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Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, California 95616, USA
(Correspondence should be addressed to A J Conley; Email: ajconley{at}ucdavis.edu)
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionDeclaration of interestReferences |
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-hydroxylase/17,20-lyase cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1), cytochrome P450, family 21, subfamily A, polypeptide 2 (CYP21A2), hydroxy-
-5-steroid dehydrogenase, 3β- and steroid -isomerase 2 (HSD3B2), the redox partner NADPH-cytochrome P450 oxidoreductase (CPR), as well as the accessory protein cytochrome b5 (b5), a marker of the primate ZR. The rhesus ZR is mature by 3 months of age based on differentiation of the innermost zone that lacks HSD3B2, but exhibits increased b5 expression during this period. Further, the ZR develops in neonates from a previously described dense band of cells which we show expresses b5, CYP17A1, CPR, and CYP21A2 throughout maturation. The fetal zone (FZ) is distinguished from the ZR by its lack of CYP21A2, and ZR development proceeded as the FZ regressed with two important implications: neither FZ regression nor ZR maturation can be monitored independently by circulating adrenal androgens, and these events must be induced by different factors in rhesus, and likely humans. Collectively these data demonstrate that ZR development begins before birth in the rhesus, proceeding concomitantly with FZ regression post-natally, suggesting that rhesus experiences morphological adrenarche during the first three months of life. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of interestReferences |
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Clearly, adrenocortical development and differentiation is quite complex in human and non-human primates (Winter 1992), involving changes in patterns of steroidogenic enzyme expression that dictate the profile of steroids produced by each zone (Mesiano et al. 1993, Conley & Bird 1997, Jaffe et al. 1998). The mature primate adrenal cortex synthesizes and secretes aldosterone, cortisol, and DS from the zona glomerulosa (ZG), zona fasciculata (ZF) and the ZR respectively. It has been suggested that the adult ZR, ZF, and ZG develop from histologically distinct zones of the fetal adrenal cortex, namely the FZ, transitional zone (TZ) and definitive zone (DZ) respectively, based on results of IHC studies (Mesiano et al. 1993). The FZ secretes androgens, primarily DS, though little cortisol or aldosterone is synthesized from the TZ and DZ during fetal life (Seron-Ferre et al. 1978, Doody et al. 1990, Nelson et al. 1990). As expected, the ZR and FZ express the steroidogenic enzymes, and accessory proteins, required for androgen synthesis, including 17-hydroxylase/17,20-lyase cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1), cytochrome b5 (b5), and NADPH-cytochrome P450 oxidoreductase (CPR; Mesiano et al. 1993, Coulter et al. 1996b, Mapes et al. 1999, 2002, Suzuki et al. 2000, Narasaka et al. 2001, Dharia et al. 2004, 2005). The adult ZF and ZG, and to a limited extent the fetal TZ and DZ as noted above, exhibit expression profiles of steroidogenic enzymes that support glucocorticoid and mineralocorticoid syntheses instead (Mesiano et al. 1993, Coulter et al. 1996b, Coulter & Jaffe 1998, Mapes et al. 1999, Suzuki et al. 2000, Narasaka et al. 2001). These enzymes include cytochrome P450, family 21, subfamily A, polypeptide 2 (CYP21A2), hydroxy--5-steroid dehydrogenase, 3β- and steroid -isomerase 1 (HSD3B2) and 11β-hydroxylase cytochrome P450 (P450c11). Thus, the temporal and spatial expression profiles of key steroidogenic enzymes, redox partners and accessory proteins, together with routine histology, allows the zones of the adult and fetal adrenal to be identified, characterized, and distinguished.
