IgE- and Fc{varepsilon}RI-mediated migration of human basophils

Maho Suzukawa1, Koichi Hirai2, Motoyasu Iikura1, Hiroyuki Nagase3, Akiko Komiya1, Chitose Yoshimura-Uchiyama1,4, Hirokazu Yamada1, Chisei Ra5, Ken Ohta3, Kazuhiko Yamamoto1 and Masao Yamaguchi1

1 Department of Allergy and Rheumatology and 2 Department of Bioregulatory Function, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
3 Department of Respiratory Medicine, University of Teikyo School of Medicine, Tokyo, Japan
4 Department of Pediatrics, University of Tokyo Graduate School of Medicine, Tokyo, Japan
5 Division of Molecular Cell Immunology and Allergology, Nihon University Graduate School of Medical Sciences, Tokyo, Japan

Correspondence to: M. Yamaguchi; E-mail: myama-tky{at}umin.ac.jp


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Local accumulation of basophils at inflammatory sites is observed in experimental antigen challenge and in allergic diseases. It is not fully known what factor(s) regulates local basophil influx in tissues, and it has not been determined whether antigens belong in a panel of basophil chemoattractants. This study was designed to elucidate whether IgE- and high-affinity receptor for IgE (Fc{varepsilon}RI)-mediated stimulation can induce human basophil migration. The migration-inducing potency of an anti-Fc{varepsilon}RI {alpha}-chain mAb, CRA-1, was examined on human basophils. CRA-1 mAb elicited significant migration of basophils. The migration-inducing potency of this mAb was maximal at 100 ng ml–1, and CRA-1 mAb at 100 ng ml–1 attracted ~10% of total inoculated basophils above baseline levels after incubation for 2.5 h. Checkerboard analysis indicated that basophil migration induced by this mAb was mainly chemotactic and partially chemokinetic. An antigen, Der f 2, also induced migration of basophils from Der f-sensitive subjects. Basophils mixed with 1 ng ml–1 of CRA-1 mAb showed an exaggerated migration response to eotaxin, indicating that Fc{varepsilon}RI cross-linkage enhances basophil migration to other chemoattractants. Induction of basophil migration by IgE- and Fc{varepsilon}RI-cross-linking stimulation may, at least in part, explain the pathogenesis of local basophil accumulation clinically observed in allergic diseases such as asthma.

Keywords: allergy, antigen, chemotaxis, non-releaser


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Basophils are the least abundant leukocytes in peripheral blood, but they possess biogenic amines such as histamine in their cytoplasmic granules. When these cells encounter specific antigens, they are stimulated and release various chemical mediators including histamine. Basophils are thus thought to be an active participant in the pathogenesis of immediate-type hypersensitivity reactions, as an important cellular source of pro-inflammatory mediators (1, 2).

In experimental antigen challenge models of the airways and skin, basophil accumulation has been demonstrated at the sites of inflammation (3, 4). Significantly increased numbers of basophils are also reported in local tissues of allergic patients such as asthmatics (5). These facts clearly show that local mechanisms exist for attracting basophils from the circulation. Influx of basophils to tissues is generally thought to be composed of three steps: adhesion, transendothelial migration and migration. Both adhesion molecules and cytokines play regulatory roles in adhesion (6) and transendothelial migration (7). Migration of basophils is mainly regulated by the interaction of soluble molecules and their receptors on the cell surface. Various factors including complement C5a (8), cytokines IL-3 and granulocyte macrophage colony-stimulating factor (9), chemokines (10) and other agents have been demonstrated to be able to induce basophil migration. However, it is not fully known which chemoattractant(s) plays a central or partial role at local inflammation sites in vivo.

