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Loss of Integrity of Thyroid Morphology and Function in Children Born to Mothers with Inadequately Treated Graves’ Disease

Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Departments of Pediatric Endocrinology (M.J.E.K., A.S.P.v.T., J.J.M.d.V., T.V.) and Radiology (R.R.v.R., A.M.J.B.S.), 1100-DE Amsterdam, The Netherlands; and Erasmus Medical Center, Sophia Children’s Hospital, Department of Neonatology (B.J.S.), 3000 CB Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Marlies J. E. Kempers, M.D., Ph.D., Academic Medical Center, University of Amsterdam, G8-205, Emma Children’s Hospital Academic Medical Center, Department of Pediatric Endocrinology, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail: m.j.kempers{at}amc.uva.nl.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: Central congenital hypothyroidism (CH-C) in neonates born to mothers with inadequately treated Graves’ disease usually needs T₄ supplementation. The thyroid and its regulatory system have not yet been extensively studied after T₄ withdrawal, until we observed disintegrated thyroid glands in some patients.

Objective: The aim was to study the occurrence and pathogenesis of disintegrated thyroid glands in CH-C patients.

Design, Setting, Patients, Participants: Thyroid function was measured and thyroid ultrasound imaging was performed in 13 children with CH-C due to inadequately treated maternal Graves’ disease after T₄-supplementation withdrawal (group Aa). In addition, thyroid ultrasound imaging was performed in six children with CH-C born to inadequately treated mothers with Graves’ disease, in whom T₄ supplementation was not withdrawn yet (group Ab) or never initiated (group Ac), in six euthyroid children born to adequately treated mothers with Graves’ disease (group B), and in 10 T₄-supplemented children with CH-C as part of multiple pituitary hormone deficiency (group C).

Main Outcome Measures: Thyroid function and aspect (volume, echogenicity, echotexture) were measured.

Results: In group A, five children had developed thyroidal hypothyroidism characterized by persistently elevated TSH concentrations and exaggerated TSH responses after TRH stimulation. In the majority of patients in groups A and C, thyroid echogenicity and volume were decreased, and echotexture was inhomogeneous. Thyroid ultrasound imaging was normal in group B children.

Conclusions: Inadequately treated maternal Graves’ disease not only may lead to CH-C but also carries an, until now, unrecognized risk of thyroid disintegration in the offspring as well. We speculate that insufficient TSH secretion due to excessive maternal-fetal thyroid hormone transfer inhibits physiological growth and development of the child’s thyroid.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
CENTRAL HYPOTHYROIDISM IS a condition characterized by impaired secretion of thyroid hormone due to a defect in the thyroid’s regulatory system. In The Netherlands, neonates with central congenital hypothyroidism (CH-C) are detected by a T₄-based neonatal screening program (1, 2). Usually, permanent CH-C is part of multiple pituitary hormone deficiencies (2). Recently, we have reported on the occurrence of isolated CH-C in neonates born to mothers with Graves’ disease, presumably with a transient course. Although maternal characteristics were heterogeneous with respect to timing of diagnosis, thyroid antibody concentrations, and treatment, one consistent feature in all mothers was inadequate treatment during pregnancy, resulting in hyperthyroidism (3). Although this type of CH-C has been reported frequently (4, 5, 6, 7, 8, 9, 10, 11, 12, 13), the course of thyroid function after withdrawal of T₄ supplementation has been studied less extensively. It has been reported that plasma concentrations of free T₄ (FT₄) and TSH remain within their reference ranges when T₄ supplementation was withdrawn after a few months (5, 6, 8, 10, 11) and that the TSH response after TRH administration recovers (5, 11, 13), suggesting a transient condition.

When evaluating the thyroid function after withdrawal of T₄ supplementation in our patients with CH-C due to inadequately treated maternal Graves’ disease, we disclosed a persistent thyroid dysfunction in some of them, as a novel outcome. To gain more insight into the occurrence and pathogenesis of this finding, we analyzed thyroid function and performed thyroid ultrasound imaging in these patients in the phase without T₄ treatment. In addition, we performed thyroid ultrasound imaging in children with CH-C as part of multiple pituitary hormone deficiencies and in children born to mothers with adequately treated Graves’ disease during pregnancy.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Children with CH-C due to inadequately treated maternal Graves’ disease (group A, n = 19)

In the Academic Medical Center (AMC), records are kept of patients whose blood and/or urine samples were sent for confirmation of diagnosis of congenital hypothyroidism, or whose pediatrician consulted our pediatric endocrinology team. When this report was prepared, 28 children with CH-C due to inadequately treated maternal Graves’ disease were known in the pediatric endocrinology department of the Emma Children’s Hospital AMC.

