(Circulation. 1997;96:4226-4231.)
© 1997 American Heart Association, Inc.
Articles |
Reduction of Serum Cholesterol in Postmenopausal Women With Previous Myocardial Infarction and Cholesterol Malabsorption Induced by Dietary Sitostanol Ester Margarine
Women and Dietary Sitostanol
From the Department of Medicine, Division of Internal Medicine, University of Helsinki (Finland).
Correspondence to Tatu A. Miettinen, MD, Department of Medicine, Division of Internal Medicine, University of Helsinki, Haartmaninkatu 4, FIN-00290 Helsinki, Finland.
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Abstract |
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Background Reduction of serum cholesterol decreases mortality in primary and especially in secondary prevention. We investigated how effectively postmenopausal women with a previous myocardial infarction reduced their serum cholesterol with dietary means by using sitostanol ester rapeseed oil margarine, alone and in combination with statins, and to what extent cholesterol metabolism was affected.
Methods and Results The first study group consisted of 22 randomly chosen women with angiographically documented coronary artery disease. Baseline studies on home diet were followed by double-blind, randomized, cross-over studies on margarine without and with sitostanol (3 g/d) ester for 7 weeks in random order. A second group of 10 women on simvastatin consumed sitostanol ester margarine for 12 weeks. Sitostanol ester margarine lowered serum total cholesterol by 13% (P<.05) and LDL cholesterol by 20% (P<.01). Sitostanol ester margarine reduced total cholesterol in all patients, LDL cholesterol <2.6 mmol/L (<100 mg/dL) in 32%, and <3.4 mmol/L (<133 mg/dL) in 73% versus none and 27% during the home diet (P<.01 for both). Combined with simvastatin, sitostanol still reduced total and LDL cholesterol by 11±3% and 16±5% (P<.01 for both). Sitostanol reduced absorption (-45%), increased fecal elimination (+45% as neutral sterols), and stimulated synthesis (+39%) of cholesterol. High cholestanol and plant sterol (high cholesterol absorption) and low baseline precursor sterol proportions (low cholesterol synthesis) predicted high decreases in serum cholesterol.
Conclusions Dietary use of sitostanol ester margarine normalizes LDL cholesterol in about one third of women with previous myocardial infarction, especially in those with high baseline absorption and low synthesis of cholesterol, and in combination with statins reduces the needed drug dose.
Key Words: cholesterol • women • myocardial infarction • diet
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Introduction |
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Recent studies have convincingly shown that effective serum cholesterol reduction by about 25% with current cholesterol synthesis inhibitors decreases significantly total and coronary mortality in primary and especially secondary prevention1 2 3 in both sexes.2 3 This also indicates that women with coronary heart disease and increased serum cholesterol should be treated effectively with cholesterol-lowering measures. The findings also suggest that hypolipidemic treatment with cholesterol synthesis inhibitors is beneficial for women with previous myocardial infarction ("coronary women") with relatively low serum cholesterol level (total cholesterol <6.2 mmol/L and LDL cholesterol from 3.0 to 4.5 mmol/L).3 The respective mean decrease in the serum total LDL cholesterol concentrations were 20% and 28%.3 On the other hand, serum cholesterol reduction can be achieved also by inhibition of cholesterol absorption. A combination of neomycin and sitostanol ester margarine almost totally inhibited cholesterol absorption, which resulted in a 37% reduction in the serum concentrations of total and LDL cholesterol.4 By sitostanol ester alone, the respective decreases were 10% and 14% in a mildly hypercholesterolemic random population.5 Sitostanol ester margarine lowers serum cholesterol by changing dietary fatty acid composition to less saturated and richer in monoenes and by causing cholesterol malabsorption. Accordingly, the purpose of the present study was to investigate how often optimal LDL cholesterol level can be reached with dietary measures by using only sitostanol ester margarine, alone or in combination with statins, in women with a previous myocardial infarction, and to which extent cholesterol metabolism is altered.
