Nutrition and Cancer

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A Prospective Study of Iodine Status, Thyroid

Function, and Prostate Cancer Risk: Followup of the First National Health and Nutrition
Examination Survey
Stephen A. Hoption Cann , Zhenguo Qiu & Christiaan van Netten
To cite this article: Stephen A. Hoption Cann , Zhenguo Qiu & Christiaan van Netten (2007) A
Prospective Study of Iodine Status, Thyroid Function, and Prostate Cancer Risk: Follow-up of
the First National Health and Nutrition Examination Survey, Nutrition and Cancer, 58:1, 28-34,
DOI: 10.1080/01635580701307960
To link to this article: http://dx.doi.org/10.1080/01635580701307960

Published online: 05 Dec 2007.

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NUTRITION AND CANCER, 58(1), 2834

C 2007, Lawrence Erlbaum Associates, Inc.
Copyright

A Prospective Study of Iodine Status, Thyroid Function, and Prostate

Cancer Risk: Follow-up of the First National Health and Nutrition
Examination Survey

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Stephen A. Hoption Cann, Zhenguo Qiu, and Christiaan van Netten

Abstract: Few studies have investigated the association between iodine status, thyroid disease, and cancer risk despite
evidence that thyroid function impacts many organs, including the prostate. We investigated iodine status and prostate
cancer risk prospectively using data from the NHANES I Epidemiologic Follow-up Study. Participants were stratified into
tertiles according to the urinary iodine/creatinine ratio, as a
marker of iodine exposure. As iodine is an integral constituent
of thyroid hormones, we also examined the relationship between thyroid disease and prostate cancer risk. Relative to
the group with low urinary iodine, the age-adjusted hazard
ratio was higher (although marginally insignificant) in the
moderate group, hazard ratio 1.33 (95% confidence interval 1.001.78), and significantly lower in the high group,
0.71 (0.510.99). Thyroid disease was associated with an
increased prostate cancer risk, 2.34 (1.244.43). Similarly,
>10 yr since thyroid disease diagnosis was associated with
an elevated risk, 3.38 (1.666.87). After adjusting for other
confounding factors, only a history of thyroid disease, 2.16
(1.134.14), and >10 yr since diagnosis of thyroid disease,
3.17 (1.546.51) remained significant. Although the role of
dietary iodine remains speculative, a role for thyroid disease and/or factors contributing to thyroid disease as a risk
factor for prostate carcinogenesis warrants additional investigation.

Introduction
An increasing number of in vitro and in vivo studies have
shown that thyroid hormones may influence the proliferation
and metabolic activity of prostate cells. Animal studies have
shown that reciprocal interactions occur between the thyroid
and prostate (1,2). In rats, prostatectomy has been shown
to cause significant reductions in triiodothyronine (T3) and
thyroxine (T4) levels in vivo; while prostatic secretions may
enhance T3 and T4 production in thyroid cells cultured in

vitro (2). In vitro studies have shown that T3 enhances cellular proliferation in prostatic LNCaP carcinoma cells (35).
Recent human studies by Lehrer et al. (6,7) have demonstrated men with prostatic hyperplasia and prostate cancer
have elevated serum T3 levels in comparison to normal controls. Although there can be various causes for raised T3
levels, in regions of iodine deficiency (<100 g iodine per L
in urine) preferential synthesis and secretion of T3 has been
observed (8). In this respect, a case-control study by Key
et al. (9) found an inverse trend between iodine intake and
prostate cancer risk. Thus, there could be an intriguing yet
largely unstudied link between prostate cancer development
and iodine and/or iodine-containing thyroid hormones.
To examine a possible protective role for iodine on
prostate cancer risk, we used prospective data from a followup study of the First National Health and Nutrition Examination Survey (NHANES I). As iodine is of primary importance
in the formation of thyroid hormones, we also examined
the relationship between thyroid disease, goiter, and prostate
cancer risk.