Inadequate treatment was concluded when Graves’ disease was either not treated at all during pregnancy (obviously in those diagnosed after pregnancy and also those who stopped medication themselves) or insufficiently treated, resulting in persistently high-plasma FT₄ concentrations during pregnancy. The children were followed in the AMC or a local Dutch hospital. All but one started T₄ supplementation after diagnosis of CH-C. Timing of diagnosis of maternal Graves’ disease, maternal thyroid function determinants measured during pregnancy or after delivery, and neonatal thyroid function determinants before the start of T₄ supplementation were known.

In 13 children, T₄ supplementation was stopped (group Aa). Their thyroid function determinants after withdrawal were monitored. In six of them, TSH response after TRH administration was measured. In 11 children, thyroid ultrasound imaging was performed (two children were not able to visit the AMC). In three of five children with persistently elevated TSH concentrations, a thyroid ¹²³I^–-uptake study was performed.

In the five children whose T₄ supplementation could not be withdrawn yet because of young age (group Ab), exclusively thyroid ultrasound imaging was performed. Also in the child in whom T₄ supplementation was never initiated (group Ac), thyroid ultrasound imaging was performed.

Of nine children with the same type of CH-C, follow-up data were not (yet) available because they had moved abroad, were lost to follow-up, or were considered too young to withdraw T₄ supplementation and thyroid ultrasound imaging. The characteristics of these nine patients, in terms of maternal characteristics or neonatal thyroid function determinants, were not different from the 19 presented.

Children born to mothers with adequately controlled Graves’ disease (group B, n = 6)

Adequate treatment was concluded when Graves’ disease was diagnosed before or in the first trimester of pregnancy, for which patients received adequate treatment resulting in normal plasma FT₄ concentrations throughout pregnancy or, when diagnosis was made in the first trimester, within a few weeks after initiation of antithyroid drugs.

To evaluate thyroid function and structure in children born to mothers with adequately controlled Graves’ disease, group B was formed. Three children already participated in an earlier study on psychomotor outcome (14). Another three children were recruited among the younger sibs from group A children. Neonatal thyroid function determinants were recorded, thyroid ultrasound imaging was performed, and thyroid function was measured again.

Children with CH-C as part of multiple pituitary hormone deficiencies (group C, n = 10)

To evaluate thyroid function and morphology in children with permanent CH-C as part of multiple pituitary hormone deficiencies, group C was formed. There were 10 patients detected by the neonatal screening program and treated since then in the AMC who were willing to participate. During one of their routine visits for treatment control, thyroid ultrasound imaging was performed.

Methods

The study protocol was approved by the institutional review board of the AMC. All parents, and patients older than 12 yr, gave their written informed consent.

Thyroid ultrasound imaging was performed in the pediatric radiology department in the AMC. Thyroid volume (if the age of the child allowed accurate measurement), echogenicity, and echotexture were recorded by one of the pediatric radiologists (R.R.v.R. or A.M.J.B.S.), and blindly reexamined by the other (A.M.J.B.S. or R.R.v.R.), as well as a pediatric endocrinologist (T.V.). All observers had to have made the same interpretation about the ultrasound to score it as being abnormal. The volume (in ml) of each thyroid lobe was estimated as follows: transversal x sagittal x longitudinal maximum diameters x 0.479 (15), and was compared with age-matched reference values (16, 17, 18). Echogenicity was scored as "decreased," "normal," or "increased." Echotexture was scored as "normal," "inhomogeneous," or "abnormal" (when substantial irregularities were visible, e.g. nodules or cysts).

In the TRH test, plasma TSH was measured 15, 30, 45, 60, 120, and 180 min after iv administration of TRH (10 µg/kg). An adequate response was defined as a maximum TSH concentration between 15 and 35 mIU/liter after 20–40 min (2, 19).

