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© 2008 American Society for Nutrition J. Nutr. 138:725-731, April 2008

Nutrition and Disease

Daily Consumption of a Dark Chocolate Containing Flavanols and Added Sterol Esters Affects Cardiovascular Risk Factors in a Normotensive Population with Elevated Cholesterol1,2

Robin R. Allen3,*, LeaAnn Carson3, Catherine Kwik-Uribe5, Ellen M. Evans4 and John W. Erdman, Jr3

3 Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, and 4 Department of Kinesiology and Community Health, University of Illinois, Urbana, IL 61801 and 5 Mars Inc., Hackettstown, NJ 07840

* To whom correspondence should be addressed. E-mail: roballen{at}uiuc.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Research Methods and Procedures
 Results
 Discussion
 LITERATURE CITED
 
Previous studies with plant sterols (PS) and cocoa flavanols (CF) provide support for their dietary use in maintaining cardiovascular health. This double-blind, placebo-controlled, cross-over study evaluated the efficacy of daily consumption of a cocoa flavanol-containing dark chocolate bar with added PS on serum lipids, blood pressure, and other circulating cardiovascular health markers in a population with elevated serum cholesterol. We recruited 49 adults (32 women, 17 men) with serum total cholesterol concentrations of 5.20–7.28 mmol/L and blood pressure of ≤159/99 mm Hg. Following a 2-wk lead-in utilizing the AHA style diet, participants were randomized into 2 groups and instructed to consume 2 cocoa flavanol-containing dark chocolate bars per day with (1.1 g sterol esters per bar) or without PS. Each 419-kJ bar was nutrient-matched and contained ~180 mg CF. Participants consumed 1 bar 2 times per day for 4 wk then switched to the other bar for an additional 4 wk. Serum lipids and other cardiovascular markers were measured at baseline and after 4 and 8 wk. Blood pressure was measured every 2 wk. Regular consumption of the PS-containing chocolate bar resulted in reductions of 2.0 and 5.3% in serum total and LDL cholesterol (P < 0.05), respectively. Consumption of CF also reduced systolic blood pressure at 8 wk (–5.8 mm Hg; P < 0.05). Results indicate that regular consumption of chocolate bars containing PS and CF as part of a low-fat diet may support cardiovascular health by lowering cholesterol and improving blood pressure.


   Introduction
TOP
 ABSTRACT
 Introduction
Research Methods and Procedures
 Results
 Discussion
 LITERATURE CITED
 
Hypercholesterolemia, especially elevated LDL cholesterol, is a major risk factor for cardiovascular disease (CVD)6. Under controlled circumstances, AHA diets and the National Cholesterol Education Program (NCEP) Step I and II diets have been shown to decrease LDL cholesterol by 10–20%, but in outpatient, free-living settings, less dramatic improvements with diet alone have been noted, with only 5% reductions frequently observed (1,2).

Plant sterols (PS), natural compounds found in foods such as vegetable oils, cereals, fruit, and vegetables, have been shown to be safe and effective in lowering circulating cholesterol levels (3–6). A systematic review of 14 randomized, controlled, double-blind trials of sterol- and stanol-enriched products in adults showed PS lowered LDL cholesterol by 8–13% when taken in amounts ranging from 1.8 to 2.5 g/d (4,7). Noting the effectiveness of these compounds in reducing cholesterol, both the AHA and the NCEP have recommended the inclusion of 2 g/d of PS as part of a healthy diet (1,7,8). In addition, the FDA has recognized that the consumption of PS may reduce the risk of CVD by lowering LDL cholesterol and has approved the use of a health claim to this effect (7,9). Currently, a number of food products containing PS are commercially available in the form of enriched margarine, milk, orange juice, yogurt, and snack bars (5,6).

The consumption of diets rich in flavonoids has also been associated with a reduced risk of CVD (10–16). While this association between the consumption of flavonoid-rich foods and CVD is drawn largely from epidemiological investigations, more recently, a number of dietary intervention trials with foods rich in distinct classes of flavonoids have yielded promising data in support of this concept (11,12,17,18). Among the flavonoids, the subclass of compounds known as flavanols has been increasingly investigated for potential cardiovascular benefits. One notable food type that can be exceptionally rich in not only the monomeric flavanols (primarily epicatechin) but also rich in the structurally related oligomers known as procyanidins is cocoa. To date, studies have shown that the consumption of cocoa flavanol (CF)-containing food products can improve endothelial function (11,12,19–23), platelet reactivity (17,18,24–27), insulin sensitivity (28), and reduce blood pressure (28–31). These studies together support the epidemiological data and suggest that the regular consumption of foods containing flavanols, including cocoa, may have important implications for cardiovascular health.

