculata becomes recognizable outside it, while a shrinking fetal zone persists inside it. These remaining cells of the fetal zone are smaller and have less vacuolated cytoplasm than fetal-zone cells at birth, but are not necrotic. At 6 months, a central rim of fetal zone is still present (McNulty et al., 1981). The ultimate fate of the dense band is not known.
Please cite this article in press as: Radi Z, Evans M. Retained fetal adrenal cortex in a cynomolgus macaque (Macaca fascicularis). Exp Toxicol Pathol (2014), http://dx.doi.org/10.1016/j.etp.2014.04.006
G Model ETP-50826; No. of Pages 3
ARTICLE IN PRESS Z. Radi, M. Evans / Experimental and Toxicologic Pathology xxx (2014) xxx–xxx
Sucheston and Cannon (1968) did not see involution of the human fetal adrenal cortex with hemorrhage and cell loss, but rather a slow regression of the fetal zone throughout the first year. During this time, they saw little mitosis or signs of cell death, and suggested that the final structure of the adrenal cortex is slowly achieved by proliferation of the definitive cortex and a transformational process whereby fetal zone cells mature into the zona fasciculata. The exact trigger for the initiation of maturation in rhesus macaque fetal cortex remains unknown. The following hypotheses have been proposed: (1) decreasing sensitivity of the fetal cortical cells to ACTH, (2) declining release of ACTH by the late-fetal and infant pituitary, (3) withdrawal of placental adrenotropic factors or ACTH-related peptides from the fetal pituitary, and (4) withdrawal of factors inhibiting cortical maturation (McNulty et al., 1981).
3
References Benirschke K, Richart R. Observations on the fetal adrenals of marmoset monkeys. Endocrinology 1964;74:382–7. Brenner MC. Studies on the involution of the fetal cortex of the adrenal glands. Am J Pathol 1940;16:787–98. Lanman JT. The adrenal fetal zone: its occurrence in primates and a possible relationship to chorionic gonadotropin. Endocrinology 1957;61:684–91. Lewis RW, Pappenheimer AM. A study of the involutional changes which occur in the adrenal cortex during infancy. J Med Res 1916;34:81–3. McNulty WP, Novy MJ, Walsh SW. Fetal and postnatal development of the adrenal glands in Macaca mulatta. Biol Reprod 1981;25:1079–89. Mesiano S, Jaffe RB. Developmental and functional biology of the primate fetal adrenal cortex. Endocr Rev 1997;18:378–403. Rosol TJ, Yarrington JT, Latendresse J, Capen CC. Adrenal gland: structure, function, and mechanisms of toxicity. Toxicol Pathol 2001;29:41–8. Scammon RE. The prenatal growth and natal involution of the human suprarenal gland. Proc Soc Exp Biol Med 1926;26:809–11. Sucheston ME, Cannon MS. Development of zonular patterns in the human adrenal gland. J Morphol 1968;126:477–91.
Please cite this article in press as: Radi Z, Evans M. Retained fetal adrenal cortex in a cynomolgus macaque (Macaca fascicularis). Exp Toxicol Pathol (2014), http://dx.doi.org/10.1016/j.etp.2014.04.006
