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Keywords:

  • cranberry;
  • diabetic;
  • flavonol;
  • glycemic;
  • proanthocyanidin

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results and Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

ABSTRACT:  Fruit and vegetable intake is typically low for type 2 diabetics, possibly due to a perceived adverse effect on glycemic control. Cranberry juice (CBJ) may represent an attractive means for increasing fruit intake and simultaneously affording positive health benefits. This single cross-over design compared metabolic responses of type 2 diabetics (n= 12) to unsweetened low-calorie CBJ (LCCBJ; 19 Cal/240 mL), carbohydrate sweetened normal calorie CBJ (NCCBJ; 120 Cal/240 mL), isocaloric low-calorie sugar water control (LCC), and isocaloric normal calorie sugar water control (NCC) interventions. CBJ flavonols and anthocyanins, and proanthocyanidins were quantified with HPLC, LC-MS, and MALDI-TOF that includes an original characterization of several large oligomeric proanthocyanidins. Blood glucose peaked 30 min postingestion after NCCBJ and NCC at 13.3 ± 0.5 and 12.8 ± 0.9 (mmol/L), and these responses were significantly greater than the LCCBJ and LCC peaks of 8.1 ± 0.5 and 8.7 ± 0.5, respectively. Differences in glycemic response remained significant 60 min, but not 120 min postingestion. Plasma insulin values 60 min postingestion for NCCBJ and NCC interventions were 140 ± 19 and 151 ± 18 (pmol/L), respectively, and significantly greater than the LCCBJ and LCC values of 56 ± 10 and 54 ± 10; differences were not significant 120 min postingestion. Metabolic responses within the 2 high and 2 low-calorie beverages were virtually identical; however, exposure to potentially beneficial nutrients was greater with CBJ. Relative to conventionally sweetened preparation, LCCBJ provides a favorable metabolic response and should be useful for promoting increased fruit consumption among type 2 diabetics or others wishing to limit carbohydrate intake.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results and Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

Clinical documentation of the differences in glycemic effect between simple carbohydrate sweetened and comparable artificially sweetened or reduced calorie products is essentially lacking. This may be useful to demonstrate the effects of dietary choices and to promote dietary compliance in people with diabetes. Consumption of excess simple sugars by people with diabetes results in poor glycemic control and increased dependence on pharmacological interventions. In healthy young nondiabetics, carbohydrate sweetened CBJ provides a predictably significant increase in blood glucose and insulin, while unsweetened CBJ is associated with no statistically significant increase in blood glucose and insulin (Wilson and others 2008). The current study reports the glycemic response of people with type 2 diabetes to carbohydrate sweetened and low-calorie unsweetened CBJ, and demonstrates why low-calorie CBJ should be desirable for people with diabetes and those seeking to maintain carbohydrate restrictive diets.

Diets rich in fruits and vegetables enhance polyphenolic intake and are protective against cardiovascular disease (Booth and others 2006). However, people with diabetes tend to have reduced fruit and vegetable intakes (Hertog and others 1993), possibly due to a paradoxical perception of possible adverse effects of fruit sugars on glycemic control. Lowered fruit intake may contribute to higher risk for CVD and its complications for persons with diabetes (Ford and Mokdad 2001). Furthermore, people with diabetes are at high risk for developing urinary tract infections (UTIs) due to the periods of glycosuria that may accompany periods of poor glycemic control. Cranberry fruit contains a rich polyphenolic content, including A-type proanthocyanidins, which have antiadhesion activity against P-fimbriated uropathogenic E. coli (Howell and others 1998; Foo and others 2000). Cranberry polyphenolics are also associated with improved protection of LDL from oxidative injury (Wilson and others 1998, 1999), lipoprotein profiles (Ruel and others 2006), and endothelium dependent vasodilation (Maher and others 2000). Thus, cranberry products may be protective against CVD and UTIs, and in turn people with diabetes should benefit from CBJ consumption. However, one caveat is that most commercially available CBJ products contain an artificially added carbohydrate load and may be problematic in this regard.

