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Psychosomatic Medicine 66:484-491 (2004)
© 2004 American Psychosomatic Society

ORIGINAL ARTICLES

Association of Fear of Terror With Low-Grade Inflammation Among Apparently Healthy Employed Adults

Samuel Melamed, PhD, Arie Shirom, PhD, Sharon Toker, MA, Shlomo Berliner, MD, PhD and Itzhak Shapira, MD

From the National Institute of Occupational & Environmental Health, Raanana, Israel and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel (S.M.); Faculty of Management, Tel-Aviv University, Tel-Aviv, Israel (A.S., S.T.); Department of Medicine "D" and Institute for Special Medical Examinations (MALRAM), Tel Aviv Sourasky Medical Center, Tel Aviv, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv Israel (S.B., I.S.).

Address correspondence and reprint requests to Samuel Melamed, PhD, Department of Occupational Health Psychology, National Institute of Occupational & Environmental Health, P.O. Box 3, Raanana 43100, Israel; E-mail: melameds{at}ioh.org.il


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: Based on evidence that psychological stress may induce a chronic inflammatory process, we hypothesized that the stress caused by chronic fear of terror may be associated with low-grade inflammation. This hypothesis was examined in employed men and women with the presence of low-grade inflammation measured by high sensitivity C-reactive protein (CRP).

METHODS: Apparently healthy employed adults (N = 1153) undergoing periodic health check-ups in a tertiary hospital in Israel completed a questionnaire. Fear of terror (scored 1–5) was assessed by three items measuring the extent to which respondents have deep concern for personal safety, elevated tension in crowded places, and fear of terror strikes causing harm to one’s self or one’s family members. The main outcome measure was the presence or absence of an elevated CRP level (>3.0 mg/L).

RESULTS: Women scored significantly higher on fear of terror compared with men (M = 2.16 vs. M = 1.68, respectively; p < .0001). Most of the study participants who scored high (4 or 5) on fear of terror, reported having experienced this feeling for 1 year or more. In women only, there was a positive association between fear of terror and risk of elevated CRP level (adjusted OR = 1.7, 95% CI 1.2–2.4) in a multivariate model adjusting for generalized anxiety, depressive symptoms, and potentially confounding demographic and biomedical variables.

CONCLUSIONS: Chronic fear of terror in women, but not in men, is associated with elevated CRP levels, which suggests the presence of low-grade inflammation and a potential risk of cardiovascular disease.

Key Words: terror, • stress, • inflammation, • depression, • C-reactive protein.

Abbreviations: CRP = C-reactive protein;; BMI = body mass index;; HDL = high-density lipoprotein;; DSM = Diagnostic and Statistical Manual of Mental Disorders;; PTSD = posttraumatic stress disorder.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGMENTS
 REFERENCES
 
Terror can strike anywhere. In the United States, this possibility became a painful reality with the vicious attack on the World Trade Center and on the Pentagon on September 11, 2001. In Israel, the civilian population has been subject to a continuous threat of terror since the onset of the second intifada (Palestinian uprising) in September 2000. In the past 3 years, over 140 terrorist incidents of shooting, knifing, and suicide bombings have been registered in major cities and towns, and residents have been constantly reminded of the potential for attacks by daily alerts issued by the police and security checks at entrances to practically all public locations. As in the United States (1), Israeli residents are uncertain as to where and when the next terror attack might occur, and this uncertainty could be regarded as a risk factor for the development of fear, anxiety, and chronic stress in individuals.

Studies of psychological reactions to terrorist attacks in the United States and in Israel reported findings of acute PTSD and distress symptoms (2–6). The degree of the response could not be predicted by objective measures of exposure to the trauma or trauma-induced loss (5–6). Wakefield and Spitzer (7) argued that the individual response to a terrorist attacks may medicalize expectable human reactions because it is often difficult to discriminate between genuine symptoms of disorder and normal distress reactions. It follows that there is a need for studies that directly assess the relationship between fear of terror, as a psychological reaction to terrorist attacks that reflect subjective appraisal of the threat to one’s physical well-being (8) and physiological outcomes. There is evidence that repeated episodes of acute psychological stress, chronic psychological stress, and psychological reactions to either condition can lead a chronic inflammatory process culminating in atherosclerosis and cardiovascular disease (for reviews see references 9–12). This body of research has led to the hypothesis that chronic fear of terror may be associated with low-grade inflammation.

