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Chrononutrition applied to formula milks to consolidate infants' sleep/wake cycle

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Some 30% of pre-weaning infants present problems of sleep during the night, especially those who are bottle-fed. The solution is for them to be breast-fed for as long as possible, or, if this is not possible, for the formula milk to reproduce breast-milk's natural circadian variations in the concentrations of tryptophan and those nucleotides which have a beneficial effect in consolidating the circadian sleep-wake cycle. To study in pre-weaning infants the effect on nocturnal sleep of the administration of formula milk dissociated into its day/night components. A prospective study was carried out on 30 pre-weaning infants of 4-20 weeks in age who preferentially showed sleep problems. The day dissociated formula, administered from 06:00-18:00, had lower levels of tryptophan and carbohydrates, and higher levels of proteins together with cytosine-5P, guanosine-5P, and inosine-5P. The night dissociated formula, administered from 18:00-06:00, had lower levels of proteins and medium-chain triglycerides, higher levels of tryptophan and carbohydrates, together with adenosine-5P and uridine-5P. In a random, double-blind, design, three one-week diets were administered: Diet A (Control): normal initiation milk; Diet B: 06:00-18:00 normal initiation milk, 18:00-06:00 dissociated night formula; and Diet C: day/night formulas with the schedule given above. The sleep patterns were analyzed by means of actimeters (Actiwatch). Statistical analysis consisted of an ANOVA with a Scheffe F-test, taking a value of p<0.05 to be statistically significant. The children receiving the week of Diet C (with the day/night formulas in synchrony with the environment) showed increased hours of actual sleep (7.68 +/- 0.54 h vs. 6.77 +/- 0.12 h for the Diet A control) and improved sleep latency (0.44 +/- 0.04 h vs. 0.60 +/- 0.08 h for the Diet A control). The same children receiving the Diet B in another different week showed an improvement in sleep efficiency (76.43 +/- 3.4% vs. the Diet A control 69.86 +/- 0.94%) and sleep latency (0.45 +/- 0.04 h vs. the Diet A control 0.60 +/- 0.08h) The parents also reported, in response to follow-up questions, an improvement in the sleep of their infants during the Diet C week. Day/night infant formula milks designed according to the principles of chrononutrition help to consolidate the sleep/wake rhythm in bottle-fed infants.
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Neuroendocrinol Lett 2007; 28(4):360–366
ORIGINAL ARTICLE
Neuroendocrinology Letters Volume 28 No. 4 2007
Chrononutrition applied to formula milks
to consolidate infants’ sleep/wake cycle
Javier C 1, David N 1, Pilar T 1, Ruben R2, Susana E 2,
Montserrat R 3, Hasan P 1, Ana B. R 1 & Carmen B 1
Department of Physiology, Faculty of Sciences, Extremadura University, Badajoz, Spain
Department of Fundamental Biology and Health Sciences, University of Islas Baleares, Spain
Scientific Division, Laboratories Ordesa S.L., Barcelona, Spain
Correspondence to: Carmen Barriga Ibars,
Department of Physiology, Faculty of Science, University of Extremadura,
Avda de Elvas s/n. 06071 Badajoz, Spain
PHONE (FAX): +34 924289388
EM A IL: cibars@unex.es
Submitted: March 13, 2007 Accepted: March 30, 2007
Key words: formula fed; tryptophan; nucleotides; sleep; newborn
Neuroendocrinol Lett 2007; 28(4):360–366 PMID: 17693960 NEL280407A33 © 2007 Neuroendocrinology Letters www.nel.edu
Abstract Some 30% of pre-weaning infants present problems of sleep during the night,
especially those who are bottle-fed. The solution is for them to be breast-fed for as
long as possible, or, if this is not possible, for the formula milk to reproduce breast-
milk’s natural circadian variations in the concentrations of tryptophan and those
nucleotides which have a beneficial effect in consolidating the circadian sleep–wake
cycle. OB JECT I VE: To study in pre-weaning infants the effect on nocturnal sleep
of the administration of formula milk dissociated into its day/night components.
MATERIALS AND ME THODS : A prospective study was carried out on 30 pre-wean-
ing infants of 4–20 weeks in age who preferentially showed sleep problems. The
day dissociated formula, administered from 06:00–18:00, had lower levels of tryp-
tophan and carbohydrates, and higher levels of proteins together with cytosine-5P,
guanosine-5P, and inosine-5P. The night dissociated formula, administered from
18:00–06:00, had lower levels of proteins and medium-chain triglycerides, higher
levels of tryptophan and carbohydrates, together with adenosine-5P and uridine-5P.
In a random, double-blind, design, three one-week diets were administered: Diet
A (Control): normal initiation milk; Diet B: 06:00–18:00 normal initiation milk,
18:00–06:00 dissociated night formula; and Diet C: day/night formulas with the
schedule given above. The sleep patterns were analyzed by means of actimeters
(Actiwatch®). Statistical analysis consisted of an ANOVA with a Scheffe F-test, tak-
ing a value of p<0.05 to be statistically significant. RESULT S: The children receiving
the week of Diet C (with the day/night formulas in synchrony with the environ-
ment) showed increased hours of actual sleep (7.68 ± 0.54 h vs. 6.77 ± 0.12 h for the
Diet A control) and improved sleep latency (0.44 ± 0.04 h vs. 0.60 ± 0.08 h for the
Diet A control). The same children receiving the Diet B in another different week
showed an improvement in sleep efficiency (76.43 ± 3.4% vs. the Diet A control
69.86 ± 0.94%) and sleep latency (0.45 ± 0.04 h vs. the Diet A control 0.60 ± 0.08h)
The parents also reported, in response to follow-up questions, an improvement in
the sleep of their infants during the Diet C week. CONCLUSION: Day/night infant
formula milks designed according to the principles of chrononutrition help to
consolidate the sleep/wake rhythm in bottle-fed infants.