Given the global prevalence of CVD, there is an increasing need for dietary approaches in the management of CVD risk. Thus, the primary aim of this study was to examine the effect of the regular consumption of a flavanol-containing chocolate bar (CocoaVia, Mars Inc.) with added phytosterols on serum cholesterol levels in a free-living population. A secondary aim was to assess the effect of the dietary treatments on blood pressure and selected markers of inflammation and adhesion molecules.


   Research Methods and Procedures
TOP
 ABSTRACT
 Introduction
 Research Methods and Procedures
Results
 Discussion
 LITERATURE CITED
 
    Subjects. Males and females aged between 24 and 70 y with fasting serum total cholesterol levels between 5.20 mmol/L and 7.28 mmol/L and a BMI of 20–40 kg/m2 were recruited from the Champaign-Urbana area. Participants were recruited by posting flyers on the University of Illinois campus, using the University of Illinois campus email system and electronic announcements, and mailing letters and posting flyers to local physicians, area hospitals, and clinics. Over 650 interested people responded and logged on to the initial screening Web site. This Web site provided an initial screening to determine applicant eligibility for the study based on age, the current use of cholesterol medications, existing hypertension, or any other chronic diseases. Candidates who were accepted by the Web site screening were then contacted by phone by the dietitian to ascertain further health history information. After this phone screening, qualified participants attended an informational meeting where they received further details on the study and were scheduled for a screening fasting serum lipid blood test. Subjects were not eligible for participation in the study if they used any cholesterol-lowering, antihypertensive, or weight loss drugs or other drugs that affect blood lipids within 6 mo of the study. Other exclusion factors included: the use of herbal supplements, including antioxidant- and sterol-containing supplements; hypertension defined as systolic >159 mm Hg and diastolic >99 mm Hg; a history of other chronic diseases including type I or type II diabetes mellitus; diagnosed CVD; or pregnant or planning to become pregnant. A fasting basic metabolic profile was conducted on the serum of applicants who met the screening criteria for the study to determine eligibility. The study protocol was approved by the University of Illinois Institutional Review Board prior to subject recruitment and all study participants gave written, informed consent. The study was conducted from April 2005 to November 2005.

    Study design. This study used a double-blind, placebo-controlled, cross-over design. After being identified as eligible for participation in the study, participants were matched on total cholesterol, BMI, and age and then randomized to either the PS or control treatment group. To control for the potential confounders associated with a change in dietary habits, all subjects were counseled by a registered dietitian to follow a 2-wk lead-in diet based on the AHA "An Eating Plan for Healthy Americans," formerly called the NCEP Step I diet (2). After a 2-wk lead-in period, subjects were scheduled for a baseline data collection, matched as described above, and then randomized to receive either the 22 g, CF-containing dark chocolate bars (CocoaVia) with PS (PS+) or without (PS–) for 4 wk. Each PS+ chocolate bar contained 419 kJ, 6 g total fat (~50% energy from fat), 0 mg cholesterol, an average of 180 mg CF (range of 168–193 mg), and 1.1 g canola sterol esters per bar. The PS– bars were matched for macro- and micronutrient content and contained the same quantity of CF, theobromine, and caffeine as the PS+ bar. Participants were instructed to consume 2 chocolate bars daily, at separate times, either with a meal or within 30 min of a meal. At 4 wk, after all data measures were collected, groups crossed over to the alternate treatment group for an additional 4 wk after which final measures were taken at 8 wk. There was no wash-out period between the interventions. The products were provided to the subjects in plainly wrapped individual bars with number codes. The investigators were unaware of the identity of the products throughout the intervention period until all analyses of the data were completed.

    Subject dietary compliance, body weight, and blood pressure measures. Research dietitians met with the subjects weekly to monitor body weight, provide the test products, and to assess compliance with the research protocol. Upon completion of weight and blood pressure measures, a light breakfast following the AHA guidelines was provided to enhance compliance to the study protocol.