The aim of the present study was to test this hypothesis in otherwise healthy, employed men and women in Israel. The presence of inflammation was measured by blood levels of CRP, found to be a powerful biomarker of systemic inflammation, a consistent predictor of coronary heart disease risk (13–20). To rule out the possibility that fear of terror may be related to CRP levels through their respective associations with general psychological distress, we controlled for general anxiety and depressive symptoms. Heightened general anxiety and depressive symptoms are part of the clinically significant psychological distress symptoms that may be evoked by terror attacks (4,5). Some studies have uncovered a positive association between depressive symptoms and CRP levels (21), whereas other studies have yielded mixed results (22) or negative results (23). The association between anxiety and CRP levels is less investigated. In this study, we also controlled several other potent confounding variables reported to correlate with CRP levels (24,25). We analyzed the data separately for men and women given the important gender differences in psychological reactions to terror (2–6) and in elevated CRP (19,26) as well as the evidence that there are gender-specific paths of influence of psychological stress on the inflammatory process (27,28).


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGMENTS
 REFERENCES
 
Study Participants
A total of 1954 persons attending the Tel Aviv Sourasky Medical Center for a routine health examination between September 2002 and June 2003 as part of periodic health check-ups were asked to participate in the Tel-Aviv Medical Center Inflammation Survey (TAMCIS). A total of 1778 subjects agreed (1099 men, 679 women), yielding a response rate of 91%. Nonparticipants did not differ from participants on any of the sociodemographic or the biomedical variables. An additional 622 subjects were later excluded from the analysis because they were in retirement (N = 55) or because of known inflammatory disease (arthritis, inflammatory bowel disease), pregnancy, steroidal or nonsteroidal treatment, acute infection, or previous myocardial infarction or stroke (N = 433), or because of missing data for one of the study parameters (N = 188). Thus, the final sample consisted of 1153 subjects (see description below).

Procedure
The study was approved by the local ethics committee. The subjects were recruited individually by an interviewer while waiting their turn for the clinical examination. They were given an explanation of the survey and asked for their voluntary participation. In return, they were promised detailed feedback of the results. Confidentiality was assured. Each responder signed a written informed consent form. All patients underwent blood sampling (after an overnight fast), anthropometric measurements, physical examination, urinalysis, stress ECG, spirometry, and vision and hearing function tests.

Instruments
The questionnaire covered background, occupational, psychological, and physical morbidity factors. Fear of terror was assessed by three items (Table 1) adapted from the studies of Silver et al. (5) and Gidron et al. (29). For each item, participants checked off one of the following responses: "not at all," "a little bit," "moderately," "quite a bit," and "extremely." They were also asked to indicate the duration (in months) of experiencing such feelings. Internal consistency (Cronbach’s alpha) of the scale was found to be 0.88. The scores on these items were averaged to yield a continuous fear of terror score (range, 1–5).


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  		TABLE 1. Degrees of Fear of Terror by Scale Items in Men and Women*
 
High-sensitivity CRP concentrations in serum were determined with the BN II Nephelometer (Dade-Behring, Marburg, Germany) analyzer, as described by Rifai et al. (30). CRP levels < 1 mg/L were considered indicative of a low risk of a future cardiovascular event, levels of 1 to 3 mg/L were of moderate risk, and levels > 3 mg/L were of high risk (31). For the present study, an elevated CRP level was defined as > 3.0 mg/L.

Potential Confounding Variables
Potential confounding factors adjusted for were: psychological distress symptoms of generalized anxiety and depressive symptoms, as well as demographic and biomedical variables that have been found to be associated with CRP concentration: age, sex, race, obesity, smoking, alcohol consumption, physical exercise, lipid levels, glucose levels, blood pressure, and hormone replacement therapy (24,25).

