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Keywords:

  • autonomic nervous system;
  • constipation;
  • diarrhea;
  • heart rate variability;
  • irritable bowel syndrome;
  • pain

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Abstract  This study examined heart rate variability (HRV) in women with irritable bowel syndrome (IBS) to determine its association with gut pain and predominant bowel pattern. Women with IBS (constipation predominant n = 45, diarrhoea predominant n = 64, alternating n = 56) and healthy controls (n = 50) were recruited from the community. Severity of gut pain was measured retrospectively. The HRV (24 h) was summarized as high-frequency (HF) power and the ratio of low-frequency (LF) power to HF power. Among those women with IBS who have severe gut pain, the 15 constipation-predominant women had lower (P = 0.01) HF power and higher (P = 0.003) LF/HF ratio (geometric means 70 and 7.5, respectively) than the 21 women with diarrhoea-predominant IBS (286 and 3.1) and controls (224 and 3.9). In contrast, among women without severe pain, there is a smaller and not quite significant difference in the opposite direction. Using a broader definition of pain severity based on several questions nearly doubles the number of subjects in the severe pain group and shows even more significant results. The relationship of predominant bowel pattern to HRV is qualitatively different in the subgroup of patients with more severe pain than in the subgroup with less severe pain.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

The autonomic nervous system (ANS) provides a linkage between the gut and the brain, and may play a role in irritable bowel syndrome (IBS).1,2 Several investigators have found ANS differences, between subjects with IBS compared with healthy controls,3–11 or among subsets of IBS patients according to predominant bowel pattern, 7,12–14 sex,10 presence of depression or anxiety,15 dyspepsia,16 or postprandial pain.17 Other researchers have failed to find ANS differences between IBS patients and healthy controls14,18–21 or among IBS subgroups based on predominant bowel pattern10 or depression.18

These discrepant results may be partly related to the variety of methods that have been utilized to test and measure ANS function. These include laboratory studies of heart rate, heart rate variability (HRV), blood pressure or skin conductance at rest and in response to a challenge, such as Valsalva maneuver, posture change, Stroop word color conflict test, hand immersion in ice water, visceral sensitivity testing or eating a meal. They also include studies of HRV over 24 h4,14,15,17 or during sleep.9,16,18

An earlier report from our group found a significant relationship of 24-h HRV to predominant bowel pattern in women with IBS, but only among a subset of subjects who reported severe IBS symptoms.17 In particular, women with severe diarrhoea-predominant IBS (IBS-D) exhibited heightened vagal tone, while those with severe constipation-predominant IBS (IBS-C) exhibited markedly reduced vagal tone and increased sympathetic-to-parasympathetic balance. These results suggest a possible qualitative difference between those with severe IBS and those with less severe IBS. It has been shown that IBS patients with severe or extreme symptoms have worse quality of life and are more likely to utilize health care services when compared with those who report milder or moderate symptoms.22–24 If the HRV differences between severe IBS vs less severe IBS subgroups hold up in further research, this may explain some of the discrepant results of earlier studies, as results will differ depending on the severity distribution in the sample being studied.

The relatively small number of subjects in our earlier report limited further exploration of the relationship between symptom severity and ANS indicators. Since that report was published, the Rome-II criteria have provided explicit definitions of constipation-predominant and IBS-D, and we have accumulated a considerably larger sample of women with IBS. The purpose of the current report is to use the larger sample to examine the relationship of HRV to both predominant bowel pattern and IBS severity, and, in particular, to evaluate separately the severity of gut pain and the severity of diarrhoea and constipation.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Protocol

Women aged 18–49 with IBS were recruited from the community and a health maintenance organization. The women were screened to confirm that they had been medically diagnosed with IBS and currently had symptoms compatible with the Rome-I criteria.25 The control group consisted of premenopausal women from the community without IBS-like gastrointestinal symptoms. Women in both groups were excluded if they had a history of gastrointestinal, cardiac, or urogenital pathology or surgery that might result in IBS-like symptoms or were taking medications that are known to affect HRV, such as tricyclic antidepressants or calcium channel blockers. A total of 36 women taking laxatives, anticholinergic, anti-emetic or antidiarrhoea medications were allowed into the study. All but seven of these women used the medications on less than 25% of days, and all stopped taking these medications at least 24 h prior to HRV measurement. Postmenopausal women were excluded, while women who were taking oral contraceptives were not excluded.

