feeding premature newborn infants

Ai�z J Cli,z Nuir l995;6l: 1037-42. Printed in USA. © 1995 American Society for Clinical Nutrition I037

Feeding premature newborn infants palmitic acid inamounts and stereoisomeric position similar to that ofhuman milk: effects on fat and mineral balance13

Virgilio P Carnielli, Iiigrid HT Luijendijk, Johannes B van

Boerlage, Herman J Degenhart, and Pieter JJ Sauer

ABSTRACT The effect of the structure of human milk

triglycerides on intestinal fat absorption remains controversial.

Twelve infants were each fed, for 1 wk in a crossover design,two formulas that differed only in triglyceride configuration.

The “a” formula contained triglycerides similar to those in

human milk (26% palmitic acid, esterified predominantly to the

sn-2 position) whereas in the “a” formula, which contained

triglycerides similar to those in formulas currently marketed,

palmitate was mainly at the sn-l,3 positions. Fatty acid, fat, and

mineral balances were measured at the end of each 1-wk

period. Myristic, palmitic, and stearic acids were absorbed

better from the 3 formula, but total fat excretion was not

reduced. During the feeding of /3 formula fecal calcium excre-

tion was lower, urinary calcium higher, and urinary phosphatelower. A formula containing triglycerides similar to those in

human milk has significant effects on fatty acid intestinal

absorption and improves mineral balance in comparison with a

conventional formula. Am J Clin Nutr 1995;61:l037-42.

KEY WORDS Formula study, synthesized triglycerides,

triglyceride structure, infant formula, palmitic acid, fatty acids,

fat absorption, premature infants, calcium absorption, mineral

balance

Introduction

Fat is the major source of energy in human milk (1) and inmost infant formulas. Whereas in human adults fat absorption

is almost complete, newborns and especially premature neo-

nates exhibit impaired absorption during the first weeks of life

(2-5). This is believed to be caused mainly by low intraduo-

denal concentrations of pancreatic lipase (6, 7) and bile salts

(8-10). In addition, the absorption of fat from infant formulas

is reported to be lower than from human milk (4, 1 1-13). This

difference has been explained by the presence of lipases in

human milk (14, 15) and by the unique stereoisomeric structure

of human milk triglycerides (1, 16) that favor their digestion

and absorption. In human milk triglycerides, palmitic acidaccounts for 20-25% of total milk fatty acids and it is

esterified mainly to the center sn-2 position of the triglyceride

glycerol (f3 position) (1, 16). In contrast, in cow milk fat or in

vegetable oils, it is predominantly esterified to the sn-i and

sn-3 positions (a positions) (16). Because the acyl chain at the

Goudoever, Eric J Sulkers, Anneke A

13 position is relatively resistant to the lipolytic action ofpancreatic lipase, the fatty acids (FAs) in the �3 position remain

intact as monoglycerides during digestion and absorption.

Therefore, in the presence of sufficient pancreatic lipase activ-

ity, free FAs and 2-monoacylglycerol are the final products of

triglyceride digestion ( i 7). 2-Monoglyceride is well-absorbed

because it readily forms mixed micellae with bile acids and

cannot form insoluble soaps with divalent cations such as

calcium and magnesium. Saturated fatty acids, which are not

well-absorbed as free FAs, are probably better absorbed asmonoglyceride. The absorption of palmitic acid, therefore,

could be greater from fat when it is esterified at the sn-2

position than when it is esterified predominantly at the sn-1,3

positions. This could also be advantageous in high-calcium-

containing diets (eg, infant formulas) by avoiding calcium soap

formation and improving intestinal absorption of calcium. Al-

though early studies by Tomarelli et al (18) in rats and by Filer

et al (19) in term newborn infants indicated better absorption of

palmitic acid when esterified to the sn-2 position of the diet fat,

more recent studies in premature infants have failed to dem-

onstrate similar benefits (20, 21). Differences in the fatty acid

composition of the formulas, apart from their palmitic acid

content, and differences in the patient populations may explain

the lack of effect. We studied whether palmitic acid in the f3position of dietary triglycerides and in amounts similar to those

found in breast milk improves fat, FAs, and calcium absorption

in preterm infants. We did this using synthetic triglycerides that

differed only in the isomeric position of palmitic acid.