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Methods |
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Patients
The study population consisted of two groups of postmenopausal coronary women. The first group, selected randomly in 1993, consisted of 30 successive coronary women with no earlier estrogen therapy. Two of these patients were excluded because of hypolipidemic medication and 6 because of living too far away. Thus the study population included 22 women. Serum lipid levels were not an excluding factor. Angiography had been performed in all women, coronary artery bypass surgery in 8, and percutaneous transluminal angioplasty in 11. Our main focus is on this group not treated with lipid-lowering agents. The second group consisted of 10 coronary women who had been treated with simvastatin 10 to 20 mg/d over 1 year. All patients were 48 to 56 years old, and they had no thyroid, liver, or renal problems or diabetes mellitus. Myocardial infarction, angioplasty, or coronary bypass operation had occurred at least 3 months earlier. Some baseline data are shown in Table 1
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Study Procedure
After the run-in period on ad libitum home diet, the patients
without previous hypolipidemic treatment were randomized to replace
21 g of their daily fat intake by rapeseed oil margarine without
(n=11) or with sitostanol ester (n=11) for the next 7 weeks followed by
switching of the margarines for another 7-week period. The amount of
sitostanol in 21 g of the margarine was 3 g. The patients
were advised to use the margarine daily in three divided doses, mostly
on a piece of bread during the three major meals. The
simvastatin group also replaced 21 g of their daily
fat intake by sitostanol ester margarine for 12 weeks.
At the baseline home diet and at the end of both 7-week treatment periods, metabolic studies were performed in the first group. Two fasting blood samples were obtained at the end of a 7-day food diary. During that period, the patients consumed capsules containing Cr2O3 (200 mg), 14C-cholesterol (4500±19 [SE] DPM), and 3H-cholesterol (11 588±42 DPM), one with each of the three daily meals. Three-day stool collections were performed at the end of the week.
In the simvastatin group, serum and lipoprotein lipids were analyzed from two fasting blood samples at the beginning of the study on the home diet and simvastatin and at the end of 12 weeks on simvastatin and sitostanol ester margarine. No further metabolic studies were performed in this group.
The study protocol was accepted by the Ethics Committee of the Second Department of Medicine, University of Helsinki.
Methods
Serum and lipoprotein total and free
cholesterol, triglycerides, and phospholipids
and HDL cholesterol were determined enzymatically with
commercial kits (Boehringer Diagnostica and Wako
Chemicals). Means of two serum total cholesterol and
triglyceride and HDL cholesterol determinations
were used for each individual at each time point. Serum lipoproteins
were separated once by density gradient
ultracentrifugation at the end of each period in a Ti
50.4 fixed-angle rotor (Beckman Instruments) into the following density
classes: VLDL <1.006 g/mL; IDL 1.006 to 1.019 g/mL; LDL 1.019 to 1.063
g/mL; and HDL 1.063 to 1.210 g/mL.
Serum sterols were determined twice at the end of each period by
gas-liquid chromatography from nonsaponifiable serum
material on a 50-m long SE-30 capillary column.6 7 8 The
procedure measures total cholesterol and
noncholesterol sterols, including cholesterol
precursors 
8-cholestenol, desmosterol and lathosterols
(sterols reflecting cholesterol
synthesis),7 9 10 11 12 13 14 plant sterols, campesterol and
sitosterol, and cholestanol (sterols reflecting cholesterol
absorption).14 15 To eliminate the effect of changing
lipoprotein level, the noncholesterol sterol values are
standardized and expressed in terms of 102xmmol/mol of
cholesterol, that is, in proportions or ratios to serum
total cholesterol.
Elimination of cholesterol from the body and cholesterol absorption efficiency were measured once in each period from the 3-day stool collections. Cholesterol absorption efficiency was calculated by the altered 14C/3H ratio in stools as compared with the fed ratio,16 and the Cr2O3 measurement17 was applied to the measurement of fecal flow. Fecal cholesterol as fecal neutral sterols (cholesterol, coprostanol, and coprostanone), bile acids, and plant sterols were quantitated by gas-liquid chromatography.6 18 19 Dietary intake of fatty acids and cholesterol were determined from the 7-day diaries by a computer method applied to the country's dietary ingredients.20
Calculations
Cholesterol synthesis was calculated by the sterol
balance technique as the difference between the sum of fecal neutral
sterols plus bile acids and dietary cholesterol. Intestinal
total influx of cholesterol was obtained by dividing fecal
neutral sterol fraction (=fecal cholesterol) by
(1-fractional cholesterol absorption). The total intestinal
influx minus dietary cholesterol represents biliary
cholesterol. Respective absorption of each intestinal
cholesterol fraction is obtained by multiplication of each
flux by absorption efficiency. Unabsorbed dietary and biliary
cholesterol fractions are differences between the
intestinal influxes and the respective absorbed fractions.
