Mutagenesis Advance Access originally published online on March 21, 2006
Mutagenesis 2006 21(2):159-165; doi:10.1093/mutage/gel010
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A combined analysis of XRCC1, XRCC3, GSTM1 and GSTT1 polymorphisms and centromere content of micronuclei in welders
1Laboratoire de Biogénotoxicologie et Mutagenèse Environnementale (EA 1784; IFR PMSE 112), Facultés de Médecine et de Pharmacie, Université de la Méditerranée, Marseille, France, 2Laboratoire de Biotoxicologie (UF 0756), Assistance Publique des Hôpitaux de Marseille, Marseille, France and 3Laboratoire de Biochimie et Biologie Moléculaire, Assistance Publique des Hôpitaux de Marseille, Marseille, France
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Abstract |
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The aims of the present study were to assess clastogenic and aneugenic properties of welding fumes using fluorescent in situ hybridization (FISH) with a human pancentromeric DNA probe. The involvement of genetic polymorphisms in DNA repair genes (p.Arg399Gln of XRCC1 and p.Thr241Met of XRCC3) and in detoxification genes (GSTM1 and GSTT1) on the centromere content of micronuclei (MN) was also evaluated. This study included 27 male welders working without any collective protection device and a control group (n = 30). The welders showed significantly higher levels of chromosome/genome damage compared to the controls. The frequencies of MN and centromere-positive MN (C+MN) per 1000 binucleated cells were significantly higher in the exposed group than in the control group (7.1
± 3.7 versus 4.9 ± 1.8; P = 0.012 and 3.5 ± 1.8 versus 2.4 ± 1.2; P = 0.018, respectively, Mann-Whitney U-test). The centromere-negative MN (C–MN) frequency was higher in the exposed subjects than in the controls (3.6 ± 3.4 versus 2.5 ± 1.4), but the Mann–Whitney U-test did not yield a significant result. In the total population, the GSTM1 and GSTT1 polymorphisms significantly affected the frequencies of C–MN and C+MN defined by FISH. GSTM1 positive subjects showed an increased C–MN frequency and GSTT1 null subjects showed an elevated C+MN frequency. When GSTM1 and GSTT1 genotypes were included in multiple regression analysis, the effect of the occupational exposure could better be demonstrated; both C+MN and C–MN were significantly increased in the welders. Our results suggest that the combined analysis of genetic polymorphisms and centromeres in MN may improve the sensitivity of the micronucleus assay in detecting genotoxic effects. |
Introduction |
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The International Agency for Research on Cancer (IARC) classified welding fumes as possibly carcinogenic to humans (group 2B) (1
). Welding processes produce gaseous and aerosol by-products that are composed of a complex mixture of metal oxides (2). The biological effects associated with welding fumes exposure are diverse and depend upon metal interactions and speciation. Epidemiologic studies have reported a significant elevated risk for lung cancer among welders (3). However, the combination of asbestos exposure and smoking may partly account for the observed excess of lung cancer. Several mechanisms of metals-induced genotoxicity, mutagenicity and carcinogenicity have been reported including direct DNA damage (4), generation of reactive oxygen species (5–7), inhibition of DNA repair (8), depletion of glutathione (9,10) and effects on DNA methylation (11). Most of these mechanisms are likely to be interrelated, and ultimately may cause abnormalities of gene function and neoplastic transformation. Several biomonitoring studies have reported the induction of DNA–protein crosslinks (12), chromosome aberrations (13,14) and micronuclei (MN) (15,16) by welding fumes. Earlier results have documented aneugenic (17–20) and clastogenic (21) properties or both (22) of different metal salts in vitro.
The cytokinesis-block micronucleus (CBMN) assay is frequently used in biomonitoring studies. MN are thought to be a biomarker either of exposure to environmental mutagens and/or carcinogens or of genome instability. MN contain either acentric chromosomal fragments formed by unrepaired double-strand breaks, or lagged chromosomes that have failed to segregate into a daughter macronucleus during mitosis. Fluorescent in situ hybridization (FISH) with a human pancentromeric DNA probe discriminates between negatively labelled MN containing acentric chromosome fragments (centromere-negative MN, C–MN) and positively labelled MN (centromere-positive MN, C+MN) containing one or several whole chromosomes (23).