Patients and methods

Formulas, subjects, and clinical design

The two infant formulas used in this study had a similar

composition and fatty acid profile, but different isomeric po-

I From the Department of Pediatrics, Sophia Children’s Hospital and

University Hospital/Erasmus University Rotterdam, Rotterdam, Nether-

lands.

2 Supported by grants from Nutricia, Zoetermeer, Netherlands.

3 Reprints not available. Address correspondence to VP Carnielli,

Sophia Children’s Hospital, Room Sp 3456, Dr Molewaterplein 60, 3015

GJ, Rotterdam, Netherlands.

Received December 22, 1993.

Accepted for publication October 31, 1994.

by guest on October 11, 2015

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1038 CARNIELLI El AL

sition of the FM in triacylgiycerols (Table 1). The f3formula

contained triglycerides similar to those in human milk: 26%(wt:wt) of FM as palmitic acid, which is predominantly ester-

ified to the sn-2 (�3) position. The a formula contained similar

amounts of palmitic acid but it was mainly esterified to thesn-1,3 (a) positions. Part of the fat in the �3 formula consistedof synthetic triglycerides known as Betapol. This is produced

by interesterifying a tripalmitin-rich palm fraction with a mix-

ture of other oils by using the sn-1,3 specific lipase from

Rhizomucor miehei (code SP-392; Novo Industries, Copenha-

gen) (22).Twelve preterm infants born after a gestation ranging be-

tween 28 and 32 wk were randomly assigned to be fed the a or

13formula for 1 wk at a postnatal age of 38 ± 7 d. The infantswere then crossed over to receive the other formula for the

subsequent week. Half of the infants were first fed the aformula and then the f3 formula whereas the other half received

the formula in the reverse order. All infants were free ofmanifest disease, were not receiving any medication, and hadgrown normally before the study. The investigators wereblinded to the type of formula given to the infants. The anthro-pometric characteristics of the patients at birth and at the end of

the 7-d feeding periods are reported in Table 2.The study was conducted according to the guidelines of the

Ethical Committee of the Erasmus University, Rotterdam,

Netherlands, which agree with the principles expressed in theDeclaration of Helsinki.

Balance studies

Intakes of the formulas were determined by weighing the

bottles or by recording the volume with syringes in the case oftube feeding. Conversion from volume into grams was done by

TABLE 1

Composition of formula fed to preterm infants’

a Formula 13Formula

Protein (%) 2.01 1.99

Fat (%) 4.08 4.16

Calcium (%) 0.102 0.099

Phosphate (%) 0.045 0.046

Magnesium (%) 0.0065 0.0067

Fatty acids (% of total fatty acids by wt)

6:0-10:0 4.5 (ND) 4.0 (ND)

12:0 12.1 (17.2) 10.6 (16.2)

14:0 5.4 (3.3) 4.9 (3.9)

16:0 25.7 (9.8) 25.4 (58.0)

18:0 2.6 (1.1) 3.7 (2.4)

20:0 0.22 (ND) 0.26 (ND)

22:0 0.11 (ND) 0.12 (ND)

24:0 0.03 (ND) 0.05 (ND)

16:lco7 0.17 (ND) 0.21 (ND)

18:1w9 34.8 (41.8) 34.8 (13.2)

20:1 0.20 (ND) 0.32 (ND)

22:1 0.03 (ND) 0.08 (ND)

24:1 0.02 (ND) 0.03 (ND)

18:2w6 12.1 (22.1) 12.6 (5.1)

18:3w3 2.0 (0.3) 2.7 (0.5)

‘ Value in parentheses is the fatty acid composition (wt:wt) of the sn-2position. Both ready-to-feed formulas are devoid of arachidonic (20:4w6)

and docosahexaenoic acid (22:6o3). ND, not determined.

TABLE 2

Clinical characteristics of preterm infants at birth and at the end of the

two 1-wk diet periods’

.

