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Rheumatology Advance Access originally published online on May 15, 2007
Rheumatology 2007 46(8):1243-1247; doi:10.1093/rheumatology/kem096
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Caspase 7 influences susceptibility to rheumatoid arthritis

J. R. García-Lozano, B. Torres, O. Fernández, G. Orozco1, A. Álvarez-Márquez, A. García2, M. A. González-Gay3, A. García4, A. Núñez-Roldán, J. Martín1,* and M. F. González-Escribano*

Servicio de Inmunología. Hospital Universitario Virgen del Rocío, Sevilla, 1Instituto de Parasitología y Biomedicina ‘López Neyra’, Granada, 2Servicio de Reumatología, Hospital Universitario Virgen del Rocío, Sevilla, 3Servicio de Reumatología, Hospital Xeral-Calde, Lugo and 4Servicio de Reumatología, Hospital Virgen de las Nieves, Granada.

Correspondence to: M. F. González-Escribano, Servicio de Inmunología, H. U. Virgen del Rocío, Avda Manuel Siurot s/n, 41013 Sevilla, Spain. E-mail: mariaf.gonzalez.sspa{at}juntadeandalucia.es


   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective. The aim of this study was to investigate the possible role of the caspase 7 (CASP7) in susceptibility to rheumatoid arthritis (RA).

Methods. Genotyping of three single nucleotide polymorphisms (SNPs) of the CASP7 gene: rs11593766 (G/ T), rs2227310 (C/G) and rs2227309 (G/A) was performed in a total of 906 RA patients and 528 matched healthy controls using TaqMan assays. All the subjects were of Spanish Caucasian origin. A relative quantification of mRNA encoding the non-functional variant of procaspase 7 (isoform ß) vs functional isoforms was performed in total RNA from 32 healthy individuals using real-time PCR.

Results. Only the rs2227309 SNP was found to be associated with susceptibility to RA. Frequency of the G allele was significantly higher among RA patients [overall frequency of the G allele 74.0% in cases vs 68.4% in controls, P = 0.001, Odds ratio (OR) = 1.32, 95% Confidence intervals (95% CI) 1.11–1.56] and a higher frequency of GG homozygous individuals was found in the RA patient group (overall frequency of GG genotype 56.0% in cases and 46.4% in controls, P = 0.0005, OR = 1.47, 95%CI 1.18–1.83). A statistically significant deviation was observed to compare the relative expression of the procaspase 7 isoform ß in samples from individuals stratified according their rs2227309 genotypes (AA + AG: 1.36 ± 0.55, n = 19, vs GG: 2.35 ± 0.74, n = 13; P = 0.0002).

Conclusion. Our results support involvement of the CASP7 gene in the susceptibility to RA. The higher production of the no functional variant of CASP7 by individuals with a particular genotype could be the basis of this association.

KEY WORDS: Caspase 7, Rheumatoid arthritis, Polymorphism, Gene expression


   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation of synovial tissue and joint destruction [1]. Although the pathogenesis of RA is unknown, the higher concordance of the disease in monozygotic twins and familial clustering provide evidences for the role of genetic factors in this pathology [2]. A low rate, as well as a high rate, of apoptotic cell death is involved in the development of various human autoimmune diseases [3]. In RA, impaired apoptosis of rheumatoid synovial cells appears to induce hyperplasia of the synovial tissues, whereas the acceleration of apoptotic cell death of osteoblasts may contribute to periarticular bone loss in patients with RA [4]. Humoral factors including cytokines and growth factors present in the rheumatoid synovial tissues modulate the expression of apoptosis-related molecules in the cells, which inhibit or stimulate the apoptotic process of synovial cells and osteoblasts. In addition, investigations of animal arthritis models suggest that an enforced induction of apoptosis of synovial cells ameliorates synovial tissue hyperplasia [5, 6]. Additionally, treatment with TNF antagonist has been shown to delay joint destruction and it has been demonstrated that both soluble TNF receptor and anti-TNF monoclonal antibodies induces apoptosis in macrophages [7]. The regulation of proliferation and cell death is vital for homoeostasis, but the mechanisms that coordinately balance these two events in RA remains largely unknown.