The current study was conducted to investigate the temporal and spatial profiles of expression of a suite of steroidogenic enzymes and accessory proteins, especially those necessary for androgen synthesis in neonatal rhesus adrenal glands. The immediate post partum and early neonatal period is a particularly dynamic one where differentiation of the adrenal cortex of rhesus macaques is concerned (McNulty et al. 1981), but it has not been extensively investigated in this species with respect to functional differentiation. Therefore, it was anticipated that better defining the cellular differentiation and zonation of the rhesus adrenal cortex during the early neonatal period would provide insight into ZR development, the event associated with adrenarche, in humans and non-human primates.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of interestReferences |
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Rhesus macaque adrenals were obtained opportunistically from approved projects at the California National Primate Research Center. Specimens were obtained from animals that were perinatal (1–14 days old; n=10) neonatal (1–3 months old; n=12), juvenile (4–14 months old; n=11) or adult (8 years or older; n=4) in age. Adrenal glands were fixed in 4% paraformaldehyde and subjected to graded ethanol baths prior to embedding. Tissues were embedded in paraffin wax (Fisher Scientific, Pittsburgh, PA, USA) and sectioned at 5 µm thickness.
Immunohistochemistry
Tissue sections were deparaffinized with Citrisolv and rehydrated through a graded ethanol series. Localization of expression of steroidogenic enzymes was visualized by avidin–biotin–peroxidase complex formation (Vectastain Elite ABC kit, Vector Laboratories, Burlingame, CA, USA), as previously described (Conley et al. 1996, Browne et al. 2006). Additional adrenal tissue sections were also subjected to routine hematoxylin and eosin staining (Fig. 1). Steroidogenic enzyme expression was detected in sections from each subject using the following primary antisera: b5 ((1:20 000), polyclonal rabbit anti-human, raised in our laboratory against purified recombinant protein provided by Drs Ron Estabrook and Manju Shet (Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA)), CYP17A1 ((1:10 000), polyclonal chicken anti-human raised in our laboratory against purified recombinant protein), CPR ((1:3000), polyclonal rabbit anti-rat raised in our laboratory against purified recombinant protein provided by Dr Ron Estabrook), CYP21A2 ((1:25 000), polyclonal rabbit anti-human provided by Dr Walter Miller (Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA)), and HSD3B2 ((1:400), polyclonal rabbit anti-human provided by Dr J Ian Mason (Centre for Reproductive Biology, University of Edinburgh Medical School, Edinburgh, UK)). PBS (0.1 M, pH 7.2 with 0.3% Triton-X (Sigma–Aldrich)) was used for tissue washes and antibody dilutions. Endogenous peroxidase activity was quenched by incubation in 0.3% H2O2 (in methanol, room temperature (RT)) for 30 min. Immunolocalization with CYP21A2 and CPR antisera utilized antigen retrieval, performed as previously described (Browne et al. 2006), prior to blocking of non-specific binding. Briefly, sections immersed in Antigen Unmasking Solution (Vector Laboratories) were heated slowly to 95 °C in a steamer, cooled gradually to RT over 45 min, and then subjected to the remainder of the IHC procedure. Non-specific binding was blocked by incubation with 1.5% normal goat serum in PBS (20 min, RT). Tissue sections were incubated with primary antibody incubation overnight at 4 °C for all antisera, followed by 30 min incubations with species-appropriate biotinylated secondary antibody (chicken: Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA; rabbit: Vectastain Elite ABC kit, Vector Laboratories) and avidin–biotin complex solution (Vectastain Elite ABC kit, Vector Laboratories). Primary antibody binding was detected with the peroxidase substrates Vector NovaRed (b5, CYP17A1; 5 min incubation) or 3-amino-9-ethylcarbazole (AEC: CYP21A2, HSD3B2, CPR; 12 min incubation; Vector Laboratories) and counterstained with Gill's hematoxylin 2 (Fisher Scientific). Tissues stained with Vector NovaRed were dehydrated with graded EtOH series and Citrisolv baths. Vector NovaRed-stained slides were coverslipped using Permount mounting medium (Fisher Scientific); slides stained with AEC were coverslipped using Faramount aqueous mounting medium (Dako, Carpinteria, CA, USA). Specificity of all antisera binding was verified by western immunoblotting of rhesus macaque adrenal microsomal samples, all of which demonstrated single bands of the expected molecular size (Figs 2–4