At birtha Formula

.

period

(3 Formula.

period

Weight (kg) 1.4 ± 0.2 2.1 ± 0.3 2.1 ± 0.3

Gestational age (wk) 29.9 ± 1.4 - -

Head circumference 27.8 ± 1.2 31.8 ± 1.1 31.6 ± 1.6

Length(cm) - 44±2 44±2

Postnatal age (d) - 38 ± 7 38 ± 6

Fat mass (%) - 8.6 ± 3.5 8.2 ± 3.1

1 � � SD; n = 12. During the first week of the study six infants were fed

the a formula and six infants were fed the f3 formula. During the second

week the formulas were reversed. There were no significant differences.

multiplying the volume by the density value of 1035 g/L,

which was identical for both formulas.Balance studies with separate collections of urine (24 h) and

feces (72 h) were performed during the last 3 d of each feeding

period. Fecal collections were carried out bracketed by carmine

red. Fifty milligrams of carmine red were dissolved in 3 mL

distilled water and given either via the nasogastric tube or in

the mouth just before the 1200 feed on days 4 and 7 of eachdiet. Intestinal transit time was assumed to be equal to the timeelapsing from the administration of the carmine red and theproduction of the first red stool; it was measured twice in each

balance period (at the beginning and at the end of the 72 h) and

the two determinations averaged. Feces were collected includ-

ing the first red stool and excluding the last red stool ‘3 d later

for each collection period. Plastic sheets were placed inside thediapers for collection. Corrections were made for accidental

losses of feces into the diapers (double weighing of the diaper)

and for the feces sticking to the buttocks of the infants (double

weighing of the cleaning swabs). The total amount of feces

collected during the 3-d balance period was weighed and

homogenized and a small sample of the homogenate was

freeze-dried. Fat excretion was determined by using a modifi-

cation of the method of Jeejeebhoy et al (23), with twice asmuch hydrochloric acid added. Calcium and magnesium were

measured with an atomic-absorption spectrophotometer (model2380; Perkin-Elmer, Norwalk, CT) after acid digestion [3 h at

300 #{176}Cin 5 mL of a concentrated mixture of HNO3 andconcentrated H2S04 (2:1, by vol)]. The total urine volume was

measured and urinary calcium and magnesium were also mea-

sured by atomic-absorption spectrophotometry. Phosphate was

measured by a colorimetric method (24). In all cases, matrix

effects were eliminated by means of the standard addition

method (25).Excretions were calculated by multiplying the volume of

feces (or urine) produced by the concentration of the com-

pounds of interest. Intestinal absorption was calculated bydividing the apparent amount absorbed (intake - excretion) bythe intake, and then multiplying by 100.

Determination of FAs in the formulas and in the feces

The individual FA content of the formulas and of the feces

was determined by gas chromatography (GC), and analyses

were done in triplicate. Fresh fecal samples of 5-10 mg each

were transesterified by HCI methanol after the addition of

nonanoic (C9), heptadecanoic (C17), and tricosanoic (C23)


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Results

Because of the crossover design the clinical characteristics of

�3-PALMITATE IN PRETERM INFANTS 1039

acids as internal standards. The separation and identification of

FA methyl esters was performed by GC (model 5890 II;

Hewlett Packard, Amstelveen, Netherlands) equipped with a

fused-silica column (Supelcowax 10, 60 m X 0.25 mm internal

diameter, 0.25-sm film thickness; Supelco, Leusden, Nether-

lands), a flame-ionization detector (280 #{176}C),and a split-split-

less injector used in splitless mode (280 #{176}C).The GC was

operated at 60 #{176}Cinitially for 5 mm, then the oven temperature

was raised 20 #{176}C/minto 205 #{176}Cand held at this temperature for

15 mm. The temperature was then increased again 0.2 #{176}C/min

to 222 #{176}C.Helium was used as a carrier gas (2 mL/min) andpeak areas were calculated with HP-Chem station software

(Hewlett Packard) using nonanoic, heptadecanoic, and trico-

sanoic acids as internal standards. Fatty acids were identifiedby comparing the retention times with known standards (NuChek Prep, Elysian, MN). All reagents were analytical grade.