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Neuroendocrinology Letters Vol. 28 No. XX 2007 Article available online: http://node.nel.edu
Infant milk and sleep
INTRODUCTION
Certain physiological functions, among which the
activity/rest rhythm is especially important, are under
circadian control. During the perinatal period, the
sleep/wake cycles are adapted to those of the mother’s
body [12]. Immediately after birth, these systems have
yet to reach the sufficient maturity to adapt to the normal
24-hour rhythm imposed by the Earth’s rotation, and the
infant needs at least three months for these rhythms to
begin to appear [4].
Melatonin, a hormone secreted principally by the
pineal gland, presents a circadian rhythm with high
nocturnal and low diurnal levels, and is responsible for
regulating the circadian sleep/wake cycle. In the newborn,
this circadian rhythm, like that of the sleep/wake cycle,
also does not appear until after 12 weeks of age [1].
The mothers milk, however, presents circadian
oscillations in many of its nutritional components that
participate in the regulation of the circadian rhythm, and
thus influences the breast-feeding infant’s sleep/wake
regulation. Indeed, the breast-fed infant shows a greater
development and a better circadian sleep/wake rhythm,
and therefore more advantageous patterns of sleep than
the bottle-fed child [8].
Tryptophan is an essential amino acid in infant nutri-
tion. It is a precursor of the neurotransmitter serotonin
and of the hormone melatonin [9]. This amino acid has
a circadian rhythm in breast-milk with maximum levels
at 03:00 h (acrophase), and it is also observed that the
acrophase and nadir (time of minimum levels in the
cycle) of the infant’s melatonin circadian rhythm coincide
with those in the mother’s milk [2]. Oral administration
of tryptophan modifies the circulating levels of serotonin
and melatonin (Hajak, 1999) [9] which are key substances
in the regulation and quality of sleep. As the mechanism
for tryptophans absorption and transport through the
blood-brain barrier is insulin-dependent, if the feed is
rich in carbohydrates and tryptophan, it will be easier
for this amino acid to be absorbed and penetrate into the
brain [12].
The nucleoside adenosine is a molecule that acts
on the A2A receptors located in the neurons of the
ventrolateral nuclei, signaling for sleep to begin [7]. The
nucleoside uridine, interacting with the gamma amino-
butyric acid (GABA) receptors in the central nervous
system, acts as a sleep promoting substance [13]. Finally,
other nutrients such as the lipids of the medium-chain
triglyceride (MCT) class act to improve the newborn’s
sleep/wake cycle thanks to their ease of digestion and
their biotransformation into energy [20].
Given this context, an infant formula was designed
that was dissociated chronobiologically into its macro-
and micro-nutrients with the aim of facilitating the con-
solidation of the sleep/wake cycle in the milk-fed infant.
In particular, the nutritional components of an infant
formula milk (Blemil Plus 1 Forte, Ordesa S.L.) were
distributed into two separate preparations according to
whether their nutritional components facilitated sleep or
wakefulness. The sleep-promoting nocturnal milk (Blemil
Plus 1 Night) contained high levels of L-tryptophan and
carbohydrates, low protein levels (to guarantee optimal
tryptophan absorption), high concentrations of MCTs,
and the nucleotides uridine 5’-monophosphate and ad-
enosine 5’-monophosphate. The wakefulness activating
milk, Blemil Plus 1 Day, contained high protein levels
and low tryptophan levels, vitamins A, C, and E which
have antioxidant capacity and stimulate wakefulness, and
the nucleotides cytidine 5’-monophosphate, guanosine
5’-monophosphate, and inosine 5’-monophosphate.
In sum, we had divided the nutritional components of
standard milk into two milks that were complementary:
a day formula to be administered from 06:00 h to 18:00
h, and a night formula to be administered from 18:00 h to
06:00 h. Nothing had been increased or eliminated from
the standard milk (Blemil Plus 1 Forte, Ordesa S.L.). Its
components had merely been dissociated according to
their effects on sleep or wakefulness, fulfilling the infant
milk directives 1996/49/CE and 2003/14/CE.
To carry out the present study, the dissociated milks
Blemil Plus 1 Day/Night were administered to infants of
less than 5 months, who preferentially presented sleep
problems. The infant’s sleep was monitored by means of
an actimeter (Actiwatch®) placed around the childs ankle
that recorded its activity/inactivity throughout the study
period (3 weeks).
MATERIALS AND METHODS
Trial protocol
The study was conducted with infants (n=30) from
the Extremadura Autonomous Community who had
preferentially presented sleep problems (more than
three nocturnal awakenings) in a prior prospective test.
In a double blind, random design, each infant was given
different formula milk combinations over a period of
three weeks (Table 1). The nutritional composition of
the Day/Night dissociated milks is given in Table 2. The
day period was considered as being from 06:00 to 18:00,
and the night period from 18:00 to 06:00. In one of the
three weeks, the infants received Diet A consisting of
standard milk (Blemil Plus 1 Forte, Ordesa S.L.) both
by day and night. In another week, they received Diet B
consisting of standard milk Blemil Plus 1 Forte during
the day (06:00–18:00), and Blemil Plus 1 Night during
the night (18:00–06.00). And in another week, they
received Diet C consisting of Blemil Plus 1 Day during
the day (06:00–18:00), and Blemil Plus 1 Night (Ordesa
S.L.) during the night (18:00–06:00).