Subjects were instructed to keep 3-d food records at baseline and every 2 wk during the study. Each record represented the food intake of 2 weekdays and 1 weekend day. The baseline records corresponded to the usual daily diet intake prior to the entrance into the study. Diet records and nutritional analyses were completed using the Nutritionist Pro, version 2.4.1 (Axxya Systems, 2005) with diet records for a given individual being analyzed by the same researcher to control for subjectivity. Subjects were interviewed to determine the number and timing of chocolate bar consumption over the previous week.

To monitor the consistency of physical activity, subjects also submitted a 2-d physical activity diary every 2 wk. Weekly body weights were measured using a balance beam scale (D439, Detecto) with participants dressed in light-weight clothes without shoes.

Seated blood pressure was measured every 2 wk by standard sphygmomanometer (model nos. 79 and 682; Prestige Medical) after sitting and resting quietly for 5 min. Measures were taken in duplicate allowing 2–3 min of rest between readings with the mean used for statistical analysis. Blood pressure measurements were taken by the same 2 researchers who were blinded to the intervention assignment.

    Serum lipids, glycemic control, inflammation, and inflammatory mediators. At the end of the 2-wk lead-in period (identified as the study baseline) and at 4 and 8 wk, blood samples were drawn after a 12- to 14-h fast; blood samples were drawn on 2 consecutive days and the results for the 2 lipid measurements were averaged. Blood samples for serum lipid analysis were collected in serum separator tubes, allowed to clot at room temperature for 15–30 min, and centrifuged at 612 x g; 10 min at 4°C. Serum samples were refrigerated within 60 min of venipuncture and remained refrigerated at 4°C until collected by Laboratory Corporation of America for analysis of the following: lipid panel including total cholesterol, VLDL, HDL, direct measurement of LDL, triacylglycerides, and high-sensitivity c-reactive protein (hs-CRP). Whole blood was collected in EDTA tubes for analysis of hemoglobin A1C (HbA1c). The lipid panel was analyzed by an enzymatic method, direct total LDL cholesterol was analyzed using an enzymatic/spectrophotometric method, hs-CRP by immunochemiluminometric assay, and HbA1c was analyzed by the Tina-quant method (Roche Diagnostics). Dr. Claudio Ferri's laboratory at the University of L'Aquila, Italy, measured the serum concentrations of the inflammatory mediators soluble CD40 ligand (sCD-40L) and intercellular adhesion molecule (sICAM-1) using commercially available ELISA kits according to the manufacturer's instructions (sCD-40L and sICAM-1, Endogen).

    Statistical and power analysis. All data analyses were conducted using SPSS version 14.0. Means, SD, and distribution statistics (skewness and kurtosis) were evaluated to ensure that assumptions of normality were met for subsequent analyses on primary outcomes. Differences among groups in baseline measurements were evaluated using Student's t test. The primary analyses utilized a repeated-measure ANOVA with treatment [PS+ or placebo (PS–)] or time as the independent variable with simple contrasts used to explore significant differences across time. Primary dependent variables were changes in serum lipids, specifically LDL cholesterol. Secondary dependent variables included hs-CRP, HbA1c, sCD-40L, and sICAM-1. Linear regression analysis was used to determine the effect of baseline serum total cholesterol on serum total cholesterol response to dark chocolate bars with PS (PS+). Because the CF level did not change over the 8-wk intervention period, the potential CF effects on blood pressure were also evaluated using a 1-way repeated measures ANOVA analysis with simple contrasts to determine significant difference from baseline. Change in body weight over the course of the treatment and randomization order were considered as potential confounding variables and were entered as a covariate into the ANOVA model. A P-value of < 0.05 was considered significant. Data are presented as means ± SD except in the figures, which present means ± SE.

This study was powered for the change in LDL cholesterol, the primary dependent variable in this study. A reduction of 3% in LDL cholesterol was considered clinically meaningful, because this would be in addition to the initial decrease in lipids accomplished by the AHA lead-in diet. This translates into a moderate effect size of 0.4 (difference between groups in LDL cholesterol change of ~0.16 mmol/L), an {alpha} (significance) level of 0.05 (1-tailed test), and a power of 80%. A sample size of 45 subjects per group would be required to find statistical difference in change in LDL cholesterol between the treatment groups should it exist. With an estimated retention rate of 90%, it was planned to recruit 50 individuals into the study.


