Hum. Reprod. Advance Access originally published online on August 18, 2006
Human Reproduction 2007 22(1):142-150; doi:10.1093/humrep/del330
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The asynaptic chromatin in spermatocytes of translocation carriers contains the histone variant 
-H2AX and associates with the XY body
1 Biologia Celular, CIR, Facultad de Medicina, Universidad de Buenos Aires and 2 PROCREARTE, Argentina
3 To whom correspondence should be addressed at: Biologia Celular, CIR, Facultad de Medicina, Paraguay 2155, Buenos Aires (1121), Argentina. E-mail: asolari{at}fmed.uba.ar
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BACKGROUND: The close apposition of multivalents with the XY body has been repeatedly described in heterozygous carriers of chromosomal rearrangements. Because in many of these carriers spermatogenesis is deeply disturbed at the spermatocyte level, the association of autosomal chromatin with the XY body may impair the spermatocyte life. METHODS: Testicular biopsies from three men carriers of three different chromosomal rearrangements have been analysed by electron microscopy (EM) and immunolocalization of meiotic proteins. RESULTS: There is an ordered transition from isolated multivalents at early pachytene to XY body association in late pachytene, as shown in a carrier of a rob t(13;14) translocation by EM and in a reciprocal translocation t(9;14) carrier by immunofluorescence. The non-synapsed ends of the quadrivalent show BRCA1 located on the axes and the variant histone
-H2AX located on the chromatin. The area covered by -H2AX increases with the association of the asynaptic ends with the XY body in the t(9;14) carrier, and the area covered with -H2AX in the t(Y;15) carrier is larger than that of the XY body of controls. CONCLUSIONS: The affinity between the inactive XY body and asynaptic regions of multivalents is given a material basis, and transcriptional inactivation is probably shared by these two chromatin types.
Key words:
chromosome rearrangements/meiosis/spermatogenesis impairment/XY body/-H2AX
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Introduction |
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The frequent association between the XY body (Solari, 1974
, 1993; reviewed in Handel, 2004) and multivalents or univalents during male meiotic prophase is known since almost four decades (Forejt and Gregorova, 1977; reviewed in Solari, 1989). In human male infertile patients, carriers of heterozygous chromosomal rearrangements, a similar XY association with multivalents (Rosenmann et al., 1985; Johannisson et al., 1987; reviewed in Gabriel-Robez and Rumpler, 1994) or univalents (Jaafar et al., 1994) has been repeatedly reported. The hypothetical, pathogenetic role of this association of autosomal chromatin with the non-transcribing (silenced; Monesi, 1965) XY body has been also reported by several authors (reviewed in Solari, 1999 and in Oliver-Bonet et al., 2005a).
Although there is significant evidence that male carriers of either autosomal or gonosomal abnormalities frequently show spermatogenesis arrest (reviewed in Van Assche et al., 1996), the particular mechanisms involved in this arrest are poorly known. One of the most interesting facts related to the mechanisms of spermatogenesis arrest is the gradual association of some ends of the rearranged chromosomes with the XY body. This interest lies mainly in the increasingly known features of the transcriptional silencing of this XY body (Monesi, 1965; McKee and Handel, 1993; Turner et al., 2002, 2005; Baarends et al., 2005). Thus, the presence of the variant histone -H2AX in the transcriptionally silenced XY body (Mahadevaiah et al., 2001; Turner et al., 2004), as well as the role of the kinase ataxia telangiectasia Rad-3 related (ATR) (Turner et al., 2005) and the DNA-damage response protein BRCA1 (Xu et al., 2003; Turner et al., 2005) in the formation of the XY body in mice, has paved the way to investigate the features of normal and abnormal XY bodies in the human infertile patients.
The biopsies from the three patients involved in this study were analysed with light microscopy (LM) and electron microscopy (EM) and the last two with immunofluorescent localization of -H2AX and BRCA1, as well as with other techniques. In this article, we first show the detailed progress of the stepwise association between trivalents of a Robertsonian translocation and the XY body through the substages of the long (about 16 days, Heller and Clermont, 1964) pachytene stage in the human. Second, we show the areas covered by -H2AX in the normal XY body, the areas covered by this variant histone in a separated quadrivalent in a carrier of a reciprocal translocation and the area variations when this quadrivalent becomes associated with the XY body. Furthermore, we measure the areas covered by -H2AX in the case of a Y-autosome translocation carrier.