Abundant expression of high-affinity receptor for IgE (Fc{varepsilon}RI) is one major characteristic of basophils as well as mast cells. Cross-linkage of Fc{varepsilon}RI by allergens and specific IgE induces cell activation, leading to the release of both granule-associated and newly synthesized mediators (1, 2). In addition, it has recently been increasingly understood that IgE and Fc{varepsilon}RI can generate intracellular signals affecting various biological aspects of cells other than release functions. In terms of cell motility, rodent mast cells are reportedly able to migrate toward specific antigens, and aggregation of IgE and Fc{varepsilon}RI initiates this migration (11, 12). Considering that migration is an essential step for blood basophils to act at local tissue sites, it is of great interest whether IgE and Fc{varepsilon}RI mediate the migration of mature human basophils. In this study, we assessed IgE- and Fc{varepsilon}RI-mediated basophil migration, and demonstrate that cross-linking stimulation of Fc{varepsilon}RI induces direct migration, and enhances chemokine-induced migration, of human basophils.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Reagents
The following reagents were purchased as indicated: Percoll (Pharmacia Fine Chemicals, Uppsala, Sweden), PBS and FCS (GIBCO, Grand Island, NY, USA), prostaglandin D2 (PGD2) (Cayman Chemical, Ann Arbor, MI, USA), human eotaxin/CCL11 (R&D, Minneapolis, MN, USA), human recombinant C5a and piperazine-N,N'-bis-2-ethanesulfonic acid (PIPES) (Sigma Chemical Co., St Louis, MO, USA), human monocyte chemoattractant protein-1 (MCP-1)/CCL2 (PeproTech Inc., Rocky Hill, NJ, USA), recombinant Der f 2 (Asahi Brewery, Tokyo, Japan) and ionophore A23187 (Calbiochem-Behring, La Jolla, CA, USA). Human recombinant IL-3 was kindly donated by Kirin Brewery (Tokyo, Japan). A mouse IgG2b anti-human Fc{varepsilon}RI {alpha}-chain mAb, CRA-1, was used; this antibody can bind to the Fc{varepsilon}RI {alpha}-chain regardless of whether or not it is occupied by IgE (13). The following antibodies were purchased as indicated: mouse IgG2b mAb with irrelevant specificity (MOPC195; Cappel, Aurora, OH, USA), FITC-conjugated goat anti-human IgE antibody (Biosource International, Camarillo, CA, USA), PE-conjugated anti-CD11b mAb (mouse IgG1, clone Bear1) and FITC- or PE-conjugated mouse IgG1 (clone 679.1Mc7) (Coulter Immunotech, Marseille, France). FITC-conjugated anti-CCR3 mAb (IgG1, clone 444) was prepared as described previously (14).

Cell preparation
Leukocytes were isolated from venous blood obtained from consenting volunteers with no history of atopic diseases. In some experiments, peripheral blood was drawn from consenting subjects with mite-sensitive allergic asthma, fulfilling the criteria for diagnosis of bronchial asthma (15). Basophils were semi-purified by density centrifugation using Percoll solutions of different densities (1.080 and 1.070 g ml–1). The purity of these Percoll-separated basophil preparations was ~12.3%. For some experiments, the Percoll-separated basophils were further purified by negative selection with MACS beads (Basophil Isolation Kit; Miltenyi BioTech, Belgisch-Gladbach, Germany) according to the manufacturer's instructions.

Migration
Basophil migration was analyzed using 24-well culture plates (IWAKI, Tokyo, Japan) and chemotaxicell (Kurabo, Osaka, Japan) with a 5-µm pore size. A total of 100 µl of PIPES buffer containing 25 mM PIPES, 119 mM NaCl, 5 mM KCl, 2 mM Ca2+, 0.5 mM Mg2+, 0.03% human serum albumin and 2 x 104 basophils was added to the upper chamber, and 300 µl of test reagent was placed in the lower chamber. After incubation for 2.5 h at 37°C, migrated cells in the lower chamber were collected and stained with 10 µg ml–1 of FITC-conjugated goat anti-human IgE for 30 min at 4°C. Cells were then analyzed using an EPICS XL System II (Coulter, Miami, FL, USA) (7). Migrated basophils were identified as cells strongly positive for IgE. The number of migrated cells might be potentially under-represented in our multistep experimental procedures using flow cytometer; to attain the data reliability, we usually spent longer time period for flow cytometric analysis of each sample under this method (7, 14). Migration was expressed as a percentage of the inoculated basophils after subtracting the spontaneous migration (5.1 ± 0.7%, n = 23) unless otherwise specified. All the experiments in this study were performed at least in duplicate.