Apoptotic cell death is coordinated in cells by a family of the cysteine-aspartic acid proteases: caspases. Based on their proapoptotic functions, caspases can be divided into two groups: initiator and executioner. Stimuli for death receptor ligands (extrinsic pathway) a variety of different agents cause the activation of initiator caspases (caspases 8, 9 and 10). Once activated these initiators are able to activate the executioner procaspases by limited proteolysis. Executioner caspases cleave different intracellular proteins involved in promoting the apoptotic phenotype. In humans, there are two executioner caspases: caspase 3 and caspase 7 [8].

Different procaspase 7 isoforms have been found [9, 10]. The first described was procaspase 7 isoform {alpha}, a 303-aa residue polypeptide chain [11]. Upon activation in vivo, a short N-terminal peptide is removed, and more importantly for generating the catalytic activity, an IQADSG site is cleaved, giving rise to a large chain (175 residues) and a small chain (105 residues), comprising the active caspase 7 [12]. There are additional isoforms of the caspase 7 that are generated by alternative splicing, the majority of which retain catalytic activity. Nevertheless, procaspase 7 isoform ß, which is the shortest (253-aa), uses the same start codon that the variant {alpha} but it has a distinct C-terminus (from the aa position 149) compared with the other variants. The procaspase 7 isoform ß lacks the active site of the enzyme and may act as a dominant inhibitor for active procaspase 7 isoforms [11]. Because of its role in apoptosis, CASP7 gene can be considered a candidate for susceptibility to autoimmune diseases. The CASP7 gene is located in the chromosomal area 10q25.1–10q25.2 where linkage with RA has not yet been published [13], although neighbouring areas such as 10q21 and 10q26 have been found to be associated to the disease [14]. The aim of this study was to investigate the possible role of the CASP7 gene in susceptibility to RA in two different ways. First, using a case-control approach to study different single nucleotide polymorphisms (SNPs) located in the CASP7 gene and second, to quantify the expression of procaspase 7 isoform ß in individuals with different CASP7 genotypes.


   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 Acknowledgements
 References
 
Subjects included in genotyping study
A total of 325 patients were included in the study (Cohort 1). Patients were recruited from two Southern Spanish hospitals: Hospital Universitario Virgen del Rocío (Seville) and Hospital Virgen de las Nieves (Granada). A total of 315 blood bank and bone marrow donors were included as healthy control subjects.

Replication cohorts
Two additional cohorts were studied. A cohort of 389 RA patients collected in the same Southern Spanish hospitals (Cohort 2) and a second replication cohort (Cohort 3) consisted of 192 RA cases and 213 matched controls, respectively recruited from a Northern Spanish hospital: Hospital Xeral-Calde (Lugo).

All the patients meet the American College of Rheumatology (ACR) 1982 revised criteria for RA [15]. All the subjects, cases and controls were of Spanish Caucasian origin matched for age and gender. Samples were obtained from subjects after they provided written informed consent. The study was approved by all local ethical committees of the corresponding hospitals.

CASP7 SNPs genotyping
DNA from patients and controls was obtained from peripheral blood using standard methods. Genotyping of three SNPs of the CASP7 gene: rs11593766 (G/T), rs2227310 (C/G) and rs2227309 (G/A) was performed using TaqMan probe assays (TaqMan® SNP Genotyping Assays, C_8147132_20, C_500779_20 and C_500778_10, respectively, Applied Biosystems, Foster City, CA, USA) on an 7500 Fast Real-Time PCR System (Applied Biosystems). Allele-specific probes were labelled with the fluorescent dyes VIC and FAM. PCR reaction was carried out in a total volume of 8 µl with the following amplification protocol: denaturation at 95°C for 10 min, followed by 40 cycles of denaturation at 92°C for 15 s and finished with annealing and extension at 60°C for 1 min. Genotyping of each sample was automatically attributed using the SDS 1.3 software for allelic discrimination.