Unsweetened CBJ (100%, v/v) contains a low carbohydrate content (70 Cal/240 mL). However, typically CBJ cocktails contain 120 to 140 Cal/240 mL serving and are sweetened with high fructose corn syrup (HFCS) or blended with sugar-rich fruit juices, such as apple or pear juice. The added caloric (carbohydrate) content improves palatability but decreases suitability for people with diabetes seeking to limit caloric intake for the promotion of glycemic control and weight management. Only a few CBJ products are marketed as “reduced” or “low-calorie” products and they typically contain some HFCS that places their caloric content at 30 to 40 Cal/240 mL. In the absence of caloric sweeteners a 27% CBJ can provide as little as 19 Cal/240 mL serving. Low-calorie CBJ may be beneficial for people with diabetes seeking to maintain euglycemic control, reduce caloric intake and improve protection from UTIs and CVD. Documentation of the glycemic response to simple carbohydrate sweetened compared with unsweetened CBJ by people with diabetes has not been reported, and may be useful for demonstrating the benefits of low-calorie preparations.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results and Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

Subjects and study design

Following approval by the Winona State Univ. Institutional Review Board, volunteers were recruited by their healthcare providers and by advertisements in the local newspaper. Criteria for study involvement included medically confirmed noninsulin dependent type 2 diabetes. Criteria for study exclusion included smoking, alcohol consumption, current use of steroidal drugs, and the treatment for cancer or occurrence of a cardiovascular event within the last 6 mo. The 6 male and 6 female subjects who participated were 65.3 ± 2.3 y old, and had a body mass index (BMI) of 34.7 ± 1.6. Among the noninsulin dependent diabetics who participated in the study, 5 persons were taking both metformin and glipizide on a daily/bidaily basis, five were taking just metformin on a daily/bidaily basis, and four were taking no oral diabetes medications.

A single cross-over design was used to test subject metabolic response to 4 different beverage interventions. On the day before evaluation of glycemic response to each beverage subjects agreed to consume no cranberry or blueberry containing products, fruits, onions, or chocolate to reduce the effect of background dietary phenolics. A uniform P.M. snackbar was provided by the investigators to generate dietary uniformity among participants prior to laboratory presentation. The 65 g Vanilla Crisp PowerBar® contained 230 Cal, 2.5 g total fat, 3 g dietary fiber, 20 g sugars, 22 g other carbohydrates, and 9 g protein. Following dinner they self-administered their bar just prior to beginning their 10 h fast from all food and beverages except water. Subjects presented to the lab on the following morning at between 5:30 and 7:30 A.M.

Subjects were randomly assigned to receive a single weight adjusted serving of conventionally dextrose sweetened normal calorie cranberry juice (NCCBJ; 27% CBJ, v/v; 130 Cal/240 mL), normal calorie control (NCC; 140 Cal/240 mL) made with dextrose, unsweetened low-calorie cranberry juice (LCCBJ; 27%, v/v CBJ; 19 Cal/240 mL), or low-calorie control (LCC; 19 Cal/240 mL) made with dextrose on 4 of 5 semiconsecutive wk. All beverages were prepared by the investigators on the morning of administration using an unsweetened 100% cranberry juice product (Just Cranberry 100% Juice, Knutsen and Sons Inc., Chico, Calif., U.S.A.) that contained 70 Cal/240 mL (18 g total carbohydrate of which 9 g were sugars), 30 mg sodium, 160 mg potassium, and 2%, 4%, and 6% of the RDI for ascorbate, calcium, and iron, this product contained no artificially added sweeteners, preservatives, or ascorbate. All bottles used in this study were part of the same lot manufactured on the same day. Caloric adjustments were made using anhydrous food-grade dextrose with 99.8% purity (Corn Products US, Westchester, Ill., U.S.A.). To reduce the influence of sweetener, artificial sweetener or their combination as confounding factors related to the glycemic response, unsweetened 27% (v/v) CBJ was chosen for use as the low-calorie product in this study.

Upon completion the trial participants were asked “Did you find the low-calorie cranberry juice to be objectionable? Yes or No.” They were then asked to comment on their yes or no answer. The flavor of the unsweetened 27% LCCBJ was found to be tart but not objectionable by any of the subjects who participated in this study.