). Normal serum was utilized instead of primary antisera in negative controls. Micrographs were taken using brightfield illumination on a DMRB microscope (Leica Corp., Rockleigh, NJ, USA) equipped with a MicroPublisher 3.3 RTV (Qimaging Corporation, Surrey, British Columbia, Canada) and Windows QCapture Suite (Qimaging Corporation). IHC runs for each enzyme included specimens from all ages to minimize variation in staining that might have occurred between different runs.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of interestReferences |
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The perinatal (1–14 days old) rhesus adrenal cortex (Fig. 1) was comprised of four distinct regions. Directly underlying the capsule was the DZ, consisting of a band of small cells, densely packed in columnar arrangements. Immediately adjacent to the DZ were the cells of the TZ, defined by their larger diameter, compact nuclei and lack of columnar organization (Fig. 1A). The innermost region of the perinatal adrenal cortex was comprised of the large, spongy cells of the FZ that were generally disorganized like the TZ cells (Fig. 1A and C). Separating the TZ and the FZ, and completely distinct from the surrounding regions, was a band of tightly packed cells with little cytoplasm, hereafter referred to as the dense band (DB-ZR; Fig. 1A and B). All perinatal specimens examined exhibited a distinct DB-ZR as illustrated in Fig. 1.
Localization of b5
In the perinatal adrenals, b5 immunostaining was detected in the TZ and throughout the FZ. Expression of b5 was patchy in both inner zones, with immunostaining more intense in the compact cells of the TZ than the large vacuolated FZ cells (Fig. 2A). The DB-ZR at the boundary between the FZ and TZ also stained strongly for b5 expression during this early perinatal period (Fig. 2B). The proportion of b5-positive cells and the intensity of expression in the TZ, FZ, and DB-ZR increased throughout these first 4 weeks of life (Fig. 2A–C). By 1 month of age (defined as the onset of the neonatal period), the cells of the DB-ZR expressing b5 persisted in between the large vacuolated cells characteristic of a functional ZF and the large, spongy b5-positive cells of a diminishing FZ (Fig. 2D). Expression was greater in the outermost cells of the DB-ZR and decreased toward the FZ, but involved nearly all cells. The FZ continued to shrink, while the DB-ZR persisted and increased in relative width throughout the neonatal period (Fig. 2E and F). By 3 months of age, the DB-ZR exhibited uniform, intense expression of b5, similar to the ZR of the adult rhesus macaque (Fig. 2F and H). A thin layer (1–2 cells thick) of b5-positive FZ cells (characterized based on the morphology previously described) persisted in juveniles (4–14 months; Fig. 2G). No FZ cells were observed in adrenal glands from adult animals (Fig. 2H), and no b5 immunostaining was detected in the DZ, ZG, ZF, or medulla of any adrenal sample. The pattern of expression of b5 expression as described above for each age was evident and consistent in all specimens examined of similar age.
Localization of HSD3B2
Expression of HSD3B2 was restricted to the DZ and the outermost region of the TZ during the perinatal period, but did not extend into the DB-ZR or FZ (Fig. 3A). As differentiation proceeded, expression of HSD3B2 was confined to the ZG and ZF of the neonatal and juvenile adrenal cortex, but remained consistently absent from the DB-ZR and FZ (Fig. 3B and C). In all specimens examined, HSD3B2 was expressed intensely in all cells of the DZ, and in sections from older animals, and nearly all ZG and ZF cells were positive. The intensity of expression was similar among cells of the outermost TZ and the ZF cells. No immunostaining was detected in cells of the medulla, DB-ZR, FZ, or ZR of any specimen. The pattern of HSD3B2 expression described above was consistent among all similarly aged specimens.