Haplotype assignment
The CASP7 gene haplotypes frequency estimation, obtained taking into account the three studied positions, was performed using Haploview, version 3.11 (available at the Web site: http://www.broad.mit.edu/mpg/haploview/download.php).

Relative quantification of mRNA encoding the procaspase 7 isoform ß vs isoforms non-ß
Total RNA from 32 healthy individuals carrying different genotypes was purified from 107 peripheral blood mononuclear cells isolated by density using QIAmp RNA Mini Kit (Qiagen, Hilden, Germany) as recommended by the manufacturer. Quantification of RNA obtained was performed by measure of the OD260. RNA integrity was verified both electrophoretically and by 260/280 nm absorption ratio. Reverse-transcription was performed in a total volume of 20 µl with SuperscriptTM First-Strand Synthesis System for RT–PCR (Invitrogen, Pasley, UK) using 1 µg of each total RNA and random primers according to the manufacturer's protocol. The kit includes RNaseOUTTM recombinant ribonuclease inhibitor as an RNase protector. Quantification of mRNA was performed by real-time PCR using a LightCycler 2.0 (Roche, Barcelona, Spain) with primers and hybridization probes designed and synthesized by TIB MOLBIOL (Berlin, Germany) (Fig. 1). For each sample, quantification of mRNA encoding isoform ß and isoforms non-ß was carried out in two independent assays. A common primer (CASP7-se) which spans exon 3–4 splice junctions was used as forward to avoid co-amplification with genomic DNA. For each assay, two different reverse primers were designed: CASP7beta-as for isoform ß and CASP7alpha-as for isoforms non-ß. Primers were tested using the BLAST algorithm to ensure that only the CASP7 gene was amplified. Specificity of isoforms ß and non-ß assays was further verified in two ways: by electrophoresis in agarose gel to check the size of the amplification products (an expected single band of molecular weight of about 230 bp and 260 bp respectively) and by the sequencing of some PCR-products using standard methods in a CEQ 8000 (Beckman Coulter) to confirm the expected sequence. In both assays, the same hybridization probes were used: CASP7-FL 3' labelled with fluorescein and CASP7-LC 5' labelled with LCRed 640 and PCR conditions were adjusted until amplification efficiency was approximately 1.9. For both assays, real time PCR was performed using the FastStart DNA master probe PCR mix (Roche) in a total volume of 20 µl using 500 nM of each primer, 200 nM of each hybridization probe, 4 mM of MgCl2 and 2 µl of cDNA. Cycle conditions were 95°C for 10 min, followed by 40 cycles at 95°C for 5 s, 65°C for 15 s and 72°C for 15 s. Each sample was tested in duplicate and a sample without template was included in each run as negative control.


Figure 1
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  		FIG. 1. Location of primers and probes used in relative quantification of mRNA encoding procaspase 7 isoform ß vs isoforms non-ß. For each sample, quantification of mRNA encoding isoform ß and isoforms non-ß was carried out in two independent assays. A common primer (CASP7-se) which spans exon 3–4 splice junctions was used as forward to avoid co-amplification with genomic DNA. For each assay, two different reverse primers were designed: CASP7 beta-as for isoform ß and CASP7alpha-as for isoforms non-ß. In both assays, the same hybridization probes were used: CASP7-FL 3' labelled with fluorescein and CASP7-LC 5' labelled with LCRed 640.

 
Data were analysed with LightCycler 4.05 software using the Calibrator normalized relative quantification with the efficiency correction method. A pool of cDNA from control samples was used as calibrator and set to a relative value of 1. A standard curve was generated for each assay using serial dilutions of PCR products obtained by conventional PCR of the calibrator sample. Measurements were performed within the linear area of the standard curves in all cases. Samples showing Cp values >35 and duplicates with a standard deviation of Cp > 0.3 were re-tested. Relative mRNA was expressed as the ratio of mRNA of isoform ß (target) and isoforms non-ß (reference) concentrations and normalized to the calibrator expression ratio.