   Results
TOP
 ABSTRACT
 Introduction
 Research Methods and Procedures
 Results
Discussion
 LITERATURE CITED
 
All primary variables used in subsequent analyses were normally distributed, having skewness and kurtosis values <2.0.

    Subject characteristics. Randomization was successful and the groups did not differ in age, BMI, or total cholesterol (Table 1); groups were balanced on sex (66% and 64% male, for PS+ and PS– groups, respectively). Forty-nine individuals met the eligibility criteria, completed baseline testing, and were enrolled into the study. Following a 2-wk lead in, these 49 individuals were randomized into treatment groups. Forty-four participants completed the 8-wk trial. Reasons for nonadherence were variable [violation of study protocol and personal reasons (n = 1); weight loss of 5.7% (n = 1); weight gain of 6% (n = 1); clinically important elevated hs-CRP and hypertriacylglycerolemia throughout trial (n = 1); unrelated medical reasons requiring surgery (n = 1)]. Notably, from the initial screening blood lipid assessment until after 2 wk of the AHA diet, serum total cholesterol levels decreased by ~7% (data not shown). At baseline, serum lipids and select biomarkers of inflammation and mediators of inflammation did not differ between the groups randomized to initially receive PS+ or PS–, except for sICAM-1 (Table 2).


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  		TABLE 1 Characteristics of subjects randomized to treatment groups consuming a dark chocolate bar with (PS+) or without sterol esters (PS–) at baseline following a 2-wk lead-in period and an AHA style diet1

 

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  		TABLE 2 Baseline serum lipids, markers of glycemic control, and inflammatory markers of subjects randomized to treatment groups1

 
    Product compliance, dietary intake, body weight, and physical activity. Both chocolate intervention products were found highly acceptable by the subjects with no significant effect of the intervention on the number of bars consumed per day or on the timing of consumption. The PS+ group consumed 98.4% of the bars, of which 98.9% were with a meal or within 30 min of a meal. The PS– group consumed 99.1% of the bars, of which 98.3% were consumed within 30 min of a meal. The only exception to this was the higher consumption of both dietary cholesterol and saturated fat during the PS+ intervention period (P = 0.04; Table 3). Even with this difference, the intakes of total fat, saturated fat, and cholesterol were within the AHA dietary guidelines.


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  		TABLE 3 Reported daily dietary intakes of subjects while consuming a dark chocolate bar with (PS+) or without sterol esters (PS–)1

 
During this study period, the body weight of the subjects did not significantly change from baseline. Subjects were able to maintain their body weight within ±3.5% of baseline, with a mean overall body weight change of –0.34% ± 1.6 (range of –3.4% to + 3.49%). In addition, reported physical activity did not change in either group during the trial.

    Serum lipids, inflammation, and glycemic control. The changes in serum lipids in response to the regular consumption of the PS+ bar reduced serum total cholesterol levels by 3% (P = 0.017) compared with the PS– intervention (Table 4). This was paralleled by a reduction of 4% in LDL cholesterol (P = 0.014). These treatment effects on serum total cholesterol and LDL cholesterol remained after controlling for change in weight (P ≤ 0.02) and randomization order (P < 0.02). During the PS+ intervention, serum total cholesterol was reduced by 0.14 ± 0.45 mmol/L (P = 0.05) and LDL cholesterol was reduced by 0.23 ± 0.46 mmol/L (P = 0.002). No other treatment effects were evident based on serum levels of VLDL cholesterol, HDL cholesterol, or triacylglycerides. There was a relation between baseline serum LDL levels and the change in serum LDL levels (r = 0.51, P < 0.001; Fig. 1), with those individuals with higher baseline serum LDL levels demonstrating greater reductions in LDL cholesterol in response to the PS+ treatment. The treatments did not affect HbA1c, hs-CRP, sICAM-1, or sCD40L (data not shown).


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  		TABLE 4 Serum lipid responses while consuming a dark chocolate bar with (PS+) or without sterol esters (PS–) for 4 wk each1

 

Figure 1
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  		FIGURE 1  Relation between baseline LDL-cholesterol and change in LDL-cholesterol in response to dietary intervention of dark chocolate bar with sterol esters (PS+; y = –0.40x + 1.34, r = –0.51; SEE = 0.40 mmol/L, P < 0.001, n = 44).