Generalized anxiety was measured by four items (feeling nervous, jittery, fidgety, and tense) adopted from French et al. (32). Depressive symptoms were measured by using the brief measure of the Patient Health Questionnaire (PHQ 9) (33,34). Residence in a city affected by terror was noted as well. (For cities affected by terror, see www.ict.org.il.)

Ethnic origin was documented as self-reported place of birth: Asia, North Africa, Eastern Europe, Europe, North or South America, Israel. BMI (kg/m2) and years of education were used as continuous variables. Smoking (current, former, never) was documented by self-report, as was alcohol consumption (yes, no), physical exercise (yes, no), and use of hormone replacement therapy (yes, no). Total serum cholesterol and triglycerides were measured with the Roche/Hitachi 747 Analyzer (Roche Diagnostics, Mannheim, Germany) and the Raichem Kit (Reagents Applications, San Diego, CA). LDL was assayed on a Roche/Hitachi 747 Analyzer with the Randox Kit (Randox Laboratories, Crumlin, UK) and was used to compute HDL levels. Hypertension was defined as a systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or current use of antihypertensive medication. Fasting glucose was determined with the glucose oxidase method using an autoanalyzer (Beckman Instruments, Fullerton, California, U.S.A.).

Statistical Analyses
The first analysis was aimed to explore the correlates of fear of terror. Pearson correlation coefficients were used to assess the relationship between fear of terror and psychological demographic and biomedical variables. Next we conducted univariate analyses to examine whether fear of terror and the other psychological, demographic, and biomedical variables are associated with serum CRP levels in men and women with normal and elevated (> 3.0 mg/L) CRP. The Student t test and chi-squared test were applied for continuous and categorical variables, respectively.

The multivariate association between fear of terror and elevated CRP was examined by means of logistic regression models in which the prediction of elevated CRP was adjusted for potential confounding factors. Anxiety, depressive symptoms, age, BMI, cholesterol, HDL levels, and fasting glucose were entered as continuous variables; whereas hypertension, physical exercise, ethnic origin, smoking status, alcohol consumption, and hormone replacement therapy use were included as dichotomous variables (low/high). Odds ratios and 95% CI were calculated. Finally, we conducted multivariate linear regression analysis to examine if fear of terror is also associated with CRP levels as a continuous variable. All possible confounding variables listed above were included as covariates. To reduce skewness of CRP values, all values ≥ 13.0 mg/L (prevalent for 3% of the study participants) were coded as 13.0 mg/L.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGMENTS
 REFERENCES
 
The Sample
The final study sample consisted of 721 men and 431 women aged 20 to 70 years. Both men and women were employed in white-collar occupations. Men were predominantly in engineering, computer-related, and administrative jobs and various academic positions. Women were primarily in academic, clerical, and computer-related jobs. Sample characteristics are presented in Table 2.


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  		TABLE 2. Sample Characteristics
 
Fear of Terror and Its Chronicity
The proportion of men and women scoring low, moderate and high on fear of terror are given in Table 1. Women had significantly higher mean score of fear of terror than men (M = 2.16 vs. M = 1.68, respectively; p < .0001). High fear of terror (high rating for at least one of the three items) was reported by 11.0% of the men and 26.6% of the women. Most of the high-fear group (83% of the men and 97% of the women) had experienced these feelings for a year or more, a fact that points to the chronicity of such a feeling.

Correlates of Fear of Terror
The correlations of fear of terror with the study variables are presented in Table 2. As expected, fear correlated modestly with both anxiety (0.32 [p < .0001] and 0.35 [p < .0001] for men and women, respectively) and depressive symptoms (0.22 [p < . 0001] and 0.24 [p < .0001]). It is important to note that fear of terror was not associated with place of residence, namely living in a city affected by terror. Fear of terror was not related to age; in women, it was negatively associated with level of education and positively with country of birth outside Israel. By and large, fear of terror was not associated with health habits, except for a positive association in women between fear of terror and alcohol consumption. None of the biomedical variables were related to fear of terror in men. In women, fear of terror was positively associated with BMI and fasting glucose levels, and negatively with hormone replacement therapy use. Thus fear of terror seems to be largely independent of biomedical variables in both sexes.

