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* Division of Molecular Medicine, Department of Medicine, and
Department of Pathology, Columbia University, New York, New York, USA;
Institute of Clinical Biochemistry and Pharmacology, University of Bonn, Bonn, Germany; and
Dept. of Basic Neurosciences, Maastricht University, Maastricht, The Netherlands
1Correspondence: Department of Medicine, Columbia University, PS 8-401, 630 W. 168th St., New York, NY 10032, USA. E-mail: nw30{at}columbia.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Abcg1 • Abcg4 • astrocyte • neuron • apolipoprotein E • efflux
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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25% of the total body cholesterol in the primate (1)
. The brain has evolved highly efficient mechanisms for maintaining constant cholesterol levels, which are important for normal brain functions and neuroregeneration (1)
. While the liver and other extrahepatic tissues acquire cholesterol both by de novo synthesis and by uptake of cholesterol carried by lipoproteins in the circulation, transport of lipoprotein cholesterol from the circulation to the brain is minimal because the blood–brain barrier effectively prevents this (2)
. As a consequence, essentially all cholesterol input into the central nervous system comes from de novo synthesis, and there appears to be a highly efficient lipoprotein-dependent cholesterol recycling process in the brain (1)
.
ATP-binding cassette transporters play a pivotal role in lipoprotein-metabolism and cholesterol-transport processes (3
4
5
6
7
8
9
10
11)
. Overexpression of ATP-binding cassette transporters G1(Abcg1) or G4 (Abcg4) promotes cellular cholesterol efflux to high-density lipoprotein (HDL) particles (12)
, whereas ATP-binding cassette transporter A1 (Abca1) is essential for lipidation of apolipoprotein A-I (apoA-I) and nascent HDL formation (7)
. Abca1-mediated cholesterol efflux also appears to be critical for removal of cholesterol from peripheral tissues such as arterial wall macrophages, and Abca1 deficiency increases macrophage foam cell formation and the risk of cardiovascular disease (7
, 13)
. Abcg1 is expressed in multiple tissues and Abcg1 deficiency leads to increased macrophage foam cell formation and neutral lipid accumulation in the lung (14)
. While Abcg4 promotes cholesterol efflux to HDL when overexpressed in cultured cells, the physiological role of Abcg4 in vivo is not known. Abcg4 is expressed at low levels in macrophages and does not appear to have a major role in cholesterol efflux in this cell type (12
, 15)
. Abca1, Abcg1, and Abcg4 are all highly expressed in the brain (16
, 17)
. A role of Abca1 in cellular lipid efflux in the brain has been strongly suggested by studies using cultured cells or Abca1-deficient mice (18
19
20
21
22)
. Abca1 activity appears to be essential for apolipoprotein E (apoE) lipidation and regulates apoE turnover (17
, 20)
. Though studies using cultured cells also suggest involvement of Abcg1 in cholesterol efflux in brain cells (19
, 21
, 22)
, the role of Abcg1 in brain cholesterol balance in vivo has not been examined. In the present study, we have characterized the distribution of Abcg1 and Abcg4 in the brain and have bred mice with single or combined deficiency of Abcg1 and Abcg4 to elucidate a potential role of these transporters in sterol metabolism in the brain.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Plasma lipoprotein preparations
Human HDL (d1.063–1.21 g/ml) was isolated by preparative ultracentrifugation from normolipidemic human plasma and stored in phosphate buffered saline containing 1 mM EDTA.
Plasmid constructs and cell transfection
The plasmid constructs expressing mouse Abcg1 or Abcg4 were prepared by cloning mouse full-length Abcg1 or Abcg4 cDNAs into pcDNA3.1 vector (Invitrogen, Carlsbad, CA, USA), and the cDNA sequence was confirmed by DNA sequencing. For transient transfection of HEK293 cells, cells in collagen-coated plates were transfected with various plasmid constructs with LipofectAmine 2000 (Invitrogen) at 37°C overnight (20 h).