Thyroid ¹²³I^–-imaging was performed by administering 2-MBq Na¹²³I^– iv; an uptake of 10–15% after 2 h was considered normal [extrapolated from the reported uptake after 24 h (20)].

The plasma FT₄ and TSH reference ranges, measured by time-resolved fluoroimmunoassays (Delfia Free T₄ and Delfia hTSH Ultra; Wallac Oy, Turku, Finland), as established in our laboratory, are 0.78–1.79 ng/dl (10.0–23.0 pmol/liter) and 0.4–4.0 mIU/liter, respectively; for neonates, the lower limit of the FT₄ reference range is 0.93 ng/dl (12.0 pmol/liter). When "FT₄" and "TSH" are mentioned in the text, their plasma concentrations are meant, unless otherwise mentioned. TSH receptor antibodies were measured using the TRAK assay (Brahms, Berlin, Germany), either with radioactive label or by luminescence.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Group Aa

The mothers were diagnosed with Graves’ disease before (n = 2, one twin pregnancy), during (n = 4), or after pregnancy (n = 6). As presented in Table 1, maternal FT₄ measured during or shortly after pregnancy was markedly elevated and accompanied by suppressed TSH (data not shown). In the neonatal period, all children had FT₄ less than 0.93 ng/dl (<12.0 pmol/liter), while TSH never exceeded 8.0 mIU/liter (Table 1). TSH-receptor antibodies were measurable in variable concentrations in both mothers and children (Table 2).

Patients with persistently elevated TSH after T₄ withdrawal (Table 3)

In patient Aa:4, T₄ withdrawal appeared successful at the age of 0.5 yr when both FT₄ and TSH remained within their reference ranges and maximum TSH response in the TRH test was normal (21.7 mIU/liter after 30 min). However, after 8 months TSH increased more than 4.0 mIU/liter, and T₄ supplementation was restarted. After another withdrawal at the age of 4.9 yr, TSH remained elevated up to 9 months (11.3 mIU/liter), and T₄ supplementation was restarted again. Also in patient Aa:5, whose TSH was within the reference range 5 months after T₄ withdrawal, TSH increased more than 4.0 mIU/liter after 1 yr. In patients Aa:8 and Aa:9, TSH increased immediately after T₄ withdrawal and remained elevated until supplementation was restarted a few months later. The maximum TSH response in the TRH test, performed during the T₄ withdrawal period, in patients Aa:4, Aa:5, Aa:8, and Aa:9 was exaggerated (47.9, 37.2, 53.0, and 127.0 mIU/liter, respectively; Fig. 1). In none of the patients were thyroid antibodies (TSH receptor antibodies > 1.5 IU/liter, thyroid peroxidase antibodies > 60 kIU/liter, or anti-thyroglobulin) detectable at ages 5.0, 2.3, 3.8, and 3.7 yr, respectively. The ¹²³I ^–-uptake, performed in patients Aa:4, Aa:8, and Aa:9, was low (4.4%, 5.2%, and 3.4%, respectively, after 120 min). In addition, in patient Aa:13, TSH increased immediately after withdrawal of T₄ and remained elevated up till 6 months after withdrawal. Because T₄ supplementation was restarted, no stimulation test could be performed yet.

View larger version (10K): [in this window] [in a new window]   FIG. 1. TRH test with normal and exaggerated TSH response. Dashed lines indicate normal TSH response, continuous lines exaggerated TSH response.

View larger version (35K): [in this window] [in a new window]   FIG. 2. Thyroid ultrasound image of child Aa:9 with thyroid disintegration, showing decreased echogenicity and inhomogeneous echotexture.

Patients with transiently elevated TSH after T₄ withdrawal (Table 3)

In four patients (Aa:1, Aa:2, Aa:11, and Aa:12), TSH spontaneously returned into the reference range, after a transient elevation (>4.0 mIU/liter) after withdrawal of T₄ supplementation. Thyroid echogenicity was decreased in patients Aa:11 and Aa:1, in combination with an inhomogeneous echotexture. Thyroid volume was decreased in patients Aa:1 and Aa:2 (Table 4).

