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American Journal of Clinical Nutrition, Vol. 86, No. 5, 1376-1383, November 2007
© 2007 American Society for Nutrition

ORIGINAL RESEARCH COMMUNICATION

Serum 25-hydroxyvitamin D in a West African population of tuberculosis patients and unmatched healthy controls1,2,3

Christian Wejse, Rikke Olesen, Paulo Rabna, Pernille Kaestel, Per Gustafson, Peter Aaby, Paul L Andersen, Henning Glerup and Morten Sodemann

1 From the Bandim Health Project, INDEPTH Network, Statens Serum Institut, Bissau, Guinea-Bissau (CW, RO, PR, PK, PG, PA, and MS); the Infectious Disease Research Unit, Skejby (CW, RO, and PLA) and the Department of Internal Medicine, Silkeborg (HG), Aarhus University Hospital, Aarhus, Denmark; the Department of Human Nutrition, Faculty of Life Science (PK) and the Department of Infectious Diseases (MS), University of Copenhagen, Copenhagen, Denmark; and the Infectious Diseases Research Group, Department of Clinical Sciences, Lund University, Malmö, Sweden (PG)

2 Supported mainly by The Danish Research Council for Developmental Research and by the Segels, Beckett, SSAC, Jakob Madsen, Lily Benthine Lund, and Skejby University Hospital research foundations. CW was supported by a PhD scholarship from the University of Aarhus.

3 Reprints not available. Address correspondence to C Wejse, Department of Infectious Diseases, Aarhus University Hospital, Brendstrupgaardsvej, 8200 Aarhus N, Denmark. E-mail: wejse{at}dadlnet.dk.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Little is known regarding vitamin D deficiency (VDD) in African populations and in tuberculosis (TB) patients. VDD has been shown to be associated with TB.

Objective: We aimed to compare the degree of vitamin D insufficiency (VDI) and VDD in TB patients and healthy adult controls in a West African population.

Design: An unmatched case-control study was performed at a Demographic Surveillance Site in Guinea-Bissau. Serum 25-hydroxyvitamin D3 [25(OH)D3] concentrations were measured in 362 TB patients and in 494 controls.

Results: Hypovitaminosis D [25(OH)D3 ≤ 75 nmol/L] was more common in TB patients, but VDD [25(OH)D3 ≤ 50 nmol/L] was more common and more severe in controls. We observed hypovitaminosis D in 46% (167/362) of the TB patients and in 39% (193/494) of the controls; the relative risk (RR) of hypovitaminosis D was 1.18 (95% CI: 1.01, 1.38). VDD was observed in 8.5% (31/362) of the TB patients and in 13.2% (65/494) of the controls. The RR was 0.65 (95% CI: 0.43, 0.98), mainly because severe VDD [25(OH)D3 ≤ 25 nmol/L] was observed in only 1 of 362 TB patients (0.2%) and in 24 of 494 controls (4.9%). After adjustment for background factors, hypovitaminosis D was not more frequent in TB patients than in healthy controls, but the mean serum 25(OH)D3 concentration remained lower.

Conclusions: Hypovitaminosis D was highly prevalent in TB patients and in healthy controls living at 12 °N; severe VDD was rare in TB patients. The finding indicates that the serum 25(OH)D3 concentration is associated with TB infection, but whether this role is a symptom or is causal was not established.

Key Words: Hypovitaminosis D • 25-hydroxyvitamin D • tuberculosis • Guinea-Bissau


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Tuberculosis (TB) constitutes a major health problem in sub-Saharan Africa (1). Vitamin D deficiency (VDD) was shown to be associated with TB in small studies from Indonesia, India, and Kenya (2–4) and in studies of foreign-born persons in Britain (5–7). African Americans have significantly lower serum 25-hydroxyvitamin D [25(OH)D] concentrations than do whites (8) and have an increased susceptibility to Mycobacterium tuberculosis infection (9). In addition, some studies suggest that certain vitamin D–receptor polymorphisms may be involved in the susceptibility to TB (10). We hypothesized that VDD is associated with TB. Hence, we carried out a population-based study in Guinea-Bissau, where the incidence of TB is high (470/100,000) (11).