In this way each infant was its own control. The actual
type of milk that was administered to the infants each
week was not known either by the parents or by the
researchers administering the trial until all the experi-
ments and statistical analyses had been completed. The
company, Ordesa S.L., then revealed which milk had
been administered to the infants each week.
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Copyright © 2007 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Javier Cubero, David Narciso, Pilar Terrón, Ruben Rial, Susana Esteban, Montserrat Rivero, Hasan Parvez, Ana B. Rodríguez & Carmen Barriga
Table 1. Combinations used in the second clinical trial of milk
formulas dissociated into their nutritional components in infants
with sleep problems.
Infant no. Week
1st 2nd 3rd
1A C B
2B A C
3A C B
4A B C
5C A B
6C B A
7B A C
8A C B
9C A B
10 C B A
11 A B C
12 B C A
13 A C B
14 C B A
15 C B A
16 B A C
17 A C B
18 C B A
19 B A C
20 A B C
21 B A C
22 A B C
23 C A B
24 B C A
25 B A C
26 C A B
27 B C A
28 A C B
29 B A C
30 C A B
Diet A: Day formula (06:00–18:00), Blemil Plus 1 Forte; night
formula (18:00–06:00), Blemil Plus 1 Forte. Diet A was taken as the
Control.
Diet B: Day formula (06:00 -18:00): Blemil Plus 1 Forte; night
formula (18:00–06:00): Blemil Plus 1 Night: formula dissociated into
its nutritional components to consolidate sleep.
Diet C: Day formula (06:00–18:00): Blemil Plus 1 Day, formula
dissociated into its nutritional components that consolidate
wakefulness. Night formula (18:00–06:00): Blemil Plus 1 Night,
formula dissociated into its nutritional components that
consolidate sleep.
Number of children used: n=30.
Table 2. Nutrient composition of the BLEMIL PLUS 1 NIGHT and
BLEMIL PLUS 1 DAY formulas, both of which satisfy the 1996/49/CE
and 2003/14/CE directives for infant milk formulas.
NUTRIENTS
(per 100 g milk powder)
BLEMIL 1 PLUS NIGHT
(3.4 g tryptophan/
100 g protein)
BLEMIL 1 PLUS DAY
(1.5 g tryptophan/
100 g protein)
Macronutrients
Proteins 10.7 g 12 g
Tryptophan total 0.40 g 0.18 g
Fats 26 g 26 g
Vegetable 16.4 g (63%) 25.7 g (98.75%)
MCT 9.6 g (37%)
Formulaid 0.3 g (1.25%)
Carbohydrates 59.3 g 58 g
Lactose 44.8 g 44.8 g
Maltodextrin 14.5 g 13.2 g
Taurine 32 mg 32 mg
L-carnitine 17 mg 17 mg
Minerals
Minerals 2.5 g 2.5 g
Sodium 175 mg 175 mg
Potassium 535 mg 535 mg
Chlorine 290 mg 290 mg
Calcium 420 mg 420 mg
Phosphorus 230 mg 230 mg
Iron 6 mg 6 mg
Magnesium 42 mg 42 mg
Zinc 4.4 mg 4.4 mg
Copper 300 mcg 300 mcg
Iodine 70 mcg 70 mcg
Manganese 50 mcg 50 mcg
Selenium 10.7 mcg 10.7 mcg
Ca/P ratio 1.8 1.8
Vitamins
Vitamin A 500 mcg/1756 IU 640 mcg/2133 IU
Vitamin D 10.3 mcg/412 IU 10.3 mcg/412 IU
Vitamin E 12.2 mg 25 mg
Vitamin K 42 mcg 42 mcg
Vitamin B1 520 mcg 520 mcg
Vitamin B2 620 mcg 620 mcg
Vitamin B6 825 mcg 825 mcg
Vitamin B12 2 mcg 2.5 mcg
Vitamin C 50 mg 60 mg
Folic acid 42 mcg 42 mcg
Calcium pantothenate 3.2 mg 3. 2 mg
Nicotinamide 6 mg 6 mg
Biotin 16 mcg 16 mcg
Nucleotides
Cytidine 5´monophosphate 7.9 mg
Uridine 5´monophosphate 5.3 mg
Adenosine 5´monophosphate 2.7 mg
Guanosine 5´monophosphate 1.6 mg
Inosine 5´monophosphate 1.6 mg
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Infant milk and sleep
The study was approved by the Research Ethics Com-
mittee of the University of Extremadura, in accordance
with the Helsinki Declaration. The parents consented
in writing, and the children were under the continuous
monitoring of their paediatricians of the Extremadura
Health Service (S.E.S).
Measurement of sleep parameters
In order to analyze the evolution of the infants’
sleep with the different adapted formulas, non-invasive
actimeters were used to record activity/inactivity. The
children wore the actimeter (Actiwatch®, Cambridge
Neurotechnology Ltd., U.K.) on their ankle, except
at bath-time. The actimeters weigh 22 g and measure
37 mm × 27 mm × 9 mm, and consist of an internal ac-
celerometer that quantifies the movements and a sensor
that accumulates them every 2 minutes. Before the study,
the parents of the children were instructed on a series of
norms to follow to try to obtain the same ambient con-
ditions of temperature, light, and sound, and the same
time in the evening for putting the infant in the cradle.
The parents kept at home a daily sleep diary, which con-
sisted of noting down the child’s periods of sleep over
24 hours, and the number of bottle feeds, as well as any
observations or incidences that occurred during that day
which could have had an influence on the infant’s rest.