Immunofluorescence confocal microscopy
Cells were fixed with 3.7% formaldehyde for 10 min and then incubated with 0.1% Triton X-100 in phosphate-buffered saline for 2 min. After washing with phosphate-buffered saline, cells were incubated with primary antibody in 4 mg/ml normal goat globulin and 0.1% saponin in phosphate-buffered saline at room temperature for 30 min. Alexa 568-labeled goat anti-rabbit IgG or Alexa 488-labeled goat anti-mouse IgG was used as the secondary antibody. After washing and fixing with 3% formaldehyde, cells were examined by fluorescence confocal microscopy.
LacZ staining
The whole brains, frozen tissue sections, or cultured cells were stained using Beta-Galactosidase Staining Kits from Millipore/Specialty Media (Billerica, MA, USA) according to the protocol from the manufacturer. The frozen tissue sections and cultured cells were counterstained with nuclear red.
Sterol synthesis assay
Sterol synthesis rate was determined using a modified protocol as described (23)
. Briefly, the cultured primary astrocytes were pulse labeled for 2 h with 20 µCi/ml [3H]acetic acid. After washing, the cellular lipids were extracted with hexane/isopropanol (3:2, v/v) and saponified with alcoholic KOH. Then, the extracted sterols were precipitated as the digitonides, which were washed with 80% ethanol twice and once with diethyl ether. The precipitates were dissolved in pyridine, and the radioactivity was quantitated using β-counter.
Cellular sterol efflux and brain sterol mass quantification
Mouse primary astrocytes or HEK293 cells were loaded with desmosterol by culturing for 16 h in 10% fetal bovine serum/Dulbecco modified Eagle medium (DMEM) containing 20 µM desmosterol. The next day, cells were washed with fresh media, then HDL was added at indicated concentration and incubated in the DMEM media plus 0.2% bovine albumin for the indicated period before the media and cells were collected for analysis. To determine sterol mass efflux, the lipid fraction was extracted from the media or cell lysates with hexane:isopropanol (3:2, v/v) and stigmasterol (5 µg/sample) was added as the internal standard. After drying under nitrogen gas, the mass of sterols dissolved in hexane was determined using gas chromatography. The gain of sterol (cholesterol or desmosterol) mass in the media after efflux was considered as sterols excreted from the cells. The cholesterol gain typically accounted for 20–30% of cholesterol associated with the HDL preparation used in the assay, and the gain for desmosterol was much greater, as there was little desmosterol associated with HDL. For determination of sterol mass in the brain, sterols and oxysterols were extracted from dried whole brain by chloroform/methanol. After deconjugation and trimethylsilylation, the sterols were quantified by gas chromatography-mass spectrometry as described (24)
.
Animals and cells
Abcg1–/–/Abcg4–/–, Abcg1–/–, and Abcg4–/– mice were derived from Abcg1P+/– or Abcg4+/– mice obtained from Deltagen Inc. (San Mateo, CA, USA) as described previously (15)
. Primary astrocytes were isolated from the mice as described (19)
.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Abcg4 was expressed primarily in the brain, as shown by Northern blot (Fig. 1
A). Lower levels of Abcg4 expression were detected in other tissues, including spleen, testis, skin, and thymus (Fig. 1A
). To determine the pattern of Abcg1 and Abcg4 expression in the brain, we used Abcg1 or Abcg4 knockout mice. The β-galactosidase gene, modified to contain a nuclear targeting signal, was under the control of the Abcg1 or Abcg4 promoter in the targeted locus, thus allowing facile determination of tissue and cell type expression. Significant lacZ activity was detected in the brain of Abcg1+/– (not shown) and Abcg4+/– mice (Fig. 1B
). When frozen tissue sections of the brain from Abcg1+/– and Abcg4+/– mice were analyzed, lacZ-positive cells were found to be widely distributed in the brains of both Abcg1+/– and Abcg4+/– mice (not shown). The most prominent staining indicating Abcg4 expression was in the hippocampus, cerebellum (Fig. 1C, E
), and olfactory bulb (not shown). In the cerebellum, Purkinje cells were highly stained in Abcg4+/– mice (Fig. 1E
). Abcg1 expression also was detected in these regions of the brain in a similar distribution to Abcg4 (Fig. 1D, F
). To determine if Abcg1 and Abcg4 are expressed in other neurons in addition to Purkinje cells, we used immunofluorescence confocal microscopy with anti-NeuN antibody as the neuronal marker and anti-β-galactosidase antibodies to detect Abcg1 or Abcg4 expression. Neu-N and β-galactosidase copositive cells were widely distributed in the brains of Abcg1+/– and Abcg4+/– mice (not shown). As shown by coexpression with Neu-N, Abcg1 and Abcg4 both were expressed in neurons in the hippocampus (Fig. 1G, H
). To determine if Abcg1 and Abcg4 are expressed in astrocytes, we isolated primary astrocytes from neonatal mice. More than 90% of the cells were confirmed to be astrocytes by immunofluorescence microscopy using glial fibrillary acidic protein (GFAP) as the astrocyte marker (Fig. 1I, J
). LacZ activity was readily detected in primary astrocytes isolated from Abcg1+/–or Abcg4+/– mice (Fig. 1L, M
). These data show widely distributed expression of Abcg1 and Abcg4 in the brain with prominent expression in hippocampus, cerebellum, and olfactory bulb, and localization of both transporters in neurons and astrocytes.