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study area
We conducted the study at the Bandim Health Project, a Demographic Surveillance Site with a current population of 92 000 in the capital of Guinea-Bissau (12° N) on the West African coastline. The staple foods are rice, small amounts of fresh water, and sea fish; soybean oil is consumed frequently. Red palm oil, fruit, vegetables, and nuts are consumed seasonally (P Kaestel, personal communication, 2006).

Study population
We described the vitamin D status in an unmatched case-control study in TB patients and healthy adult controls from the same area. From November 2003 to February 2006 we included 362 TB patients in a treatment trial for TB (ISRCTN35212132). Inclusion criteria for cases were as follows: diagnosis of TB according to World Health Organization guidelines (12), residence in study area, and age >15 y. Field assistants visited the 3 health centers and the TB hospital in the study area daily and invited new incident TB patients starting treatment to come to the inclusion site the following day. We assessed demographic variables in a baseline questionnaire and collected nonfasting blood samples at inclusion. Mean lag time from the start of treatment to inclusion and time of blood sampling was 7 d, 311 of 362 patients were included within 2 wk after treatment initiation.

We enrolled a random population sample from the study area between April 2005 and February 2006 and obtained blood samples from 494 adults for a study of genetic risk factors for TB (13). We included trios consisting of mother, father, and child (regardless of age) from each house and collected blood samples from all. Only the adults were included in the present study. We drew a random list of houses from the study database; houses with a case of TB during the past 2 y were excluded, as were individuals who had experienced a cough for >2 wk or who had previously had TB. In case of refusal or if the household did not have a relevant trio, residents of the neighboring house were solicited. A demographic questionnaire was completed, and anthropometric measures were made.

We conducted the study in accordance with the Helsinki Declaration, and the procedures followed were in accordance with the ethical standards of the Bandim Health Project. Ethical approval was obtained from the ethics committee within the Ministry of Public Health in Guinea-Bissau and by the Central Ethical Committee of Denmark.

Anthropometric measures
Height was measured with a meter scale; the weights of the TB patients and controls were measured with the same weight scale. Body mass index was calculated as weight (kg)/height squared (m).

Seasonality
In Bissau the rainy season lasts from June to November. During the rainy season it is cloudy and sunlight exposure is diminished, but the days are slightly longer. We coded samples taken from December through May as being from the dry season (mean sunshine: 224 h/mo) (14); samples collected from June through November were coded as being from the rainy season (mean sunshine: 147 h/mo).

Tuberculin skin test
Laboratory technicians performed the tuberculin skin test (TST) using purified protein derivative (PPD) as a measure of tuberculin reaction. We applied Tuberculin (PPD, 0.1 mL SSI RT23 2T.U.) intradermally in the ventral aspect of the forearm. We read TST reactions by measuring 2 diameters of the area with skininflammation with a ruler and ballpoint technique after 48–72 h (15). We used 10 mm as the cutoff for a positive reaction, referred to as latent TB infection (LTBI) (16, 17).

Socioeconomic index
Socioeconomic status was drawn from the Bandim Health Project database on the 750 individuals with a valid identification number. This index divides the population into the poorest, less poor, and richest according to household information on type of roof, indoor toilet, electricity, and TV (18, 19).

Laboratory measurements
Serum was harvested and stored at –20 °C. Samples were transported to Denmark every 3 mo and stored at –80 °C. Samples were analyzed in batches at the Department of Clinical Biochemistry, Aarhus University Hospital, in February, June, and October 2006. We measured serum 25-hydroxyvitamin D2 [25(OH)D2, ergocalciferol] and serum 25-hydroxyvitamin D2 [25(OH)D3, cholecalciferol] by isotope-dilution liquid chromatography–tandem mass spectrometry on an API3000 mass spectrometer (Applied Biosystems, Foster City, CA) using a method adapted from Maunsell et al (20): routine isotope-dilution liquid chromatography–tandem mass spectrometry assay for simultaneous measurement of the 25-hydroxy metabolites of vitamins D2 and D3. The method was calibrated by using Serum Calibration Standards from an external supplier (ChromSystems, Munich, Germany). The quality control was performed by daily analysis of internal control samples and participation in the DEQAS Vitamin D External Quality Assessment Scheme. The interassay and intraassay CVs were 9.4% and 9.7%.