This diary helped us to better understand, interpret, and
evaluate the results given by the Actiwatch® system.
Analysis of sleep of the milk-fed infants
Once the actimeter was removed from the child’s
ankle, it was immediately analyzed by computer using
the “Sleep Analysis” software package (Cambridge
Neurotechnology Ltd., U.K.). This gives measurements
of the following parameters: (1) actual time of noctur-
nal sleep; (2) minutes of immobility of the infant in its
cradle during the night; (3) sleep latency, the time that
the infant takes to fall asleep from when it is placed in
the cradle; (4) percentage of nocturnal awakenings; (5)
sleep efficiency, the time the infant is asleep out of the
total time it is in the cradle.
At the end of the study, the parents were asked in
which week they had observed improvement in their
infant’s sleep.
The statistical study of the results was carried out
using an ANOVA (analysis of variance) with a Scheffe
F-test, with p<0.05 being taken as the level of significance
for differences between groups.
RESULTS
The analysis of the Actiwatch data indicated an
improvement in the infants’ nocturnal sleep in both the
week with Diet B (Control/Night) and that with Diet C
(dissociated Day/Night milk). Figure 1 shows how in the
weeks with Diets C the children showed a significant
increase (p<0.05) in the hours of actual sleep with respect
to Diet A (7.68 ± 0.54 h with Diet C vs. 6.77 ± 0.12 h with
Diet A=control).
With Diet C (Day/Night milks), as is shown in Fig-
ure 2, there was a significant reduction (p<0.05) in sleep
latency (the time the infant takes to fall asleep after being
placed in the cradle) (0.44 ± 0.04 h vs. Diet A=control
0.60 ± 0.08 h, p<0.05)). This significant reduction in
latency was also observed with Diet B (Day/Night milks
0.45 ± 0.04 h vs. Diet A=control 0.60 ± 0.08 h.
There were no significant differences between the
diets in the technical parameters of Minutes of Immobil-
ity (Figure 3) or Percentage of Awakenings (Figure 4).
Figure 5 shows the Percentage Nocturnal Sleep Ef-
ficiency. There was a significant increase (p<0.05) in this
parameter with Diet B (76.43 ± 3.4% vs. Diet A=control
69.86 ± 0.94%), i.e., there was an increase in the percent-
age of time that the infant was really asleep when it was
in the cradle.
Figure 1. Daily hours of actual nocturnal sleep (X±SD) of infants of
4–20 weeks of age, fed for 3 weeks with three different formula
diets: Diet A (Control), Normal Initiation Milk; Diet B, 06:00–18:00
Normal Initiation Milk and 18:00–06:00 dissociated Night for-
mula and Diet C, Day/night formulas at the schedule described
above; a: statistically significant with respect to the week with
Diet A (p<0.05). (n=30).
Figure 2. Nocturnal sleep latency (X±SD) of infants of 4–20 weeks
of age, fed for 3 weeks with three different formula diets: Diet A
(Control), Normal Initiation Milk; Diet B, 06:00–18:00 Normal Ini-
tiation Milk and 18:00–06:00 dissociated Night formula; and Diet
C, Day/night formulas at the schedule described above. a: statis-
tically significant with respect to the week with Diet A (p<0.05).
(n=30).
364
Copyright © 2007 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Javier Cubero, David Narciso, Pilar Terrón, Ruben Rial, Susana Esteban, Montserrat Rivero, Hasan Parvez, Ana B. Rodríguez & Carmen Barriga
Most of the parents (53%), in response to post-trial
survey questions, gave a subjective evaluation of an
improvement in their infant’s sleep during the week of
Diet C (Figure 6), with this percentage being lower for
the week with Diet B (35%) and even lower with Diet A
(12%). Both Diets C and B used Blemil Plus 1 Night from
18:00–06:00.
DISCUSSION
Infant food manufacturers have concerned them-
selves with obtaining milk formulas that approximate
breast-milk as closely as possible. Nevertheless, complete
equality is impossible due, among other causes, to the
proteins or cellular elements of the milk of each animal
species being essentially different. But in addition there
are documented differences in relatively simple compo-
Figure 6. Sleep improvement % as reflected in the responses to the
questionnaire given by the parents of infants 4–20 weeks of age,
fed for 3 weeks with three different formula diets: Diet A (Con-
trol): Normal Initiation Milk, and Diet B: of 06:00–18:00 Normal
Initiation Milk and 18:00–06:00 dissociated Night formula and
Diet C: Day/night formulas in the scheduled times previously.
(n=30).
Figure 3. Minutes per day of nocturnal immobility (X±SD) of infants
4–20 weeks of age, fed for 3 weeks with three different formula
diets: Diet A (Control): Normal Initiation Milk, Diet B: of 06:00–
18:00 Normal Initiation Milk and 18:00–06:00 dissociated Night
formula and Diet C: Day/night formulas in the scheduled times
previously. (n=30).
Figure 4. Number of nocturnal awakenings (X±SD) per day of in-
fants 4–20 weeks of age, fed for 3 weeks with three different
formula diets: Diet A (Control): Normal Initiation Milk, Diet B: of
06:00–18:00 Normal Initiation Milk and 18:00–06:00 dissociated
Night formula and Diet C: Day/night formulas in the scheduled
times previously. (n=30).