Localization of CYP21A2
Expression of CYP21A2 was localized throughout the DZ, TZ, and DB-ZR of the adrenal cortex of perinatal adrenal glands (Fig. 3D), and immunostaining was intense and uniform throughout the DZ and outermost TZ. All cells of the TZ expressed CYP21A2. CYP21A2 expression in the DB-ZR was patchy, with the cells at the TZ/DB-ZR border exhibiting the greatest intensity and the number of positive cells. By contrast, CYP21A2 expression was essentially absent from the FZ, even faintly immunopositive cells were rare (Fig. 3D). This pattern of CYP21A2 expression persisted through the perinatal and neonatal stages with marked expression throughout the ZG, ZF, and DB-ZR, but a relative lack of CYP21A2 expression in the FZ (Fig. 3E and F). By contrast, the proportion of DB-ZR cells that were immunopositive for CYP21A2 greatly increased with age in neonates (Fig. 3E) to include all cells in this band, rather than those primarily at the TZ border, as in the perinatal adrenals. CYP21A2 expression was undetected in the remaining FZ cells (Fig. 3E). In the adrenal cortex of juvenile rhesus macaques (Fig. 3F), CYP21A2 was expressed in nearly all cells of the ZG and ZF, with continued patchy expression throughout the established ZR. The FZ cells of the juvenile adrenal similarly lacked CYP21A2 expression and continued to decrease in cell numbers and general size compared with the neonatal adrenal. No cellular expression was observed in the medulla of any adrenal samples. This was a consistent pattern evident in all specimens examined of similar age.
Localization of CYP17A1
CYP17A1 was detected throughout the TZ and FZ of the perinatal adrenal cortex (Fig. 4A). Expression was sparse and faint in the large, vacuolated cells of the FZ, while nearly all cells of the outer TZ exhibited intense staining. Expression of CYP17A1 that was observed in the cells of the DB-ZR was intermediate in intensity compared with FZ and TZ staining (Fig. 4A). A similar pattern of CYP17A1 expression was observed in neonatal adrenal specimens (1–3 months old), with CYP17A1 localized throughout the large cells of the ZF and the compact cells of the DB-ZR (Fig. 4B). Expression of CYP17A1 was barely detectable in the vacuolated cells of the FZ during this period. After the establishment of a morphologically mature ZR (more than 3 months old), CYP17A1 expression was observed throughout the ZF and ZR, with expression in nearly all cells of the ZF and patchy expression throughout the ZR (Fig. 4C). ZF cells exhibited generally greater intensity of CYP17A1 expression than ZR cells. There was no detectable expression of CYP17A1 in the medulla, DZ, or ZG of samples studied. As for other enzymes examined, the pattern of expression was consistent in all specimens of similar age.
