Journal of Food Research; Vol. 2, No. 5; 2013
ISSN 1927-0887
E-ISSN 1927-0895
Published by Canadian Center of Science and Education

The Beneficial Effects of SesaVitaTM on Lipid Profiles and Blood
Glucose Levels in Subjects With Prediabetes and Mild-To-Moderate
Hyperlipidemia in India
H. N. Shivaprasad1, M. Bhanumathy1, Ceyhun Tamer2, G. Sushma1, K. R. Raveendra3 & K. Venkateshwarlu4
1

R & D Centre, Olive Lifesciences Pvt. Ltd., Tumkur-572 106, India

2

BioActives Europe GmbH, Voltenseestr. 2, 60388 Frankfurt, Germany

3

Bangalore Medical College & Research Institute, Bengaluru-560 002, India

4

Srinivasa Clinic & Diabetic Care Centre, Girinagar, Bengaluru-560 050, India

Correspondence: M. Bhanumathy, R & D Centre, Olive Lifesciences Pvt. Ltd., Tumkur-572 106, India. Tel:
91-8042-1135-36/37. E-mail: bhanumathy@olivelifesciences.com
Received: July 19, 2013
doi:10.5539/jfr.v2n5p104

Accepted: August 20, 2013

Online Published: August 26, 2013

URL: http://dx.doi.org/10.5539/jfr.v2n5p104

Abstract
Individuals suffering from Type 2 diabetes develop prediabetes before progression of diabetes. In case ofprediabetes people, the blood glucose levels are higher than normal but not sufficient to be diagnosed as diabetes.
On the basis of existing reports on Sesame extract, SesaVitaTM which is an herbal food supplement containing
Sesame seeds (Sesamum indicum L.) extract may provide an option for management of prediabetes. The
objective of this study was to determine the beneficial effects of SesaVitaTM in prediabetes and mild to moderate
hyperlipidemia subjects. This randomized, placebo-controlled, double-blind study comprised of 13 female and
07 male patients with prediabetes and mild to moderate hyperlipidemia, aged between 18 and 65 years. Twenty
subjects were randomized to receive SesaVitaTM (500 mg/day) or placebo along with therapeutic lifestylechanges for 6 weeks. The primary outcome was the measure of efficacy in terms of change in serum lipid profileand glycaemic levels on week 3 and 6. Secondary outcome measures include safety and tolerability evaluated byphysical examination and clinical laboratory evaluations. Improvements in lipid profile and glycaemic levels
were observed in SesaVitaTM treated group when compared with placebo and baseline. A statistical significant
reduction was observed in low density lipoprotein cholesterol (LDL-C), total cholesterol (TC), oral glucose
tolerance test (OGTT) and fasting blood sugar (FBS) levels during week 3 and 6 when treated with SesaVitaTM
extract. No adverse events occurred and all safety parameters were within normal ranges during the study. This
study revealed that the treatment with SesaVitaTM was safe and well tolerated; may be beneficial in the
management of prediabetes and mild-to-moderate hyperlipidemia.
Keywords: SesaVitaTM, prediabetes, hyperlipidemia, Sesamum indicum, lipid profile, glycaemic level
1. Introduction
Prediabetes, also known as intermediate hyperglycaemia, is a high-risk state for diabetes. It is defined as
glycaemic variables that are higher than normal, but lower than the diabetes threshold (Tabák, Herder, Rathmann,
Brunner, & Kivimäki, 2012). According to the American Diabetes Association (ADA), prediabetes is a fasting
plasma glucose (FPG) of at least 100 mg/dL (5.6 mmol/liter) but less than 126 mg/dL (7.0 mmol/liter), which isfrequently termed as impaired fasting glucose (IFG), or an abnormal 2-hours response to a 75-g oral glucose
tolerance test (OGTT) of at least 140 mg/dL (7.8 mmol/liter) and less than 200 mg/dL (11.1 mmol/liter), which isoften termed as impaired glucose tolerance (IGT) (Aroda & Ratner, 2008). About 5-10% of people per year withprediabetes will progress to diabetes, with the same proportion converting back to normoglycaemia. Experts
have projected that by the year 2030, the prevalence of prediabetes will be more than 470 million people (Tabák,
Herder, Rathmann, Brunner, & Kivimäki, 2012).
Prediabetes people may suffer from the factors such as hyperlipidemia, hypertension and insulin
resistance-linked obesity which increase the risk of heart disease. Simultaneous presence of insulin resistanceand β-cell dysfunction-abnormalities were found in prediabetes people that start before glucose changes are104www.ccsenet.org/jfr