Figure 5. Nocturnal sleep efficiency % (X±SD) of infants 4–20 weeks
of age, fed for 3 weeks with three different formula diets: Diet A
(Control): Normal Initiation Milk, Diet B: of 06:00–18:00 Normal
Initiation Milk and 18:00–06:00 dissociated Night formula and
Diet C: Day/night formulas in the scheduled times previously.
a: statistically significant with respect to the week with Diet A
(p<0.05). (n=30).
nents such as the high uridine and tryptophan content of
breast-milk which, until now, has not been reflected in
commercial infant milk formulas. Indeed, the tryptophan
concentration of breast-milk is 2.5% of the total proteins,
whereas in most commercial formulas the corresponding
measured tryptophan content is 1.5% [10].
There are marked circadian variations in the compo-
sition of human milk that must have a key functional
importance in the development of pre-weaning infants.
Nevertheless, until now no infant food formulas have
been developed that take these aspects into consideration,
although the information on the circadian variability of
milk has been known for decades [17]. For example,
several studies have demonstrated that the acrophase
and nadir of the circadian variability depend on the
component in question: the amino acid tryptophan has
maximum levels in breast-milk during the night [2],
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Infant milk and sleep
while the maximum values are at dusk for the sleep-in-
ducing peptide [8], sodium, potassium, and cortisol [11],
and folates and lipids [19].
Sleep disturbances are receiving increasing attention
on the part of health professionals, given the importance
they present in relation to the general state of health. One
of the groups that present these disturbances is that of
parents of young children. Infants’ sleep problems not
only affect their own nervous system development, but
also affect the work rhythm and mood of the parents
[6].
The development of the circadian rhythm of sleep
begins in foetal life, since periods of wakefulness are fol-
lowed by NREM and REM activity [16]. The circadian
rhythm has an endogenous character, and is generated
by a central clock located in the hypothalamic suprachi-
asmatic nucleus (SNC) which is present by mid-gestation
in the human [18]. The newborn’s ultradian rhythm
has to evolve to a circadian rhythm in synchrony with
the external environment, which is not achieved until
approximately 12 weeks in age [1]. Nevertheless, not
all infants achieve this transformation since 30% of
pre-weaning infants present sleep problems [5]. Despite
the endogenous nature of the rhythm, certain periodic
environmental factors, such as the light/dark cycle or
feeding patterns, can act as synchronizers (zeitgebers) of
the circadian rhythms. Indeed, in the first moments of
life, the interactions of the mother and the baby are fun-
damental for the optimal development of the circadian
rhythm.
Given these facts, and the involvement of the com-
ponents present in breast-milk in the development of
the sleep/wake rhythm, dissociated Day/Night formula
milks for pre-weaning infants were designed to take ac-
count of the function of the substances that intervene in
the infant’s sleep/wake behaviour. To this end, the night
milk contained the sleep neuromodulating nucleotides
uracil and adenine [13,7], MCTs that because of their
easy digestion facilitate sleep in pre-weaning infants
[20], high levels of tryptophan [9] and of carbohydrates
to raise circulating insulin levels and facilitate transport
through the blood-brain barrier [21], and low levels of
proteins in order to reduce the competition of trypto-
phan with other neutral amino acids both in intestinal
absorption and passage through the blood-brain barrier
[14,15]. The day milk contained the nucleotides thymine,
cytosine, and guanine, and, to compensate the nutrient
composition of the night milk, high levels of proteins and
vitamins A, C, and E, and low levels of tryptophan and
carbohydrates.
The results obtained by our group in a first trail already
published [3] showed us that dissociated Day/Night
milks help to consolidate the circadian sleep/wake cycle.
Bearing in mind that these Day/Night milks were admin-
istered during the last of the three weeks that this first
test lasted, and in order to evaluate whether those results
might have been due to the fact that, after three weeks,
the pre-weaning infants were naturally more mature in
the consolidation of the sleep/wake cycle, in this second
test the day/night milks were randomly administered
over the three weeks, using a double blind protocol.
In this second study, we recruited 30 children under
the supervision of their paediatricians, and who presented
no health problems when they began the trial. For three
weeks, the children wore an Actiwatch® round their ankle
which recorded their daily activity/inactivity during the
time the study lasted. On the basis of previous trials car-
ried out by our team, and given the time that must elapse
for the absorption and transformation of tryptophan into
serotonin and melatonin [21], it was considered that the
dissociated Night milk should be administered from
18:00 to 06:00, and the dissociated Day milk from 06:00
to 18:00, in the quantities recommended by the paedia-
tricians that the parents noted daily in the sleep diaries.
The actimetry results for the week with Diet B and
the week with Diet C, both with Blemil Plus 1 Night
administered from 18:00–06:00, showed an increase in
nocturnal rest. This was corroborated by the opinions
that the parents had noted in the diaries. Nevertheless, it
has to be noted that the there was a greater bias in the re-
sults obtained through the parents’ opinions due to their
subjectivity in collecting the data. This data is therefore
less reliable than the results of the more technical sleep
analysis represented by the Actiwatch system.
Although both Diets C and B showed an improvement
in night rest, the optimal week chrononutritionally was
the week with Diet C (Day/Night milks), since the two
formulas complement their nutritional components in
harmony with breast-milk.
Artificial milk dissociated into its day/night compo-
nents administered during each child’s week with Diet
C led to a significant increase with respect to the Diet A
week (control) in the quantity and quality of sleep during
the time the child was in the cradle, as was quantified in
the actual nocturnal sleep parameter. The results of this
second study therefore confirmed our initial hypothesis,
since the best values of the sleep parameters were always
obtained during the week in which the infants took the
Blemil Plus 1 Day/Night combination, in synchrony with
their environment.