Methods
Study Design
The First National Health and Nutrition Examination Survey (NHANES I) was a multistage, national probability sample of the US civilian noninstitutionalized population conducted from 1971 to 1975 (10,11). Baseline data collection
included demographics, medical history, standardized medical examination, dietary history, laboratory tests, and anthropometric measurements. The NHANES Epidemiologic
Follow-up Study (NHEFS) was a prospective cohort study
of NHANES I participants who were aged 2574 yr when
the original survey was conducted, which included 5,811
males (1215). For the NHEFS study, subjects (or proxy respondents if deceased) were traced and interviewed again in

Stephen A. Hoption Cann and Christiaan van Netten are affiliated withDepartment of Health Care and Epidemiology, University of British Columbia, 5804
Fairview Ave., Vancouver, BC, V6T 1Z3, Canada. Zhenguo Qiu is affiliated with Population Health and Information, Cross Cancer Institute, Alberta Cancer
Board, 11560 University Ave., Edmonton, AB, T6G 1Z2 Canada.

19821984, 1986, 1987, and 1992. Data were also collected

from hospital records, including pathology reports, and if
deceased, death certificates. This tracing accounted for 90%
of the original cohort 2574 yr of age.
Exposure Variables

1992), discharge diagnoses from hospital stays, and/or death

certificates. We excluded 1,577 men without a measurement
of urinary iodine at baseline. Of this remaining cohort, there
were 197 cases of prostate cancer of which a further 10 subjects were excluded due to prostate cancer at baseline. Thus,
the final analytical cohort consisted of 4,234 men, including
187 cases of prostate cancer.

From the laboratory tests, medical history interview, and

medical examination, the following exposure variables were
derived.

Prostate Cancer Incidence

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Iodine Status
Urinary iodine concentrationswere determined by the Iodine Research Laboratory, Universityof Massachusetts Medical Center (Worcester, MA). Spot urine samples were
collectedfrom fasting participants (1016 h before the
morningexamination or for 6 h before the afternoon or
evening examination). Urinary iodine concentrations (UIC)
weredetermined using the Sandell-Kolthoff reaction as modified by Benotti et al. (16), a catalytic reaction of iodide on
the oxidation of arsenic (III) by cerium (IV). For the measure
of iodine concentration, a creatinine adjustment was used to
correct for volume fluctuations between samples. Measurement of the urinary iodine/creatinine ratio is one of the most
widely used methods of estimating iodine intake and was
used as the surrogate measure of iodine status in cohort participants at baseline.
Thyroid Disease
In the medical history interview, participants were asked
about their history of thyroid disease (without specifying
subtype) and time since diagnosis (<10 yr or >10 yr). This
was split into a history (past or present) of thyroid disease or
no history. An examination of risk according to a history of
hypothyroidism or hyperthyroidism could not be undertaken
as this was only determined in a small subset of the cohort.
In the medical examination, a physical assessment of thyroid size was performed and classified according to World
Health Organization (WHO) criteria used for grading goiters
(i.e., grade 0 = no goiter; grade 1 = palpable goiter; grade
2 = visible goiter; grade 3 = very large goiter). This was
categorized as goiter (grades 13) or no goiter (grade 0).

Incident events were based on documentation of an event

occurring during the period between the participants baseline examination and last follow-up interview. The date of
record for incident events were identified by date of first
hospital admission with an established study event or date
of death from a study event in the absence of hospital or
nursing home documentation of such an event. Only invasive prostate cancer diagnoses International Classification of
Diseases, Ninth Revision (ICD-9) code of 185 were categorized as cases. Subjects who self reported a baseline history
of prostate cancer without other confirmatory documentation
were included with noncases.
Statistical Analyses
Noncases were censored on the last date known to be
alive and without prostate cancer. For each baseline characteristic, the frequencies of potential risk factors mean value
or percentage of study participants were separately calculated by tertile of iodine intake (i.e., low, moderate, high).
The 2 test was used to identify those potential confounding
factors. Cox proportional hazard regression analyses were
performed to explore the relationship between iodine status,
thyroid disease, goiter, and the subsequent development of
prostate cancer. The Statistical Analysis Software (SAS) was
used to estimate the hazard ratios (HRs) and corresponding
95% confidence intervals (CI). Age was used as the time
scale for all time-to-event analyses (17).
Ethical Considerations
The study protocol was approved by the Clinical Research
Ethics Board of the University of British Columbia.