Fear of Terror Associated With Elevated CRP
Elevated CRP levels (> 3.0 mg/L) were found in 24.5% of the men and 31.1% of the women. These figures correspond to those obtained in earlier studies (19). A preliminary logistic regression analysis (results not shown) was conducted to test the hypothesis of interactive effect of fear of terror x gender of CRP levels. This interactive term was added to the model along with fear of terror, gender, and all variables listed in Table 3 included as covariates. As expected, a significant interaction (p < .05) was uncovered, thus supporting our a priori decision to analyze the data separately for men and women. As indicated in Table 3, women with elevated CRP had a higher mean score on fear of terror (2.3) compared with those with normal CRP levels (2.0, p = .026). No such trend was observed for men. Furthermore, no significant difference in the mean anxiety or depressive symptoms scores was observed with men or women with elevated CRP compared with those with normal CRP.


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  		TABLE 3. Characteristics of Study Participants with Normal and Elevated CRP*
 
Sample Characteristics Associated With Elevated CRP
Consistent with findings reported in the literature, (24,25), elevated CRP was significantly associated with ethnic origin (p = .043 in men), higher BMI (p < .0001 in both sexes), lower education level (p = .018 and 0.013 for men and women respectively), lower alcohol consumption (p = .003 in women), less physical exercise (p = .011 and 0.009, in men and women, respectively), high cholesterol levels (p = .003 in women), high triglycerides levels (p=.07 and p<.0001 in men and women, respectively), low HDL cholesterol (p = .02 in men), high levels of fasting glucose (p = .0009 and <.0001 in men and women, respectively), and hypertension (p = .022 in men).

Multivariate Analyses
The association between fear of terror and risk of elevated CRP was tested through logistic regression analyses (Table 4). The control variables entered were anxiety, depressive symptoms, and all correlates of CRP that had been found in the literature or in our univariate analyses to be significantly associated with it (see Table 3). Fear of terror was associated with increased risk for elevated CRP in women (adjusted OR = 1.7, 95% CI 1.2 to 2.4), but not for men (adjusted OR = 0.9, 95% CI 0.6 to 1.3). No association between anxiety and CRP levels was uncovered. However, in men, depressive symptoms were significantly associated with increased risk of elevated CRP (adjusted OR = 3.3, 95% CI 1.1 to 9.4). No such association was found for women (adjusted OR = 1.2, 95% CI 0.5 to 3.1).


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  		TABLE 4. Adjusted* Odds Ratio of Elevated CRP Associated with Fear of Terror, Anxiety, and Depressive Symptoms
 
Complementary multivariate linear regression analyses were conducted in order to examine the association between fear of terror with CRP treated as a continuous variable. Included in these analyses were the same covariates applied in the above logistic regression models. The results have shown essentially the same trend. The adjusted R-square in men was 0.136. No significant association was found for fear of terror (ß = 0.04, p = .31) or anxiety (ß = –0.01, p = .80). However, as before, depressive symptoms were positively and significantly associated with CRP levels (ß = 0.11, p = .029). The adjusted R-square in women was 0.293. Again, fear of terror was positively associated with CRP levels (ß = 0.16, p = .0026), while no significant association was found for either anxiety (ß = –0.07, p = .17) or depression (ß = 0.01, p = .80).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 ACKNOWLEDGMENTS
 REFERENCES
 
There is substantial evidence that mass violence in general, particularly terrorism, is associated with mental health impairments (35). However, the potential association between fear of terror and low-grade inflammation has never been explored. We evaluated 1153 otherwise healthy, employed adults who underwent a routine annual physical examination. We found that women generally scored higher on fear of terror than men (p < .0001). Eleven percent of the men and 26.7% of the women had experienced high fear of terror, most of them for 1 year or more. Fear of terror was common to people throughout the country, and it was not limited to those living in cities/towns directly affected by terror. Other studies of psychological reactions to terrorist attacks in the United States (3,4) and Israel (7) reported similar findings.