Statistics
The mean±SE values were calculated, and the changes were
analyzed by the paired t test or ANOVA. The
correlation coefficients were determined by the Pearson's
product-moment correlation coefficient. Logarithmic transformations
were used when appropriate.
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Results |
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The coronary women had been on a cholesterol-lowering diet since discharge from the hospital. Thus dietary cholesterol intake was low, 247 mg/d, and the diet contained 15 energy % (E%) of saturated, 13 E% of monoenic and 6 E% of polyenic fatty acids, and 36 E% of fat (Table 1
). The polyunsaturated/saturated fatty
acid ratio was 0.43. Replacement of 21 g of the baseline dietary
fat by the same amount of the rapeseed oil margarine without or with
sitostanol ester reduced dietary cholesterol intake
slightly but significantly by about 15% (P<.05) and had no
effect on fat intake but tended to increase the intake of monoenic and
polyenic fatty acids and decrease saturated fatty acid intake so that
the polyunsaturated/saturated fatty acid ratio increased significantly
to 0.52±0.02. Body weight was not changed during the 14-week
period.
Home Versus Margarine Diet
Serum lipids for the 22 coronary women with no previous
hypolipidemic treatment are shown in Table 2. The shift from the home diet to the
rapeseed oil margarine significantly reduced total, VLDL, and LDL
cholesterol and HDL triglycerides (-5%;
P<.05).
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A relatively high campesterol content in the rapeseed oil margarine
increased the campesterol proportion in serum by 13%
(P<.01), but, in contrast to our earlier
findings,21 had no effects on the precursor sterol
proportions (Table 3). Fecal steroid
output and cholesterol absorption were not
consistently changed (Table 4).
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Sitostanol Ester Margarine Diet
Serum Lipids
Table 2 shows that the rapeseed oil margarine with sitostanol
ester lowered serum total and LDL cholesterol by 8% and
15%, respectively, from those without sitostanol, and 13% and 20%
from the home diet values. The higher the home LDL
cholesterol concentration, the higher was its decrease
(r=-.434; P<.05). Thirty-two percent of the
patients had their LDL cholesterol level <2.6 mmol/L
(<100 mg/dL), a recommended level according to the NCEP
guidelines,22 and 73% <3.4 mmol/L (<133 mg/dL)
during the sitostanol ester margarine treatment, the respective figures
being none and 27% during the home diet (P<.01 for both
comparisons). Even though the mean levels of VLDL, HDL, and total
triglycerides only tended to decrease, the higher their
home values, the higher were the changes (r=-.553 to
-.792, P<.01 to .001). The ratio of HDL/LDL
cholesterol was increased by 24% and 26% from the
margarine and home diet periods, respectively. Fig 1 shows that 32% of the patients
exhibited a decrease in serum cholesterol from the home
values by margarine without sitostanol, the respective value being
100% when sitostanol was present.
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In the coronary women treated with
simvastatin over 1 year, sitostanol ester reduced total
cholesterol by 11±3% and LDL cholesterol by
16±5% (P<.05 for both, Table 5). The respective
simvastatin-induced reductions had been -23% and -35%,
and the respective overall reductions, accordingly, were -32% and
-46%. Seven of the patients exceeded 2.6 mmol/L during
simvastatin, only two exceeded that during the combined
treatment.
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Noncholesterol Sterols
The serum cholesterol reduction from the home
period by the sitostanol ester margarine was associated with up to 33%
decreases in the proportions of cholestanol, campesterol, and
sitosterol and by up to 14% increases in those of the precursor
sterols (Table 3). In fact, the higher the decreases in the plant
sterol proportions, especially in that of sitosterol, the higher were
the reductions in the total and LDL cholesterol
(r=up to .676, P<.01). The higher the home or
margarine period proportions of cholestanol and plant sterols, the
higher were their sitostanol-ester induced reductions (Table 6). The higher the basal precursor sterol
proportions, the lower was the LDL cholesterol decrease,
whereas the high cholestanol proportion, clearly less than those of
plant sterols, predicted high LDL cholesterol lowering
(Table 6).