This study was reviewed and approved by the University Institutional Review Board prior to recruitment. Participants gave written informed consent, then completed questionnaires and were oriented to the study procedures by a research nurse. During the woman's mid-luteal phase (7 ± 2 days after a positive lutenizing hormone surge), electrodes for a Holter recorder (Spacelabs Medical, Redmond, WA, USA) were placed in the morning and worn for 24 h as subjects went about their normal daily activities. The mid-luteal phase was selected, in order to control for menstrual cycle phase while avoiding menses-related symptoms.

Measures

Descriptive characteristics, bowel and psychological symptoms  Demographic information was collected and body mass index (BMI) was computed. Information on symptoms over the past year was collected with the bowel disease questionnaire (BDQ).26 The BDQ starts with the question ‘Have you had an ache or pain in your stomach or belly (gut) in the past year?’ and includes questions on characteristics of this pain, such as severity, frequency and duration, plus questions on other symptoms and stool characteristics. The symptom checklist-90R (SCL-90) measures psychological distress over the prior week.27 It includes 90 symptom items that are rated from 0 (not at all) to 4 (extreme). All 90 items are used to compute a global severity index, and subsets of items are used to compute anxiety and depression subscales. History of psychological distress was elicited with the diagnostic interview schedule, which identifies individuals who meet the criteria for a variety of psychiatric disorders such as depression and anxiety.28 Other potential confounding variables were obtained from the BDQ (smoking and alcohol use), the Hassles scale29 (stress) and a daily diary30 (mean daily smoking, alcohol and caffeine consumption, medication use and stress).

Heart rate variability  The 24-h ambulatory Holter analog ECG tape recordings (7-lead, 3-channel) were processed by a SpaceLabs Medical FT-2000 automated Holter analysis workstation; details of the procedures used have been published previously.14 The low-frequency (LF) band spectral power (ms−2) was defined as the average over 24 h of the integration of the Fourier HRV spectra between frequencies 0.04 and 0.15 Hz, and is thought of as measuring a mixture of sympathetic modulation and parasympathetic modulation. The power (variance) in the high-frequency (HF) band was estimated by integration of the HRV spectra between frequencies of 0.15 and 0.40 Hz, and is usually interpreted as an index of vagal modulation. The LF/HF ratio was computed as LF power/HF power and is usually interpreted as an index of the balance between the sympathetic and parasympathetic branches of the ANS, with higher values implying either greater sympathetic or less vagal influence. The 24-h mean heart period was calculated as the simple arithmetical average of all normal R-R intervals, measured in milliseconds.

Definition of subgroups

Predominant bowel pattern  Predominant bowel pattern subgroups were defined based on the Rome-II criteria.31 These criteria are based on three constipation symptoms (fewer than three stools per week, hard stools, straining) and three diarrhoea symptoms (more than three stools per day, loose stools, urgency) from the BDQ. Subjects specified whether each symptom occurred ‘often’, defined as 25% of the time. Subjects were classified as IBS-C, if they had either (i) at least one constipation symptom and no diarrhoea symptoms or (ii) at least two constipation symptoms and only one diarrhoea symptom. Subjects were classified as IBS-D, if they had either (i) at least one diarrhoea symptom and no constipation symptoms or (ii) at least two diarrhoea symptoms, did not have hard stools and had only one of the other constipation symptoms. Subjects who did not meet the criteria for either IBS-C or IBS-D but had at least one constipation symptom and at least one diarrhoea symptom were classified as alternators (IBS-A).