We defined vitamin D insufficiency (VDI) as a serum 25(OH)D3 concentration of 51–75 nmol/L, mild VDD (mVDD) as a serum 25(OH)D3 concentration of 26–50 nmol/L, and severe VDD (sVDD) as a 25(OH)D3 concentration of ≤25 nmol/L according to Vieth (21) and Holick (22). We refer to hypovitaminosis D as any of the above and VDD as all with a serum 25(OH)D3 concentration ≤50 nmol/L. We analyzed all samples for 25(OH)D2 and 25(OH)D3 (23).

Serum calcium and albumin were measured by absorbance (Corba Integra; Roche Diagnostics, Mannheim, Germany). We corrected total serum calcium for individual variations in albumin by using the following equation: adjusted serum calcium (mmol/L) = total serum calcium (mmol/L) x 0.00086 x [650 – serum albumin (µmol/L)]. The reference range according to Roche Diagnostics (24) is 2.10–2.75 mmol/L.

Statistical analysis
The study had 99% and 74% power, respectively, to detect a 10% and a 5% difference in prevalence of VDD (<50 nmol/L) among TB patients and controls. Categorical variables with missing information were given a separate category, thereby preserving the power of the study. Analyses were adjusted for family relation by clustering. Pearson chi-square was used to assess statistical differences in proportions between groups (P < 0.05), Student's t test was used to assess differences in means between 2 groups when there was a normal distribution, and Wilcoxon's rank-sum test was used when nonparametric analysis was needed (25). Logistic regression analysis was used to adjust for categorical differences between cases and controls; linear regression analysis was used to adjust for differences in mean serum concentrations. Spearman's rank correlation coefficient ({rho}) was used for correlation analysis. A 2-sided P < 0.05 was considered significant. Statistical analyses were performed with STATA software (version 9; StataCorp, College Station, TX).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Only 7 samples (2 TB patients, 5 controls) had detectable concentrations of 25(OH)D2; 25(OH)D2 concentrations ranged from 25 to 44 nmol/L and were found in subjects with 25(OH)D3 values in the range 36–137 nmol/L. Only 25(OH)D3 concentrations are discussed below.

Prevalence of hypovitaminosis D in TB patients and healthy controls
Characteristics of TB cases and healthy adult controls are described in Table 1Go. Mean and median 25(OH)D3 concentration were significantly lower in TB patients than in healthy controls.


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  		TABLE 1. Characteristics of 362 tuberculosis (TB) patients and 494 healthy adult controls1

 
We observed hypovitaminosis D in 46% (167/362) of the TB patients and in 39% (193/494) of the healthy controls; the relative risk (RR) of hypovitaminosis D was 1.18 (95% CI: 1.01, 1.38) in TB patients compared with controls. We observed sVDD [25(OH)D3 ≤ 25 nmol/L] in only 1 of 362 TB patients (0.2%) and in 24 of 494 controls (4.9%). VDD + sVDD (all with 25(OH)D3 ≤ 50nmol/L) was observed in 8.5% (31/362) of the TB patients and in 13.2% (65/494) of the healthy controls. Hence, the RR of VDD was 0.65 (95% CI: 0.43, 0.98) for TB patients compared with controls. The proportions of various degrees of lack of vitamin D in the 2 groups are displayed in Figure 1Go.


Figure 1
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  		FIGURE 1.. Distribution of the degree of hypovitaminosis D among the tuberculosis (TB) patients and controls.

 
We investigated whether the duration of TB treatment was important to vitamin D status, but found only a weak correlation between 25(OH)D3 concentration and days passed since the start of the 4-drug treatment regimen (Spearman's {rho} = 0.08, P = 0.12).

The controls were not matched, and the men were overrepresented in the TB group. Mandingas were overrepresented in the healthy control group, which possibly reflected differences in family structure, because Mandinga adults are more likely to be married and to have been present in the trios.

We found significant differences in schooling and nutritional variables; TB patients had less formal schooling and significantly lower BMI and albumin values. The total 25(OH)D3 concentrations were also significantly lower in TB patients than in controls.