Patients with normal TSH after T₄ withdrawal (Table 3)

In four patients (Aa:3, Aa:6, Aa:7, and Aa:10), TSH remained within the reference range after T₄ withdrawal. In patient Aa:7, T₄ was withdrawn for the first time at the age of 3.2 yr but was immediately restarted when FT₄ decreased to 0.5 ng/dl (5.9 pmol/liter) after 1 month. After a second attempt (age 3.5 yr) to withdraw T₄ supplementation, FT₄ decreased again and remained low up to 4 months (0.6 ng/dl, 8.1 pmol/liter). Also, in patient Aa:10, FT₄ was borderline (0.8 ng/dl, 10.3 pmol/liter) 6 months after withdrawal. In patients Aa:7 and Aa:10, the maximum TSH response in the TRH test was within the normal range (17.0 and 15.1 mIU/liter, respectively; Fig. 1) and substantially higher than in the neonatal period (2.3 and 8.5 mIU/liter, respectively). In patient Aa:10, thyroid echogenicity was decreased with inhomogeneous texture (Table 4).

Group Ab

Mothers of group Ab children were diagnosed with Graves’ disease before (n = 1), during (n = 1), or after pregnancy (n = 3). FT₄ during or after pregnancy was markedly increased (Table 1), and TSH was suppressed.

In the neonatal period, all children had FT₄ less than 0.93 ng/dl (<12.0 pmol/liter) and TSH less than 4.0 mIU/liter (Table 1). Thyroid echogenicity was decreased in two patients, echotexture inhomogeneous in one, and thyroid volume decreased in one patient (Table 4).

Group Ac

In patient Ac:1, who was never treated with T₄, FT₄ increased from 0.6–1.0 ng/dl (8.2–12.8 pmol/liter) within 4 wk after birth. TSH remained within the reference range, except at the age of 1 yr, when once 4.2 mIU/liter was measured. Maximum TSH response in the TRH test was insufficient at the age of 1 month (4.4 mIU/liter after 30 min) but normal at the age of 1.1 yr (26.4 mIU/liter after 40 min). He was released from out-clinic controls at the age of 1.5 yr [FT₄ 1.1 ng/dl (14.2 pmol/liter), TSH 4.0 mIU/liter]. At the age of 9.5 yr, both FT₄ (1.1 ng/dl, 13.7 pmol/liter) and TSH (2.6 mIU/liter) were within their reference ranges. His thyroid gland had a normal volume with inhomogeneous echotexture (Table 4).

Group B

The four mothers of the six group B children were known to have Graves’ disease before pregnancy (five pregnancies), or diagnosed already in the sixth week of pregnancy (one pregnancy). During pregnancy, mothers were treated with antithyroid drugs throughout pregnancy (three pregnancies), with T₄ after ¹³¹I^–-treatment before pregnancy (two pregnancies), or without any medication (one pregnancy). One of the mothers, diagnosed before pregnancy, was hyperthyroid until antithyroid drug treatment became intensified, resulting in FT₄ less than 1.94 ng/dl (<25.0 pmol/liter) from the 18th week of pregnancy onwards. In the mother with hyperthyroidism diagnosed in early pregnancy, FT₄ was less than 1.94 ng/dl (<25.0 pmol/liter) from the 16th week of pregnancy onwards, after antithyroid drug treatment became effective. In the other four pregnancies, FT₄ was less than 1.94 ng/dl (<25 pmol/liter) throughout pregnancy. TSH-receptor antibodies were measurable in variable concentrations in both mothers and children (Table 2).

Neonatal thyroid function was normal in all six children. At recall (median age 8.8 yr, range 1.3–11.4), all children were considered healthy. FT₄ was within the reference range in all six children, while TSH was in five (Table 5). Of note, child B:2 had been very nervous for the blood sampling and was extremely stressed during the venepuncture. His TSH was slightly elevated (4.8 mIU/liter), which we ascribed to his nervousness. To support this, two more stress-responsive determinants [prolactin (51 ng/ml) and cortisol (20.1 µg/dl, 555 nmol/liter)] were analyzed retrospectively and were indeed found to be elevated. Thyroid echogenicity, texture, and volume were normal in all children (Table 5 and Fig. 3).