Severe IBS subgroups  Several items on the BDQ measure characteristics of the ‘… ache or pain in your stomach or belly (gut) …‘. This pain will be referred to as ‘gut pain’. Indicators of high gut pain severity included the questions ‘How bad is the ache or pain usually?’ (‘severe – affects your lifestyle’), ‘When this pain occurs, how long does it usually last?’ (‘more than 2 h’), ‘How many times did you get this pain in the last year?’ (‘2 days a week or more’), ‘Have your activities been interrupted in the past year because of aches or pains in your stomach or tummy?’ (‘yes’), and ‘When in your life did this ache or pain first begin as close as you can recall’ (‘more than 2 years ago’). Initial analyses split subjects into severe and less severe gut pain subgroups based on the first item. Subsequent analyses combined several items into a composite definition of ‘high’ and ‘low’ gut pain subgroups, based on results from analyses of individual pain items. This composite definition is described later, in the results section.

In addition, two items on the BDQ evaluate the severity of IBS symptoms other than pain, namely the severity of diarrhoea and constipation. One questions asks ‘How bothersome’ is your ‘diarrhoea/constipation’ (‘Severely bothersome when occurs’) and another asks ‘Have your activities been interrupted in the past year because of problems with your bowels’ (‘yes’). Subgroups with severe IBS and less severe IBS, based on these two items, were also explored.

Statistical analysis

Chi-square tests, t-tests and analysis of variance were used to compare demographic characteristics between IBS and control women and across the subgroups of women with IBS. The HRV measures are highly skewed; therefore log transformation was applied to these measures. The geometric mean of the HRV measures is presented descriptively, because it is a more appropriate measure than the mean when analyses are done on the log scale. The geometric mean is defined as the antilog of the mean of the log-transformed data.

Analysis of covariance controlling for age, BMI and mean heart period was used to compare log(HF power), log(LF power) and log(LF/HF ratio) among the IBS-C, IBS-D and control groups, and the pain severity subgroups. Contrasts were used to test for differences among control, IBS-C and IBS-D, and the interaction between pain severity and predominant bowel pattern. No adjustments were made for multiple comparisons, so the results should be interpreted with this in mind. The IBS-A group is not included in statistical analyses, as the main focus is on the IBS-C and IBS-D groups; however, descriptive results for IBS-A are included in some figures for the purpose of comparison. Additional analyses were carried out to determine whether the results would change when potential confounders such as psychological distress and caffeine consumption were controlled for.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

There were no statistically significant differences between the 165 women with IBS and the 50 control women on race (88%vs 82% white, IBS vs control), marital status (54%vs 46% married), education (61%vs 68% with a college degree), occupation type (38%vs 40% professional or manager), income (59%vs 45% with income >$30 000), age (mean ± SD of 32.9 ± 7.7 vs 32.2 ± 7.6), or BMI (24.8 ± 5.7 vs 24.5 ± 5.2). The SCL-90 global severity index was higher in the IBS group, mean 0.63 ± 0.46, than in the control group, mean 0.30 ± 0.27, P < 0.001.

The first two rows of Table 1 show the geometric means of HF power and the LF/HF ratio for control and IBS subjects. The HF power is somewhat lower and LF/HF ratio is somewhat higher among IBS subjects when compared with controls; but these differences are not statistically significant. In the third row of results in Table 1, IBS subjects are divided into IBS-C and IBS-D. The HF power is lower and LF/HF ratio is higher in IBS-C than in IBS-D, both not quite significant. IBS-A subjects (not shown in Table 1) had geometric means 191 and 3.8 for HF power and LF/HF ratio, respectively. Geometric mean of LF power was 937 among control subjects and 854 and 926 for IBS-C and IBS-D, respectively. These results are in the same direction as for HF power, being somewhat higher for IBS-D than for IBS-C. This similarity of results also holds for the other analyses presented in Table 1 and the figures, with LF power showing differences in the same direction as for HF power but with a somewhat weaker effect. Due to space considerations, LF results are not included in Table 1 or in the figures.

Table 1.   Geometric means of heart rate variability measures for control women and women with IBS, and subgroups of women with IBS
 Sample sizesHF powerP-valuesLF/HF ratioP-values
  1. HF, high frequency; LF, low frequency; IBS-C, constipation-predominant IBS; IBS-D, diarrhoea-predominant IBS; high pain = pain for at least 2 years and at least one of the following: pain is severe, activities interrupted by pain, pain lasts at least 2 h; low pain = either pain for less than 2 years or none of the three pain indicators for high pain; NS = P > 0.20. All P-values are from analysis of covariance controlling for age, body mass index and mean heart period.