With this second trial, we have again shown that,
in the first months of life, a feed that is suited to that
time of the day can act as a zeitgeber (time giver or
synchronizer), helping maturation in consolidating the
sleep/wake cycle. Our results lend further support to the
principle underlying chrononutrition research that it is
not only necessary to consider feeding from a nutritional
standpoint, but that it should also be in harmony with
the environment and in concordance with intestinal
motility, digestive secretions, hormone levels, liver me-
tabolism, metabolic rate, and variations in the sensitivity
of target cells. Knowledge of the proper rhythm of feed-
ing in synchrony with our internal rhythms is of great
importance both for healthy individuals and for subjects
with certain pathologies such as sleep disorders, obesity,
and diabetes.
366
Copyright © 2007 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Javier Cubero, David Narciso, Pilar Terrón, Ruben Rial, Susana Esteban, Montserrat Rivero, Hasan Parvez, Ana B. Rodríguez & Carmen Barriga
In sum, the use of infant milk formulas with chrono-
biologically adapted nutritional components improves
the consolidation of the sleep/wake cycle in bottle-fed
infants.
ACKNOWLEDGMENTS
This work was financed by Laboratories Ordesa S.L.
through project 003-2003, and to the M.E.C. for the re-
search grant FPU reference AP2003-3894 given to David
Narciso, and our laboratory technician Elena Circujano.
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... Insulin mediates the selective uptake of LNAAs into muscle, thereby reducing their levels in the plasma [87]. This effect was utilized by Cubero et al. (2007) in a prospective study conducted on formula-fed infants (n = 30) with disrupted sleep/wake cycles [42]. In this study, the researchers attempted to emulate the varying levels of L-TRP in human milk that occurs through the day and night by dissociating a commercial infant formula to a daytime milk containing low L-TRP (1.2 g/100 g protein), low carbohydrates and higher protein levels; and a L-TRP enriched nighttime milk (3.4 g/100 g protein), higher carbohydrates and lower protein. ...
... Insulin mediates the selective uptake of LNAAs into muscle, thereby reducing their levels in the plasma [87]. This effect was utilized by Cubero et al. (2007) in a prospective study conducted on formula-fed infants (n = 30) with disrupted sleep/wake cycles [42]. In this study, the researchers attempted to emulate the varying levels of L-TRP in human milk that occurs through the day and night by dissociating a commercial infant formula to a daytime milk containing low L-TRP (1.2 g/100 g protein), low carbohydrates and higher protein levels; and a L-TRP enriched nighttime milk (3.4 g/100 g protein), higher carbohydrates and lower protein. ...
... The infants were fed three different formula combinations consisting of the standard formula (that had not been modified), and the daytime formula, and nighttime formula. Objective sleep data (actigraphy) showed that the daytime/nighttime modified formula and the standard/nighttime formula combination reduced sleep onset latency; the daytime/nighttime modified formula also significantly increased total sleep time (p < 0.05 for all) [42]. Although not specifically studying the effect of carbohydrates on L-TRP uptake, Bravo et al. (2013) reported improvements in actual sleep time (p < 0.01), sleep efficiency (p < 0.001), and immobile time (p < 0.01) following morning and evening consumption of an L-TRP rich cereal in a simple blind assay in older people (n = 35). ...
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... In addition to direct environmental circadian signals, infants maintain their connection to the maternal SCN by receiving maternal time cues through breast milk. Data from animal and human studies suggest that the diurnal fluctuations in breast milk evolved to send vital time-of-day information-a form of chrononutritionto promote the development of an entrained circadian clock [118]. Human milk expressed during the day contains higher levels of cortisol [119], tyrosine [120], and immune factors [121], whereas night milk is comprised of increased levels of leptin [122], melatonin [123], and tryptophan [120]. ...
... Here, it serves as a regulator of the infant circadian system. Compared to formula fed infants, breastfed infants show more regular nocturnal increases in 6-sulfatoxymelatonin, a metabolite of melatonin excreted in urine [127], higher sleep efficiency, less fragmented sleep [118], longer nocturnal sleep duration, and lower incidence of infant colic [125]. In the absence of breast milk, supplementation with exogenous melatonin may promote circadian clock development; however, this research remains unexplored. ...
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... To test the effect of this amino acid on sleep, tryptophan was added to formula milk, along with 5'AMP and 5'UMP to children 4-20 weeks of age. Children that received formula with this amino acid and nucleotides from 18:00 to 06:00 h showed a reduction in their latency to sleep as well as an increase in their hours of sleep (62). In another study of the same group, 8-16 month old children were fed a cereal enriched with tryptophan, 5'AMP, and 5'UMP during the night. ...
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During pregnancy the human fetus receives timed cues from the circadian rhythms of temperature, metabolites, and hormones from the mother. This influence is interrupted after parturition, the infant does not secrete melatonin and their circadian rhythms are still immature. However, evolution provided the solution to this problem. The newborn can continue receiving the mother's timed cues through breastmilk. Colostrum, transitional, and mature human milk are extraordinary complex biofluids that besides nutrients, contain an array of other non-nutritive components. Upon birth the first milk, colostrum, is rich in bioactive, immunological factors, and in complex oligosaccharides which help the proper establishment of the microbiome in the gut, which is crucial for the infants' health. Hormones, such as glucocorticoids and melatonin, transfer from the mother's plasma to milk, and then the infant is exposed to circadian cues from their mother. Also, milk components of fat, proteins, amino acids, and endogenous cannabinoids, among others, have a markedly different concentration between day and night. In the present review, we give an overview of nutritive and non-nutritive components and their daily rhythms in human milk and explore their physiological importance for the infant. Finally, we highlight some interventions with a circadian approach that emphasize the importance of circadian rhythms in the newborn for their survival, proper growth, and development. It is estimated that ~600,000 deaths/year are due to suboptimal breastfeeding. It is advisable to increase the rate of exclusive breastfeeding, during the day and night, as was established by the evolution of our species.