Journal of Food ResearchVol. 2, No. 5; 2013detectable. The associations between prediabetes and early forms of nephropathy, chronic kidney disease, small
fibre neuropathy, diabetic retinopathy and increased risk of macrovascular disease were evidenced byobservational reports (Tabák, Herder, Rathmann, Brunner, & Kivimäki, 2012). Management of individuals
suffering from prediabetes includes reduction of cardiovascular disease risk factors, specifically lipid and bloodpressure abnormalities. Intensive lifestyle intervention is required to prevent progression from prediabetes todiabetes (Twigg, Kamp, Davis, Neylon, & Flack, 2007).
Medicinal plants, since times immemorial, have been used in virtually all cultures for controlling and preventing
diabetes. In Asian countries, Sesame (Sesamum indicum L.) has been used to improve the nutritional status andprevent various diseases for thousands of years ago. Sesame is a traditional healthy food and it is not only rich inoil (about 50%) and protein (about 20%), but also rich in lignans including sesamin and sesaminol (up to 1.5%)(Chen et al., 2005). Modulation of fatty acid metabolism, inhibition of cholesterol absorption and biosynthesis,
antioxidant and vitamin E-sparing effects, hypotensive effects, improvement of liver functions in connection
with alcohol metabolism and antiaging effects are the pharmacological activities of sesame seed lignans(Kamal-Eldin, Moazzami, & Washi, 2011). The other activities of sesame lignans include acceleration of alcohol
decomposition in the liver, immunoregulatory and anticarcinogenicity (Namiki, 2007).
In particular, the investigation of dietary substances to lower or regulate cholesterol and blood glucose levels isof special interest. A study reported that the sesamin isomers reduced blood cholesterol level in rats fed withcholesterol-enriched diet owing to increased faecal excretion of cholesterol and inhibition of the activity of liver
microsomal 3-hydroxy-3-methyl-glutaryl CoA reductase (Namiki, 2007). In another study, dietary sesame
appeared to exert beneficial effects on serum lipids and to improve antioxidant capacity in hypercholesterolemicpatients (Chen et al., 2005). Therefore, the aim of the current study was to evaluate the beneficial effects of
SesaVitaTM, an herbal food supplement containing Sesame seeds (Sesamum indicum L.) extract in the
management of healthy lipid profile and blood glucose level in prediabetic and mild to moderate hyperlipidemic
subjects.
2. Methods
2.1 Study Design
This study was a 6-week, randomized, double-blind, placebo-controlled experimental trial to determine theefficacy and safety of SesaVitaTM as a dietary supplement for lowering lipids and blood sugar levels.
2.2 Study Site
The study was conducted between April 2012 and June 2012; and carried out in Srinivasa clinic and diabetic carecenter, Bangalore, India.
2.3 Ethics Approval
The study protocol was reviewed and approved by the Institutional Ethics Committee, Bangalore; and allenrolled subjects provided their consent before the start of the study. The trial was conducted in accordance withthe principles of Good Clinical Practice and the Declaration of Helsinki.
2.4 Recruitment of Target Participants
Only participants who fulfilled the inclusion criteria for this current study were recruited. For example, age:
18-65 years old, and some hyperlipidemia as well as prediabetes conditions. Participants suffering from mild tomoderate hyperlipidemia should have low density lipoprotein-cholesterol (LDL-C) range 160-189 mg/dL[considered high as per Adult Treatment Panel (ATP) III guidelines, but used in this study as baseline values],
TC > 200 mg/dL and with none or one of the risk factors such as current cigarette smoking, family history ofpremature coronary heart disease (CHD) [CHD in male first degree relative <55 years; in female first degree
relative < 65 years], hypertension (BP > 140/90 mmHg or on antihypertensive medication), and with low
high-density lipoprotein cholesterol (HDL-C < 40 mg/dL). Participants suffering from prediabetes should have
impaired glucose tolerance [2-hours post 75-g OGTT levels in the range of ≥ 140 to ≤ 200 mg/dL] or impaired
fasting blood sugar (FBS levels in the range of ≥ 110 to ≤ 125 mg/dL). Along with these criteria, participants
should be mentally competent and able to understand all study requirements and sign the informed consent form.
Some volunteers, though interested in this study were excluded from participation according to the following
exclusion criteria: If their age was < 18 or > 65 years; if they were suffering from advanced chronic illness thatwould impair follow-up or monitoring; women who were pregnant or breastfeeding and women of childbearing
age; those participants who were unable to complete follow up and were on any medication that would affectevaluation like statins and; patients with mental illness or dementia, with a history of drug and/or alcohol abuse,105