Statistical analyses
Genotypic and allelic frequencies of the markers studied were obtained by direct counting. The chi-square test was performed to compare distributions for statistical analysis. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated according to Wolf 's method. The software used was Statcalc (Epi Info 2002; Centers for Disease Control and Prevention, Atlanta, GA, USA). P-values <0.05 were considered statistically significant.

Results of relative mRNA expression are showed as mean ± standard deviation. Statistical analysis of the mean of the relative expression of the CASP7 isoform ß was performed using the ANOVA test included in Epi Info 2002 because the variances were homogeneous (Barlett's test P > 0.05).


   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 Acknowledgements
 References
 
Association study
The study population was found to be in the Hardy–Weinberg equilibrium for all the polymorphisms analysed. Table 1 shows the distribution of alleles of the three CASP7 polymorphisms studied in RA patients and controls (Cohort 1). Frequency of the G allele of the rs2227309 SNP was significantly higher among RA patients (73.7 vs 67.5% in the control group, P = 0.01, OR = 1.35, 95% CI 1.05–1.73). The distribution of the rs2227309 genotypes showed a higher frequency of GG homozygous individuals in the RA patient group (57.2 vs 44.8% in the control group, P = 0.002, OR = 1.65, 95% CI 1.19–2.29). No significant differences in the distribution of rs11593766 and rs2227310 genotypes and alleles were observed among RA patients and controls.


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  		TABLE 1. Allelic frequencies of three SNPs studied in the CASP 7 gene in Spanish rheumatoid arthritis patients and healthy control population (Cohort 1)

 
To confirm association between the CASP7 rs2227309 SNP and RA, we carried out a replication study. We found a statistical significant association with the G allele in the Cohort 2 (73.7 vs 67.5% in the control group, P = 0.01, OR = 1.35, 95% CI 1.06–1.71). A higher frequency of GG homozygous individuals was also found in this RA cohort (54.8 vs 44.8%, P = 0.01, OR = 1.49, 95% CI 1.10–2.04). Data from the Cohort 3 showed the same trend as the other two cohorts: frequency of the G allele among RA patients 75.3 vs 69.7% in controls (P = 0.08, OR = 1.32, 95% CI 0.96–1.82) and frequency of GG homozygous individuals higher among patients than among controls (56.2 vs 48.8%) (Table 2).


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  		TABLE 2. Allelic and genotypic frequencies obtained in replication cohorts (Cohorts 2 and 3) for SNP rs2227309

 
No significant differences in the distribution of the rs2227309 SNP alleles were observed among the three patient cohorts or among the two control cohorts; hence, we combined all cohorts to form a RA case-control group. The overall frequency of the G allele was 74.0% in cases vs 68.4% in controls (P = 0.001, OR = 1.32, 95% CI 1.11–1.56) and overall frequency of GG genotype was 56.0% in cases and 46.4% in controls (P = 0.0005, OR = 1.47, 95% CI 1.18–1.83) (Table 2).

Next, we analysed the possible influence of the CASP7 gene in the disease outcome. No differences were observed when patients were stratified according to their gender, SE status, presence of rheumatic nodules or rheumatoid factor in the distribution of the SNPs included in this study (data not shown).

Table 3 shows data for the most common CASP7 haplotypes (frequency upper 5% in controls) found in our population. Statistically significant differences in the distribution of these haplotypes among patients and controls were not observed. The frequency of both haplotypes bearing rs2227309G was slightly higher and, conversely, the frequency of both haplotypes bearing rs2227309A was slightly lower among patients.