High-performance liquid chromatography analysis of CBJ

The polyphenolic contents of the 100% pure CBJ were identified using previously described HPLC (Wilson and others 2008) and quantified as described subsequently. Phenolic acids, flavonol glycosides, anthocyanins, and proanthocyanidins were isolated from CBJ using a sephadex column. Isolated fractions were concentrated using a Rotavapour (model RE 111, Buchi, Flawil, Switzerland) at 45 °C under reduced pressure prior to HPLC analysis. Analytical detection and quantification of phenolic acids and flavonol glycosides were completed with HPLC using in house isolated standards (chromatograph from Waters, Milford, Mass., U.S.A.) and a C18 Luna column (4.6′ 150 mm; particle size 5 μm; Phenomenex, Torrance, Calif., U.S.A.) (Vvedenskaya and others 2004; Wilson and others 2008). Oligomeric proanthocyanidins were identified and quantified using a Dionex (Sunnyvale, Calif., U.S.A.) HPLC apparatus consisting of a G-40 gradient pump, model 100 PDA detector, model AS50 autosampler/thermal compartment, and model ED50 detector. In addition to identification and quantification of proanthocyanidins based on HPLC retention time, identifications were further confirmed using matrix-assisted laser desorption ionization mass spectra (MALDI-TOF-MS; Applied Biosystems, Foster City, Calif., U.S.A.) (Klem and others 2006; Wilson and others 2008). Anthocyanins were separated, identified, and quantified (Seeram and others 2004; Wu and Prior 2005) using Dionex HPLC as described previously equipped with Luna C-18 column (Phenomenex). The spectrums were recorded between 210 and 550 nm at 1.5-nm steps in PDA and 1.2 volts in the electrochemical detector with 520 nm as a detection wavelength for anthocyanins quantification.

Postingestion analysis of blood glucose and plasma insulin

A venous blood sample was collected 15 min after presentation to the laboratory, after which subjects received their assigned beverage intervention, sampling was repeated 30-, 60-, and 120-min postingestion. An Accu-Chek blood glucose analyzer (Roche Diagnostics Inc., Indianapolis, Ind., U.S.A.) calibrated with Sugar-Chex Linearity standards (Streck, Omaha, Nebr., U.S.A.) was used to obtain blood glucose values immediately after blood collection. Blood glucose area under the curve (AUC) values were calculated for the 120 min study period using the trapezoidal rule (Wilson and others 2008). Plasma insulin was measured from freshly thawed samples with a 2-site immunoenzymatic assay and the DxI automated immunoassay system (Beckman Instruments, Chaska, Minn., U.S.A.) at Mayo Clinic Rochester (Rochester, Minn., U.S.A.). Hemoglobin A1C values were obtained midway through the study using a turbidim inhibition immunoassay and a Dimension Clinical Chemistry System (Dade Behring Inc. Newark, Del., U.S.A.).

Statistical analysis

All data are expressed as mean ± standard error of the mean (SEM). The data were analyzed using a repeated measures analysis of variance (ANOVA) to identify significant differences among interventions, among time points, and the interaction between intervention and time. Significant differences among least squares means (P < 0.05) were determined using the Tukey–Kramer adjustment. A repeated measures analysis was used to account for the lack of independence between measurements on the same subject (SAS Inst. Inc., Cary, N.C., U.S.A.).

Results and Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results and Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

Favorable glycemic response of people with diabetes

Mean fasting blood glucose of all subjects prior to administration of the 4 test beverages as part of the single cross-over design was 7.0 ± 0.4 mmol/L . Peak blood glucose values (Figure 1) were achieved 30 min postingestion for NCCBJ, NCC, LCCBJ, and LCC at 13.3 ± 0.5, 12.8 ± 0.9, 8.1 ± 0.5, and 8.7 ± 0.5 mmol/L, respectively. The increase from baseline was statistically significant within the NCCBJ and NCC groups at 30 and 60 min. The responses within the LCCBJ and LCC interventions were not significantly different from baseline. The AUC values following the NCCBJ and NCC interventions were 1290 ± 54 and 1320 ± 75 mmol glucose/min respectively, which were significantly greater than the respective LCCBJ and LCC AUC values of 951 ± 57 and 955 ± 64 mmol glucose-min. No statistically significant differences in AUC were observed between the NCCBJ and NCC or the LCCBJ and LCC interventions.