Flow cytometry
CD11b expression experiments were performed using Percoll-separated basophils. Following stimulation, cells were incubated with 10 µg ml–1 of either PE-conjugated anti-CD11b mAb or PE-conjugated control mouse IgG1 and then stained with FITC-conjugated anti-human IgE antibody at 10 µg ml–1. Stained cells were analyzed by flow cytometry. The median values of fluorescence intensity of basophils were converted to the numbers of molecules of equivalent soluble fluorochrome units (MESFs), as previously described (16). Surface receptor levels were semi-quantified using the following formula: {Delta}MESF = (MESF of cells stained with anti-CD11b mAb) – (MESF of cells stained with control IgG).

CCR3 expression experiments were performed using MACS-separated basophils. Following stimulation, cells were stained for 30 min with 10 µg ml–1 of either FITC-conjugated anti-CCR3 mAb or FITC-conjugated control mouse IgG1 before flow cytometric analysis.

Degranulation
Basophil degranulation was examined using Percoll-separated basophils. Briefly, cells were re-suspended in PIPES buffer containing 2 mM Ca2+, 0.5 mM Mg2+ and 0.03% human serum albumin, and then stimulated at 37°C for 45 min in polystyrene tubes. The supernatants were stored at 4°C until histamine assay by an automated fluorometric technique (17). Histamine release was expressed as a percentage of the total cellular histamine after subtracting the spontaneous release (2.8 ± 0.8%, n = 9).

Statistics
All data are expressed as the mean ± SEM. Differences between values were analyzed by the one-way analysis of variance test. When this test indicated a significant difference, Fisher's protected least significant difference test was used to compare individual groups.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Anti-Fc{varepsilon}RI {alpha}-chain mAb, CRA-1, induces basophil migration
We first examined whether Fc{varepsilon}RI cross-linkage induces human basophil migration, by using an anti-Fc{varepsilon}RI {alpha}-chain mAb, CRA-1. As shown in Fig. 1(A), there was clear basophil migration toward CRA-1 mAb at 100 ng ml–1 (10.1 ± 1.9%, n = 7). The migration-inducing potency of CRA-1 mAb was statistically significant (P < 0.05). Basophil migration toward various known chemoattractants such as eotaxin, MCP-1, PGD2 and C5a is also included in Fig. 1(A). In clear contrast to the control IgG2b mAb which completely failed to increase the number of migrated basophils, CRA-1 mAb demonstrated induction of basophil migration at concentrations as low as 10 ng ml–1, and maximal migration was seen at 100–1000 ng ml–1 of this mAb (Fig. 1B). We next tested the migratory responses using semi-purified basophils (purity 12.3 ± 2.9%) and MACS-separated basophils (purity 99.0 ± 0.6%) simultaneously. CRA-1 at 100 ng ml–1 induced significant migration in both basophil preparations; no statistical difference was seen in the magnitude of migratory responses between the two preparations (P = 0.27) (Fig. 1C), indicating that CRA-1 mAb can exert the migration-inducing capacity via its direct action on basophils.



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Fig. 1. Anti-Fc{varepsilon}RI {alpha}-chain mAb, CRA-1, induces basophil migration. (A) Percoll-separated basophils were tested for migration toward lower chambers containing various known chemoattractants or CRA-1 at 100 ng ml–1 (n = 7). (B) Concentration-dependent basophil migration induced by CRA-1. Bars represent the SEM (n = 4). *P < 0.01, **P < 0.001, versus migration toward control mouse IgG2b. (C) Both Percoll- and MACS-separated basophils were tested for migration toward CRA-1 or control mouse IgG2b at 100 ng ml–1 (n = 4). Bars represent the SEM. *P ≤ 0.01. (D) Time course of basophil migration induced by eotaxin (50 nM) and CRA-1 (10 ng ml–1). Data are representative of two separate experiments. The percentages of background migration in the absence of any reagent were 1.4, 3.2, 4.3, 8.7 and 5.5% at 1, 2, 3, 5 and 7 h, respectively.