Prostate Cancer Risk Factors

Information about other possible prostate cancer risk factors including race (white vs. nonwhite), marital status (yes
vs. no), income (high vs. low-middle), and alcohol consumption (yes vs. no), and region (northeast, midwest, south, west)
as strata were obtained from baseline data.
Study Population
Of the 5,811 men of the NHEFS study, 252 cases of
prostate cancer were identified from diagnoses of prostate
cancer at follow-up interviews (19821984, 1986, 1987, and
Vol. 58, No. 1

Results
In Table 1, a comparison of the frequencies of potential risk factors at baseline per category of iodine/creatinine
ratio (i.e., low, moderate, high) is presented. The mean age of
men at examination in our study sample was 52.7 yr old, approximately 16.5% of the participants were non-white. The
majority of subjects reported high (36.6%) or low (32.9%)
household incomes, with a minority of middle income earners (26.4%). Most subjects reported alcohol use at baseline
(77.2%). Significant associations were observed between the
29

Table 1. Baseline (197174) Characteristics of Study Population by Tertile of Iodine/Creatinine Ratio

Iodine/creatinine categories (g/g)

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Demographic
variables
Age
2544
4564
6574
Race
White
Other
Married at baseline
Family income
Low
Middle
High
Alcohol at baseline
Region
Northeast
Midwest
South
West
a The

<201, n = 1452
n (%)

201345, n = 1554
n (%)

>345, n = 1228
n (%)

537 (38.5)
406 (31.5)
509 (32.9)

503 (36.0)
492 (38.2)
559 (36.1)

356 (25.5)
391 (30.3)
481 (31.1)

1100 (31.1)
352 (50.3)
1168 (33.5)

1319 (37.3)
235 (33.6)
1304 (37.4)

1115 (31.6)
113 (16.1)
1014 (29.1)

491 (35.3)
347 (31.1)
560 (36.2)
1165 (35.6)

496 (35.6)
422 (37.8)
559 (36.1)
1201 (36.7)

405 (29.1)
348 (31.2)
429 (27.7)
904 (27.6)

379 (41.6)
334 (33.1)
379 (33.4)
360 (30.6)

322 (35.3)
385 (38.2)
404 (35.6)
443 (37.6)

211 (23.1)
289 (28.7)
353 (31.1)
375 (31.8)

<0.001

<0.001

0.043
0.075

<0.001
<0.001

P -values from 2 test.

adjustment variables (with family income approaching significance) and the categorized iodine/creatinine ratios by the
2 test, as seen in Table 1.
The majority of cases had a low to moderate iodine status (Table 2). In the Cox regression model, moderate iodine/creatinine levels were associated with a borderline increased risk of disease relative to low levels, HR = 1.33 (95%
CI 1.001.78). However, in the multivariate model the risk
was no longer significant, HR = 1.31 (95% CI 0.981.75). In
contrast, high intake was significantly associated with a reduced risk of prostate cancer, HR = 0.71 (95% CI 0.510.99);
and following multivariate adjustment it remained reduced,
but was no longer significant, HR = 0.75(95% CI 0.53
1.05). There was no association between use of table salt and
prostate cancer risk. A reported history of thyroid disease was
associated with a greater than two fold increase in risk, HR =
2.34 (95% CI 1.244.43), which remained significant following the multivariate adjustment, HR = 2.16 (95% CI 1.13
4.14). Similar to having a history of thyroid disease, use of
thyroid medication at baseline tended to be associated with an
increased risk, but this was not significant whether adjusted
for age or multivariate analysis 1.35 (95% CI 0.434.22). An
increasing time since first diagnosis of thyroid disease (>10
years) also was associated with elevated hazards in both the
age, HR = 3.38 (95% CI 1.666.87), and multivariate models, HR = 3.17 (95% CI 1.546.51). The presence of a goiter
(WHO grades 13) as determined by physical exam was not
associated with prostate cancer risk HR = 0.94 (95% CI 0.30
2.95), although goiter was uncommon among cases, with
only three having signs of an enlarged thyroid upon physical
exam.