The major finding of the present study is that chronic fear of terror in women is associated with low-grade inflammation, expressed by a heightened concentration of CRP, supporting our hypothesis. Fear of terror was associated with a 1.7-fold greater risk of elevated CRP (95% CI 1.2 to 2.4). This was true even after controlling for general anxiety, depressive symptoms, use of hormone replacement therapy, and several other potent confounding variables found to be associated with CRP levels in earlier studies (36,37) and on univariate analyses in the present study. In contrast to the results for women, we did not find any significant association between chronic fear of terror and CRP levels in men.

It is noteworthy that although fear of terror has been found to be significantly and positively associated with anxiety levels and depressive symptoms in both sexes, the elevated CRP levels in the women in the present study were directly associated with fear of terror and were not mediated by general psychological distress indexed by the above symptoms. On the other hand, depressive symptoms were found in the multivariate analysis to be positively associated with CRP levels in men (OR = 3.3, 95% CI 1.1 to 9.4), but not in women (OR = 1.2, 95% CI 0.5 to 3.1). This differential of depression association with CRP levels for men and women replicate a similar recent finding in the study by Danner et al. (38), where a recent history of major depressive episode was used as the predictor variable. These findings here stay in contrast to the lack of association between depressive symptoms and CRP levels, in both men and women, found in the study by Steptoe et al. (23). These positive findings lend further support to the suggestion that low-grade systemic inflammation could represent a mechanism linking depression to cardiovascular risk.

An additional complementary finding here that the associations reported above were also observed with CRP levels taken as a continuous variable, pointed to a linear positive association between fear of terror and CRP levels in women, and between depressive symptoms and CRP levels in men. Thus, conduction of multivariate regression analyses with CRP treated as a continuous variable, overcame a possible information loss that may have may have been the result of using CRP as a dichotomous variable. The significant results indicate that the observed association between fear of terror or depressive symptoms is not an outcome of using a predetermined cut-off point for CRP levels. It was also noteworthy to learn that the percentage of variance in CRP levels explained by predictor variables here, was much higher for women (29.3%) than for men (13.6%).

The finding here of an association between fear of terror and elevated CRP levels may have important long-term health implications. Recent studies suggest that inflammation may be associated with risk of atherosclerosis (39,40), myocardial infarction and stroke (41,42), and insulin resistance and diabetes mellitus (43,44). Several large-scale prospective studies of apparently healthy individuals have shown that the baseline level of CRP, a major biomarker of inflammation, is an independent predictor of future cardiovascular events (14,15,17,18,45–49). These studies included men and women, both Europeans and Americans. CRP was also found to be a predictor of the development of peripheral vascular disease (47,48). Furthermore, recent studies suggest that elevated CRP concentration by itself may play a proinflammatory role (49) and contribute to the development of the atherothrombotic process (for a review, see 50). Griselli et al. (51) found that CRP infusion induced larger myocardial infarctions in rats, and Danenberg et al. (52), using a human CRP-transgenic mouse model, described a prethrombotic phenotype directly attributable to the presence of human CRP in vivo. Taken together, these data indicate that women who chronically experience high fear of terror and display elevated CRP levels might be at risk of tissue damage and of future cardiovascular events.

Although we might have expected an association between chronic psychological stress and elevated CRP levels in apparently healthy people on the basis of available theoretical models (9–12), to the best of our knowledge, ours is the second study to document such a linkage. A former study by Schnorpfeil et al. (53) demonstrated a positive association between job demands and CRP levels. Other studies have focused mainly on acute stress (54) or stress associated with invasive medical procedures in sick persons (55,56) or PTSD (57).

In our study, women turned out to be highly vulnerable. First, women expressed higher fear of terror than men. This is consistent with the recurring finding in studies conducted in both the United States (2–6) and Israel (6) that women have a higher prevalence than men of PTSD, depression, and other psychological distress symptoms in response to terrorist attacks, and that women are more likely than men to suffer adverse mental health effects in response to all types of disasters (35). Second, only among the women was fear of terror associated with a significant increase in CRP level.