Localization of CPR
Expression of CPR was detected in all cells of all zones and throughout the adrenal cortex of all specimens regardless of age. Adrenocortical cells at the corticomedullary junction exhibited the greatest CPR expression in the majority of samples (Fig. 4D–F); otherwise, expression was uniform throughout the cortex. Cellular expression of CPR was undetectable in the medulla of any adrenal specimen.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of interestReferences |
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In comparison to humans, DS concentrations in the rhesus fetus are generally lower during gestation, but increase immediately pre-partum (Seron-Ferre et al. 1983, Walsh et al. 1984). This pre-partum rise in fetal serum DS coincides with increasing adrenal expression of CYP17A1 and b5 during late fetal development (Mapes et al. 2002). Results of the current IHC studies show that the establishment of a morphologically mature ZR in the neonatal rhesus macaque resembles human adrenarche (Havelock et al. 2004), although its appearance coincides with regression of the FZ. The earliest studies investigating this phenomenon in the rhesus reported only that adrenal androgens declined in animals older than 2–4 months of age (Cutler et al. 1978, Smail et al. 1982), and not observing any preceding increase, concluded therefore that this species does not experience an adrenarche. However, our data demonstrate that rhesus ZR development begins in late gestation (Mapes et al. 2002) and as shown here is essentially completed in the third month of life. Whereas regression of the FZ and maturation of the ZR are temporally separated by years in humans, both events occur concurrently, compressed within the first two months of life in the rhesus macaque. In contrast to the onset of ZR differentiation, which is pre-pubertal in both rhesus and human, the peak in DS concentrations differs markedly, preceding puberty in rhesus, but post-dating puberty in humans by more than a decade. This does not indicate any fundamental difference exists between human and rhesus adrenal with respect to ZR development. In fact, it is entirely consistent with the physiological independence of ZR development from gonadal function, as evidenced in normal children and those with precocious puberty (Sklar et al. 1980, Palmert et al. 2001, Remer et al. 2005). Although the decline in DS (adrenopause) is readily detectable in the rhesus, adrenarche is certainly not. Since both the FZ and ZR have the capacity for DS synthesis and secretion (Conley et al. 2004), we propose that the loss of androgen secretion from the regressing FZ likely masks increased secretion by the developing ZR, making adrenarche in the rhesus macaque a cryptic event when based on circulating DS concentrations alone.
The concurrence of FZ regression with ZR differentiation during neonatal rhesus adrenocortical development described here has additional implications for the regulation of these processes. Despite observations suggesting human FZ regression occurred by massive cellular collapse involving necrosis (as reviewed (Lanman 1953)), it is more likely that involution of the FZ is gradual (Scammon 1926, Benner 1940, Sucheston & Cannon 1968). In agreement with the latter reports, McNulty et al. (1981) noted a gradual reduction in FZ width without necrosis or signs of involution in the neonatal rhesus adrenal cortex. Using the markers b5 and CYP21A2, in addition to morphology, our data confirm that the rhesus FZ undergoes a progressive, if more rapid, regression post-natally than that seen in humans. However, what the concurrence of FZ regression with ZR development suggests is that different growth factors or regulatory processes mediate these two events. Although able to stimulate CYP17A1 expression in cultured fetal adrenal cells (Di Blasio et al. 1987), proopiomelanocortin (POMC) likely plays more of a permissive (as reviewed (Parker & Odell 1980, Auchus & Rainey 2004)), rather than an inductive role, in adrenal development as POMC and cortisol levels remain steady during this developmental window (Apter et al. 1979, Parker & Odell 1980). Epidermal growth factor (EGF), which promotes steroid synthesis in cultured human fetal adrenal cells, may play a role in maturation of the FZ or developing ZR (Jaffe et al. 1981). EGF increases expression of HSD3B2 in the TZ and DZ and stimulates fetal adrenal gland growth (Coulter et al. 1996c). IGFs may also regulate adrenal growth via IGF receptors and binding proteins that are localized throughout the fetal adrenal cortex in rhesus (Coulter et al. 1996a). IGF1 was correlated positively with increased androstenedione levels in Hispanic and African-American women who experienced premature adrenarche (l'Allemand et al. 2002). Additionally, IGF2 expression in human fetal adrenal cells is induced by POMC (Voutilainen & Miller 1987), further evidence linking IGFs with POMC and adrenal growth. The rhesus may prove useful in studying regulatory factors, and their interactions, as putative determinants of FZ regression and ZR induction in short-term studies because of the much shortened period of adrenocortical differentiation.