30

P -valuea

Discussion
The association between dietary iodine intake and incidence of prostate cancer remains unclear. In the group
with the highest iodine status, there was a decreased risk
of prostate cancer, but it lost significance following multivariate adjustment. A previous case-control study by Key
et al. (9) found a non-significant reduced risk for prostate
cancer in subjects with the highest iodine intake (OR = 0.75,
95% CI 0.511.11, P -value for trend 0.077), where iodine
intake was estimated from a dietary questionnaire. It may
be that an iodine intake higher than the recommended daily
allowance (RDA) could afford protection against prostate
cancer, but this cannot be conclusively determined from
the present study. The mean iodine level in our cohort was
50 g/L. In contrast, the Japanese have a comparatively high
iodine intake as shown in a study by Nagata et al. (18) where
the mean UIC in four different regions ranged from 810 to
1,620 g/L. A large study in Sapporo, a city in Northern
Japan, observed a mean iodine level of 3,400 g/L (19).
Low rates of prostate cancer are seen in Japan where iodine
intake is commonly above the RDA of 150 g/day (20). In
fact, in the developed world Japan has one of the lowest ageadjusted prostate cancer incidence rates, 12.6 per 100,000;
in the United States by comparison, the rate is 124.8 per
100,000 (21). However, Japanese immigrants to the United
States, and their successive generations, have incidence rates
that gradually increase to that of Caucasian men in the United
States (22). A chronological correlation study by Tominaga
and Kurioshi (23) examined the association between cancer
mortality in Japan and changing dietary patterns over time.

Nutrition and Cancer 2007

Table 2. Prostate Cancer Risk According to Markers of Iodine Status and Thyroid Function
Hazard Ratios (HR)
Age-adjusteda

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Study variables
Iodine/creatinine (g/g)
Low (<201)
Moderate (201345)
High (>345)
P -value for trendd
Use of salt shaker
Rarely/occasionally
Frequently
Thyroid disease
Never
Ever
Thyroid medication use
No
Yes
Years since 1st diagnosis
No diagnosis
<10 yr
>10 yr
Goiter at baseline
No
Yes

Cases (%)

HR (95% CI)

Multivariate-adjustedb,c
HR (95% CI)

61 (32.6%)
81 (43.3%)
45 (24.1%)

1.00
1.33 (1.001.78)e
0.71 (0.510.99)
0.405

1.00
1.31 (0.981.75)
0.75 (0.531.05)
0.460

128 (68.4%)
59 (31.6%)

1.00
1.05 (0.771.42)

1.00
0.99 (0.731.36)

177 (94.7%)
10 (5.3%)

1.00
2.34 (1.244.43)

1.00
2.16 (1.134.14)

184 (98.4%)
3 (1.6%)

1.00
1.35 (0.434.22)

1.00
1.27 (0.404.00)

178 (95.2%)
1 (0.5%)
8 (4.3%)

1.00
0.64 (0.094.59)
3.38 (1.666.87)

1.00
0.54 (0.083.89)
3.17 (1.546.51)

184 (98.4%)
3 (1.6%)

1.00
0.94 (0.302.95)

1.00
0.93 (0.302.92)

a Age

used as time scale for all time-to-event analyses.

for age as mentioned previously, race (white vs. other), marital status (yes vs. no), income (high vs. middle to low)d , and alcohol consumption
(yes vs. no), and region (northeast, Midwest, south, west) as strata.
c High income had significant effect within each strata (region): HR = 1.57, 95% CI 1.15-2.16, P -value = 0.005.
d The P -values in log-trend test using the continuous variable of iodine/creatinine.
e The HR was marginally insignificant: 95% CI = 0.9991.782.
b Adjusted