In conclusion, we show an enlargement of the areas covered by the variant histone when the XY body becomes associated with a quadrivalent and significant differences between the amounts of -H2AX of a normal XY body and that of the mixed, autosome-XY body of the Y-autosome translocation carrier. A mechanism for the gradual association with the XY body is suggested.
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The three patients analysed in this study were referred to Dr G.Rey-Valzacchi because of infertility. All the research procedures regarding these three patients were submitted and accepted by the ethics committee of the School of Medicine [Facultad de Medicina, Comite Independiente de Etica de Investigacion, (CIEI), UBA, Buenos Aires, Argentina].
In each of the three patients, the physical and instrumental examination gave negative results for an obstructive origin of azoospermia (cases 2 and 3) or a traumatic or infectious origin of severe oligospermia (case 1). A karyotype from blood lymphocyte cultures was performed for each of these patients, showing the presence of different chromosome rearrangements in each of the three cases.
Case 1. C.D. is a 27-year-old man who presents a severe oligospermia with plasmatic levels of FSH within the normal range. The karyotype from peripheral blood lymphocytes showed 46, XY, rob t(13q;14q). The mother of the propositus had two spontaneous abortions of unknown origin.
Case 2. E.L-C. is a 32-year-old azoospermic patient, with plasmatic levels of FSH within the normal range. His karyotype is 46, XY, t(Y;15)(q11.1;q21).
Case 3. G.J. is an azoospermic man of 29 years of age, with plasmatic levels of FSH within the normal range. His karyotype is 46 XY, t(9;14)(p11;q11).
Bilateral testicular biopsies were indicated for histopathological diagnosis and for the recovery of germ cells for possible ICSI treatment. The tissue was divided into pieces for LM and EM and for immunolocalization of proteins. A karyotypically normal man with an obstructive azoospermia and having complete spermatogenesis was used as a control for meiotic protein immunolocalization.
One testicular piece was processed for histopathological diagnosis with routine methods. Another piece of tissue was fixed in 2% glutaraldehyde, post-fixed with 1% osmium tetroxide in 0.1 M cacodylate buffer (pH 7.2), embedded in Araldite and sectioned in thin (0.08 µm thick) and semi-thin (0.5 µm thick) slices for EM and LM, respectively. Semi-thin sections were stained with toluidine blue to examine the germ cells in detail. For spermatocyte microspreads of synaptonemal complexes (SCs), slides were fixed with 4% formaldehyde + 0.1% Triton X-100 for EM and with 1% formaldehyde + 0.25% Triton X-100 for immunostaining. The latter slides were kept at –70°C until used for fluorescence microscopy.
Electron micrographs were obtained using a Siemens Elmiskop electron microscope (Siemens AG, Berlin, Germany) and were scanned with an HP ScanJet 3400C (Precissionscan LTX version 1.0, Mexico).
For immunolocalization of meiotic proteins, the slides were processed as previously described (Sciurano et al., 2006). Primary antibodies were used as follows: a rabbit anti- -H2AX (Abcam Ltd., Cambridge, UK) at 1 : 1000 dilution in phosphate-buffered saline (PBS), a rabbit anti-BRCA1 (Santa Cruz Biotech, CA, USA) at 1 : 50 and a mouse anti--H2AX at 1 : 5000 (Upstate Biotech, Lake Placid, NY, USA) were incubated at 37°C overnight. The following primary antibodies were incubated at 4°C: a mouse anti-SC protein (SYCP1) at 1 : 10 (P.J.Moens and B.Spyropoulus, York University, Toronto, Ontario, Canada) and a rabbit anti-SYCP3 at 1 : 500 (P.J. Moens and B. Spyropoulus). For double immunodetection exclusively on the same specimen, two successive rounds of incubations with primary antibodies were applied. All incubations were performed overnight in a humid chamber. After washing, the following secondary antibodies were used at 1 : 50 dilution in PBS for 1h: a fluorescein isothiocyanate (FITC)-labelled goat anti-rabbit, a tetramethyl-rhodamine isothiocyanate (TRITC)-labelled goat anti-mouse and a TRITC-labelled goat anti-rabbit. Slides were counterstained with 4,6-diamidino-2-phenylindole (DAPI) (0.2 µg/ml) and mounted in glycerol with 1,4-diazobicyclo-(2,2,2)-octane (DABCO) antifade. All spermatocyte microspreads were examined using a LEICA DM microscope (Leica Microsystems, Wetzlar, Germany) with the corresponding filters and photographed with a Leica DFC 300 FX digital camera (Cambridge, UK). The separate images were superimposed using the program Adobe Photoshop 5.0 (Adobe Systems Inc., USA).