  2. *P-value comparing IBS-C to Control. †P-value comparing IBS-D to Control. ‡P-value comparing IBS-C to IBS-D. §P-value for interaction between pain severity and predominant bowel pattern.

Control subjects50224NS 3.9 NS
IBS subjects165195 4.0 
 IBS-C, DIBS-CIBS-D IBS-CIBS-D 
All IBS subjects45, 641612270.104*, NS†, 0.070‡ 4.93.70.162*, NS†, 0.051‡ 
Split subjects by pain severity, as defined by single item
 Mild/moderate pain30, 43245203NS*, NS†, NS‡0.059§3.94.0NS*, NS†, NS‡0.024§
 Severe pain15, 21702860.007*, NS†, 0.010‡7.53.10.010*, NS†, 0.003‡
Split subjects by pain severity, composite definition
 Low pain14, 273791890.132*, NS†, 0.063‡0.000§3.14.20.180*, NS†, 0.112‡0.001§
 High pain31, 371102600.002*, NS†, 0.001‡6.03.30.007*, NS†, 0.000‡

The two panels on the left of Fig. 1 show the results of further splitting of the sample of women with IBS, according to severity of gut pain. Results for controls and IBS-A are shown in this figure for comparison, though the focus remains on IBS-C vs IBS-D differences. There is a striking interaction between pain severity and predominant bowel pattern. Among women with severe gut pain, HF power is significantly lower and LF/HF ratio significantly higher in IBS-C than in IBS-D (see Table 1 for P-values), while among women with only mild or moderate gut pain, there is a slight non-significant difference in the opposite direction.

image

Figure 1.  Ninety-five percentage confidence intervals for heart rate variability measures in women with and without IBS, by predominant bowel pattern (constipation-predominant, diarrhoea-predominant, alternator) and severity of gut pain.

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Similar analyses, not shown here, split women into severe IBS and less severe IBS subgroups based on the severity of bowel habit irregularity rather than gut pain severity. Those analyses showed no evidence of an interaction between severity of IBS and predominant bowel pattern. Thus, it is the severity of gut pain, in particular, rather than the severity of IBS, in general, that moderates the relationship of HRV to predominant bowel pattern.

Additional analyses, not presented here, show that this interaction between gut pain severity and predominant bowel pattern is also evident when alternative questions related to gut pain severity or duration are used to divide subjects into low-pain and high-pain subgroups: gut pain that lasts more than 2 h, activities interrupted because of gut pain, or gut pain has been present for at least 2 years. However, there is no interaction between gut pain frequency (at least twice a week) and predominant bowel pattern in the prediction of HRV. These observations prompted the definition of gut pain subgroups based on a composite of pain items. A ‘high’ gut pain group is defined as women with IBS, who have had gut pain for at least 2 years, and also answer ‘yes’ to at least one of the three items: pain is severe, pain lasts at least 2 h or activities are interrupted by pain. The complement to this group, those with ‘low’ gut pain, either have none of the three gut pain indicators or have had pain for less than 2 years. The two panels on the right of Fig. 1 show the results of splitting the IBS sample into low gut pain vs high gut pain subgroups according to this composite definition. The corresponding geometric means and P-values are given in Table 1.

Fig. 2 presents plots of HF power and LF/HF ratio by age, further illustrating the interaction between pain and predominant bowel pattern. Among women with high gut pain (panels B and D), there is little overlap between those with IBS-C and those with IBS-D, especially among older women. For example, among women older than 30 in panel D, almost all of those with IBS-C are in the upper half of the plot, while almost all of those with IBS-D are in the lower half of the plot. The sample sizes are relatively large, meaning the differences are not because of just a few individuals. In contrast, among women with low gut pain (panels A and C), there is a trend towards the opposite pattern: In panel C, women with IBS-D are more common in the upper half of the plot while women with IBS-C are more common in the lower half.

image

Figure 2.  Heart rate variability measures vs age among women with IBS, by predominant bowel pattern (constipation-predominant, diarrhoea-predominant) and gut pain severity subgroup. The fitted line for control women (without IBS) is shown but the data points are not shown.