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Absorption and Fecal Output of Cholesterol
Fecal steroids, shown in Table 4, revealed that
cholesterol absorption efficiency was decreased by 45%,
resulting in up to 45% and 28% increases in fecal elimination of
cholesterol as neutral sterols alone or in combination with
bile acids, respectively. Sitostanol ester increased fecal elimination
of both dietary and biliary cholesterol (Table 4), which
was balanced by enhanced synthesis, up to 39%, and turnover of
cholesterol.
Cholesterol absorption was negatively correlated with
cholesterol synthesis on the home, margarine, and
sitostanol ester margarine diets (Fig 2).
The sitostanol-induced change in LDL cholesterol was
significantly associated with the change in cholesterol
absorption efficiency (r=.443). In addition (Table 6), the
high home proportions of the serum plant sterols and cholestanol and
absorption efficiency of cholesterol predicted their high
reductions by sitostanol ester margarine (r value ranged
from -.678 to -.863, P<.001). On the other hand, the
higher the synthesis at home, the smaller was the increase in synthesis
and the smaller the decrease in cholesterol absorption. The
changes in the plant sterol and cholestanol proportions were negatively
related to those of fecal plant sterols shown for sitostanol (identical
with dietary intake) in Fig 3 and
cholesterol synthesis. However, the decrease of serum
cholesterol was not related to the dietary intake of
cholesterol, indicating that the total and LDL
cholesterol concentrations were decreased similarly in
subjects on diets low or high in cholesterol.
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Discussion |
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The present findings showed for the first time that sitostanol ester margarine effectively inhibited cholesterol absorption, which then reduced the LDL cholesterol levels in 32% of the patients to <2.6 mmol/L (<100 mg/dL) compared with none during home diet in postmenopausal women with coronary heart disease. Thus the 15% reduction of serum total and 20% of the LDL cholesterol level were reduced to about 5% by the rapeseed oil margarine and 10% to 15% by sitostanol ester present in that margarine. Combination of sitostanol ester margarine to simvastatin therapy further reduced serum total and LDL cholesterol by 11% and 16%, respectively, so that most of the women exceeding the 100 mg/dL limits were now below that value. These results indicate that one third of coronary women can be treated normolipidemic by dietary sitostanol ester margarine only. The simultaneous use of sitostanol ester and statin is more effective than statin alone, reducing the statin dose needed or even eliminating the drug.
The serum cholesterol lowering by sitostanol in the present coronary female patients is roughly similar to that obtained earlier in other mainly male subjects on scheduled 3 to 3.4 g/d of sitostanol.23 24 The present findings in fecal elimination of cholesterol and serum noncholesterol sterols indicated that cholesterol absorption was markedly reduced by the sitostanol addition, increasing fecal output of cholesterol as neutral sterols, but having no effect on fecal bile acids and, accordingly, on bile acid synthesis. However, the increase in fecal elimination of cholesterol was balanced by a compensatory increase in turnover and synthesis of cholesterol, shown by the sterol balance data and cholesterol precursor sterols in serum, limiting the actual decrease in serum cholesterol. However, in view of the cholesterol-lowering diet, which the patients were using in home conditions, the advice to replace 21 g of their dietary fat by the sitostanol ester margarine further changed the diet to be more beneficial for cholesterol lowering so that the 15% usual fall in LDL cholesterol by sitostanol itself was increased to 20% by the combined action of both margarine and sitostanol. This effect is about equal to that obtained by 10 mg of lovastatin or pravastatin,25 26 indicating that sitostanol ester margarine can be considered to be beneficial also from the economic point of view.
Sitosterol has been suggested to inhibit more effectively
intestinal absorption of dietary than biliary
cholesterol.27 Accordingly, an unaltered serum
cholesterol level by capsules, containing sitostanol in oil
as suspension, was considered to be caused by ineffectiveness of
sitostanol in subjects on a diet low in
cholesterol.28 We believe that dietary intake
of sitostanol in fat-soluble form, as it is in our sitostanol ester
margarine, was more effective than that in insoluble form (suspension).
In the present series, the dietary intake of
cholesterol was low, about 207 mg/d, with a range from 77
to 383 mg/d, yet there was no correlation between the decrease in the
serum total or LDL cholesterol levels with the dietary
intake of cholesterol. In addition, the calculations in
Table 4 indicated that absorption of both dietary and biliary
cholesterol were partly inhibited by sitostanol. Even if no
dietary cholesterol were absorbed during the sitostanol
period (fecal unabsorbable dietary cholesterol equaled
dietary cholesterol intake of 207 mg), fecal output of
biliary cholesterol was still significantly increased.