Statistical analysis

Data are presented as group mean ± SE unless otherwise

stated. Comparison of means was made by Student’s t test for

paired data after analysis of variance (ANOVA) showed no

significant period effect for all the studied variables. Correla-

tions between the data were by simple linear regression. All

calculations were performed with the statistical package SYS-TAT, version 5.2 (SYSTAT, mc, Evanston, IL).

the patients at the time of each study were almost identical

(Table 2). The intake of the formulas was similar between the

a and 13 periods: 154 ± 4 and 158 ± 5 mL . kg � . d ‘,

respectively. Fecal output, although somewhat higher in the

infants when fed the a formula (6.1 ± 0.8 and 4.3 ± 0.6g � kg ‘ . d� � for a and f3 formulas, respectively), was not

significantly different by treatment. Neither water (66 ± 2 and

60 ± 2%) nor fat (1.5 ± 0.2 and 1.3 ± 0.3 g � kg_i . d1)

accounted for this difference in stool weight. No differences

were found in urine production, 87 ± 2 and 91 ± 5

mL . kg ‘ . d � in infants fed the a and f3 formulas, respec-

tively. Mean intestinal transit time was also not significantly

different between diet periods: 29 ± 4 and 30 ± 5 h, respec-

tively, for the a and /3 formula.The fecal concentrations of the major FAs are reported in

Table 3. When fed the a formula, the infants had significantlyhigher concentrations of myristic (14:0), palmitic (16:0), and

stearic (18:0) acids and significantly lower concentrations of

oleic (18:1w9) and linoleic (18:2co6) acids in their feces than

when fed the 13 formula. Linolenic acid (18:3w3) in feces was

not significantly different between the two groups. Fat and FA

balance data are reported in Table 4. The intestinal absorptionof myristic, palmitic, and stearic acids was significantly better

when infants received the �3 formula than when they were fed

the a formula. Intestinal absorption of oleic and of linoleic

acids was not significantly different between the a and /3

periods. Total fat excretion was on average 0.2 g � kg � . d

lower and fat absorption 5% higher with the /3 formula than

with the a formula, but these differences were not statistically

significant (Table 4).

TABLE 3

Concentrations of selected fatty acids in feces of infants fed the a

formula for 1 wk and the /3 formula for 1 wk’

Fatty acid a Formula /3 Formula

12:0

(mg/g wet feces) 6.8 ± 0.6 5.1 ± 0.7

(% of fecal fat) 2.7 ± 0.1 1.9 ± 0.22

14:0

(mg/g wet feces) 11.8 ± 1.0 7.7 ± 0.8�

(% of fecal fat) 4.7 ± 0.2 2.8 ± 0.22

16:0

(mg/g wet feces) 140.4 ± 10.0 106.0 ± 9.8�

(% of fecal fat) 56.3 ± 1.6 38.6 ± 1.62

18:0

(mg/g wet feces) 28.7 ± 2.1 22.4 ± 1.7�

(% of fecal fat) 1 1.5 ± 0.4 8.5 ± 042

18:1w9

(mg/g wet feces) 36.3 ± 4.6 82.3 ± 9.12

(% of fecal fat) 14.3 ± 1.4 29.8 ± 1.72

18:2w6

(mg/g wet feces) 9.6 ± 2.3 25.5 ± 5.22

(% of fecal fat) 3.7 ± 1.0 8.8 ± 1.0�

18:3w3

(mg/g wet feces) 0.9 ± 0.1 1.5 ± 0.3

(% of fecal fat) 0.4 ± 0.06 0.5 ± 0.06

‘i±SE;n= 12.2-5 Significantly different from a formula: 2 p < 0.001, � P = 0.004,

4 P = 0.002, � P = 0.01.

During the /3 formula period, fecal excretion of calcium wassignificantly lower, 58.8 ± 7.8 and 82.0 ± 9.9 mg . kg’ . d1

(P < 0.05), whereas urinary calcium excretion was higher, 4.0

± 0.7 and 2.3 ± 0.5 mg . kg’ . d’ (P < 0.05), than during

the a formula period (Table 4). The intestinal absorption ofphosphorus was not different between periods; however, the

urinary excretion of phosphorus was significantly lower during

the /3 than the a periods (11.4 ± 1.9 and 16.7 ± 2.3

mg . kgt . d’, respectively, P < 0.02). On the /3 formula the

infants retained significantly more phosphorus than when fed

the a formula (58.1 ± 3.3 and 49.2 ± 2.7 mg . kgt . d’,respectively, P < 0.03). Urinary phosphorus losses were

inversely and significantly correlated with calcium absorption(r -0.43, P = <0.05).

Magnesium data were not different during the two dietperiods (Table 4). Palmitic acid was the major fecal fatty acidin the majority of the infants. We found significant correlationsbetween fecal calcium excretion and the excretions of fat and

of the major fatty acids. Palmitic acid showed the highestcorrelation coefficient, followed by oleic acid and linoleic acid(Figure 1).