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Abcg1 and Abcg4 deficiency increase desmosterol levels in the brain
In order to evaluate the potential roles of Abcg1 and Abcg4 in brain sterol metabolism, we measured the levels of various sterols, including cholesterol, sterol intermediates in cholesterol synthesis (desmosterol, lanosterol, and lathosterol), oxysterols (27-OH-cholesterol, 24(S)-OH-cholesterol), and phytosterols (sitosterol and campesterol). Abcg1 or Abcg4 deficiency alone did not significantly affect the levels of sterols in the brain except for brain desmosterol levels, which were increased by 1.4-fold in Abcg1–/– mice, and lathosterol levels, which were slightly elevated in Abcg4–/– mice (Table 1
). Since Abcg1 and Abcg4 are expressed in similar regions and in the same types of cells in the brain (Fig. 1)
, they may have overlapping functions. To test this possibility, we generated Abcg1–/–/Abcg4–/– double-knockout mice. Brain desmosterol levels were increased by 2.4-fold in the double-knockout mice (Table 1)
. Brain lanosterol, lathosterol, and 27-OH-cholesterol levels also were significantly increased by 1.9-, 1.5-, and 1.7-fold, respectively. In contrast, brain cholesterol, 24(S)-OH-cholesterol, and plant sterol levels were unchanged (Table 1)
. The more pronounced increases in levels of desmosterol, lanosterol, lathosterol, and 27-OH-cholesterol in the brains of the double-knockout mice than either of the single-knockout suggest that Abcg1 and Abcg4 have overlapping activities and can functionally compensate for one another in maintenance of levels of these sterols in the brain.
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Abcg1 and Abcg4 promote cellular cholesterol and desmosterol efflux to HDL from astrocytes
Because desmosterol accumulation was prominent in brains of the double-knockout mice and has been reported to activate liver-X receptor (LXR) (26)
, we focused our subsequent investigations on desmosterol. To evaluate directly the effect of the transporter deficiency on sterol balance and synthesis, we used primary astrocytes isolated from the mutant mice or their wild-type littermates. Remarkably, desmosterol levels were increased 4-fold in Abcg1–/–/Abcg4–/– astrocytes and approximately 2-fold in Abcg1–/–/Abcg4+/– or Abcg1+/–/Abcg4–/– astrocytes (Fig. 2
A). In contrast to the unaltered brain cholesterol levels in the mutant mice, cholesterol mass also was moderately increased in the mutant astrocytes (Fig. 2B
).
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The accumulation of some sterol biosynthetic intermediates in astrocytes of the double-knockout mice could be the consequence of enhanced production or reduced efflux. To determine if the sterol accumulation was caused by increased production, we measured sterol synthesis in the cultured primary astrocytes using [3H] acetate as the tracer. The cellular total sterol synthesis rate was decreased in the mutant astrocytes relative to that of the wild-type astrocytes (Fig. 2C
). Therefore, the increased levels of desmosterol and cholesterol in the mutant astrocytes could not be explained by increased sterol synthesis. Furthermore, the decreased sterol synthesis rate was consistent with the increased accumulation of desmosterol and cholesterol because these sterols are known to inhibit cholesterol synthesis via a feedback regulation (27)
.