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Additional analyses were carried out to explore whether the results are confounded by differences in psychological distress, medication use, or demographic and lifestyle characteristics. Age, current psychological distress and history of psychological distress did not differ significantly across the four groups (IBS-C with low gut pain, IBS-D with low gut pain, IBS-C with high gut pain, IBS-D with high gut pain). Women with IBS-C and high pain were more likely to be non-white (26%vs 4–8% in the other three groups, P = 0.041) and have a professional job (61%vs 24–43%, P = 0.009). However, there was very little change in the results when each of the following factors was controlled for separately: professional job category, current psychological distress, history of psychological distress, mean level of stress, mean minutes per day of exercise, mean daily consumption of caffeine or alcohol. Further sensitivity analyses excluded each of the following small subgroups, one at a time: women who were non-white, women with any use of medication that could affect HRV (laxatives, anticholinergic, anti-emetic or antidiarrhoea medications), women who smoked, women who used large amounts of alcohol, or women who consumed large amounts of caffeine. None of these exclusions led to a substantial change in results. Therefore, it is concluded that the main results of this study are not merely an artefact because of confounding by these factors.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

This study has shown that HRV is related to both gut pain and predominant bowel pattern. There is a highly significant interaction effect with strong IBS-C vs IBS-D differences among women with high gut pain, in contrast to smaller non-significant differences in the opposite direction among women with low gut pain. Others have examined the relationship between HRV and predominant bowel pattern7,10,12–14 or gut pain severity, 17 but this is the first report to show the importance of gut pain severity in the relationship of HRV to predominant bowel pattern.

These results have important implications for understanding the role of the ANS in IBS. Several explanations may account for the HRV differences seen among the women with high pain. Firstly, constipation and diarrhoea may be due to inherently different ANS balance. That is, constipation may result from low vagal tone while diarrhoea may be associated with heightened vagal tone. This is consistent with the expected relationship between vagal tone and gut motility and secretion. However, this does not explain why similar ANS differences are not observed in IBS-C and IBS-D patients with low gut pain.

Secondly, constipation and diarrhoea may be the results of centrally mediated differential responses to gut pain. Some individuals may react to the presence of pain with a predominantly vagal response (diarrhoea) when compared with those whose response is predominantly sympathetic (constipation). However, such responses may only be apparent if the pain reaches a certain acuity level. Thus, this hypothesis links the presence of gut pain and HRV differences with bowel pattern alterations. Wilder-Smith and colleagues32 using functional magnetic resonance imaging found that constipated and diarrhoea IBS patients differed significantly from each other and healthy controls in their brain activation responses to rectal pain. In addition, they noted that the brain regions that differed were those areas involved with autonomic and descending modulatory responses to pain.

Thirdly, chronic constipation accompanied by gut pain may over time result in ANS changes, i.e. vagal withdrawal. This theory is consistent with the observation that sympathetic dominance in this group is associated with older age and longer time since diagnosis.

The bulk of the literature to date on the relationship between the ANS and IBS has focused on ANS afferents, e.g. vagal or sympathetic modulation of descending inhibitory pathways.11,32 There is, however, evidence that efferent neural stimuli to the intestine have a direct effect on enterocyte secretion and motility.33–35 Enterochromaffin (EC) cells are innervated by sympathetic and parasympathetic fibres. Isolated ileum EC cells and intact mucosa have been shown to release serotonin in response to norepinephrine, suggesting that sympathetic nervous system dominance may result in serotonin release and subsequent changes in motility and secretion.33–35

The relative occurrence of diarrhoea vs constipation changes from month to month within individuals, leading some to conclude that classifying IBS patients by predominant bowel pattern is not meaningful or useful.36 However, the results of this study refute that view – using retrospective data to classify patients into bowel pattern subgroups led to very large and interesting differences in HRV measures between groups.