 
    Blood pressure. The treatments did not affect either systolic blood pressure (–7.3 ± 8.3 vs. –8.2 ± 7.7 mm Hg; P = 0.52) or diastolic blood pressure (–3.7 ± 6.6 vs. –4.1 ± 7.7 mm Hg; P = 0.73); therefore, data for both interventions were pooled to determine the effect of CF on blood pressure over time. Regardless of the PS content of the intervention, the consumption of CF did not change throughout the entire 8-wk intervention. The consumption of chocolate bars containing CF reduced systolic and diastolic blood pressures (Fig. 2). Within 4 wk of initiating the consumption of the dark chocolate bars containing CF, systolic blood pressure decreased by 8.2% (P < 0.001), with a 5% reduction relative to baseline being evident at 8 wk (P < 0.001). Diastolic blood pressure was reduced at wk 4 (8.2%; P < 0.001) and wk 6 (3.4%; P < 0.05) and tended to still be reduced at wk 8 (2.2%; P = 0.09). The effect on systolic blood pressure remained after controlling for any change in body weight over the 8-wk period (5%; P = 0.027); however, the trend for the treatment effect on diastolic blood pressure was no longer evident (P = 0.29).


Figure 2
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  		FIGURE 2  Systolic blood pressure (A) and diastolic blood pressure (B) in response to 8 wk of dietary treatment of dark chocolate bars (PS+ and PS– combined) containing CF. *One-way repeated measures ANOVA analysis with simple contrasts to determine significant difference from baseline, P < 0.05. Values are mean ± SE, n = 44.

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Research Methods and Procedures
 Results
 Discussion
LITERATURE CITED
 
This study demonstrates that, in the context of a balanced AHA diet, "An Eating Plan for Healthy Americans," the regular consumption of cocoa flavanol-containing chocolate bars with added PS can significantly lower serum total and LDL cholesterol levels over the course of 4 wk. As the consumption of the PS– bar in the context of a low-fat diet was not shown to reduce blood cholesterol levels, these reductions in serum lipids are attributable to the inclusion of products containing PS into this diet. In addition to these effects on blood lipids, another interesting finding of this study was that regular consumption of the cocoa flavanol-containing bars was associated with a significant reduction in systolic blood pressure. Importantly, these effects were observed without an adverse effect on body weight, supporting the concept that the inclusion of these types of specially formulated foods into a balanced diet may help to support cardiovascular health.

The results of this study add to the growing body of scientific evidence demonstrating that the inclusion of PS-enriched foods into the diet can reduce total and LDL cholesterol blood concentrations in the range of 5–15% (32–39). Interestingly, using a study design similar to what was used in our study, Maki et al. (35) found that as part of a NCEP Step I diet, the inclusion of a reduced-fat spread containing 2.2 g of sterol esters daily for 5 wk reduced (relative to baseline) total cholesterol and LDL cholesterol by an average of 4.0% and 5.4%, respectively. The reductions (from baseline) in serum total and LDL cholesterol demonstrated in this study are more modest than have been reported in some of these other studies. However, it is difficult to undertake a direct comparison with other published data for a number of reasons, including: 1) differences in starting cholesterol levels; 2) divergence in the duration of intervention periods; 3) variations in the type of PS used (e.g. free sterol vs. sterol ester, stanol ester vs. sterol ester); and 4) disparate recommendations regarding the incorporation of controlled dietary guidelines. All of these are factors that can influence the effect size of the cholesterol reduction and thus complicate the evaluation of the relative effectiveness of PS-containing products used in different studies.

Cocoa and cocoa-containing products, including chocolate, can be rich sources of a subclass of flavonoids known as flavanols and their structurally related oligomers known as procyanidins. Over the past decade, there has been increased interest in the potential health benefits related to dietary flavonoids, and in particular, flavanol consumption. There have been many observational studies to date that have reported a positive correlation between the consumption of dietary flavonoids, including flavanols, and a reduced risk for CVD (10,13–16,41–44). Interestingly, there is also epidemiological evidence to support that the regular consumption of cocoa-containing foods may confer similar cardioprotective benefits (14,40,43). The Kuna Indians, an indigenous population in Panama, have been shown to have a very low incidence of age-related hypertension (43,45,46) and have a low rate of CVD disease mortality (47). This much lower prevalence of hypertension and related CVD mortality has been suggested to be related to their regular consumption of a cocoa rich in CF (43,47,48). In addition, a study published last year examining the relationship between cocoa intake and CVD mortality among a cohort of elderly men and a recent prospective study of flavonoid intake and CVD mortality in postmenopausal women found that cocoa and chocolate intake specifically were associated with significant reductions in blood pressure, CVD, and all-cause mortality over a 15-y period (14,40), as well as reductions in CVD risk (40).