Genetic polymorphism might be involved in interindividual variations of DNA repair and detoxification processes. Indeed, chromosome/genome damage, measured by CBMN assay in combination with FISH, could be influenced by genetic polymorphism. The X-ray repair cross-complementing gene 1 (XRCC1) is a key factor in the base excision repair pathway and is required for an efficient repair of DNA single-strand breaks (24). The X-ray repair cross-complementing gene 3 (XRCC3) is involved in the repair pathway of homologous double-strand breaks; it directly interacts with and stabilizes Rad51 (25). The XRCC1 variant allele coding Gln amino acid at position 399 (p.Arg399Gln) is associated with cancers of the head/neck, breast, lung and colon/rectum; a positive association between the XRCC3 variant allele coding Met amino acid at position 241 (p.Thr241Met) is shown in bladder cancer, malignant melanoma and gastric cancer (26). Glutathione S-transferases (GST) M1 (GSTM1) and T1 (GSTT1) are polymorphic enzymes responsible for the glutathione conjugation and can detoxify a number of various reactive species (27). Due to a homozygous deletion, the GSTM1 gene is lacking in 50% of Caucasians (28). The GSTM1 null genotype has been associated with an increased risk of lung, skin, bladder and colon cancers (29). Similarly, a deletion polymorphism also exists for GSTT1 and 13–28% of Caucasians are lacking the GSTT1 gene (28). GSTT1 null genotype has been found to be overrepresented in patients with astrocytomas and meningiomas (30).
The aims of the present study were to assess clastogenic and aneugenic properties of welding fumes and the involvement of genetic polymorphism in chromosome breakage and loss. We have previously reported an increase of the micronucleated lymphocyte rate in a group of welders compared to a control group (16). Our findings indicated no influence of DNA repair genotype on baseline MN frequency (16). In the present study, we have additionally characterized the content of MN and analysed the GSTM1 and GSTT1 genotypes of the subjects. To this end, we performed FISH using a human pancentromeric DNA probe to discriminate between the presence of chromosomal fragments and whole chromosomes in binucleated micronucleated lymphocytes of the welders and the matched-controls. We also determined the influence of genetic polymorphism in the XRCC1, XRCC3, GSTM1 and GSTT1 genes on the centromere content of MN.
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Subjects
Male welders (n = 27), working in areas without any collective protection device, were recruited from 16 workshops in the building-trade in the south of France. They were involved in manual metal arc, tungsten inert gas and metal inert/active gas weldings. The work processes of the selected welders consisted of welding, torch cutting, grinding, scraping and painting on mild and galvanized steels. Stainless steel or aluminum represented <5% of the handled metals. The workers had been exposed to welding fumes for 3–45 years. They were welding on average 14.6 h ± 6.9 a week. The control group (n = 30) was selected from the male working population and had no history of occupational exposure to welding fumes or any known physical or chemical agent in the workplace. The controls were recruited from general or administration services of different facilities related to the building industries in the south of France (office workers). The two groups studied were similar for their age (welders: 43.9 years ± 12.6; controls: 43.1 years ± 11.0), but the controls included somewhat more smokers (welders: 37%; controls: 53%). For each selected subject, relevant data on personal or familial medical history, smoking habits, alcohol consumption, drug intake and recent X-ray diagnostic examination were elicited via a standard questionnaire prior to blood sampling. We also ensured that each welder was working the month before sampling. Non-smoker subjects were never smokers or former smokers who had stopped to smoke for at least 1 year earlier. Exclusion criteria for both exposed and control subjects were history of radiotherapy and/or chemotherapy and use of therapeutic drugs known to be genotoxic or toxic for the reproduction. All subjects were informed of the objectives of the study and gave their written informed consent. The local ethical committee approved the research procedures of this study.