www.ccsenet.org/jfr

Journal of Food ResearchVol. 2, No. 5; 2013subjects allergic to any medication. Twenty subjects who fulfilled the inclusion criteria such as suffering fromprediabetes and mild to moderate hyperlipidemia were recruited in this study.
2.5 Sample Preparation
The investigational substance (SesaVitaTM) is developed by M/s. Olive Lifesciences Pvt. Ltd., Bangalore, India.
Sesame seeds were washed and dried, and sesame oil was extracted using organic solvent at room temperaturefor 4-hours. Thereafter, the miscella was filtered, and the product was concentrated and crystallized usingorganic solvent at room temperature. Crystals were filtered out and dried under vacuum. The dried material was
re-dissolved in an organic solvent and refluxed with activated charcoal for 2-hours. The material was passed
through hyflo bed and concentrated the clear filtrate to thick paste. Organic solvent washings were given to thickpaste at room temperature to get the pure crystals. Crystals (SesaVitaTM) were filtered out, pulverized and dried
under vacuum at 70 ºC.
2.6 Procedure
Twenty subjects were randomized to receive SesaVitaTM or placebo (microcrystalline cellulose) along withtherapeutic lifestyle changes (TLC) for 6 weeks (Figure 1). SesaVitaTM (n = 11) or placebo (n = 9) were orally
administered twice a day (500 mg/day in two divided doses) 20 minutes before breakfast and dinner. The dosing
schedule was maintained for the duration of the study.

Figure 1. Study flow chart
FBS: Fasting blood sugar, HDL-C: High density lipoprotein cholesterol, LDL-C: Low density lipoproteincholesterol, OGTT: Oral glucose tolerance test, VLDL-C: Very low density lipoprotein cholesterol.
2.7 Follow-Up
The subjects were followed-up for six weeks.
Initial visit (Day 0): The participants were randomized to one of the two groups (Placebo and SesaVitaTM). Their
medical history was recorded using questionnaires and their physical examination was performed. The
106

www.ccsenet.org/jfr

Journal of Food ResearchVol. 2, No. 5; 2013

corresponding test substance was dispensed and recommended to follow therapeutic lifestyle changes which
includes low fat diet, weight management and increased physical activity to all the participants.
Follow-up visits: During week 3 and 6, the changes in serum lipid profile and glycaemic levels were measured.
The physical examination and clinical laboratory evaluations [Electrocardiogram (ECG), haematology,
biochemical tests, liver function tests and urine analysis] were carried out on week 6.
2.8 Assessment of Efficacy
The efficacy was assessed by measuring serum lipid profile (LDL-C, total cholesterol, very low-density
lipoprotein cholesterol, HDL-C and triglycerides) and glucose levels (FBS and OGTT) on week 3 and 6 inpatients with prediabetes and mild to moderate hyperlipidemia. Serum lipid profile was measured using
commercially available kit of metro lab auto analyzer. Glucose levels were measured using glucometer(Accu-chek active glucose monitor).
2.9 Assessment of Safety
On completion of 6-weeks treatment, each subject was specifically questioned about the presence or absence ofany side effects which the patient or the physician may attribute to the drug treatment. Along with this, physicalexamination and clinical laboratory evaluations such as ECG, haematology, biochemical tests, liver function test
and urine analysis were carried out during initial and final visits.
2.10 Statistical Analysis
The data presented here are given as mean values with standard error of the mean (SEM). Statistical analysis was
performed using unpaired t test and one-way ANOVA followed by Dunnett’s t test. The statistical significancewas set at (a), (*) p < 0.05 and (b), (**) p < 0.01. The above statistical applications were performed using Instatver. 5.00, GraphPad Software Inc., San Diego, CA, USA.
3. Results
A total of 20 patients who fulfilled the selection criteria and voluntarily consented were enrolled in the current
study and randomly assigned into two groups (Placebo and SesaVitaTM). The characteristics of the patients
including age, weight, height, pulse rate, blood pressure (diastolic and systolic), serum lipid profile andglycaemic levels of all groups at baseline are summarized in Table 1.
Table 1. Characteristics of the patients at baseline
Placebo (n=9)
49.11±2.73
66.14±3.14163.00±2.5988.22±2.54126.88±1.3782.22±1.22