To measure the areas labelled with -H2AX, we analysed the digitized images using the program ImageJ 1.30 v (NIH, USA, available at http://rsb.info.nih.gov/ij/Java 1.3.1_03). The area unit was arbitrarily chosen and kept constant in all the area measurements.
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Histology of the three testicular biopsies (LM)
Case 1
The histopathological analysis indicated a partial arrest of the spermatogenesis at the spermatocyte stage (Figure 1A). In agreement with the observations of the ejaculates, few spermatids were seen in the seminiferous tubules.
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Cases 2 and 3
Although Sertoli cells, spermatogonia and leptotene spermatocytes have a normal appearance, all the tubules showed full spermatogenic arrest at the first spermatocyte level. No spermatids or mature sperm were observed in semi-thin or in routine paraffin sections. Cell degeneration and death were seen, as nuclear pycnosis, at the lumen of the seminiferous tubules. Furthermore, some tubules presented a moderate increase in the thickness of the tubular wall (cases 2 and 3; Figure 1B and C, respectively). A reduced diameter of tubules (106 µm in average) was seen in case 2 (normal value = 140–200 µm).
Diagrams of the meiotic multivalents
As the three patients have different chromosome rearrangements, the analysis of meiotic spermatocytes shows three different configurations. The first patient shows a typical trivalent formed by the normal chromosomes 13 and 14 and the fused t(13;14) (Figure 2A).
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The quadrivalents and the relative lengths of the synaptic regions from the two reciprocal translocations (cases 2 and 3) are illustrated in schematic drawings of the pachytene configurations (Figure 2B and C, respectively).
The stepwise closeness and association of the Robertsonian trivalent with the XY body (case 1)
The analysis of 56 spermatocytes in a man, carrier of a rob t(13;14), revealed that the majority of these cells have a trivalent with two non-synapsed or ‘free’ short arms corresponding to chromosomes 13 and 14 and the fusion product (Figure 3A). However, a low percentage of the trivalents (9%) showed ‘heterosynapsis’ of those free ends (Figure 3B and C). These heterosynapsed trivalents were never associated with the XY body. The histogram (Figure 4) shows that the non-associated trivalents (with free short arms) are reduced in number as pachytene progresses, whereas the associated ones are increased at the late stages of pachytene. Although in early pachytene spermatocytes the trivalent is often completely separated from the XY pair (types I and II in substages of pachytene; Solari, 1980) (Figure 3A and B), the advanced stages show smaller distances between trivalents and the XY pair (Figure 3D) followed by a tangled association between the trivalent axes and the XY-axes (Figure 3E).
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The XY body in controls: the proteins BRCA1 and
-H2AXDuring pachytene, the variant histone
-H2AX disappears from the autosomes and is found only in the XY body in the control (Figure 5A). Measurements from 27 spermatocytes at early stages of pachytene show that the average total area of -H2AX in the XY body is 0.77 units (Table I).
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Simultaneous immunolocalization of the variant histone and BRCA1 shows that the latter protein is localized along the unsynapsed axes of the X and Y chromosomes in normal (control) spermatocytes. BRCA1 is absent on the pseudoautosomal region (PAR) (Figure 5A).