Blood samples
Blood samples were collected between 7 and 8 a.m. before work shifts and outside the working facilities. Blood samples were obtained by venipuncture on Monday (at the beginning of a work week) from all subjects for CBMN analysis (lithium heparin tubes) and for genotyping (EDTA tubes). All samples were kept on ice and in the dark and were processed within 6 h. Sample processing for the exposed and control groups was performed in the laboratory by the same operator for each analysis (CBMN and FISH analyses, genotyping analysis) in a blind manner.
CBMN assay
The CBMN assay was performed as previously described (16,31). For each slide, 1000 Giemsa-stained binucleated lymphocytes with a well-preserved cytoplasm were scored for the presence of MN according to previously described criteria (32). The number of MN was expressed as binucleated micronucleated cell rate (BMCR) per 1000 cells.
FISH with a pancentromeric DNA probe
Fluorescent hybridization with a human pancentromeric probe directly labelled with fluorescein isothiocyanate (FITC) was performed as described by Digue et al. (33) with slight modifications. Briefly, the cells were treated with proteinase K 50 ng/ml (Boehringer, Mannheim, Germany) at 37°C for 10 min. In situ DNA was denatured with 70% formamide/2x SSC for 2 min at 70°C. The DNA probe (Cambio, Cambridge, United Kingdom) was denatured at 85°C for 10 min. Following an overnight hybridization at 37°C, slides were washed in 50% formamide/2x SSC for 5 min at 37°C. The cells were then counterstained with propidium iodide in VectashieldTM antifade (Vector Laboratories, Burlingame, CA, USA). The previous frequency analyses (on Giemsa-stained slides) were used as a basis for calculating the frequencies of MN, C+MN and C–MN per 1000 binucleated cells. Binucleated cells with well-preserved cytoplasm were examined for the presence of MN by one microscopist on coded slides. If one or several yellow spots (FITC-labelled centromeres) were observed inside MN, the MN was classified as C+MN. A negatively labelled MN was classified as C–MN. The number of fluorescent spots per MN was also recorded and the C+MN were classified as MN harbouring a single centromere (C1+MN) or several centromeres (Cx+MN). The results were expressed as the total number of MN, the numbers of C–MN, C+MN, C1+MN and Cx+MN in 1000 binucleated cells. A total of 191 MN, 97 C–MN and 94 C+MN were scored in the exposed group in 27 000 binucleated cells. A total of 147 MN, 76 C–MN and 71 C+MN were scored in the control group in 30 000 binucleated cells.
Genetic polymorphism
The type of DNA damage expected from exposure to welding fumes dictated the choice of genes for analysis. The DNA polymorphisms of XRCC1 and XRCC3 genes were detected by sequencing amplified PCR fragments using PCR and sequencing primers as described in http://snp500cancer.nci.nih.gov. In the present report, DNA sequence variation was named according to the recommendations of den Dunnen and Antonarakis (34,35). The guanosine to adenine substitution in XRCC1 gene leading to a Arg399Gln amino acid change and the cytidine to thymidine substitution in XRCC3 gene leading to a Thr241Met amino acid change were monitored. Sequence analysis was performed on a CEQ 8000 Beckman sequencing device. The presence of homozygous deletions of GSTM1 and GSTT1 genes were detected by PCR as described by Abdel-Rahman et al. (29). The homozygous deletion of the GSTM1 and GSTT1 genes resulted in the absence of amplification of 215 and 480 bp DNA fragments, respectively. A band at 312 bp (corresponding to exon 7 of CYP1A1 gene) was always present and was used as an internal control to document successful PCR amplification.
Statistical analysis
The normality of variable distributions was evaluated by the Kolmogorov–Smirnov goodness-of-fit test. Since some of the data departed from normality, the differences between donor groups were calculated with the non-parametric Mann–Whitney U-test and the Chi-squared test for quantitative and qualitative variables, respectively. The association between quantitative variables was tested using non-parametric Spearman's rank correlation analysis. The statistical analysis included multiple regression analyses (backward multivariate regression) to examine the possible influence of several independent variables (smoking habits, age, exposure and genetic polymorphism) on the genotoxic endpoints (BMCR, MN, C+MN and C–MN). Statistical significance was set at P < 0.05. Statistical analysis was performed with SPSS 10.1 program for Windows (SPSS, Chicago, IL, USA).