Age (years)
Weight (kgs)
Height (cms)
Pulse rate/min
BP systolic (mmHg)
BP diastolic (mmHg)
Lipid profile (mg/dL)
LDL-C
165.04±1.19
TC237.77±4.17
VLDL-C
28.15±1.79
HDL-C
43.21±2.39
TG147.77±7.31
Glycaemic values (mg/dL)
FBS
116.11±1.76
OGTT170.55±6.93

SesaVitaTM (n=11)
50.09±3.71
64.04±1.50
162.27±2.2977.72±2.24127.27±3.35
81.36±1.62167.59±1.45
235.81±5.08
24.13±2.6745.10±1.76
112.27±15.38
110.45±6.20
167.90±4.28

Data is presented as mean ± SEM.
BP: Blood pressure, LDL-C: Low density lipoprotein cholesterol, TC: Total cholesterol, VLDL-C: Very low
density lipoprotein cholesterol, HDL-C: High density lipoprotein cholesterol, TG: Triglycerides, FBS: Fastingblood sugar, OGTT: Oral glucose tolerance test.

107www.ccsenet.org/jfr

Journal of Food ResearchVol. 2, No. 5; 2013

Changes in serum lipid profile and glycaemic levels of the treated group are summarized in Table 2. Incomparison with the placebo group, SesaVitaTM treated group showed a significant decrease (p < 0.01) in LDL-C
level at week 3 and 6. No significant differences were found in other serum lipids among the groups; however, anon-significant decreasing tendency was observed in total cholesterol and TG levels at week 3 and 6. In addition,
SesaVitaTM showed a significant decrease (p < 0.05, p < 0.01) in FBS level at week 3 and 6, respectively whencompared to placebo. No significant differences were found in OGTT level between the groups; however, adecreasing tendency was observed at week 3 and 6.
When compared to baseline SesaVitaTM group showed a significant decrease (p < 0.01) in LDL-C level at week 3
and 6. In addition, during week 6 it also showed a significant decrease (p < 0.01, p < 0.05) in total cholesterol
and FBS level respectively. It also showed a significant decrease (p < 0.05, p < 0.01) in OGTT level at week 3
and 6, respectively. The physical examination and clinical laboratory investigations performed on day 0 andweek 6 in placebo and treated groups were found to be within normal limits. No adverse events were reported inpatients treated with SesaVitaTM. Thus, the treatment with SesaVitaTM was found to be safe and well tolerated by
all patients during the complete intervention period.
Table 2. Effect of SesaVitaTM on serum lipid profile and glycaemic levels in patients with prediabetes and mild tomoderate hyperlipidemia
Placebo

SesaVitaTM

Baseline

165.04±1.19167.59±1.45

Week 3158.55±1.18144.36±3.03**b

Week 6

153.55±1.59135.81±4.02**b

Baseline

237.77±4.17235.81±5.08

Week 3229.66±3.75

220.90±5.79

Week 6225.33±3.89

210.36±4.85b

Baseline

28.15±1.79

24.13±2.67

Week 324.22±1.94

31.81±3.77

Week 623.66±2.38

29.09±3.22

Baseline

43.21±2.3945.10±1.76

Week 346.88±1.6445.00±1.85

Week 648.11±1.9645.81±1.63

Baseline

147.77±7.31

112.27±15.38

Week 3145.44±7.05

120.22±12.14

Week 6143.55±6.58

118.54±9.26

Baseline

116.11±1.76

110.45±6.20

Week 3111.11±1.86102.00±1.35*

Week 6109.22±1.5497.45±1.69**aBaseline

170.55±6.93167.90±4.28

Week 3162.00±6.57148.36±5.73a

Week 6158.00±5.66

146.36±4.53b

Variables
Lipid profile (mg/dL)
LDL-C

TC

VLDL-C

HDL-C

TG

Glycaemic levels (mg/dL)
FBS

OGTT

Data is presented as mean ± SEM. *Comparison with placebo; a, bComparison with baseline; *p < 0.05,**p < 0.01; ap < 0.05, bp < 0.01
FBS: Fasting blood sugar, HDL-C: High density lipoprotein cholesterol, LDL-C: Low density lipoproteincholesterol, OGTT: Oral glucose tolerance test, TC: Total cholesterol, TG: Triglycerides, VLDL-C: Very low
density lipoprotein cholesterol.
108