The distribution of -H2AX in the spermatocytes of the Y-autosome translocation carrier (case 2)
Spermatocyte spreads of SCs from the t(Y;15) carrier show quadrivalents that are formed by three synapsed ends and two free ends (Figures2B and 6A). One terminal component of the quadrivalent is always the X chromosome, which is associated with the translocation product Y15 through the PAR of the XY pair. The typical thickness and excrescences of the X- and Y-axes (Solari, 1980) allow the identification of these segments in the quadrivalents. The other free end is much shorter than the asynaptic segment of the X chromosome. This terminal axis is identified as the translocation product 15Y. The other two synapsed regions correspond to the SCs between the intact chromosome 15 and the two translocation products Y15 and 15Y.
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The immunolocalization of proteins in pachytene spermatocytes with an antibody against
-H2AX revealed the presence of this protein in the chromatin domains of the unsynapsed segments of the X and Y chromosomes as well as the autosomes (Figure 5B). These segments, which are variable in size, are located in the intact chromosome 15 and in the translocation products Y15 and 15Y. In a population of 37 spermatocytes, the average total area of -H2AX was 0.96 units, indicating that this area was significantly larger in t(Y;15) than in controls (Table I). Furthermore, the immunodetection of BRCA1 showed this protein decorating the X-axis (excluding the PAR) and the asynaptic segments of the axes of the translocation products and the chromosome 15 (Figure 5C).
The distribution of -H2AX in a t(9;14) quadrivalent without association with the XY chromosomes and when associated with the XY body (case 3)
The analysis of the SCs in early pachytene spermatocytes showed a quadrivalent having three synapsed segments and two free short ends. A diagram of the pachytene configuration shows the quadrivalent and the relative lengths of the synaptic regions (Figure 2C). One terminal axis corresponds to the intact chromosome 14 which forms a long SC with the translocation product 914 but has an unsynapsed short arm (Figures 2C and 6B). The other end of the quadrivalent was identified as the translocation product 149 on the basis of its relative length and its subterminal attachment to a nucleolar structure. Part of this translocation product forms the shortest SC with the intact chromosome 9. The longest SC corresponds to the association between the chromosome 9 and the longest translocation product 914 (Figure 2C). When late pachytene spermatocytes were observed, the majority of the quadrivalents had their free arms invading the XY pair and forming a tangled structure with the axes of the sex chromosomes (Figure 6C). These observations were similar to the associations between the rob t(13;14) trivalents and the XY body (discussed below).
The localization of the -H2AX protein in the quadrivalents and in the XY body allowed the measurement of the labelled area variations during pachytene (Figure 7A–D). Immunostained spermatocytes showed that this protein was restricted to small areas of the unsynapsed segments in the quadrivalents, in addition to the XY chromatin domain. As expected, the average of the sum of areas of -H2AX in the non-associated quadrivalent and the XY body (0.99) was significantly larger compared with the area of the isolated XY body in controls (0.77) (Table II). These observations were consistent with the previous results in the t(Y;15) translocation carrier. As pachytene progresses, the area of -H2AX in the asynaptic segments becomes larger in the quadrivalent when it is associated with the XY body (compared with non-associated quadrivalents) (Table II). In 40 examined spermatocytes at early pachytene, the average total area of -H2AX (from quadrivalents associated with the XY body) is 1.16, whereas the area of non-associated quadrivalents (plus the isolated XY body) is 0.99 (Table II). On the contrary, the observed pachytene spermatocytes showing completely synapsed quadrivalents (1%) did not present -H2AX in the quadrivalent. These quadrivalents were not seen in association with the XY body (Figure 7E).
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In the t(9;14) translocation carrier, BRCA1 was located on the asynaptic axial regions of the XY pair and on the asynaptic regions of the involved autosomal axes of the quadrivalent (Figure 7F).