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Results |
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CBMN assay
The average BMCR was significantly higher in the welders than in the controls (6.3
± 2.9 versus 4.7 ± 1.8; P = 0.029) as previously described by Iarmarcovai et al. (16). Smoking or drinking habits did not have a significant effect on BMCR. BMCR was not correlated with age or duration of occupational exposure to welding fumes.
FISH with a pancentromeric DNA probe
As shown on Figure 1, the MN and C+MN frequencies were significantly higher in the exposed group than in the control group (7.1 ± 3.7 versus 4.9 ± 1.8; P = 0.012 and 3.5 ± 1.8 versus 2.4 ± 1.2; P = 0.018, respectively). No significant difference of the frequencies of C1+MN and Cx+MN could be observed for the welders compared with the controls (1.9 ± 1.5 versus 1.4 ± 1.2 and 1.7 ± 1.2 versus 1.1 ± 0.9, respectively). The C–MN frequency was higher in the exposed subjects (3.6 ± 3.4) than in the controls (2.5 ± 1.4), but the difference was not statistically significant with the non-parametric Mann–Whitney U-test. The centromere content of MN did not differ between the two groups, the average C+MN/MN ratios were 52.1% ± 25.7 and 48.9% ± 22.2 in the exposed and control populations (P = 0.659), respectively. The average Cx+MN/MN andCx+MN/C+MN ratios were 26.4 and 48.0% in the exposed population and 23.7 and 48.9% in the control population. Our results showed that in welders and in controls (i) about 50% of the MN were C+MN, (ii) about 25% of the MN were Cx+MN and thus, (iii) about 50% of the C+MN were Cx+MN. No significant difference in the frequencies of MN, C+MN and C–MN was observed between smokers and non-smokers within control, exposed or total populations. MN and C–MN were significantly positively correlated with donor age in the exposed population (Spearman's test, r = 0.393; P = 0.043 and Spearman's test, r = 0.445; P = 0.020, respectively). Only C–MN was significantly positively correlated with donor age in the total population (Spearman's test, r = 0.266; P = 0.045).
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Genetic polymorphism
Genotypes of XRCC1, XRCC3, GSTM1 and GSTT1 were analysed to assess a possible association between their distributions (Table I) and C–MN and C+MN frequencies. Allele frequencies of XRCC1 and XRCC3 were similar to those observed in another Caucasian population (26
). The prevalence of the deleted GSTM1 and GSTT1 genotypes (66 and 25% of all subjects, respectively) were in accordance with previously described frequencies among Caucasian population (29).
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No significant difference between the XRCC1 genotypes was observed in the frequencies of BMCR, MN, C+MN and C–MN within control, exposed or total populations (Table II). No significant difference between the XRCC3 genotypes was noted in the frequencies of BMCR, MN, C+MN and C–MN within control, exposed or total populations (Table III). The frequencies of BMCR, MN and C+MN were not significantly different within control, exposed or total populations for individuals having a homozygous deletion of the GSTM1 (null genotype) and heterozygous or homozygous for the non-deleted gene (positive genotype). GSTM1 positive subjects showed a higher C–MN frequency than GSTM1 null subjects in both the total and the control populations (Table IV). GSTT1 genotype had no significant effect on BMCR, MN and C–MN frequencies. GSTT1 null subjects showed higher C+MN and C1+MN frequencies than GSTT1 positive subjects in the total population (Table V).
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Among smokers, in the total population, GSTM1 positive (n = 8) subjects showed a higher C–MN frequency than GSTM1 null (n = 18) subjects (4.5
± 2.3 versus 2.8 ± 3.7; P = 0.019). Among smokers, in the total population, GSTT1 null (n = 6) subjects showed higher MN and C+MN frequencies than GSTT1 positive (n = 19) subjects (8.7 ± 3.4 versus 5.2 ± 3.9; P = 0.014 and 4.0 ± 0.9 versus 2.3 ± 1.3; P = 0.006, respectively). When age, smoking and genetic polymorphisms of GSTM1 and GSTT1 were included in a multivariate linear regression analysis, an effect of exposure on the baseline frequencies of both C–MN and C+MN was observed (Table VI). The multiple linear regression analysis after adjustment for age and smoking showed a clear effect of GSTM1 and GSTT1 genotypes on the baseline frequencies of C–MN and C+MN, respectively. GSTT1 positive genotype was on borderline significance on C1+MN and Cx+MN frequencies (data not shown; P = 0.078 and P = 0.053, respectively). Overall, these results suggest that the GSTM1 genotype affects the frequency of C–MN and GSTT1 genotype that of C+MN.