www.ccsenet.org/jfr

Journal of Food ResearchVol. 2, No. 5; 2013

4. Discussion
The findings from this investigation has provided valuable information on the probable efficacy and safety of
SesaVitaTM in managing prediabetes and mild to moderate hyperlipidemia by lowering serum cholesterol andglycaemic levels. Treatment with SesaVitaTM in patients suffering from prediabetes and mild to moderate
hyperlipidemia was found in this study to improve the lipid profile and glycaemic levels when compared to theplacebo group and baseline. The high performance liquid chromatography (HPLC) characterization of
SesaVitaTM revealed the presence of 71.11% w/w total sesamin complex. Thus, the lowering plasma cholesteroland glycaemic levels might be related to the amounts of sesamin complex from sesame seeds.
The effects of sesamin, a lignan from sesame seeds, on various aspects of cholesterol metabolism were examinedin rats maintained on various dietary regimens. It has been reported that, following administration of sesamin at
dietary level of 0.5% for 4 weeks significantly reduced the concentration of serum and liver cholesterol withirrespective of the presence or absence of cholesterol in the diet. (Hirose et al., 1991). A clinical study in
hypercholesterolemic patients reported that daily oral intake of sesamin for 4 weeks significantly decreased total
and LDL cholesterol concentrations (Hirata et al., 1996). Sesamin as a dietary supplement administered in
hyperlipidemic rats reduced plasma and liver total cholesterol and LDL cholesterol concentrations (Kamal-Eldin
et al., 2000). The hypocholesterolemic effect of sesamin is probably through inhibition of intestinal absorption ofcholesterol, increased excretion of cholesterol into bile and decreased activity of 3-hydroxy-3-methylglutaryl
coenzyme A reductase (Hirose et al., 1991).
The earlier studies have reported that the serum lipids in hyperlipidemia can be improved by the dietary plantseeds or nuts, which have favorable fatty acid and nutrient profiles. A few functional components of sesame
seeds shares with nuts are low levels of saturated fatty acids and high levels of monounsaturated andpolyunsaturated fatty acids. In addition, to prevent hypercholesterolemia there are other bioactive molecules suchas plant protein, dietary fiber, phytochemicals and lignans in nuts and sesame. (Iwamoto et al., 2000; Durak, etal., 1999; O'Byrne, Knauft, & Shireman, 1997; Chisholm et al., 1998; Curb et al., 2000; Zambón et al., 2000).
Treatment with SesaVitaTM in patients with prediabetes and mild to moderate hyperlipidemia which exhibited
improvements in serum lipid profile and glycaemic levels may be due to presence of sesamin complex, lignans
present in sesame seeds. Changes in lifestyle, including a balanced diet and regular physical exercise may serveas adjunct therapies for decreasing LDL cholesterol and glycemia levels. Thus, sesame extract can be used as
dietary supplement in the management of healthy lipid and glucose levels in patients with prediabetes and mild
to moderate hyperlipidemia.
5. Conclusion
Based on the results obtained in this study, it can be concluded that patients with prediabetes and mild tomoderate hyperlipidemia treated with sesame extract for 6 weeks are likely to realize positive changes in theirlipid profiles and blood glucose levels. Thus, the herbal supplement (SesaVitaTM) may be beneficial for
maintaining healthy lipid and glucose levels in patients with prediabetes and mild to moderate hyperlipidemia.
References
Aroda, V. R., & Ratner, R. (2008). Approach to the patient with prediabetes. The Journal of Clinical
Endocrinology and Metabolism, 93, 3259-3265. http://dx.doi.org/10.1210/jc.2008-1091
Chen, P. R., Chien, K. L., Su, T. C., Chang, C. J., Liu, T. L., Cheng, H., & Tsai, C. (2005). Dietary sesame
reduces serum cholesterol and enhances antioxidant capacity in hypercholesterolemia. Nutrition Research,
25, 559-567. http://dx.doi.org/10.1016/j.nutres.2005.05.007
Chisholm, A., Mann, J., Skeaff, M., Frampton, C., Sutherland, W., Duncan, A., & Tiszavari, S. (1998). A diet richin walnuts favourably influences plasma fatty acid profile in moderately hyperlipidaemic subjects.
European Journal of Clinical Nutrition, 52, 12-16. http://dx.doi.org/10.1038/sj.ejcn.1600507
Curb, J. D., Wergowske, G., Dobbs, J. C., Abbott, R. D., & Huang, B. (2000). Serum lipid effects of ahigh-monounsaturated fat diet based on macadamia nuts. Archives of Internal Medicine, 160, 1154-1158.
http://dx.doi.org/10.1001/archinte.160.8.1154
Durak, I., Köksal, I., Kaçmaz, M., Büyükkoçak, S., Cimen, B. M., & Oztürk, H. S. (1999). Hazelnut
supplementation enhances plasma antioxidant potential and lowers plasma cholesterol levels. Clinica
Chimica Acta, 284, 113-115. http://dx.doi.org/10.1016/S0009-8981(99)00066-2
Hirata, F., Fujita, K., Ishikura, Y., Hosoda, K., Ishikawa, T., & Nakamura, H. (1996). Hypocholesterolemic effectofsesamelignaninhumans.
Atherosclerosis,
122,135-136.
109