To evaluate the role of Abcg1 and Abcg4 in desmosterol and cholesterol efflux, we examined efflux of these sterols from primary astrocytes. When sterol mass levels in serum-containing cell culture media after 48 h incubation with the wild-type astrocytes were determined, there had been significant cholesterol release from the cells (Fig. 3
A). We also detected substantial desmosterol mass efflux from astrocytes at 25–30% of the level of cholesterol efflux (Fig. 3A
). To explore whether desmosterol efflux from astrocytes was HDL dependent, we determined desmosterol efflux at various concentrations of HDL. Indeed, desmosterol was released from the primary astrocytes to HDL in a dose-dependent fashion (Fig. 3B
). Next, we examined the role of Abcg1 and Abcg4 in desmosterol and cholesterol efflux after desmosterol loading. When cells were incubated in desmosterol-enriched cell culture media, the Abcg1–/–/Abcg4–/– astrocytes accumulated more desmosterol than other groups of astrocytes (80% more than the wild-type astrocytes). Desmosterol efflux was moderately but significantly decreased in the mutant astrocytes (Fig. 3D
). In addition, cellular cholesterol efflux to HDL also was reduced in the mutant astrocytes under similar conditions despite increased cellular cholesterol mass in the mutant cells (Fig. 3C
). Together, these results indicate that Abcg1 and Abcg4 promote cellular cholesterol and desmosterol efflux from astrocytes in vivo. Because the maximum effect on cellular sterol accumulation and efflux was observed only with complete deficiency of both Abcg1 and Abcg4, and a single copy of functional Abcg1 or Abcg4 could partly compensate for the defect in sterol balances (Fig. 2
and 3)
, these data strongly suggest that Abcg1 and Abcg4 mediate cholesterol and desmosterol efflux in vivo in a parallel fashion.
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We noticed a significant level of desmosterol efflux into media even in the absence of added HDL (Fig. 3B
). Given the high level of expression of Abca1 and apoE in astrocytes (17)
, we wondered if this level might be mediated by Abca1-mediated efflux of desmosterol to apoE. To test this hypothesis, we carried out overexpression studies in HEK293 cells. The result showed that overexpression of Abcg1 or Abcg4 but not Abcg2 promoted both cholesterol and desmosterol efflux to HDL (Fig. 4
A, B). In addition, Abca1 overexpression increased desmosterol efflux to both apoA-1 and apoE (Fig. 4C, D
). Finally, we showed that apoA-I significantly increased desmosterol efflux from primary astrocytes in the presence or absence of Abcg1 and Abcg4 expression (Fig. 4E
). The fact that sterol efflux to lipid-poor apoA-1 is primarily mediated by Abca1 (28)
indicates that Abca1-mediated desmosterol efflux occurs in double-knockout astrocytes, compensating for the deficiency of Abcg1 and Abcg4.
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Abcg1 and Abcg4 deficiency increased expression of LXR target genes and apoE secretion
We showed previously that Abcg1 deficiency resulted in induction of several LXR target genes such as Abca1 in macrophages, possibly by modulating LXR activity (29)
. To test whether Abcg1 and Abcg4 affect LXR activity in the brain, we measured the expression of LXR target genes. Abca1 mRNA and protein levels were significantly increased in the brain of the double- but not single-knockout mice (Fig. 5
A, B, D). Activity of the Abcg1 promoter was monitored by measuring a 5' transcript upstream of the targeted region. This showed an induction of Abcg1 expression in the brain of Abcg1–/– and Abcg1–/–/Abcg4–/– mice but not in Abcg4–/– mice (Fig. 5E
). Levels of brain Srebp-1c mRNA, apoE mRNA, and protein levels did not show significant change (Fig. 5A, F
). Brain Abcg4 mRNA levels were unchanged in Abcg1–/– mice (not shown). To further evaluate the role of Abcg1 and Abcg4 in regulation of LXR activity, we determined Abca1 expression in the primary astrocytes. Consistent with the in vivo data, both Abca1 mRNA (not shown) and protein levels were significantly increased in the mutant cells (Fig. 6
A). The increase in Abca1 expression was more pronounced in the Abcg1–/–/Abcg4–/– astrocytes than in Abcg1+/–/Abcg4–/– or Abcg1–/–/Abcg4+/– astrocytes (Fig. 6A
). Interestingly, apoE secretion as well as cellular apoE levels were significantly increased in the Abcg1–/–/Abcg4–/– astrocytes (Fig. 6B, C
) while apoE mRNA levels were not significantly altered (not shown). These results are consistent with our previous findings in macrophage that Abcg1 deficiency induced expression of Abca1 leading to increased apoE secretion (29)
. Together, these data indicate that Abcg1 and Abcg4 deficiency result in induction of LXR target gene expression in the brain, including compensatory up-regulation of Abca1.