 
It has been reported that ~2 h of incubation is sufficient to detect apparent migration of basophils toward eotaxin or other known chemoattractants (9, 10). In contrast, CRA-1-induced basophil migration revealed a slower process: after incubation for 2 h, we observed only a small number of migrated basophils, but their number continued to increase until up to 7 h of incubation (Fig. 1D). At the 7-h time point, the percentage of basophils which had migrated toward CRA-1 at 10 ng ml–1 was comparable to that toward eotaxin at 50 nM. It should be noted that basophils from some donors demonstrated apparent spontaneous migration after 3 h or longer incubation in the absence of any chemoattractant. Accordingly, we decided that routinely the 2.5-h time point is appropriate for clearly distinguishing active attraction of basophils by CRA-1 from spontaneous migration.

Checkerboard analysis
Checkerboard analysis was performed by adding 1–100 ng ml–1 of CRA-1 mAb to the upper and/or lower wells. The most potent migration of basophils was observed when the optimal concentration of CRA-1 mAb was included only in the lower chambers, whereas weak migration was also seen when CRA-1 mAb was added to both chambers (Table 1). These results suggest that CRA-1-induced basophil migration was mainly chemotactic and partially chemokinetic.


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Table 1. Checkerboard analysis of Fc{varepsilon}RI-mediated basophil migration

 
Comparison of the effects of CRA-1 on various biological functions of basophils
It has already been established that cross-linkage of basophil surface Fc{varepsilon}RI results in degranulation and up-regulation of surface CD11b expression (6). We next compared the concentration-dependent effects of CRA-1 on basophil migration, CD11b expression and degranulation. To adjust the experimental design for cell treatment procedures among these three indices, migration of basophils was analyzed using cell preparations mixed with CRA-1 mAb before inoculation to the upper wells, and non-directional migration was thus measured. As shown in Fig. 2, all three indices of basophil activation demonstrated CRA-1 dose dependency within the tested concentration range. Maximal migration of basophils was observed at 100 ng ml–1 of CRA-1, but the extent of histamine release and up-regulation of surface CD11b expression plateaued at 1000 ng ml–1 of CRA-1. When the effective dose of 50% (ED50) concentration of CRA-1 was compared, half-maximal induction of basophil migration and CD11b up-regulation (ED50: within 1–10 ng ml–1) occurred at a slightly lower concentration of CRA-1 than that of histamine release (ED50: within 10–100 ng ml–1).



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Fig. 2. Effects of CRA-1 on various functions of basophils. Percoll-separated basophils were used, and the effects of CRA-1 on basophil migration, histamine release and CD11b expression were assessed. Data are the mean ± SEM (n = 4), calculated based on percentages of the maximum for each donor. *P < 0.01, **P < 0.001, versus the baseline in the absence of CRA-1. The actual percentage of maximal migration in the presence of CRA-1 was 14.6 ± 3.8%. The maximal level of surface CD11b expression in CRA-1-treated cells was 86.6 ± 10.6% above the baseline value.

 
Basophils migrate toward antigen
We next tested whether human basophils can migrate toward a specific antigen. Basophils were obtained from subjects with mild allergic asthma showing positive radioalloergosorbent test (RAST) for Der f. These basophils not only released histamine, but also migrated toward Der f 2 at sub-nanogram per milliliter doses (Table 2). In contrast, basophils from non-allergic subjects with negative RAST for Der f failed to be degranulated by, or migrate toward, Der f 2. These results indicate that sensitized basophils can migrate to a specific antigen.


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Table 2. Degranulation and migration of sensitized basophils by Der f 2

 
Non-releasing basophils do not migrate toward CRA-1
It is known that basophils from 10 to 20% of normal subjects do not degranulate in response to IgE- or Fc{varepsilon}RI-dependent stimulation (18). Using basophils from such non-releasers, we studied CRA-1-induced migration. As shown in Table 3, non-releaser basophils failed to migrate toward CRA-1 but did migrate toward an Fc{varepsilon}RI-independent chemoattractant, eotaxin. These results imply that an Fc{varepsilon}RI-dependent early signal transduction component essential for degranulation, presumably Syk (19, 20), is critically involved in Fc{varepsilon}RI-dependent migration of basophils.