They found that westernization of Japanese dietary habits

was significantly associated with increasing mortality rates
for prostate, breast and other cancers. Although there are
many dietary differences between Japan and the west, a diet
rich in seafood is a prominent difference. In Japan, iodine
intake can vary widely with dietary habits. Iodine rich foods
such as saltwater fish, and seaweed in particular (24), explain why Japan probably has the highest national iodine
consumption in the world (20). One Japanese case-control
study (25) has suggested that iodine rich seaweed may protect against prostate cancer. In this study, a reduced relative
risk (RR = 0.47, 95% CI 0.230.97) was observed for older
men who had a high consumption of seaweed (25). Another
Japanese study found a trend towards a reduced prostate cancer risk for moderate (RR = 0.74, 95% CI 0.531.03) to high
(RR = 0.86, 95% CI 0.601.24) seaweed consumption vs.
low (26). These associations, however, may be due to a protective effect of nutrient factors in seaweed other than iodine.
Additionally, there are other dietary factors in Japan that may
be protective against prostate cancer, the most prominent being omega-3 fatty acids from fish and other seafoods (27)
and soy products (28,29).
Iodine is an essential trace element primarily known for
its role in thyroid hormones. Emerging experimental evidence, however, has shown that iodine may have many alternative metabolic functions, including a broad range of
anti-proliferative (20,30,31), anti-inflammatory (30), antioxVol. 58, No. 1

idant (31,33), and anti-microbial properties (3437). Two

iodine transporters, the sodium-iodide symporter (NIS) and
pendrin, have been cloned and molecularly characterized recently. These transport proteins are most prominently expressed in the thyroid, where iodine-containing thyroid hormones are produced. However, they have also been found in
hormone-dependent ovarian, breast, testicular and prostatic
tissues (3840), suggesting some physiological role for iodine in these tissues, including the prostate.
Deficient iodine intake has been associated with an increased risk of other cancers including stomach (41) and
aggressive thyroid malignancies (42). Venturi et al. (43) has
reviewed both animal and human data to support the theory
that deficient iodine intake may increase the risk of stomach and thyroid cancer. For example, in patients with stomach cancer, Behrouzian and Aghdami (41) recently observed
that cases had significantly lower urinary iodine levels compared to controls. With respect to thyroid cancer, in comparison to adequate/high iodine intake areas (where mean
urinary iodine levels are >100 g/L), iodine deficient regions have a higher proportion of aggressive follicular and
anaplastic carcinomas and a lower proportion of the less aggressive papillary cancers (42). Similarly, an increased development of thyroid tumors was seen in animals fed on a low
iodine diet (44,45). The potential for a similar etiological
relationship for both prostate and thyroid cancer has
been suggested by a recent analysis of US Surveillance,
31

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Epidemiology and End-Results (SEER) data (46). It was

observed that there was a significant increased risk for
prostate cancer following a diagnosis of thyroid cancer (expected/observed = 1.31, 95% CI 1.161.48). Conversely, a
significant increased risk for thyroid cancer following a diagnosis of prostate cancer (expected/observed = 1.21, 95%
CI 1.011.43). Studies in animals have suggested that iodine may also protect against the development of mammary
cancer (20,31,4749). Iodine deficiency in animals has been
shown to lead to the development of mammary hyperplasia
(48,50). In contrast, iodine supplementation in both animals
(48) and humans (5153) has been shown to reverse these
proliferative abnormalities. A peroxidase-catalysed reaction
between iodine and arachidonic acid leads to the formation of
-iodolactone, which appears to be a key regulator of apoptosis (54) and cellular proliferation in the thyroid (55). Interestingly, -iodolactone could not be detected in human tissues
when iodine deficiency was present, but was detected following increased iodide administration (56). Thus, production of
anti-proliferative iodolipids tissues may only occur in individuals with a relatively high iodine intake. Whether these
iodolipids have activity in extrathyroidal tissue remains to be
determined.
We also examined the association between salt shaker
usage and prostate cancer risk, but no association was found.
One case-control study in Poland found that a history of
frequent table salt usage was associated with a significantly
decreased risk of breast cancer (OR = 0.36, 95% CI 0.23
0.58) (57). It was proposed that the protective effect may have
been due to the iodine content of the iodized salt (57). Table
salt can be an important source of iodine intake, although
only about 5060% of table salt sold in the United States is
iodized (58). In the NHANES I study, quantitative data on
sodium intake from table salt was not collected and the data
on salt shaker usage did not provide information on its use
in cooking. There was no correlation between the urinary
iodine/creatinine ratio and salt shaker usage.
A history of thyroid disease was associated with a more
than two-fold higher HR even after the multivariate adjustment. A similar trend was seen in subjects who were using
thyroid medication at baseline and in subjects who were at
>10 yr since a diagnosis of the condition. To our knowledge, no previous study has examined the association between thyroid disease and prostate cancer risk. Animal studies have shown that reciprocal interactions occur between
the thyroid and prostate, where thyroid hormones regulate a
wide range of prostatic metabolic functions, and in turn, the
prostate can influence T3 and T4 production. In rats, prostatectomy has been shown to cause significant reductions in
T3 and T4 levels in vivo; whereas prostatic secretions have
been show to enhance T3 and T4 production in thyroid cells
cultured in vitro (2). In vitro studies have shown that T3
enhances androgen-stimulated cellular proliferation in prostatic LNCaP carcinoma cells at lower, but not at the higher
androgen levels (>1010 M) studied (3). Zhang et al. (4)
and Hsieh and Juang (5) also showed that T3 had a proliferative effect on LNCaP cells, which was attenuated by
32