The fecal calcium content was significantly correlated withmyristic (r 0.42, P = 0.04), palmitic (r = 0.46, P = 0.039),and stearic (r = 0.42, P = 0.025) acids, ie, the major saturated

fatty acids, but not with the mono- or the polyunsaturated fattyacids. No correlation was observed between the fecal concen-trations of fat or of individual fatty acids and phosphorus or

magnesium.

Discussion

The results of this study support the importance of thestructure of dietary triglyceride on intestinal FA absorption and


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TABLE 4

Fat, fatty acid (FA), and mineral balances of infants fed the a formula

for 1 wk and the /3 formula for 1 wk’

a Formula 13 Formula

Fat

Intake (g . kg� . d�) 6.3 ± 0.6 6.6 ± 0.7

Fecal excretion (gkg1 .d_i) 1.5 ± 0.2 1.3 ± 0.2

Intestinal absorption (%) 76 ± 3 81 ± 4

FA intestinal absorption (%)12:0 95±1 97±1

14:0 80±3 90±22

16:0 51±6 73±42

18:0 9±12 61±52

18:1w9 88±3 82±4

18:2w6 91±3 84±5

18:3w3 95±1 96±1

Calcium

Intake (mg . kg � . d i) 162.1 ± 5.1 162.2 ± 4.9

Fecal excretion (mg . kg’ . d’) 82.0 ± 9.9 58.8 ± 7.8�

Intestinal absorption (%) 49.2 ± 5.9 63.7 ± 5.1

Urinary excretion (mg . kg � . d i) 2.3 ± 0.5 4.0 ± 073

Retention (mg . . d i) 77.9 ± 10.5 99.5 ± 8.2

(%) 47.7 ± 5.9 61.3 ± 5.0

Phosphorus

Intake (mg . kg � . d i) 71.9 ± 2.2 75.3 ± 2.3

Fecal excretion (mg . kg � . d i) 6.0 ± 1.2 5.8 ± 1.0


Urinary excretion (mg�kg’ .di) 16.7 ± 2.3 11.4 ± 1.9�’

Retention (mg . kg_i . d_i) 49.2 ± 2.7 58.1 ± 3#{149}35

(%) 69.0 ± 4.0 77.0 ± 3.8

Magnesium

Intake (mg . kg � . d i) 10.4 ± 0.3 1 1.0 ± 0.3

Fecal excretion (mg . kg � . d 1) 6.1 ± 0.7 5.6 ± 0.7


Urinary excretion (mg . kg_i . d_i) 1.4 ± 0.3 2.8 ± 0.8

Retention (mg.kg_i .d_i) 2.9 ± 0.9 2.6 ± 0.9

(%) 27.5 ± 8.5 23.2 ± 8.8

‘.f ± SE; n = 12.2-5 Significantly different from a formula: 2 p < 0.01, -� � < 0.05,

4 P < 0.02, � P < 0.03.

on mineral metabolism. The perception that the positionaldistribution of the FM in human milk and in formula triglyc-eride is important during the processes of digestion and ab-sorption is not new (26) and this problem has attracted the

interest of researchers for many years (18-21). No conclusive

data had been obtained to date. Our study was novel becausewe used synthetic triglycerides, and were thus able to produceinfant formulas with profiles identical to those of major FM,differing only in the isomeric position of FM in the triacyl-glycerols. Formulas, as opposed to human milk, do not containlipolytic enzymes, which improve fat absorption; therefore, theonly difference between the study periods was the structure ofthe dietary triglycerides. A different study including a humanmilk-fed group would not have been as informative as thepresent study because of the uncontrolled effects of the lipo-lytic enzymes and variable mineral content. Furthermore thecrossover design is well suited for the study of prematureinfants known to have a large variability in intestinal fat ab-

sorption (20). Thus we could study the two formulas in thesame infant and during two periods of comparable gastrointes-tinal function. A drawback of our study was its inability

Calcium Excretion (mg #{149}kg� #{149}d1)

FIGURE 1. Correlations between the excretion of calcium and of 16:0,

18:1, and 18:2.o6. All regressions are statistically significant. FA, fatty

acid.