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Table 3. Non-releasing basophils fail to show Fc{varepsilon}RI-mediated migration

 
Synergistic effect of CRA-1 on chemoattractant-induced basophil migration
Finally, we investigated whether CRA-1 affects basophil migration induced by other chemoattractants. Treatment with CRA-1 at 1 ng ml–1 did not alter the level of surface CCR3 expression by basophils (Fig. 3A). However, it did greatly enhance basophil migration toward eotaxin although the low concentration of CRA-1 induced little or no migration in the absence of eotaxin in the lower chamber (Fig. 3B). CRA-1 at 0.1 ng ml–1 enhanced eotaxin-induced basophil migration moderately compared with its 1-ng ml–1 dose. Slight and variable enhancement of eotaxin-induced migration was also observed in basophils treated with 10 ng ml–1 or higher concentrations of CRA-1. However, such high concentrations of CRA-1 affected basophil functions in a complicated manner, such as up-regulation of random migration and down-regulation of surface Fc{varepsilon}RI and CCR3 levels (data not shown). These results indicate that nanogram per milliliter doses of CRA-1 synergistically enhance eotaxin-induced basophil migration without up-regulating the surface expression of CCR3. We also investigated this synergistic effect using basophils from two separate non-releasers. However, the enhancement of eotaxin-induced migration was not seen with these basophils (data not shown), indicating that not only Fc{varepsilon}RI-mediated direct migration but also enhancement of eotaxin-induced migration of basophils is hampered in the non-releasing phenotype.



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Fig. 3. CRA-1 enhances basophil migration induced by eotaxin. (A) After stimulation with either CRA-1 or control IgG2b at 1 ng ml–1 for 2.5 h, surface CCR3 expression on basophils was assessed by flow cytometry. Basophils stained with FITC–control mouse IgG1, in place of FITC–anti-CCR3 mAb, are shown as shaded area. Data are representative of two separate experiments, showing similar results. (B) Basophils were mixed with either CRA-1 or control IgG2b (1 ng ml–1) and then placed in the upper chamber. Eotaxin at 10 nM was added to the lower chamber. Spontaneous migration of untreated basophils in the absence of eotaxin in the lower chamber was 4.8 ± 0.8%. The bars represent the SEM (n = 4).

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In this study, we have demonstrated that human peripheral basophil preparations can migrate in response to IgE- and Fc{varepsilon}RI-cross-linking stimulation. Most of our experiments were performed using an anti-Fc{varepsilon}RI {alpha}-chain mAb, CRA-1. This antibody is highly selective for the Fc{varepsilon}RI {alpha}-chain, with very low non-specific binding to Fc{varepsilon}RI-negative cells (13), suggesting that CRA-1 mAb interacts with basophils solely via its Fab portion. In addition, the basophil migration induced by this mAb was considered not to be an indirect event mediated by contaminating cells since it was observed even when using highly pure basophil preparations. Moreover, the Der f 2 antigen attracted basophils obtained from Der f-sensitive subjects. These results collectively imply that human basophils do migrate in response to stimulation via IgE and Fc{varepsilon}RI.

The intracellular mechanism(s) by which Fc{varepsilon}RI-dependent signals direct basophil migration is of special interest. We found that basophils from non-releasers, which do not degranulate in response to IgE-mediated stimulation, failed to migrate toward CRA-1 mAb, although binding of CRA-1 on these basophils' surface was confirmed by flow cytometry. Furthermore, up-regulation of eotaxin-induced basophil migration was not observed in non-releasers. Although the overall signal defect(s) in non-releaser basophils might not be fully clarified, one important point is the Syk deficiency (19, 20). This early signal tyrosine kinase is probably critically involved in cell motility changes following Fc{varepsilon}RI cross-linkage, as well as in degranulation.