Multivariate analysis
To assess whether the difference in vitamin D status between TB patients and healthy controls was due to background factors, we conducted univariate and multivariate analyses of hypovitaminosis D and deficiency (mVDD + sVDD), respectively, controlling for sex, season, ethnic group, religion, schooling, socioeconomic index, age-group, and BMI group. Only variables that affected the vitamin D estimate for TB by >10% were entered in the final multivariate analysis.

In the analysis for hypovitaminosis D, the univariate estimate was an OR of 1.33 (95% CI: 1.01, 1.76); when adjusted for clustering the OR was 1.33 (95% CI: 0.99, 1.78). Only BMI group affected the estimate and, when adjusted for BMI, TB was no longer associated with hypovitaminosis D (OR = 1.19; 95% CI: 0.87, 1.62), but low BMI was significantly associated with hypovitaminosis in this model (OR = 1.38; 95% CI: 1.0, 1.9).

The univariate estimate for the association between TB diagnosis and VDD was 0.62 (95% CI: 0.39, 0.97); when adjusted for clustering the OR was 0.62 (95% CI: 0.38, 1.0). Of the variables in Table 1Go, only the socioeconomic index affected this estimate. In a model including the 750 subjects with an available socioeconomic index, TB was significantly negatively associated with risk of VDD (OR = 0.53; 95% CI: 0.32, 0.90). In this model, the most poor socioeconomic group was insignificantly associated with risk of deficiency (OR = 2.1; 95% CI: 0.50, 9.0).

In a linear regression analysis, we assessed the influence of confounding factors on mean differences in 25(OH)D3 concentrations between TB patients and controls for the same background factors as in Table 1Go. None of these variables changed the significant difference shown in Table 2Go between TB patients and controls by >5%. In a subgroup analysis of the 735 individuals with all background variables, the mean difference between TB patients and controls remained highly significant; 25(OH)D3 concentrations were lower in TB patients (8.1 nmol/L; 95% CI: 2.3; 13.9 nmol/L) than in controls. In this model, only lack of formal schooling was significant and raised mean 25(OH)D3 concentrations by 6.4 nmol/L (95% CI: 0.9, 11.8 nmol/L).


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  		TABLE 2. Analysis of predictor variables by vitamin D concentration1

 
Vitamin D status in healthy controls
A significant interaction of sex was observed on the association between TB status and vitamin D status (Table 2Go). With a cutoff at 50 nmol/mL (VDD), further significant interactions of ethnic and religious groups and a tendency for an interaction with rainy season (P = 0.09) were seen on the association between TB status and vitamin D status. For comparison with other populations, we therefore present 25(OH)D3 concentrations in the healthy population sample and risk factors for suboptimal vitamin D status.

Hypovitaminosis D was found in 42% (77/182) of the samples taken in the dry season and in 37% (116/312) of the samples taken in the rainy season (NS). However, for sVDD there was a difference because nearly all samples with sVDD were taken in the rainy season; the prevalence was 1% (1/182) in samples taken in the dry season and 7% (23/312) in those taken in the rainy season (P = 0.001). Mean 25(OH)D3 concentrations did not differ by season, as shown in Table 1Go.

Hypovitaminosis D was observed in 49% (77/157) of Moslems compared with 34% (82/243) of Christians and 36% (34/94) of animists (P = 0.007). The Fula ethnic group was highly associated with hypovitaminosis D and VDD; 63% (32/51) had 25(OH)D3 concentration ≤75 nmol/L (P < 0.001) and 22% (11/51) had 25(OH)D3 concentrations ≤50 nmol/L (P = 0.06), which was also observed in 21% (27/131) of the Pepel ethnic group (P = 0.003). Sex, BMI group, and no formal schooling were not found to be significantly associated with hypovitaminosis D or VDD.

The TST reaction was measured in only 426 adult controls, because not all of the controls could be located for test reading 2–3 d after application. We found a tendency toward a higher frequency of LTBI for those with VDD: 35% (18/51) with VDD and 25% (92/375) without VDD had a 25(OH)D3 concentration ≤50 nmol/L (P = 0.09).