image

Figure 1—. Postingestion blood glucose was significantly increased following consumption of normal calorie cranberry juice and normal calorie control beverage 30 and 60 min postingestion. Significant differences (P < 0.05) within interventions relative to 0 min are signified by # and significant differences among interventions within times are indicated by different letters (mean ± SEM; n= 12).

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The acute metabolic effects of sugar-sweetened cranberry beverages compared with unsweetened low-calorie products have, to our knowledge, never been reported among diabetic subjects. Conversely, the diabetic glycemic response to orange juice and carbonated beverages has been characterized (Sullivan and Scott 1991) and the response is similar to observed data for the normal calorie interventions in the current study. In the current study, blood glucose peaked 30 min postingestion in all groups (Figure 1). NCCBJ was associated with a significant 96% increase in blood glucose, in contrast LCCBJ was associated with only a modest 16% increase that was not significantly different from the baseline value. Glycemic responses of the 2 isocaloric control interventions were virtually identical to those containing 27% CBJ. Changes in plasma insulin (Figure 2) were similarly significant 60 min postingestion, with the low-calorie interventions having no significant increase. In this regard it was also noteworthy that the peak glycemic response to the LCCBJ and LCC interventions was not significant from baseline, even in the absence of concurrent antidiabetic therapy.

image

Figure 2—. Postingestion plasma insulin concentration increases significantly following consumption of normal calorie cranberry and control beverages. Significant differences (P < 0.05) within interventions relative to 0 min are signified by # and significant differences among interventions within times are indicated by different letters (mean ± SEM; n= 12).

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HFCS and fruit juices are commonly used in commercial CBJ products to improve palatability and contain fructose. The presence of fructose in a glycemic load has been suggested to induce a more favorable glycemic response (Crapo and others 1980). However, it is in our opinion doubtful that the use of HFCS could have made the differences between our 2 normal and low-calorie treatments statistically significant. Approximately, 5% of the total carbohydrate content in a 42% HFCS is made up of oligomers and other carbohydrates (Hanover and White 1993). We chose to use a precisely characterized sugar (99.8% anhydrous dextrose) for caloric balancing because it represented an exactly quantifiable material.

Our previous CBJ study examined the glycemic response of healthy nondiabetic college aged students (Wilson and others 2008) where peak blood glucose following consumption of LCCBJ (38 Cal/480 mL/70 kg) and NCCBJ (280 Cal/480 mL/70 kg) interventions was 5.4 ± 1.0 and 7.7 ± 0.3 mmol/L, respectively. In the current study, diabetic peak blood glucose was considerably greater than that observed for persons without diabetes, in spite of the fact that the glycemic load (grams sugar/serving) administered was half that administered to the nondiabetics. This highlights the significant role that carbohydrate consumption has on the metabolic responses of persons with and without diabetes.

Baseline fasting plasma insulin of all subjects prior to administration of the 4 test beverages was 76.2 ± 20.6 pmol/L. Peak plasma insulin values (Figure 2) were achieved 60 min postingestion and were statistically significant from baseline only for the NCCBJ and NCC groups. Differences verses baseline were no longer significant 120 min postingestion. Plasma insulin and blood glucose were not correlated for the NCCBJ and NCC interventions, with R2-values of 0.02 and 0.04, respectively.