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Recently, Yang et al. (26)
showed that desmosterol strongly induced Abca1 expression by activating LXR when tested among a battery of sterols in several types of cells. To determine if this might be responsible for induction of Abca1 in the mutant mice and astrocytes, we treated the astrocytes with desmosterol. Desmosterol treatment markedly increased both Abca1 protein and mRNA levels in primary astrocytes (Fig. 7
A, B). At the highest dose tested in our studies (10 µM desmosterol), these cells accumulated 3.5 µg/mg protein desmosterol, a value comparable to the levels of desmosterol in the double-knockout astrocytes (Fig. 2A
). Likewise, desmosterol treatment of neuron-2a cells, a neuronal cell line, also increased Abca1 expression in a dose-dependent fashion (Fig. 7C
). These data indicate that desmosterol accumulation in mutant mice or cells is a plausible explanation for increased expression of Abca1. In contrast to the robust increase in Abca1 mRNA and protein levels in astrocytes after desmosterol or TO901317 treatment, apoE mRNA levels were not significantly altered by 10 µM desmosterol and only moderately increased by TO901317 treatment (not shown), suggesting that apoE is a less responsive LXR target gene as compared with Abca1 in astrocytes. Consistent with these results, a recent study shows much more pronounced increase of Abca1 mRNA levels than that of apoE in hippocampus but not in frontal cortex after TO901317 treatment of the mice (30)
, with a concomitant greater increase of apoE protein. The latter could reflect the increased Abca1 expression and apoE secretion, as shown in Fig. 6
. Abcg4 expression was not altered by desmosterol or TO901317 (not shown).
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The efflux of cholesterol and, potentially, desmosterol from astrocytes has been proposed to be an important part of the mechanism responsible for the production of HDL-like lipoproteins in the central nervous system and the recycling of cholesterol between astrocytes and neurons (1
, 31)
. The defective efflux of cholesterol and desmosterol from the mutant astrocytes suggest a role of Abcg1 and Abcg4 in these processes. To further test this, we labeled the wild-type and the double-knockout astrocytes with [3H]cholesterol. The efflux of the cholesterol tracer was initiated by incubating with fresh media containing HDL, the conditioned media were collected and transferred to neuro-2a cells, and the transfer of the cholesterol tracer from astrocytes to neurons was determined. The transfer was significantly reduced from the double-knockout astrocytes relative to the wild-type astrocytes (Fig. 8
). These results are consistent with the idea that Abcg1 and Abcg4 actively promote cholesterol and desmosterol efflux to HDL-like lipoprotein particles and could be involved in the recycling of sterols in the central nervous system.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Once produced in cells, desmosterol, lanosterol, and lathosterol mainly serve as precursors for cholesterol synthesis. However, these sterols, like cellular cholesterol, may also be released from cells by efflux. Studies from several groups have shown that these particular sterol intermediates are the major newly synthesized cellular sterols released from cells along with cholesterol (32
, 33)
. Interestingly, these studies have also shown that the efflux of newly synthesized cholesterol precursors, such as desmosterol and lathosterol, is promoted by HDL or serum (32
33
34)
. We now provide evidence that Abcg1 and Abcg4 have a physiological role in mediating efflux of cholesterol and cholesterol biosynthetic intermediates from cells such as astrocytes to HDL in the brain. Knockouts of both Abcg1 and Abcg4 were required to see substantial accumulation of sterols in astrocytes and brain, indicating overlapping roles and mutual compensation of these 2 transporters in sterol efflux processes.