View larger version (32K): [in this window] [in a new window]   FIG. 3. Thyroid ultrasound image of child B:4 with a normal thyroid, showing normal echogenicity and normal echotexture.

Nine CH-C patients had multiple pituitary hormone deficiencies and were treated with T₄ (n = 9), growth hormone (n = 8), hydrocortisone (n = 7), and testosterone (n = 2); 1 patient had isolated CH-C and was treated with T₄. In all patients FT₄ was within the reference range, and TSH suppressed (Table 5).

Thyroid ultrasound imaging showed decreased echogenicity in two patients, increased echogenicity in three, nodules in one, inhomogeneous echotexture in five, and decreased thyroid volume in six patients (Table 5).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
Disturbance of the fetal and neonatal thyroid hormone state, as one of the adverse effects of maternal Graves’ disease during gestation, is an important issue because it constitutes the risk of damage to the developing brain. The occurrence, type, and severity of thyroid dysfunction in the offspring are dependent on the presence of maternal thyroid antibodies and the use of antithyroid drugs (6, 21). Recently, we reported on children with CH-C born to mothers with gestational hyperthyroidism due to inadequately treated Graves’ disease. This entity illustrates that disturbances in the maternal thyroid hormone state during gestation may influence pre- and postnatal thyroid function in the offspring too (3). We followed these children extensively, especially after withdrawal of T₄ supplementation, to establish whether the condition would be transient or permanent. In all patients the pituitary dysfunction, as observed in the neonatal period, improved later on. However, until now, in five children, the apparently transient CH-C appeared to be succeeded by persistent thyroidal hypothyroidism. This novel finding constitutes another, unexpected adverse effect of maternal Graves’ disease.

The thyroid condition in these five patients was characterized by persistent hyperthyrotropinemia, an exaggerated TSH response in the TRH test, and thyroid glands with small volume and inhomogeneous echotexture. The onset of this thyroid condition is uncertain because thyroid ultrasound imaging was not performed systematically after birth. Besides, the initially coexistent TSH deficiency as well as subsequent (adequate) T₄ supplementation will have masked and prevented the biochemical expression of the thyroid dysfunction (3).

The other eight patients with CH-C due to gestational hyperthyroidism ended up (after withdrawal) with plasma TSH concentrations within the reference range, sometimes after a transient elevation. In six of them, concomitantly measured FT₄ concentrations were within the reference range; the two with low and low-normal FT₄ concentrations, respectively, had normal TSH responses in the TRH test, so hypothyroidism could not be established in either of them. On the other hand, the inhomogeneous echotexture and/or decreased thyroid echogenicity or volume, in the majority of patients with CH-C due to gestational hyperthyroidism, suggests that thyroid tissue is affected. The fact that TSH was not (persistently) increased in some patients in whom T₄ was withdrawn might be explained by ongoing pituitary-hypothalamic insufficiency (CH-C). In addition, the fetal hyperthyroidism to which our patients had been exposed might have shifted the pituitary’s set point for TSH secretion [in analogy to the shift in the opposite direction as observed in children exposed to fetal or perinatal hypothyroidism (22)], explaining the tendency to lower FT₄ in the subgroup of patients with persistently normal TSH. Although none of the patients had clinical problems after withdrawal, T₄ supplementation was restarted when either FT₄ or TSH continued to be outside the reference range.

Permanent and transient congenital hypothyroidism of thyroidal origin, occasionally described in children born to mothers with autoimmune hypothyroidism, has been attributed to cytotoxic effects of maternal antibodies (23, 24, 25). Although thyroid antibodies were not demonstrated in any of our patients with persistent thyroid dysfunction at the time T₄ supplementation was withdrawn, they had been detected (in variable concentrations) in the neonatal period (Table 2), as reported previously (3). To gain more insight into the possible role of antibodies in the thyroid problem in our group A patients, we also investigated thyroid function and structure in a group of children born to mothers with Graves’ disease adequately treated during pregnancy, in other words, in whom autoimmunity was not associated with hyperthyroidism. In their children, obviously without CH-C, we did not observe biochemical or ultrasound signs of a thyroid problem. So, this novel disease entity appeared to be restricted to children in whom CH-C preceded, rather than to be associated with thyroid antibodies of maternal origin, although our data do not allow exclusion of antibodies as an additional causal factor. A suitable (additional) control group (gestational hyperthyroxinemia without autoimmunity) would have been "not affected" children born to mothers with thyroid hormone resistance, but such cases never came to our attention. Indeed, the report of Anselmo et al. (26) dealing with this subject has shown that maternal thyroid hormone resistance can lead to pituitary dysfunction in the child, in line with our observations, but these authors did not (yet) report on the long-term consequences for thyroid morphology and function in the offspring.