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The gradual increase of XY association with abnormal autosomal ends and the escape of the heterosynapsed ends from XY association
An association between multivalents and the XY body was first described in mice carriers of autosomal reciprocal translocations, which were observed in sterile males (Forejt and Gregorova, 1977
). Among subfertile human males, carriers of Robertsonian translocations show variable degrees of association between the XY body and trivalents (reviewed by Gabriel-Robez and Rumpler, 1994). Despite this variable frequency of association, most of the observed cases show a correlation between the degree of XY body association with trivalents and spermatogenesis impairment (Johannisson et al., 1987, 1993; Gabriel-Robez and Rumpler, 1994), and a similar correlation has been observed in some carriers of reciprocal translocations (Yu et al., 1995). Some of the conflicting results may have arisen by the use of scoring by LM instead of EM, as in EM observations, there is an established progression of the XY features through the pachytene substages (Solari, 1980), which allows comparisons between different cases. In the present article, we used the pachytene substaging in exclusive EM analyses and in a substantial number of spermatocytes. The increment in XY body–trivalent associations is strongly correlated with the advancement of pachytene in human spermatocytes, as suggested by previous observations (Johannisson et al., 1987; Yu et al., 1995). Thus, the specific conditions for XY–trivalent associations (discarding the presence of heterosynapsis) are best at late pachytene.
Previous observations have also suggested that heterosynapsis between the free arms of trivalents and quadrivalents inhibits the association of these multivalents with the XY body (Gabriel-Robez and Rumpler, 1994; reviewed in Solari, 1999). Recent observations on two human reciprocal translocations showing very different frequencies of heterosynapsis give further support to this suggestion (Oliver-Bonet et al., 2005b). The present results agree with these previous observations, as it is shown that no heterosynapsed arms of cases 1 and 3 are ever found associated with the XY body. Furthermore, we show that heterosynapsed arms lack the variant histone -H2AX, in contrast to free arms.
It should be mentioned that the behaviour of free or unsynapsed arms in humans mirrors that of the recently reported autosomal asynaptic regions of spermatocytes from mice: if free ends associate in a non-homologous way, they lose the variant -H2AX histone (Turner et al., 2005, 2006). Thus, as previously suggested (Solari, 1999), heterologous synapsis may be a way to ‘escape’ from the damaging results of asynapsis and association with the XY body, both of which have been suspected to activate a pachytene checkpoint that may lead to apoptosis (Odorisio et al., 1998) or a damaging transcriptional inactivation (Solari, 1999; Oliver-Bonet et al., 2005a).
The presence of -H2AX in asynaptic chromatin and the XY body
-H2AX is a phosphorylated form (at serine 139) of the minor histone H2AX (reviewed in Redon et al., 2002). The biological significance of -H2AX has been highlighted in recent years, as it is a crucial constituent for the repair of DNA double strand breaks (DSBs) in somatic cells (Redon et al., 2002) and it is also an essential component for the normal development of male meiosis (Celeste et al., 2002; Fernandez-Capetillo et al., 2003). It is becoming increasingly clear that -H2AX takes part in at least two separate kinds of processes in male meiotic prophase. First, -H2AX is formed immediately after the occurrence of DSBs during leptotene, which are dependent on the meiosis-specific protein SPO11 (reviewed in Keeney, 2001), and disappears at the end of zygotene from the synaptic autosomes. Second, -H2AX is formed and maintained in the XY body, from the beginning of pachytene to the end of this long stage (Mahadevaiah et al., 2001; Fernandez-Capetillo et al., 2003). The first process is dependent mainly on the kinase ataxia telangiectasia-mutated (ATM), whereas the second one is dependent on the kinase ATR (Turner et al., 2005), and it is thought to be independent from the DSBs induced by SPO11 (Mahadevaiah et al., 2001; Fernandez-Capetillo et al., 2003), although this independence has been questioned (Bellani et al., 2005).
The present finding that the non-synapsed ends of multivalents have -H2AX gives some chemical basis to the previously observed similarities between autosomal asynaptic regions and the XY body. Thus, it has been previously reported that human autosomes remaining as univalents during pachytene (for instance chromosome 21 in human male trisomics; Johannisson et al., 1983) show axial thickenings and nodular excrescences. It might be suggested that the axial thickening and splitting might be associated with the finding of BRCA1 along these axes, as shown in the cited observations.
The extent of -H2AX is highest when autosomal ends are inside the XY body
Recent observations on mice carriers of chromosomal rearrangements have shown that autosomal segments that remain unsynapsed at pachytene display labelling for -H2AX. This occurs both in loops that may synapse heterologously later in pachytene, with loss of the -H2AX labelling (Mahadevaiah et al., 2001) and in mice carriers of Searle’s translocation [t(X;6)16H; Turner et al. 2005.]. In both of these instances, the axes of the asynaptic segments show labelling for the protein BRCA1 (Turner et al., 2005).