It is known that IgE and Fc{varepsilon}RI are important molecules for the initiation of antigen-induced immediate-type hypersensitivity reactions. Recent progress in basic and clinical research has revealed that IgE and Fc{varepsilon}RI on the surface of mast cells and basophils may be more profoundly involved in the pathogenesis of allergy than had been previously conceived. Others and we have shown that IgE can regulate the surface expression of Fc{varepsilon}RI in various types of Fc{varepsilon}RI-positive cells such as mast cells and basophils (16, 21, 22). Recent reports have shown that IgE itself can regulate apoptosis of mouse mast cells (23, 24). With regard to cell motility, IgE aggregation has been demonstrated to induce rodent mast cell migration (11, 12). Ishizuka et al. (12) recently reported that sensitized mouse mast cell line MC/9 cells and bone marrow-derived cultured mast cells migrate toward a specific antigen and that the migration is chemotactic. Our results presented herein are basically similar to their mast cell findings. And, importantly, we found that eotaxin-induced migration of basophils is augmented by treatment of the cells with CRA-1 mAb at a concentration as low as 1 ng ml–1, although this concentration is unable to evoke significant degranulation. It is noteworthy that such weak stimulation can affect basophils; our results coincide with a previous report that concentrations of stimulus lower than those required for histamine release enhance basophil adherence to vascular endothelium (25). Since treatment with CRA-1 failed to increase the level of basophil surface CCR3 expression, the intracellular signal pathway following eotaxin and CCR3 interaction may be up-regulated. Such a migration-enhancing action arising from Fc{varepsilon}RI cross-linkage might be similar to that known in mast cells (26). Thus, previous reports and the present study collectively imply that the effect of IgE- and Fc{varepsilon}RI-dependent stimulation on cell locomotion, in both direct and indirect (enhancing) ways, might be a phenomenon common to both Fc{varepsilon}RI-abundant basophils and mast cells.

Local influx of basophils at inflammatory sites is an important aspect of allergen-induced late-phase reactions as well as allergic diseases such as asthma (35). In normal conditions, basophils reside only in circulating blood; thus, there must be some mechanism(s) that induces basophil migration into local tissues during allergic reactions. Since the first description of in vitro basophil chemotaxis by Kay and Austen (27), various agents have been identified as basophil chemoattractants, including complement (8), bacteria-derived peptides (9, 28), cytokines (9), chemokines (10), enzymes such as urokinase (28) and, in this study, specific antigens. Our results showing that allergens can induce basophil migration may need to be taken into account when we try to identify potential chemoattractant(s) in clinical allergy. Moreover, our findings that eotaxin-induced migration is up-regulated in basophils treated with low levels of CRA-1 mAb might explain, at least in part, the pathogenesis of basophil accumulation at inflammatory sites in allergic diseases, where prolonged antigen exposure and various pro-inflammatory mediators co-exist (29).

Recent studies have shown that Fc{varepsilon}RI-positive cells include not only mast cells and basophils but also eosinophils, macrophages, dendritic cells, neutrophils and platelets in humans (3034). In this context, it will be of great interest to assess whether IgE- and Fc{varepsilon}RI-mediated migrations occur in all of these Fc{varepsilon}RI+ cells, and, if so, to analyze to what extent this mechanism can account for the clinical efficacy of the IgE-targeting approach to treatment of allergic diseases.


    Acknowledgements
 
We thank C. Tamura and S. Takeyama for their skilled technical assistance and excellent secretarial work, respectively. This work was supported by a grant from the Ministry of Education, Science, Sports and Culture of Japan, and a grant of Long-range Research Initiative (LRI) grant from Japan Chemical Industry Association.


    Abbreviations
 
ED50   effective dose of 50%
Fc{varepsilon}RI   high-affinity receptor for IgE
MCP-1   monocyte chemoattractant protein-1
MESF   molecules of equivalent soluble fluorochrome unit
PGD2   prostaglandin D2
PIPES   piperazine-N,N'-bis-2-ethanesulfonic acid
RAST   radioalloergosorbent test

    Notes
 
Transmitting editor: S. J. Galli

Received 4 March 2005, accepted 29 June 2005.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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