Who, then, is most responsive to the sitostanol ester margarine? The highest decrease in serum total and especially LDL cholesterol was obtained in patients with the highest respective baseline levels. These subjects also had the highest cholesterol absorption, as shown by absorption percentage or especially the serum cholestanol and plant sterol proportions, and the lowest precursor sterol proportions. The findings indicate that the basal serum precursor sterols predict the subjects mostly responsive to cholesterol malabsorption. Similar association between serum cholesterol decrease and noncholesterol sterol proportions has been observed earlier in sitostanol ester series of mainly male subjects.23 24 In addition, serum cholesterol value and cholesterol absorption efficiency are positively correlated with each other in a normal male population.29 It is thus obvious that the higher the baseline total and LDL cholesterol concentrations and the serum cholestanol and plant sterol proportions and the lower the baseline precursor sterol proportions, the higher is the decrease in LDL cholesterol during sitostanol ester margarine also in postmenopausal coronary women. This would mean that sitostanol ester margarine, causing cholesterol malabsorption, is most effective in subjects in whom cholesterol absorption is high and cholesterol synthesis is correspondingly low.
As already noted, one third of the coronary women in this study obtained LDL cholesterol that was <2.6 mmol/L only with dietary means. Currently published studies2 3 clearly suggest that effective cholesterol lowering beneficially prevents recurrent coronary events. Accordingly, a combination of cholesterol malabsorption by sitostanol ester with statin could be beneficial, especially for the patients not responding satisfactorily to sitostanol ester margarine alone. As shown above, the subjects with high cholesterol synthesis are nonresponders to sitostanol ester and should be beneficially responding to statins. Recent preliminary studies of a 4S subgroup suggest, in fact, that subjects with low synthesis and high absorption of cholesterol did not respond, whereas those with high synthesis and low absorption responded to simvastatin-induced reduction of major coronary events.30 A synergistic effect has been recently found31 and observed also in the present study for cholesterol lowering by combined statin and sitostanol treatment. Thus it can be expected that a combination of sitostanol ester margarine to simvastatin treatment of coronary patients with high cholesterol absorption (detected by high baseline serum cholestanol and plant sterol and low precursor sterol proportions) will improve the response to reduced recurrence of coronary events.
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Acknowledgments |
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This study was supported by grants from the Finnish Academy of Medical Sciences, the Finnish Heart Research Foundation, the Paulo Foundation, the Juho Vainio Foundation, and the Helsinki University Hospital.
Received May 12, 1997; revision received September 5, 1997; accepted September 11, 1997.
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 R. A. Rajaratnam, H. Gylling, and T. A. Miettinen Cholesterol Absorption, Synthesis, and Fecal Output in Postmenopausal Women With and Without Coronary Artery Disease Arterioscler. Thromb. Vasc. Biol., October 1, 2001; 21(10): 1650 - 1655. [Abstract] [Full Text] [PDF]
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 R. J. Nicolosi, T. A. Wilson, C. Lawton, and G. J. Handelman Dietary Effects on Cardiovascular Disease Risk Factors: Beyond Saturated Fatty Acids and Cholesterol J. Am. Coll. Nutr., October 1, 2001; 20(90005): 421S - 427. [Abstract] [Full Text]
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A. H. Lichtenstein and R. J. Deckelbaum Stanol/Sterol Ester-Containing Foods and Blood Cholesterol Levels : A Statement for Healthcare Professionals From the Nutrition Committee of the Council on Nutrition, Physical Activity, and Metabolism of the American Heart Association Circulation, February 27, 2001; 103(8): 1177 - 1179. [Abstract] [Full Text] [PDF]