In a logistic regression analysis, we examined the following background factors: age group (15–35, 35–50, and 50–87 y), sex, BMI group (13–20, 20–25, and 25–42), season, lack of formal schooling, ethnic groups (Balanta, Fula, Mandinga, Pepel, and others), and religious groups (Animist, Christian, and Moslem) as potential determinants of VDD and hypovitaminosis D. Female sex, Fula ethnic group, and Moslem religion were significantly associated with VDD, whereas only the Fula ethnic group was significantly associated with hypovitaminosis in this model (Table 2Go).

In a subgroup of 422 healthy controls with TST results, the ORs were 1.2 (95% CI: 0.8, 2.0) and 1.8 (95% CI: 0.9, 3.5), respectively, for hypovitaminosis or deficiency among individuals with LTBI when we controlled for significant background factors.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
VDD and VDI occurred frequently in a large sample of healthy individuals and TB patients from a West African capital, as studies in other sub-Saharan populations also have shown (26–29). Among healthy controls, there was an insignificant tendency for individuals with LTBI to have VDD in both crude and adjusted analyses, which suggests a causal role of VDD in acquiring TB. Associations were also seen in the Fula and Pepel ethnic groups, but, after adjustment for background factors, only the association with Fula ethnicity and hypovitaminosis remained. The Fula group is the most light-skinned group in Guinea-Bissau, and we have no explanation for why they have a greater prevalence of hypovitaminosis because they are not known to be less exposed to the sun than the other ethnic groups in the area.

We hypothesized a relation between hypovitaminosis D and TB, and we found that hypovitaminosis D was indeed more frequent because of more frequent VDI in this group. However, we also found much less severe VDD among TB patients, which was unexpected. The lower prevalence of sVDD in active TB patients contrasts with other studies of vitamin D status in TB patients (2–7). The absence of sVDD among TB patients was surprising because TB patients were in a much worse nutritional condition than were the healthy controls with considerably lower BMI and albumin concentrations. The worse nutritional status of TB patients explains the higher degree of VDI among TB patients to some extent, because hypovitaminosis was not significantly more frequent among TB patients after the adjustment for BMI, which suggests that hypovitaminosis is a feature of bad nutritional status. However, mean 25(OH)D3 concentrations remained lower after adjustment for BMI, and the dietary intake of vitamin D is usually not considered sufficient to maintain good vitamin D status if sunshine is avoided (30, 31). Dietary differences are also unlikely to explain the contradictory finding of the absence of sVDD but significantly more prevalent VDI among TB patients.

The present study was, however, limited by the lack of detailed diet information. Fish is consumed regularly in the region of study, both freshwater and saltwater fish, but intake varied considerably within the different groups of the population (P Kaestel, personal communication, 2006). We have no data on the vitamin D content of these fish or individualized information on the intakes, but only fatty fish have significant amounts of vitamin D (32). All TB patients reported having eaten fish during the past week and may have, because of their disease, been allowed larger portions of the available meat in the family.

This study was further limited by the lack of information on sun exposure in the individuals, but we found more cases of hypovitaminosis D in the rainy season and virtually all cases of severe VDD were found in the rainy season. However, we found no clear seasonal difference, as was also reported in a study from Puerto Rico at the 18th latitude (33). Different exposures to sunlight may, to some extent, explain our findings, because controls were more often included in the study in the rainy season, which should be associated with a higher risk of sVDD. We would, however, expect this difference in timing of sampling to bias toward a lower mean 25(OH)D3 concentration in controls, which we did not find, and adjustment for season did not change the mean difference between TB patients and controls. The fact that formal schooling was less frequent among TB patients may have been the reason why more individuals in this group than in the control group engaged in outdoor manual labor, which could have led to more sun exposure in the TB group. This may explain why VDD was absent, but would also be expected to lead to higher mean 25(OH)D3 concentrations.

The absence of VDD in the TB patients may also be explained by the long diagnostic delay during which they may have been prescribed multivitamins, likely to be ergocalciferol. We sampled 6 different multivitamin brands from 5 pharmacies in Bissau. The 3 major brands are sold cheaply in small plastic bags and are the most common; they all contained ergocalciferol. Much more expensive brands that contain cholecalciferol are also available, but they are rarely sold. Hence, the rare occurrence of 25(OH)D2 in our measurements makes it unlikely that frequent multivitamin supplementation accounted for the differences found.