There have been a number of dietary intervention trials performed in recent years with cocoa products containing CF that provide additional evidence to suggest that consumption of these foods may have important cardiovascular health benefits. Multiple studies with CF-containing foods have shown that the consumption of these foods can improve endothelial function (19–21,23,49), platelet function (17,24,25,27,30), and insulin sensitivity (28), as well as reduce blood pressure (28–31). Thus, in the context of the above, the demonstration in this study of a significant reduction in systolic blood pressure among the normotensive study participants who regularly consumed the flavanol-containing chocolate bars is not completely unexpected. The magnitude of the reductions in both systolic and diastolic blood pressures observed here are consistent with what has been reported by others in both moderately hypertensive (28–30) and normotensive populations (40). Moreover, consistent with previously published studies, reductions in BP were observed within 2 wk of initiating consumption of the flavanol-containing chocolate products.

Potential limitations of the study design are the relatively short treatment duration and the lack of a wash-out period between treatments. These research design features may have attenuated the changes in serum lipids. Another limitation is the fact that a product low in CF was not used; thus, it is possible that the changes in BP could be attributed to other factors, including the adoption of the AHA "An Eating Plan for Healthy Americans." Reductions in BP have been shown to occur rapidly with even moderate reductions in sodium intake; however, an examination of the self-reported dietary information demonstrates that the diets during the study were not low in sodium and were in fact above the Dietary Reference Intake of 2300 mg for sodium. Furthermore, potassium intake was also considerably less than the recommended intake of 4700 mg/d. Because no preintervention diet history was collected, it is possible that the adoption of the AHA diet could have led to modest reductions in blood pressure during the course of the study. However, despite the fact that the diets did not change significantly over the course of the 8-wk intervention, systolic blood pressure at week 8 was significantly lower than the baseline measurement (wk 0). This finding suggests that the regular ingestion of CF may have played a role in the observed reduction in blood pressure. Additional well-designed studies focused on evaluating the specific effect of CF consumption on blood pressure are clearly warranted.

In conclusion, the results of this study indicate that the regular consumption of a flavanol-containing chocolate bar with added PS (CocoaVia) as part of a low-fat diet can significantly lower blood cholesterol levels. Furthermore, because a modest reduction in systolic blood pressure was also observed, the results of this study suggest that the regular consumption of products containing CF may offer an added CV benefit. The fact that in this study these portion-controlled products could be included without the occurrence of any significant weight gain supports the concept that in the context of a healthy, balanced diet, these types of functional foods may be helpful in the dietary management of CVD risk.


   ACKNOWLEDGMENTS
 
We thank Dr. Claudio Ferri (University of L'Aquila, Italy) for performing the sCD40L and sICAM-1 analyses.


   FOOTNOTES
 
1 Supported in part by a grant from Mars, Incorporated, Hackettstown, NJ and by the University of Illinois. Back

2 Author disclosures: R. R. Allen, L. Carson, E. M. Evans, no conflicts of interest. J. W. Erdman is a consultant and Chairs the Mars Scientific Advisory Council (MSAC); MSAC advises Mars, Inc. on scientific research especially related to nutrition and health. C. Kwik-Uribe is the Research Manager for Mars, Inc. Back

6 Abbreviations used: CF, cocoa flavanol; CVD, cardiovascular disease; Hba1c, glycosylated hemoglobin; hs-CRP, high-sensitivity c-reactive protein; ICAM-1, intercellular adhesion molecule; NCEP, National Cholesterol Education Program; PS, plant sterol; PS+, with plant sterol; PS–, without plant sterol; sCD-40 L, soluble CD40 ligand. Back

Manuscript received 4 October 2007. Initial review completed 18 October 2007. Revision accepted 14 December 2007.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Research Methods and Procedures
 Results
 Discussion
 LITERATURE CITED
 

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