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Discussion |
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In our previous article, we reported that BMCR is increased in the peripheral lymphocytes of the welders and that XRCC1 and XRCC3 genotypes do not influence BMCR (16
). In the present study, we characterized the origin of MN by using FISH with a pancentromeric DNA probe and additionally analysed the GSTM1 and GSTT1 genotypes of the subjects.
The centromere content of MN did not differ between the exposed subjects and the controls: 52.1 and 48.9% of the MN were C+MN in welders and in the control group, respectively. The proportion of C+MN observed in the control population agrees with the literature data: 30–80% of spontaneous MN are C+MN as measured by CREST antibody or FISH (36). A significantly higher frequency was observed for C+MN in exposed subjects than in controls, thus indicating that aneugenic effects were partly responsible for the elevated BMCR in welders. The C–MN frequency was higher in the exposed subjects than in the controls suggesting that clastogenic effects of welding fumes were also involved even if a simple comparison of distributions between groups did not yield a significant result. Benova et al. (37) found no difference in the proportion of C+MN and C–MN between a group of chromium platers (hexavalent chromium exposure) and a control group both in peripheral lymphocytes as well as in exfoliated buccal cells. Huvinen et al. (38) indicated no increase in C+MN and C–MN frequencies in nasal cells between 48 workers employed in stainless steel production after exposure to hexavalent or trivalent chromium and 39 referents from cold rolling mills. Palus et al. (39) reported that lead and cadmium induced clastogenic as well as aneugenic effects in peripheral lymphocytes of battery workers. Furthermore, DNA damage caused by welding fumes has been shown to differ from single metal exposure due to either additive or synergistic effects of multiple genotoxic compounds (6,40). Interactions of metal salts with cytoskeletal motor proteins (e.g. tubulin, kinesin) have been found to be responsible for the observed aneugenic effects (19,20).
In the present article, we separately analysed C1+MN and Cx+MN, because aneugenic events leading to MN containing a single centromere and two or more centromeres may arise through different pathways of C+MN formation. Chromosome migration impairment should lead to an increase of C1+MN frequency whereas centrosome defects should induce Cx+MN. In the present study, the frequencies of C1+MN and Cx+MN were similar within welders and controls suggesting no qualitative difference in C+MN content. Additional studies that target cellular defects on the centrosome (microtubule nucleation, organization of the spindle poles and cell cycle progression) are required for a better understanding of the production of aneuploid progeny cells (41,42).
In the present work, the frequency of C–MN increased with age. Several studies have indicated that the effect of age on MN frequency was mainly due to C+MN (36). An increase in C–MN frequency with age has been rarely reported (36). Nevertheless, this age-dependent C–MN increase could be related to the decrease in DNA repair activities with age (43). In the present study, smoking did not have a significant effect on chromosome/genome damage. Micronutrients (vitamins and minerals) are required as cofactors for enzyme activities or as part of the structure of proteins involved in DNA synthesis and repair, prevention of oxidative damage as well as maintenance of DNA methylation. Thus, micronutrient deficiencies could also induce genome damage (44). We did not determine the impact of diet and vitamins status on the MN index due to the relatively small sample size in the present work.
The level of genotoxic damage may be influenced by individual susceptibility factors such as genetic polymorphism which affects genomic stability and carcinogen metabolism (45). Chromosome breakage and chromosome loss involve different cellular and/or molecular dysfunctions. Thus, genetic polymorphisms might affect C+MN and C–MN in a different way. This study took into consideration the involvement of genetic polymorphisms in DNA repair genes and in detoxification genes on chromosome/genome damage as evaluated by CBMN assay in combination with FISH. DNA polymorphism of other products involved in DNA repair, such as hOGG1, should be considered in further investigations (46). No influence of XRCC1 and XRCC3 genotypes on baseline MN frequency was observed as previously reported (16). XRCC1 and XRCC3 are key factors of the base excision repair pathway and of the double-strand breaks repair pathway, respectively.