In the control group of CH-C patients with multiple pituitary hormone deficiencies, in whom adequate T₄ supplementation invariably caused longstanding extremely low TSH concentrations (22), we observed extremely decreased thyroid volumes. Likewise, in patients with inactivating mutations in the TSH receptor gene, thyroid hypoplasia is a common feature (27). These observations led us to the hypothesis that early and longstanding insufficient TSH action hampers normal thyroid growth and development. A unique feature of the group of patients with CH-C born to mothers with gestational hyperthyroidism is that after a period of insufficient TSH action, the pituitary still started functioning several months after birth. Subsequently, persistent TSH elevation enables the disclosure of irreversible thyroid dysfunction, and demonstrates that the ultrasound features represent severely affected thyroid tissue. The loss of integrity of both thyroid morphology and function, after a phase in which the development and function of the thyroid’s regulatory system was hampered, suggests a developmental defect at the follicular level. We believe that the term "thyroid disintegration" best describes this phenomenon, which somehow combines thyroid dysgenesis and thyroid destruction.

Thyroid hormone plays an essential role in brain development during pre- and early postnatal life. Therefore, T₄ supplementation was initiated in our patients with CH-C as soon as the diagnosis was established. Although it might be that the institution of T₄ supplementation (further) impaired thyroid growth and integrity, we consider well-established preservation of brain development by instituting adequate T₄ supplementation a higher priority than the eventual preservation of thyroid tissue.

Because of its retrospective character, our study had some limitations, e.g. variation in the age of the children at the time of investigation. Whenever possible, a prospective design is more suitable to provide complete and structured information, but for obvious ethical reasons, the present issue cannot be studied in a prospective design. Monitoring maternal thyroid function will lead to immediate correction of any tendency to hypothyroidism or hyperthyroidism, aiming to prevent disturbance of the thyroid hormone state in both mother and child. Based on our previous (3) and present observations, we suppose that once maternal hyperthyroidism is prevented, the occurrence of the described type of central and thyroidal hypothyroidism in the offspring will also be prevented. So, we got a rather unique opportunity to learn about the pediatric consequences of inadequately treated maternal Graves’ disease.

In summary, inadequately treated maternal Graves’ disease resulting in gestational hyperthyroidism might not only lead to (transient) hyperthyroidism in the fetus and (presumably transient) CH-C in the newborn infant but also carries the until now unrecognized risk of thyroid tissue disintegration, resulting in (presumably permanent) loss of the patient’s capacity to maintain euthyroidism. We speculate that the long-term lack of TSH action due to the hyperthyroid fetal environment, possibly prolonged by the postnatal T₄ supplementation, interferes with thyroid development and results in loss of integrity in terms of thyroid morphology and function.

Long term follow-up is needed to evaluate the incidence and further consequences of this novel pathological entity, and to reveal the most appropriate diagnostic and treatment approach. In the meantime, careful monitoring of thyroid function determinants and thyroid imaging should be part of the diagnostic workup in children born to mothers with Graves’ disease.

	Acknowledgments

 
We thank all patients and their parents for their participation. We also thank the pediatricians, internists, and gynecologists for providing clinical data of their patients. Special thanks go to Brenda Wiedijk (Pediatric Endocrinology Department of the Emma Children’s Hospital Academic Medical Center) for her assistance in collecting all clinical data.

	Footnotes

 
Disclosure Statement: The authors have nothing to declare.

First Published Online May 15, 2007

Abbreviations: CH-C, Central congenital hypothyroidism; FT₄, free T₄.

Received September 20, 2006.

Accepted May 8, 2007.

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