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  		TABLE 3. Haplotypes found in the CASP7 gene in our population having into account the three SNPs included in this study: rs2227309- rs2227310- rs11593766

 
Expression analysis
A relative quantification of mRNA encoding the non-functional variant of procaspase 7 (isoform ß) vs functional isoforms was performed in total RNA from 32 healthy individuals carrying different genotypes (Fig. 2). A statistically significant deviation was observed to compare the relative expression of the procaspase 7 isoform ß in samples from healthy subjects stratified according to their rs2227309 genotypes (AA + AG: 1.36 ± 0.55, n = 19, vs GG: 2.35 ± 0.74, n = 13; P = 0.0002). AA and AG samples were grouped together because association was found only with GG genotype. Although the number of samples was low to perform statistical analysis, we did not observe any gene-dose effect in the procaspase 7 isoform ß expression between the AA and AG genotypes (AA: 1.33 ± 0.41 vs AG: 1.38 ± 0.64) (Fig. 3).


Figure 2
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  		FIG. 2. LightCycler PCR amplification curves of the procapase 7 isoform ß and functional isoforms in some samples.

 

Figure 3
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  		FIG. 3. Relative expression levels of the procapase 7 isoform ß vs functional isoforms in healthy control samples stratified according to their rs2227309 genotypes.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
Acknowledgements
 References
 
This work constitutes the first attempt in establishing a relationship between caspase 7 and susceptibility to RA. Regarding SNPs studied in the CASP7 gene, the rs11593766 SNP, which is located is in the N-terminal end of the proteins, produces an E to D change in different amino-acid positions of all procaspase 7 isoforms. The other two SNPs studied are located in the C-terminal end of the protein. The rs2227310 SNP produces an E to D change in different amino-acid positions of isoforms non-ß and a S244T change in the isoform ß. The rs2227309 SNP is synonymous in the isoforms non-ß and produces a K249R change in the isoform ß [9]. The rs2227309 was the sole SNP found to be associated with susceptibility to RA and it produces amino-acid change only in isoform ß. Caspase 7 is an executioner caspase which requires cleavage of the IQADSG site to turn into the active form [12]. The isoform ß has a distinct C-terminus (from the amino-acid position 149 of the isoform {alpha}) compared with the other variants and, as a consequence, it lacks the cleavage site and the residues involved in substrate recognition and catalysis. The isoform ß may act as a dominant inhibitor of the active forms [11]. One possible explanation for our results in the association study could be the differences in the levels of the isoform ß among individuals with different rs2227309 genotypes. To check this hypothesis, the expression of the isoform ß was quantified in a group of 32 healthy individuals with different rs2227309 genotypes using a relative quantification mRNA method in mononuclear blood cells. Statistically significant differences in the expression of isoform ß were observed among genotypes. Individuals with GG genotype had the highest expression of isoform ß, 1.7-fold more than AA and AG individuals. Thus, in the healthy population, mononuclear cells from individuals with GG genotype could have a lower apoptotic activity based on a higher relative quantity of the no-functional isoform. We did not perform an expression analysis in patients because they received different treatments that can modify the apoptotic pathway. Experimental data obtained in mice support decreased apoptosis in the absence of caspase 7 [16]. Multiple data support that impaired apoptosis is a characteristic of several autoimmune diseases, and administration of factors that stimulate apoptosis reduce inflammation [3–7].

Validation of genetic association studies requires replication using independent data set [17]. Three different set of patients and two different set of controls were included in the present work. Further replications of these data in other populations are necessary to confirm association between the CASP7 gene and RA. CASP7 has been proposed like a positional candidate to susceptibility to insulin-dependent diabetes mellitus (IDDM) [18]. In addition, inactivating mutations in the CASP7 gene have been associated with different types of human cancers [19]. Therefore, the involvement of this polymorphism in other autoimmune and non-autoimmune disease must be also investigated.