www.ccsenet.org/jfr

Journal of Food ResearchVol. 2, No. 5; 2013

http://dx.doi.org/10.1016/0021-9150(95)05769-2
Hirose, N., Inoue, T., Nishihara, K., Sugano, M., Akimoto, K., Shimizu, S., & Yamada, H. (1991). Inhibition ofcholesterol absorption and synthesis in rats by sesamin. Journal of Lipid Research, 32, 629-638.
Iwamoto, M., Sato, M., Kono, M., Hirooka, Y., Sakai, K., Takeshita, A., & Imaizumi, K. (2000). Walnuts lower
serum cholesterol in Japanese men and women. The Journal of Nutrition, 130, 171-176.
Kamal-Eldin, A., Frank, J., Razdan, A., Tengblad, S., Basu, S., & Vessby, B. (2000). Effects of dietary phenolic
compounds on tocopherol, cholesterol, and fatty acids in rats. Lipids, 35, 427-435.
http://dx.doi.org/10.1007/s11745-000-541-y
Kamal-Eldin, A., Moazzami, A., & Washi, S. (2011). Sesame seed lignans: Potent physiological modulators andpossible ingredients in functional foods & nutraceuticals. Recent Patents on Food Nutrition and Agriculture,
3, 17-29. http://dx.doi.org/10.2174/2212798411103010017
Namiki, M. (2007). Nutraceutical functions of sesame: A review. Critical Reviews in Food Science and Nutrition,
47, 651-673. http://dx.doi.org/10.1080/10408390600919114
O'Byrne, D. J., Knauft, D. A., & Shireman, R. B. (1997). Low fat-monounsaturated rich diets’ containing
high-oleic
peanuts
improves
serum
lipoprotein
profiles.
Lipids,32,
687-695.
http://dx.doi.org/10.1007/s11745-997-0088-y
Tabák, A. G., Herder, C., Rathmann, W., Brunner, E. J., & Kivimäki, M. (2012). Prediabetes: A high-risk state fordiabetes development. Lancet, 379, 2279-2290. http://dx.doi.org/10.1016/S0140-6736(12)60283-9
Twigg, S. M., Kamp, M. C., Davis, T. M., Neylon, E. K., & Flack, J. R. (2007). Prediabetes: A position statementfrom the Australian Diabetes Society and Australian Diabetes Educators Association. The Medical Journalof Australia, 186, 461-465.
Zambón, D., Sabaté, J., Muñoz, S., Campero, B., Casals, E., Merlos, M., Laguna, J. C., & Ros, E. (2000).
Substituting walnuts for monounsaturated fat improves the serum lipid profile of hypercholesterolemic men
and women. A randomized crossover trial. Annals of Internal Medicine, 132, 538-546.
http://dx.doi.org/10.7326/0003-4819-132-7-200004040-00005
Copyrights
Copyright for this article is retained by the author(s), with first publication rights granted to the journal.
This is an open-access article distributed under the terms and conditions of the Creative Commons Attribution
license (http://creativecommons.org/licenses/by/3.0/).

110