The simultaneous increased frequency of VDI and the complete absence of sVDD among the TB patients possibly explained the different vitamin D metabolism of the TB patients and controls. Liu et al (34) recently showed an effect on host vitamin D metabolism induced by infection with Mycobacterium tuberculosis via stimulation of toll-like receptors and induction of the 1,25-hydroxylating enzyme. Whether such an influence on vitamin D metabolism is of importance to serum 25(OH)D3 concentrations or whether serum 25(OH)D3 concentrations are important to host defense against TB remains to be shown, but a possible mechanism may be that VDD predisposes to the acquisition of LTBI or to the progression toward active TB disease, which then leads to increased production of vitamin D metabolites by granulomas (35, 36).

Perhaps simple random variation is the most obvious reason for our findings. Twenty-three of the 24 controls with sVDD were sampled during June-July 2005 within the same area of the city, and this group of 23 account for the differences in sVDD among TB patients and controls; hence, we may have encountered a cluster with prevalent sVDD. TB patients and controls had similar proportions of mVDD (Figure 1Go). It is also possible that TB patients with sVDD were the first to die; some identified TB patients died before inclusion in the study, and their vitamin D status is unknown. Mortality rates are very high in the study area, even among TB patients receiving treatment (11, 37–40). Furthermore, when TB patients overall have lower mean 25(OH)D3 concentrations but are absent in the group with lowest concentrations, selection bias is a possibility. As we follow this population prospectively, we will be able to assess the mortality risk associated with hypovitaminosis D in future studies.

There was, however, an important interaction of sex on the association between TB status and vitamin D status that modulated the risk of hypovitaminosis significantly. Sex has also been shown to modify the association between mortality risk and vitamin A supplementation in the study area (42), and we interpret this finding to possibly indicate that TB disease plays a role in vitamin D metabolism.

We found a lower albumin-corrected calcium concentration in the TB patients than in the healthy controls, which was also present when calcium concentrations were not corrected for albumin. This finding was likely explained by the fact that hypovitaminosis was more frequent among TB patients than among controls; calcium absorption is known to be impaired when 25(OH)D3 concentrations are <75 nmol/L (41).

A limitation of this study was the unmatched case-control design, which impedes strong conclusions when comparing TB patients and the random population sample. A prospective study following individuals with vitamin D insufficiency for the development of TB and changes in vitamin D status during the course of disease and treatment would, however, be difficult and costly.

In conclusion, hypovitaminosis D was highly prevalent among TB patients and healthy controls in a West African country; hypovitaminosis D was more frequent among the TB patients, but sVDD was very rare in this group. After adjustment for socioeconomic and demographic factors, hypovitaminosis D was not more frequent among TB patients than among healthy controls, but the mean differences in serum 25(OH)D3 concentrations remained lower. Furthermore, we reported a contradictory finding of less sVDD among the TB patients. The findings support the conclusion that the serum 25(OH)D3 concentration plays a role in TB infection, whether this role is a symptom or is causal was not established.


   ACKNOWLEDGMENTS
 
We thank the dedicated field staff in Bissau, the hard working laboratory staff in Aarhus, Jens Nielsen for statistical consultancy, and Lene Heickendorf and Holger Jon Møller for advice about the vitamin D measurements.

The authors' responsibilities were as follows—CW (primary investigator): initiated the study and drafted the first version of the manuscript; RO: collected samples from the healthy control cohort; PR: collected clinical and demographic data; PG: provided advise on the field study design; PLA and HG: primarily responsible for the conception of the study and the data interpretation. PA and MS: helped draft the protocol and supervised the study conduct. All authors took part in the interpretation of the data and revision of the manuscript and participated intellectually and practically in the study. The authors solemnly declared that they had no personal or financial support or involvement with organizations with financial interest in the subject matter and had no conflicts of interest to disclose.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication February 27, 2007. Accepted for publication June 28, 2007.




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