... Furthermore, nucleotides such as purine adenosine 5′ monophosphate (5′GMP) and pyrimidineuridine 5′ monophosphate (5′UMP) in breastmilk are controlled by circadian rhythms and peak at night [99]. Formula enriched with 5′GMP, 5′UMP, and tryptophan improved sleep parameters in infants including sleep duration, assumed sleep, and wake periods [100,101], indicating that not only the type of nutrition is important during this time, but the timing also plays an important role in developing the sleep/wake cycle. Given that the gut microbiota is also involved in the production of tryptophan [102] and the proper development and function of brain structures involved in maintaining the sleep-wake cycle [76,90], we postulate that it plays additional roles in the development of sleep patterns. ...
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... The presence of melatonin in breast milk and the circadian variation exhibited suggests that at night, infants who are breastfed may have better sleep patterns when compared to infants fed on milk that was expressed at a different time of day (Hahn-Holbrook et al., 2019) or those fed infant formula (Cohen Engler et al., 2012;Cubero et al., 2007). However, animal studies suggest that not all melatonin crosses the infants' gastrointestinal tract (Rowe & Kennaway, 2002), highlighting the need for more research in this area. ...
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... Basándonos en las conocidas propiedades de la melatonina como hipnótico, cronorregulador y modulador de la motilidad intestinal, es posible que la melatonina administrada a esas horas con la leche materna ocasione una reducción de la actividad gastrointestinal nocturna y con ello del llamado cólico del lactante, promocionando una mejor calidad de sueño. Diversos estudios han demostrado la absorción de la melatonina a través del tracto gastrointestinal y existen datos que apuntan que la melatonina añadida a las fórmulas infantiles favorece un desarrollo más temprano de los ritmos circadianos que consolidan el sueño nocturno (6) . ...
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... Мелатонин вырабатывается шишковидной железой из серотонина в основном в темное время суток [49]. Результатом употребления перед сном молочной каши, обогащенной триптофаном, является улучшение ночного сна [50,51]. В частности, у детей в возрасте 8-16 мес с нарушениями сна, выражавшимися в более 3 ночных пробуждениях, при кормлении кашей, обогащенной триптофаном, улучшилось качество и увеличилась продолжительность сна [52]. ...
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Cereals are one of the main sources of energy, complex carbohydrates, vegetable proteins and fats, as well as vitamins, minerals and other important biologically active compounds used in everyday diets. The undeniable health benefits makes these products necessary in the human diet. Hypoglycemic conditions are unacceptable in the period of active growth and development of the brain, as they can disrupt its functioning; to maintain normoglycemia, especially after nightly fasting, it is important to have breakfast with cereals. This is especially important for brain maturation in children with subsequent long-term impact on the development of cognitive functions. Tryptophan-enriched cereals are useful for correcting the sleep-waking cycle in children, especially young children, and also they have a positive effect on mood. Whole grains products help to reduce the risk of cardiovascular diseases, diabetes mel-litus, obesity, colon cancer, due to their prebiotic effect.
... In addition, the chronobiological changes in the normal components of the diet can improve infantile development of sleep/wake rhythms. For instance, day/night infant formula milks designed according to the principles of chrononutrition help to consolidate the sleep/wake rhythm in bottle-fed infants (Cubero et al., 2007). The administration of tryptophan enriched milk during night-time improves sleep parameters, associated with an increased use of serotonin to melatonin synthesis in infants (Aparicio et al., 2007). ...
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Background The circadian clock is an evolved autonomous timekeeping system that aligns body functions to the solar course, by anticipating/coordinating the required metabolic activities; such internal clock responds to several exogenous stimuli (Zeitgebers) able to synchronize the endogenous rhythm. A disrupted circadian rhythm leads to several neurodegenerative and metabolic illness such as obesity, diabetes, and psychiatric disorders. Scope and approach Circadian rhythm disorders have no current medical treatment, but chrononutrition has emerged as an important tool to enhance metabolic and nutritional health in sleep disorders. This review highlights the effects of meal timing, food types, nutrients and several bioactive xenobiotic compounds (chronobiotics) on circadian clocks. The potential application of diet therapies is discussed particularly to deal with certain metabolic disorders related to circadian misalignment. Key findings and conclusions: The desynchronization of circadian rhythms negatively influences health necessitating the development of molecular modulators of circadian rhythms including food components, meal timing, or different diet types that can help correct circadian disorders attenuating the burden of chronic diseases. However, there is limited research on the chronobiotic effect of specific foods/compounds in clinical trials. Animal studies evaluating the chronobiological response, resulting from the ingestion of a particular food, are also limited; most available studies (in vitro and animal models) report the effect of a single nutrient (e.g., caffeine, palmitate, among others) which is difficult to translate to real-life situations. This review offers the perspective of a chronobiotic-based approach, identifying targets for health improvement, which are current lifestyle-associated issues.
Chapter
Circadian rhythms are generated by an endogenous circadian timing system. The biological clock, a key component of the circadian timing system, is anatomically located in the suprachiasmatic nucleus of the anterior hypothalamus and its functioning is grounded on a genetic-based negative feedback loop mechanism. Circadian rhythms are entrained to the 24-hour cycle by so-called Zeitgebers or synchronizers that can be environmental such as the dark/light cycle, social such as school start time, or biological such as melatonin. One of the most widely investigated circadian rhythms is the sleep/wake cycle, the organization of which can be understood within the theoretical framework of the two-process model of sleep regulation. Looking at this model from a developmental perspective, it can be supposed that sleep (S) or the homeostatic process may be preponderant over the circadian (C) process in early life because homeostasis is an intrinsic basic function of living beings aimed at avoiding possible interference from the environment. The C process, on the contrary, is supposed to help the S process to gradually tune with environmental changes. It is probable that this is the reason why the C process undergoes a progressive development that is completed at the end of adolescence, changing the balance between the two processes, and becoming preeminent compared with the S process. After the C process completes its maturation, it starts to progressively weaken with age, leading to a new balance between the two processes.