GSTM1 and GSTT1 contribute to resistance against oxidative stress. Our data indicated that, in the total population, GSTM1 positive subjects have a higher C–MN frequency and GSTT1 null subjects a higher C+MN frequency. Previous studies have reported that GSTM1 positive donors showed increased baseline MN frequency (47,48). Laffon et al. (49) found a similar tendency without a statistical significance. On the other hand, several studies have reported no influence of GSTM1 genotype on baseline MN frequency (50–55). The present study suggests that GSTM1 positive individuals have an increase especially in C–MN frequency. This effect may have been left unnoticed in the previous studies, because the centromere content of MN was not evaluated. The possibility of a higher C–MN frequency in GSTM1 positive subjects requires confirmation and a mechanistic explanation.
Several studies have shown no effect of GSTT1 genotype on baseline MN frequency (47,49,51–54,56,57). As opposed to these previous studies, we report a positive association with GSTT1 null genotype and C+MN frequency. The difference between the earlier articles and our study on the effect of GSTT1 genotype may again be explained by the centromere detection (the effect is limited to C+MN). To our knowledge, only one study has previously combined the analysis of genetic polymorphism and the detection of centromeres in MN. Vlachodimitropoulos et al. (58) indicated that the homozygous deletion of GSTT1 gene increased the sensitivity of whole-blood lymphocytes to the induction of MN after exposure to 1,2:3,4-diepoxybutane (DEB). The effect of the GSTT1 null genotype by DEB was highly significant for C–MN and to a lesser extent for C+MN.
Enhanced frequencies were observed for C–MN and C+MN in the welders in comparison with the controls but the difference was not statistically significant with the non-parametric Mann–Whitney U-test for C–MN. When GSTM1 and GSTT1 genotypes, which influenced the baseline frequency of C–MN and C+MN, respectively, were included in the statistical analysis, the exposure effect on C–MN and C+MN could better be demonstrated. The multiple linear regression analysis showed that both C+MN and C–MN frequencies were statistically significantly increased in the exposed subjects, when genotypes were taken into account. However, the small numbers of subjects restricted the conclusions on the possible associations among genotypes, occupational exposure and smoking in determining MN frequencies. Numerous genetic polymorphisms might modulate the human response to genotoxic insult. Thus, the studies of various gene–gene interactions and their modulation of genotoxic effects in their whole complexicity are required on larger populations (59). The genotype data must be analysed with methods that can detect small contributions from several genes, while also dealing with the errors that arise when many markers are tested (59).
In conclusion, the increased micronucleus frequency observed in welders appeared to be due to both aneugenic and clastogenic effects. The effect of the occupational exposure could be demonstrated especially when GSTM1 and GSTT1 genotypes, affecting the baseline frequency of C–MN and C+MN, respectively, were taken into account. Our findings suggest that the combined analysis of genetic polymorphisms and centromeres in MN may improve the sensitivity of the micronucleus assay in detecting genotoxic effects.
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Acknowledgments |
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We acknowledge the occupational physicians from APAMETRA BTP (Dr Fassi, Dr Pittilloni, Dr Vigneron, Dr Braunstein, Dr Salengro and Dr Canonne) for their active collaboration. We thank Pierre-Alexis Brabis and André Lanteaume for statistical advice and the Direction Régionale du Travail, de l'Emploi et de la Formation Professionnelle (PACA, France) for financial support (contract grant number 93CA 2004-004.0).
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Notes |
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* To whom correspondence should be addressed. Tel: +33 4 91 32 45 71; Fax: +33 4 91 32 45 72; Email: gwenaelle.iarmarcovai{at}medecine.univ-mrs.fr
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Received on December 8, 2005; revised on February 19, 2006; accepted on February 20, 2006.
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