Phenolic composition of cranberry juice

Cranberry juice is unique among fruit juices because it has a relatively low natural carbohydrate content compared to its high content of vitamins, minerals, and polyphenolic compounds. The pure CBJ used in this study contained a total of 706 μg polyphenolics/mL (Table 1). Several flavonols were present with free quercetin, quercetin-3-β-galactoside, myricetin-3-β-galactoside being the most prominent flavonol constituents. The CBJ was also rich in degrees of polymerization (DP) associated with proanthocyanidins (Figure 3). Specifically, 3 types of epicatechin trimer A-type formed the predominant constituents, with tetramers (DP-4), hexamers (DP-6), nonamers (DP-9), unidecamers (DP-11), dodecamers (DP-12), tridecamers (DP-13), tetradecamers (DP-14), and pentadecamers (DP-15) also being detectable and quantifiable. The CBJ utilized in this study (Table 1) was rich in glycosylated flavonols (quercetin and myricetin), and anthocyanins, as well as oligomeric proanthocyanidins that are considered to be beneficial for CBJ-dependent UTI and cardiovascular effects.

Table 1—.  HPLC analysis of cranberry juice flavonol, proanthocyanidin, and anthocyanidin content listed in order of HPLC-retention time.
Flavonol compoundsμg/mLProanthocyanidin compoundsμg/mL
  1. bStructure based on LC-MS data.

  2. dStructure based on in-house standards.

  3. eIdentity based on MALDI-TOF-MS analysis.

  4. fDP = degree of polymerization.

5-caffeoylquinic acida,b,c (M.W. 353)0.018Catechinb,d (M.W. 289)0.062
Myricetin-3-β-galactosidea,b (M.W. 479)147Epicatechinb,d (M.W. 289)0.231
Myricetin-3-α–xylopyranosidea,b,c (M.W. 449)2.76 Dimersb,c,e (M.W. 576)1.76 
Myricetin-3-α–arabinofuranosidea,b,c (M.W. 449)0.112Trimersb,c,e (DPf-3; M.W. 863)2.05 
Quercetin-3-β-galactosidea,b,c (M.W. 463)323Trimersb,c,e (DP-3; M.W. 864)4.21 
Quercetin-3-α–arabinopyranosidea,b,c (M.W. 433)9.39 Trimersb,c,e (DP-3; M.W. 867)0.077
Quercetin-3-α–arabinofuranosidea,b,c (M.W. 433)11.4   Tetramersb,c,e (DP-4; M.W. 1153)0.062
Quercetin-3-α–xylopyranosidea,b,c (M.W. 433)0.198Tetramersb,c,e (DP-4; M.W. 1154)0.026
Quercetin-3-rhamnopyranosidea,b,c (M.W. 447)49.6   Tetramersb,c,e (DP-4; M.W. 1152)1.10 
3′-methoxyquercetin-3-β-galactosidea,b,c (M.W. 477)0.109Pentamersc,e (DP-5; M.W. 1437)0.058
Dimethoxymyricetin-hexosidea,b,c (M.W. 507)54.7   Hexamersc,e (DP-6; M.W. 1727)0.190
Methoxymyricetin-pentosidea,b,c (M.W. 345)3.16 Heptamersc,e (DP-7; M.W. 2014)0.031
Methoxyquercetin-pentosidea,b,c (M.W. 447)1.28 Octamersc,e (DP-8; M.W. 2304)0.019
3′-methoxyquercetin-3-α-xylopyranosidea,b,c (M.W.447)1.09 Nonamersc,e (DP-9; M.W. 2595)0.520
Q-3-O-(6″-p-coumaroyl)-β-Galactosidea,b,c (M.W. 609)1.20 Decamersc,e (DP-10; M.W. 2881)0.020
Quercetina,b,c,d (M.W. 301)72.2   Polymersc,e (DP-11; M.W. 3168)0.320
Q-3-O-(6″-p-benzoyl)-β-Galactosidea,b,c,d (M.W. 567)7.53 Polymersc,e (DP12; M.W. 3455)0.285
Methoxy Kaempferol derivativea,b,c (M.W. 581)10.3   Polymersc,e (DP13,DP14,DP15; M.W. 3742, 4029, 4317)0.003
Anthocyanin compounds: order of column retention (μg/mL)
 Cyanidin-3-galactosideb,g 1st (M.W. 449)11.9   Peonidin-3-galactosideb,g 3rd (M.W. 433)17.5   
 Cyanidin-3-arabinosideb,g 2nd (M.W. 419)28.6   Peonidin-3-arabinosideb,g 4th (M.W. 463)31.4   
image