ANS balance has also been associated with psychiatric history. For example, parasympathetic tone has been shown to be decreased in patients with panic disorder.37,38 In an earlier study, we reported that women with IBS and a history of an anxiety disorder or depression had lower HRV compared with those without this history.15 However, in the current study, we found no differences in psychological distress, either current or history of, between the gut pain severity and predominant bowel pattern subgroups. The sensitivity analyses showed that our HRV results are not an artefact because of confounding by psychological distress or by the other potential confounding variables that were examined.

Others have found differences between IBS-C and IBS-D ANS measures that are similar to the current finding within the high-pain group,7,12,14 which would be consistent if those prior studies included mostly high-pain patients. Patients recruited from gastroenterology clinics may consist mainly of high-pain patients. The recruitment of patients from the community and a health maintenance organization in the current study resulted in a broader distribution of symptom severity, which allowed us to make the comparisons based on gut pain severity reported in this article.

This study has focused on IBS-C vs IBS-D differences, because those are the extreme groups in terms of predominant bowel pattern. In general, HRV measures for IBS-A are in between that of the IBS-C and IBS-D groups, often closer to the IBS-D group. Further investigation of the characteristics of the IBS-A group is warranted.

This study included only relatively young women, so it is not clear whether the results would generalize to men or postmenopausal women. A possible limitation of this study is that the composite definition of the high-pain subgroup was a post hoc combination of several variables. However, each of the variables that went into this composite showed a significant effect in a common direction, and the primary effect of combining them was to produce a larger high-pain subgroup. With this broader definition, it is only a minority of women with IBS who do not exhibit strong IBS-C vs IBS-D difference, namely those with low pain. The low-pain women have either had IBS only a short time, or have minimal pain that does not interfere with activities and lasts less than 2 h. On the spectrum of disease,39 they may be closer to the normal healthy population than to those with IBS and high pain. The important role of pain severity in IBS is evident in other ways as well. Those with severe gut pain have increased health care utilization 40 and decreased quality of life.23,41

The relationship between pain and HRV has been studied in other populations. Some studies show that subjects with chronic pain conditions such as fibromyalgia,42,43 gastro-oesophageal reflux disease44 or angina45 have decreased HF power and/or increased LF/HF ratio. There is also evidence that acute relief of chronic pain leads to an increase in HF and/or a decrease in LF/HF ratio.46,47 Tousignant-Laflamme et al.48 found that in healthy volunteers, acute pain led to a significant decrease in NN50, a time-domain measure of vagal modulation, and a nearly significant increase in LF/HF ratio. Those results are all consistent with more severe pain being associated with lower HF and higher LF/HF ratio, in agreement with results from the present study for the IBS-C group but not the IBS-D group.

However, other researchers find more mixed results. Park and Watanuki49 found that 10 women with severe primary dysmenorrhoea had higher HF and no significant difference in LF power or LF/HF ratio compared with women with less severe perimenstrual pain, when HRV was measured during the menstrual phase. Campbell et al.50 showed that adolescent men with higher pain sensitivity at age 14 had higher HF power and lower LF/HF ratio at age 22. Among patients with non-cardiac chest pain, Tougas et al.51 found that acute pain because of acid infusion was associated with an increase in HF and a decrease in LF/HF. Terkelsen et al.52 found that experimentally induced acute pain led to increased heart rate and LF, but no change in HF. These mixed results imply that the relationship between pain and HRV is not simple and may depend on whether the pain is chronic or acute and other factors.

In summary, the complex relationship of gut pain severity and predominant bowel pattern to HRV in IBS raises intriguing questions about the aetiology of IBS. In particular, why is it that the very strong HRV differences in IBS-C vs IBS-D appear only among women with high gut pain and not among women with low gut pain? Or put another way, why is the strong association of more severe pain with lower HF and higher LF/HF ratio only present in IBS-C and not IBS-D? Clearly gut pain severity and predominant bowel pattern are important, and both of these factors should be considered when analysing ANS function in IBS.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

This research was supported by grants from NINR, NIH (NR01094 and P30-NR04001).

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  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
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