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R. M. Krauss, R. H. Eckel, B. Howard, L. J. Appel, S. R. Daniels, R. J. Deckelbaum, J. W. Erdman Jr, P. Kris-Etherton, I. J. Goldberg, T. A. Kotchen, et al. AHA Scientific Statement: AHA Dietary Guidelines: Revision 2000: A Statement for Healthcare Professionals From the Nutrition Committee of the American Heart Association J. Nutr., January 1, 2001; 131(1): 132 - 146. [Full Text]
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 R. M. Krauss, R. H. Eckel, B. Howard, L. J. Appel, S. R. Daniels, R. J. Deckelbaum, J. W. Erdman Jr, P. Kris-Etherton, I. J. Goldberg, T. A. Kotchen, et al. AHA Dietary Guidelines : Revision 2000: A Statement for Healthcare Professionals From the Nutrition Committee of the American Heart Association Stroke, November 1, 2000; 31(11): 2751 - 2766. [Full Text] [PDF]
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R. M. Krauss, R. H. Eckel, B. Howard, L. J. Appel, S. R. Daniels, R. J. Deckelbaum, J. W. Erdman Jr, P. Kris-Etherton, I. J. Goldberg, T. A. Kotchen, et al. AHA Dietary Guidelines : Revision 2000: A Statement for Healthcare Professionals From the Nutrition Committee of the American Heart Association Circulation, October 31, 2000; 102(18): 2284 - 2299. [Full Text] [PDF]
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T. A Miettinen, M. Vuoristo, M. Nissinen, H. J Jarvinen, and H. Gylling Serum, biliary, and fecal cholesterol and plant sterols in colectomized patients before and during consumption of stanol ester margarine Am. J. Clinical Nutrition, May 1, 2000; 71(5): 1095 - 1102. [Abstract] [Full Text] [PDF]
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T. A. Miettinen, T. E. Strandberg, H. Gylling, and f. t. F. I. o. t. S. S. S. S. Group Noncholesterol Sterols and Cholesterol Lowering by Long-Term Simvastatin Treatment in Coronary Patients : Relation to Basal Serum Cholestanol Arterioscler. Thromb. Vasc. Biol., May 1, 2000; 20(5): 1340 - 1346. [Abstract] [Full Text] [PDF]
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 R. A. Rajaratnam, H. Gylling, and T. A. Miettinen Independent association of serum squalene and noncholesterol sterols with coronary artery disease in postmenopausal women J. Am. Coll. Cardiol., April 1, 2000; 35(5): 1185 - 1191. [Abstract] [Full Text] [PDF]
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M. A. Hallikainen, E. S. Sarkkinen, and M. I. J. Uusitupa Plant Stanol Esters Affect Serum Cholesterol Concentrations of Hypercholesterolemic Men and Women in a Dose-dependent Manner J. Nutr., April 1, 2000; 130(4): 767 - 776. [Abstract] [Full Text]
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 M. Law Plant sterol and stanol margarines and health BMJ, March 25, 2000; 320(7238): 861 - 864. [Full Text]
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A. F. Vuorio, H. Gylling, H. Turtola, K. Kontula, P. Ketonen, and T. A. Miettinen Stanol Ester Margarine Alone and With Simvastatin Lowers Serum Cholesterol in Families With Familial Hypercholesterolemia Caused by the FH-North Karelia Mutation Arterioscler. Thromb. Vasc. Biol., February 1, 2000; 20(2): 500 - 506. [Abstract] [Full Text] [PDF]
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C. L. Williams, M. C. Bollella, B. A. Strobino, L. Boccia, and L. Campanaro Plant Stanol Ester and Bran Fiber in Childhood: Effects on Lipids, Stool Weight and Stool Frequency in Preschool Children J. Am. Coll. Nutr., December 1, 1999; 18(6): 572 - 581. [Abstract] [Full Text] [PDF]
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T. T. Nguyen The Cholesterol-Lowering Action of Plant Stanol Esters J. Nutr., December 1, 1999; 129(12): 2109 - 2112. [Abstract] [Full Text]
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H. Gylling, P. Puska, E. Vartiainen, and T. A. Miettinen Serum sterols during stanol ester feeding in a mildly hypercholesterolemic population J. Lipid Res., April 1, 1999; 40(4): 593 - 600. [Abstract] [Full Text]
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M. A Hallikainen and M. I. Uusitupa Effects of 2 low-fat stanol ester–containing margarines on serum cholesterol concentrations as part of a low-fat diet in hypercholesterolemic subjects Am. J. Clinical Nutrition, March 1, 1999; 69(3): 403 - 410. [Abstract] [Full Text] [PDF]
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H. Tunstall-Pedoe Nuts to you (... and you, and you) BMJ, November 14, 1998; 317(7169): 1332 - 1333. [Full Text]
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