Figure 3—. HPLC chromatogram demonstrating constituent proanthocyanidin content of cranberry juice and their degrees of polymerization (DP): Peaks 1 to 3 correspond to dimers (DP-2), peaks 4 to 7 to trimers (DP-3), peaks 8 to 10 to tetramers (DP-4), peak 11 to pentamers (DP-5), peak 12 to hexamers (DP-6), peak 13 to heptamers (DP-7), peak 14 to octamers (DP-8), peak 15 to nonamers (DP-9), peak 16 to decamers (DP-10), peak 17 to undecamers (DP-11), peak 18 to dodecamers (DP-12), peak 19 to tridecamers (DP-13), peak 20 to tetradecamers (DP-14), and peak 21 to pentadecamers (DP-15).

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Our previous study provided a qualitative analysis of CBJ polyphenolic constituent content (Wilson and others 2008). The current study provides a quantitative analysis of CBJ flavonols and anthocyanins, and several high molecular weight proanthocyanidins using HPLC, LC-MS, and MALDI-TOF. While HPLC methods have been developed previously for the quantification of oligomeric proanthocyanidins after degradation and derivatization (Sun and others 1998), to our knowledge, this is the 1st CBJ report to quantify these large oligomeric proanthocyanidins (DP-4, -6, -9, -11, -12, -13, -14, and -15).

It has been suggested that phenolic compounds such as quercetin may inhibit gastric uptake of glucose in the porcine model (Cermak and others 2004), and that quercetin and myricetin may inhibit GLUT4-mediated glucose uptake by rat adipocytes (Strobel and others 2005). These effects could alter the postglycemic response and in people without diabetes and a trend toward this effect was observed following CBJ consumption (Wilson and others 2008); however, in the current investigation, the metabolic responses of NCCBJ and NCC interventions were nearly identical. Hence the polyphenolic composition of CBJ does not appear to mediate the human glycemic response in people with type 2 diabetes.

Study population characteristics

The persons with type 2 diabetes chosen for participation in this study are typical of the adults typically seen in clinical practice. They were 65.3 ± 1.9 y old with a BMI of 34.7 ± 1.6 and a HbA1c of 6.7 ± 0.1%, which is associated with moderate glycemic control (ADA 2006). Peak blood glucose following the NCCBJ and NCC interventions typically exceeded the 10.0 mmol/mL upper limit recommendations. Additionally, peak blood glucose values in the NCCBJ and NCC groups should have exceeded the renal threshold for glycosuria; however, urine samples were not collected in this study to characterize this effect.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results and Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

The current study demonstrates the significant difference in the metabolic response to carbohydrate sweetened and low-calorie CBJ preparations. The ADA (2008) promotes the use of juice as a means of increasing fruit consumption. The substitution of three 240 mL servings of NCCBJ/d with unsweetened 27% CBJ, or a juice utilizing noncaloric sweeteners, would reduce caloric intake by approximately 300 Cal/d, this would provide for improved flexibility within the exchange system. Furthermore the consumption of LCCBJ by people with type 2 diabetes would simplify pharmacological adjustments needed to maintain postingestion euglycemia. The potential benefits of carbohydrate restriction with respect to the treatment of type 2 diabetes has also begun to be reappraised (Accurso and others 2008), and low-calorie CBJ preparations may also become important in this regard. The current study of people with diabetes provides nutrition educators with compelling evidence that a low-calorie cranberry juice will help increase fruit consumption while improving glycemic control.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results and Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

The authors wish to thank L Coon, CM Hayes, NM Swanson, AN Roepke, JB Johnson, KL Carlson, TN Koch, AM Blilie, L Heath for their help with participant management and phlebotomy, T Hooks for assistance with statistics, and the Winona Health Dietetics program for their help with participant recruitment. This study was supported by a L21 grant from Winona State Univ. (TW and SLM) and NIH NCCAM 5R01AT002058 (APS and NV).

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  2. Abstract
  3. Introduction
  4. Methods
  5. Results and Discussion
  6. Conclusions
  7. Acknowledgments
  8. References
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