The present observations in human carriers of chromosomal rearrangements show the same protein localization as in asynaptic regions of meiotic chromosomes from mice. Then, we probed the area variations of -H2AX in the asynaptic autosomal segments, before and after the association with the XY body in Patient 3. Our observations show that in the associated multivalents, the area of -H2AX is highest, suggesting that the amount of the variant histone is enhanced by the association with the XY body. This fact may be interpreted as a ‘spreading effect’ from the silenced XY body towards the segments that remain synapsed in the quadrivalent. However, the alternative view that the amount of -H2AX in the autosomes is unrelated to the state of the XY body cannot be dismissed by the present results.
Although a ‘spreading’ effect of the inactive chromatin of the XY body over attached, autosomal chromatin has been earlier suggested by the EM analysis of Searle’s translocation in the mouse (Reader and Solari, 1969; Solari, 1971) and a ‘spreading effect’ has been also observed as an extension of the poorly labelled gonosomal region in spermatocytes incubated with 3H uridine from mice carriers of Searle’s translocation (Jaafar et al., 1989), such a ‘spreading’ effect may not be related to the well-known spreading effect of the somatic, X chromosome inactivation towards autosomal regions in X-autosome translocations (reviewed in White et al., 1998). The somatic spreading effect relies on the activity of the Xist gene, and the activity of this gene has been proved to be non-essential for meiotic sex chromosome inactivation (MSCI) (Turner et al., 2002). Thus, the present observations on larger areas of -H2AX chromatin in the multivalents associated with the XY body may be the result of another mechanism, as yet unknown. Furthermore, the basis for the association between the XY body and asynaptic chromatin may be a passive phenomenon, as discussed below.
Hypotheses on the mechanisms of the autosome–XY body association
The present results show a stepwise increase of the multivalents associated with the XY body throughout the long pachytene stage. This is not a particular feature of multivalents having asynaptic ends, as a supernumerary chromosome 21 is also associated with the human XY body at pachytene (Johannisson et al., 1983). Furthermore, a heterochromatic univalent frequently associates with the XY body in the human (Jaafar et al., 1994); and the experimentally generated mice with one or two ring mini-chromosomes (Voet et al., 2003) show that these ring mini-chromosomes associate with the XY body during pachytene in the mouse.
Turner et al. (2005) have shown in mice that non-synaptic, autosomal regions at pachytene are excluded from the domains covered by markers of transcription and therefore, they are presumably non-transcribing. Then, the common feature shared by the diverse kind of elements that become associated with the XY body is the lack (or weakness) of transcription. In that regard, it would be tempting to speculate that the association between multivalents and the XY body is the passive result of the exclusion from the transcriptionally active regions of the pachytene nucleus. Although the spatial distribution of transcribing and silenced chromatin domains in the human meiotic nucleus is scarcely known, 3H uridine labelling of human spermatocytes shows a RNA synthetic pattern similar to that found in mice (Saussine et al., 1994). On the contrary, in human somatic cells, it has been suggested that non-transcribing sequences are predominantly located in the nuclear periphery or at the nucleoli (Scheuermann et al., 2004). Thus, further studies on the 3D distribution of transcribing domains in the spermatocyte nucleus will add valuable data on this subject.
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We thank Dr Peter B.Moens and Barbara Spyropoulus (York University, Ontario, Canada) for the generous provision of SYCP1 and SYCP3 antibodies. The able technical support of C.Deparci is thankfully acknowledged. The histopathological diagnostic of the pieces was made by Professor Roberto Ponzio and is gratefully thanked. R.B.S. is a fellow from Conicet. A.J.S. and M.I.R. are members of the Carrera del Investigador and Profesional de Apoyo, respectively. Grants from UBACYT (M008) and Conicet 2137 to A.J.S. are acknowledged.
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Submitted on April 20, 2006; resubmitted on May 19, 2006; accepted on July 17, 2006.
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