Early evidence of a gender difference in CRP response to stress was provided by laboratory studies of the effect of acute stress exposure on proinflammatory cytokines such as interleukin (IL)-6. IL-6 plays an important role in mediating inflammation and is a central stimulus for the acute-phase response (58). It also induces the hepatic synthesis of CRP. Steptoe et al. (27) found that responsivity to acute stress was manifested by an increase in tumor necrosis factor (TNF)-{alpha} in men and an increase in IL-6 and IL-1 receptor antagonist in women. Accordingly, in the study of Rohleder et al. (28), the sensitivity of glucocorticoid, which specifically inhibits the production of proinflammatory cytokines in monocytes and macrophages, increased in men at 1 hour after exposure to psychosocial stress. Similar findings were found for lipopolysaccharide-induced cytokine production. These differential inflammatory responses to stress may reflect different susceptibilities of women and men to immunologic stimuli. Women seem to be more susceptible to autoimmune or inflammatory diseases, with female-to-male ratios of 4:1 for rheumatoid arthritis (59), 9:1 for systemic lupus erythematosus (60), and 19:1 for autoimmune thyroid disease (61). Further studies are needed to examine if the present findings can be replicated and perhaps extended to other chronic stressors, such as work stress or care giving to a chronically ill family member.

Limitations
This study has a number of limitations. First, our findings were based on cross-sectional data; therefore, the temporal ordering of the association between fear of terror and CRP levels cannot be definitively established. It is possible that instead of fear of terror leading to inflammation, inflammation leads to subjective appraisal of the situation as posing a threat to one’s life and to the lives of one’s loved ones. There is compelling evidence that levels of proinflammatory cytokines (IL-1, TNF-{alpha}, IL-6) serve as a signal to the brain, inducing adverse effects on affect and cognitive function and thereby contributing to anxiety, depression, learned helplessness, and cognitive disturbances (62–65). Indeed, the presence of one or the other may set off a vicious cycle, ultimately leading to an exacerbation of the threat appraisal, immunosuppression, and inflammation.

Second, our sample of subjects undergoing a periodic health examination may not be representative of the general population. Most of the individuals were highly educated, white-collar workers who exhibited generally good health-behavior patterns: they smoked little, exercised regularly, and drank alcohol only in moderation. Furthermore, only one man and one woman in the sample met the criteria of major depressive symptoms (33). This rate is much lower than that in the adult community. The point of prevalence of major depressive disorder in the adult community sample varies from 5% to 9% for women and 2% to 3% for men (66). Owing to their superior health habits, our subjects may have been more resilient to the effects of stress. However, it is even more likely that the significant findings obtained here with regard to fear of terror linked with CRP will be replicated in the less resilient general population.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
ACKNOWLEDGMENTS
 REFERENCES
 
This study demonstrates for the first time, in a sample of apparently healthy workers, that the psychological reaction of chronic fear of terror has a negative impact on health in women. Women turned out to be highly vulnerable compared with men. They not only appraised the situation as more threatening and expressed higher fear of terror, but this also appears to have negative implications to their physical health. As fear of terror was associated in this group with a 1.7-fold risk of elevated CRP, a marker of low-grade inflammation and a strong risk factor for diabetes and future cardiovascular events.

Terrorist acts and the threat of terrorism may continue to affect populations worldwide. International studies are needed to explore the extent of fear of terror in other countries, and the relative risk of physical morbidity in women. The replication of our findings in longitudinal studies and in larger and more representative samples may have important health-care policy implications for primary care physicians, nurses and community mental health professionals with regard to stress management interventions (67–69).


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGMENTS
REFERENCES
 
This study was supported by the Israel Science Foundation Grant 962/02-01 and the Preventive Activities Program of the Ministry of Labor and Social Welfare of the Government of Israel.

Received for publication January 5, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 ACKNOWLEDGMENTS
 REFERENCES
 

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