In conclusion, our results support the relationship between the CASP7 gene and the susceptibility to rheumatoid arthritis. The higher production of the no functional variant of caspase 7 by individuals with a particular genotype could be the basis of this association.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
References
 
This work was supported by grants: Fondo de Investigaciones Sanitarias (PI 04-0067), Plan Nacional de I+D+I (SAF03-3460) and Junta de Andalucía, grupos CTS-197 and CTS-180.

The authors have declared no conflicts of interest.


   Notes
 
*These authors share senior authorship in this study. Back


   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature (2003) 15:356–61.
  2. Oliver JE, Worthington J, Silman AJ. Genetic epidemiology of rheumatoid arthritis. Curr Opin Rheumatol (2006) 18:141–6.[Web of Science][Medline]
  3. Mahoney JA, Rosen A. Apoptosis and autoimmunity. Curr Opin Immunol (2005) 17:583–8.[CrossRef][Web of Science][Medline]
  4. Stanczyk J, Ospelt C, Gay RE, Gay S. Synovial cell activation. Curr Opin Rheumatol (2006) 18:262–7.[Medline]
  5. Zhang H, Gao G, Clayburne G, Schumacher HR. Elimination of rheumatoid synovium in situ using a Fas ligand ‘gene scalpel’. Arthritis Res Ther (2005) 7:R1235–43.[CrossRef][Web of Science][Medline]
  6. Peng SL. Fas (CD95)-related apoptosis and rheumatoid arthritis. Rheumatology (2006) 45:26–30.[Abstract/Free Full Text]
  7. Catrina AI, Trollmo C, Klint E, et al. Evidence that anti-tumos necrosis factor therapy with both etanercept and infliximab induces apoptosis in macrophages, but not lymphocytes, in rheumatoid arthritis joints. Arthritis Rheum (2005) 52:61–72.[CrossRef][Web of Science][Medline]
  8. Fuentes-Prior P, Salvensen GS. The protein structures that shape caspase activity, specificity, activation and inhibition. Biochem J (2004) 384:201–32.[CrossRef][Web of Science][Medline]
  9. accessed October 2006. Available at: http://www.ncbi.nlm.nih.gov/entrez/.
  10. accessed October 2006. Available at: http://vega.sanger.ac.uk/Homo_sapiens/.
  11. Fernandes-Alnemri T, Tokahashi A, Armstrong R, et al. Mhc3, a novel human apoptotic cysteine protease highly related to CPP32. Cancer Res (1995) 55:6045–52.[Abstract/Free Full Text]
  12. Stennicke HR, Salvensen GS. Caspases - controlling intracellular signals by protease zymogen activation. Biochim Biophys Acta (2000) 1477:299–306.[CrossRef][Medline]
  13. Tiso N, Pallavicini A, Muraro T, et al. Chromosomal localization of the human genes, CPP32, Mch2, Mch3, and Ich-1, involved in cellular apoptosis. Biochem Biophys Res Commun (1996) 225:983–9.[CrossRef][Web of Science][Medline]
  14. Jawaheer D, Seldin MF, Amos CI, et al. Screening the genome for rheumatoid arthritis susceptibility genes A replication study and combined analysis of 512 multicase families. Artrhitis Rheum (2003) 48:906–16.[CrossRef]
  15. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum (1988) 31:315–24.[Web of Science][Medline]
  16. Lakhani SA, Masud A, Kuida K, et al. Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science (2006) 311:847–51.[Abstract/Free Full Text]
  17. Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG. Replication validity of genetic association studies. Nat Genet (2001) 29:3069.
  18. Babu SR, Bao F, Roberts CM, et al. Caspase 7 is a positional candidate gene for IDDM 17 in a Bedouin Arab family. Ann NY Acad Sci (2003) 1005:340–3.[CrossRef][Web of Science][Medline]
  19. Soung YH, Lee JW, Kim HS, et al. Inactivating mutations of CASPASE-7 gene in human cancers. Oncogene (2003) 22:8048–52.[CrossRef][Web of Science][Medline]
Submitted 18 December 2006; revised version accepted 21 March 2007.
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