androgens only in the former study. Hsieh and Juang (5)

did not observe any influence of T3 on the proliferation of
other prostatic cell lines (PZ-HPV-7, CA-HPV-10, PC-3, PC3). In contrast, for rabbits receiving long-term T4 injections
prostatic weight was lowered, while prostatic glandular epithelial secretions remained unchanged (59). We did not have
information on the original diagnosis (i.e., hyperthyroidism
or hypothyroidism) for subjects reporting thyroid disease;
however, hyperthyroidism is often treated with surgery or
radioiodine ablation therapy, both of which commonly result in hypothyroidism. Thus, the eventual therapy for both
hyperthyroidism and hypothyroidism is often the same, replacement hormone therapy with T4.
Many studies have examined the association between thyroid disease and breast cancer (20), however, thyroid diseases
such as Graves disease and autoimmune thyroiditis are much
more common in females than males (60). This may be one
reason for the lack of studies in this area for prostate cancer.
The association between breast cancer and thyroid disease
remains controversial (61,62). Two recent epidemiological
investigations, a cohort study China (60) and a case-control
study in Turkey (64), found the incidence of goiter to be
significantly higher in subjects with gastric cancer in comparison to those without cancer; however, no conclusions
could be drawn with respect to goiter in our cohort as it
was not frequently observed. In Japan, despite the higher
iodine intake, the overall prevalence of hyperthyroidism
and hypothyroidism is similar to that of the United States
(65).
Limitations of our study include the measure of iodine
status, which was derived from spot fasting urine samples
taken at baseline. No measurements of iodine status were
made during the follow-up period, therefore we were not
able to measure any potential changes in dietary iodine intake over the follow-up period. Using a single spot urine
sample to estimate the usual dietary iodine intake among individuals would produce random measurement error, which
tends to bias relative risk estimates toward one (effect to
null) in follow-up studies. This is a conservative bias as it
would induce false-negative results. Similarly, other measures were determined at baseline such as marital status,
income, alcohol consumption, and region of residence, and
may be expected to change over time. While urinary iodine
measurements were made for the majority of the analytical cohort (72.9%), 1,577 men were excluded who did not
have such a measurement, leading to a loss of 55 subjects
with prostate cancer. The history of thyroid disease obtained
during the medical interview was based upon a self-reported
and not a clinically verified history.
In conclusion, a role for iodine in the development of
prostate cancer remains unclear. Perhaps, epidemiological
studies carried out in Japan, where there is a broader
range of iodine intake, would provide a more conclusive
answer to this question. Recently, there has been increasing
interest in the use of radioiodine therapy for prostate and
other cancers through enhanced expression of the NIS
gene in malignant tissues (66,67). Considering the innate
Nutrition and Cancer 2007

anti-proliferative capabilities of non-radioactive iodine

(20,68), it is unfortunate in little investigative attention has
been directed in this area. Further investigations into the
role of thyroid disease in the etiology of prostate cancer are
warranted, particularly in light of the reciprocal influence of
that these two organs have upon one another.

14.

15.

Acknowledgments and Notes

16.
This study was supported by a grant from the Cancer Research Society, Inc. Address correspondence to Stephen A. Hoption Cann, Department of Health Care and Epidemiology, University of British Columbia,
5804 Fairview Ave, Vancouver, BC, V6T 1Z3, Canada. E-mail: hoption.
[email protected].

17.

18.

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Submitted 27 March 2006.

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