to provide information on the effect of the dietary triglycerideon growth of the infants, because of its relative short study

periods.When fed the a formula the infants had in their feces

significantly higher concentrations of myristic, palmitic, andstearic acids, and significantly lower concentrations of oleic

and linoleic acids than when fed the /3 formula. A similarpattern of fecal FA concentrations was described by Verkade et

al (21), who compared the fecal FAs of a group of prematureinfants fed a lard-modified formula containing 88% of itspalmitic acid in the sn-2 position (and only 14% of oleic) with

a group fed a formula that had only 16% of palmitate but 40%

of the oleic acid in the same position. These authors foundhigher concentrations of oleic acid and lower concentrations ofmyristic and palmitic acids in the feces of the infants fed thelard-modified formula. In the above-mentioned study impor-

tant differences in the FA profiles of the formulas (ie, medium-chain triglycerides were present in the control formula but notin the lard-modified formula) prevented the authors from draw-

ing firm conclusions on the effects of the sn-2 palmitic acid.Nevertheless, the fecal concentrations of palmitic and oleicacids showed a pattern similar to our results.

If we had measured only the fecal concentrations of the FM

(qualitative data) we would have probably discussed the ad-vantage of the sn-2 position and the negative effect of esteri-

fication to the sn-1,3 positions. However, because the fecaloutput was higher (although not significantly) during the aformula period than during the /3 formula period, the FAbalance data show better intestinal absorption of myristic,

palmitic, and stearic acids during the /3 formula period, but nosignificant differences for oleic and linoleic acids. The latterFM were significantly more abundant in the feces of infantsfed the /3 formula than of those fed the a formula. The largevariability introduced when excretions are calculated (fecal

concentrations are multiplied by the more variable fecal output)may have contributed to the lack of statistical difference. Wecannot explain the larger (although not significant) fecal outputduring the a formula period. Other factors than those measuredby us (FM, fat, water, and minerals) may account for the

difference. The balance data indicate that the improvement inabsorption of the saturated FAs outweighed the slightly re-


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/3-PALMITATE IN PRETERM INFANTS 1041

duced absorption of the other FAs. We speculate that the

advantage of the /3 position could be even greater in term

infants. Lipid digestion and absorption are reported to be better

in term infants than in preterm infants, because of a larger

contribution of pancreatic lipase (6, 7) and more abundant bile

salts. The latter are extremely important for monoglyceride

absorption (8-10).

The relationship between fecal calcium and fecal fat or fecalFA has long been explored (27). Increasing calcium intakes in

children (28) and in neonates (12) increases the excretion of fat

and of saturated FAs. In our study, the intake of calcium was

similar from both formulas so we can only speculate that

during the a formula a larger amount of free intraluminal

palmitate may have trapped the calcium, perhaps via formation

of calcium soaps (26). The observation of lower fecal calcium

in the infants fed the /3 formula is supported by the concomitant

observations of higher calcium and lower phosphorus in the

urine. During the /3 formula period the mean calcium retentionincreased by 22 mg . kg � . d �. Note that this was achieved

with a formula containing 26% of FAs as palmitic acid (unlike

most of the infant formulas on the market), with most at the

sn-2 position, as is found in human milk. Improvements in

calcium balance have also been reported in infants fed formula

in which a large part of the fat blend was replaced by medium-

chain triglycerides (29, 30). Alternatively, increased retention

of �“22 mg Ca . kg � . d � could be achieved by an increaseddietary intake of =40-50 mg Ca . kg � . d’ (31). An increase

in the calcium content in the formula, however, could increase

the precipitation of calcium in the formula (32, 33), or have

detrimental effects on fat and FA absorption (12). Note that

during the j3 formula period the infants had a mean calcium

retention of 100 mg . kg ‘ . d ‘, and this value is “70% of

the calculated intrauterine retention (34).

In conclusion, we demonstrated that the isomeric position ofFM in dietary triglycerides has significant effects on the in-testinal metabolism of the FM. The use of the /3 formula,

which contained triglycerides with a structure similar to those

in human milk (26% of FAs as palmitic acid, which is pre-

dominantly esterified to the /3 position), was associated with an

improvement in the absorption of myristic, palmitic, and stearic

acids and of mineral balance. We emphasize that the structure

of human milk triglycerides offers advantages even in the

absence of the lipolytic enzymes of human milk. U

We gratefully acknowledge the help of Daniella Roofthooft in contrib-

uting to the recruitment of the patients during the initial part of the study.

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