The expression of b5 throughout the developing and mature ZR further highlights the importance of b5 in the modulation of androgen synthesis (Onoda & Hall 1982, Shinzawa et al. 1985, Mapes et al. 1999). The enzymatic activities of CYP17A1 are differentially regulated, as evidenced in children undergoing adrenarche and patients with isolated 17,20-lyase deficiency (Kaufman et al. 1983, Geller et al. 1997, Van Den Akker et al. 2002, Sherbet et al. 2003). The accessory protein b5 (Onoda & Hall 1982, Katagiri et al. 1995, Lee-Robichaud et al. 1995), serine phosphorylation of CYP17A1 (Zhang et al. 1995), and/or increased molar ratios of CPR (Yanagibashi & Hall 1986) stimulate 17,20-lyase activity over 17-hydroxylase activity, increasing the capacity for DHEA production (Pandey & Miller 2005). While b5 facilitates electron transfer with some microsomal P450s (Kurian et al. 2004), evidence suggests this is not the mechanism of action for stimulation of 17,20-lyase activity (Auchus et al. 1998). An allosteric action of b5, thought to promote complex formation between CYP17A1 and CPR, has been suggested (Auchus et al. 1998, Pandey & Miller 2005). Co-localization of CYP17A1 and b5 has been demonstrated previously in androgenic tissues of human and non-human primates (Mapes et al. 1999, 2002, Suzuki et al. 2000, Dharia et al. 2004, Pattison et al. 2007) and in human adrenal disease (Yanase et al. 1998). Increased expression of b5 may account for increased adrenal androgen production with endocrinological disorders (Sakai et al. 1993), in addition to stimulation of synthesis during endocrinological transitions. However, the role of b5 in adrenarche has not been as carefully evaluated in human tissues, and further studies are necessary to determine its contribution to changes in adrenal androgen secretion during development.
Classically, adrenarche has been defined based on circulating DS concentrations, one of the few easily measured markers of this event. Recent longitudinal studies conducted from early childhood (Remer & Manz 1999, Palmert et al. 2001, Remer et al. 2005), adding to earlier reports (Sizonenko et al. 1976, Parker et al. 1978, Ilondo et al. 1982, Kelnar & Brook 1983), indicate that adrenarche is associated with a gradual, rather than abrupt, rise in adrenal androgen production, but this is not the pattern seen in the rhesus macaque. As noted earlier, DS levels are high in the rhesus soon after birth, but decline rapidly between 2 and 3 months of age then more gradually throughout the rest of life (Koritnik et al. 1983, Seron-Ferre et al. 1983, 1986, Kemnitz et al. 2000). Although our data suggest that the concurrence of FZ regression with ZR differentiation likely make it difficult to distinguish these events from each other based on circulating DS, there may be other equally important confounding factors. For instance, it has been suggested that efficient metabolism of DHEA, specifically 16-hydroxylation, in early childhood and adolescence may mask a significant portion of the adrenal androgens secreted during early human development, most often estimated from DHEA and DS levels only (Remer et al. 2005). In addition, changes in glucuronidation (Guillemette et al. 1996) and even sulfotransferase itself, which we have shown is expressed in the rhesus adrenal (Parker et al. 2000), along with other routes of androgen metabolism (Remer et al. 2005), may alter apparent adrenal androgen output. All of the above make peripheral hormone levels potentially poor indices of adrenal development in non-human primates. Adrenarche can be defined in histochemical and even biochemical terms if tissues are available for such analyses and, though not clinically useful, are relevant nonetheless because circulating hormone concentrations may not accurately reflect the underlying biology, especially in non-human primate models.
We believe that the late gestational, perinatal, and neonatal rhesus macaque is a suitable model for study of adrenarche, and potentially also for hyperandrogenic syndromes such as polycystic ovarian disease (Abbott et al. 2008). The processes and factors involved in primate adrenal maturation are complex, as evidenced by the gender and gonadal differences in ZR function in marmosets (Pattison et al. 2007). Studies examining the capacity for androgen production during this dynamic period, as well as investigation into the regulation of ZR development, are necessary to properly characterize the morphological adrenarche exhibited by the rhesus.
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Declaration of interest |
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Funding |
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Acknowledgements |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of interestReferences |
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Received in final form 1 September 2008
Accepted 4 September 2008
Made available online as an Accepted Preprint 11 September 2008
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