Some of the sterols accumulating in Abcg1–/–/Abcg4–/– cells such as desmosterol and 27-OH cholesterol are LXR activators (26
, 35)
, and double-knockout astrocytes showed induction of LXR target genes such as Abca1. The role of Abcg1 and Abcg4 in promoting efflux of sterols that are LXR activators likely explains how deficiency of individual transporters is partly compensated by up-regulation of other transporters with overlapping function. While the focus of this study was the brain, accumulation of sterols such as desmosterol and 27-OH cholesterol in Abcg1–/– macrophages could potentially explain our previous observation that a variety of LXR target genes are induced in Abcg1–/– macrophages (29)
. The Abcg1–/–/Abcg4–/– mice showed moderate levels of accumulation of desmosterol and other sterols in astrocytes and the brain. However, the phenotype is relatively subtle, and much more dramatic accumulations are seen in conditions such as desmosterolosis resulting from mutations in desmosterol reductase. A recent study showed that the desmosterol reductase-deficient mice had increased hepatic expression of LXR target genes (36)
, a result consistent with our findings. We showed that desmosterol undergoes efflux from double-knockout astrocytes, even in the absence of added HDL (Fig. 3)
, and that apoA-1 stimulates desmosterol efflux in these cells. This suggests that desmosterol accumulation is limited in Abcg1–/–/Abcg4–/– mice because of the up-regulation of Abca1 and apoE secretion likely secondary to activation of LXRs by retained desmosterol and 27-OH cholesterol. Thus, we expect to see more pronounced alterations in sterol levels and/or distributions in the brain in mice with combined Abca1-, Abcg1-, and Abcg4 deficiency.
Abcg transporters function either as heterodimers, (e.g., Abcg5/Abcg8) (9)
or homodimers (e.g., Abcg2) (37)
. Although overexpression experiments suggest promiscuous association of various Abcg transporters (38)
, the genetics of sitosterolemia indicate that Abcg5/8 function as heterodimers (38
, 39)
. Similarly, Abcg1 and Abcg4 can form heterodimers when overexpressed (40)
, but the finding that significant sterol accumulation in brain requires knockout of both transporters indicates they do not likely function primarily as heterodimers, as this would result in the same phenotype in single- and double-knockout mice and cells. Abcg5/Abcg 8 appear to have fairly broad substrate specificity for a variety of plant sterols and cholesterol. The accumulation of several sterol biosynthetic intermediates in the brains of the double-knockout mice suggests that Abcg1 and Abcg4 also have fairly broad substrate specificity. However, plant sterols do not accumulate in the brain or other tissues in Abcg1/Abcg4-knockout mice. We have recently shown that Abcg1 promotes efflux of 7-ketocholesterol to HDL in macrophages loaded with oxidized LDL, protecting these cells from oxysterol-induced toxicity (41)
. In contrast, Abca1 did not promote efflux of 7-ketocholesterol to apoA-1. Thus, Abcg1 promotes efflux of a wide variety of oxysterols and cholesterol from cells, with only partial overlap in function with Abca1.
We can only speculate on the potential physiological significance of an active transport system resulting in efflux of desmosterol and other sterol biosynthetic intermediates from cells. As noted above in the case of oxidized LDL loading of macrophages, efflux can constitute a mechanism to prevent accumulation of cytotoxic sterols in cells. Indeed, accumulating cholesterol precursors likely account for the developmental defects resulting from inborn errors of cholesterol biosynthesis, because these defects are ameliorated by cholesterol biosynthesis inhibition (42)
. Efflux of sterol biosynthetic intermediates seems wasteful in view of the high energy requirement of cholesterol biosynthesis. Moreover, viable cholesterol-free mice with desmosterol accounting for 99% of all sterols have been generated (43)
, suggesting that desmosterol is not cytotoxic and is able to largely substitute for cholesterol in mammalian biology. Thus, Abcg1 and Abcg4 may participate in a recycling process of sterols, including cholesterol, desmosterol, and possibly other sterol biosynthetic intermediates, between astroglial cells and neurons or between neurons in different states (44)
, and our media transfer data provide preliminary support for this idea (Fig. 8)
.
Received for publication September 25, 2007. Accepted for publication October 25, 2007.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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