Chapter
Nutritional intake and sleep are interrelated processes. Research has demonstrated several mechanisms by which nutrition promotes sleep and hunger promotes vigilance. Particular diets and dietary compounds can induce sleepiness and affect sleep quality. Dietary intake may also influence the timing of the circadian sleep–wake rhythm. Sleep can affect nutrition, and sleep abnormalities may disrupt energy homeostasis. Certain dietary substances or disorders can adversely affect sleep. Dietary modifications may help treat certain sleep disorders, but more research is necessary to evaluate specific effects on sleep. Research is also needed to evaluate the effects of sleep disorder treatment on nutrition and energy homeostasis.
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The sleep-inducing mechanisms of L-Tryptophan (L-Trp) are generally thought to be mediated by a central serotonergic activation. Evidence is presented that some effects of L-Trp on sleep may be mediated by melatonin, a Trp-metabolite with sedative properties. Trp effects on vigilance, sleep, and plasma-melatonin concentrations were measured after double-blind application of 0, 1, 3, and 5 g L-Trp in nine and five healthy probands during daytime and nighttime, respectively. A significant sleep-inducing effect was observed after L-Trp administration during daytime and nighttime. The infusions of L-Trp caused a massive elevation of plasma melatonin levels. This effect was significant both during the night and the day, indicating that the increment of circulating melatonin may be of extrapineal origin.
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Delta-sleep-inducing peptide (DSIP)-like material was detected in human breast milk of two women by RIA with a recovery of about 90%. The high concentration of DSIP-like immunoreactivity (DSIP-LI) in colostrum (30 ng/ml) decreased to about 10 ng/ml in milk. The concentration continued to decrease over the next 2 months in one women. In the same woman, a significant circadian rhythm of the amount of breast milk DSIP was found with the peak in the afternoon and the trough in the morning. A significant effect of the sampling procedure was detected in the other woman examined; lower amounts of DSIP-LI were found when the milk was collected before and higher concentrations after nursing. Gel chromatography revealed that most of the immunoreactive DSIP-LI in milk and colostrum occurred in a form larger than the nonapeptide. The presence of DSIP itself, however, was demonstrated by high pressure liquid chromatography, which also showed additional peptides reacting with the antibody. Digestion of the large immunoreactive DSIP-LI by trypsin produced a peak on Sephadex G-10 that coeluted with DSIP. This peak contained three immunoreactive fractions with retention times on high pressure liquid chromatography similar to DSIP, phosphorylated DSIP, and N-tyrosine-DSIP. Plasma samples taken during pregnancy were assayed for DSIP but no difference from normal values was found. Slightly higher amounts were found in placenta than in blood, which might be due to interfering substances. No Tyr-MIF-1 or corticotropin-releasing hormone was detected by RIA in human breast milk. Peptides and proteins of milk can be absorbed from the gastrointestinal tract of babies, but it is not known if the DSIP-LI in human milk is involved in the induction of a sleep-wake cycle in neonates.
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Cortisol (F), Na, and K were measured in human milk samples taken every 4 h during 28 24-h cycles in 19 subjects. F in milk, measured by radioimmunoassay of unchromatographed extracts, demonstrated a circadian variation similar to that of plasma F and was dexamethasone-suppressible. Values ranged from 220 +/- 41 (SE) ng/dl at 2300 h to 1,214 +/- 210 at 0700 h. When milk extracts were chromatographed, a similar circadian variation was seen, and F ranged from 87 +/- 27 (SE) ng/dl at 2300 h to 784 +/- 164 at 700 h. The morning values of F exceeded previous estimates of corticosteroid binding capacity in milk, indicating the possibility of significant levels of unbound F. The subjects were divided into three groups according to time postpartum: I, 3.5-6 wk; II, 8-18 wk, and III, 20-32 wk. In milk, normalized values of F (unchromatographed) and electrolytes (x/means) were compared, with x the value at time t and means the mean value for a 24-h cycle. A significant circadian variation was seen in milk for (x/means)Na, (x/means)K, (x/means)Na/K, and x/means)F. Correlation of (x/means)F with (x/means)Na 4 h later was negative in all three groups (r = -0.36 to -0.56, P less than 0.10-0.001) as was (x/means)F vs. (x/means)Na/K (r = -0.33 to -0.61, P less than 0.10-0.001); (x/means)F vs. (x/means)K 4 h later was positive (r = 0.38 to 0.52, P less than 0.05-0.001). Dexamethasone administration caused a significant decrease in milk means Na and an increase in meansK in all five subjects (P less than 0.01). Thus, milk Na and K concentrations appeared regulated by adrenal corticosteroids.
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The emergence of spontaneous fetal motility during the first 20 weeks of gestation was studied longitudinally in 11 healthy nulliparae, using real-time ultrasound. The aim of this investigation was to study the onset and developmental course of spontaneously generated specific fetal movement patterns. 60-min observations were repeated weekly from 7 to 15 weeks and at 16/17 and 18/19 weeks. The qualitative aspects of fetal motility and posture were analyzed during video recording. Sixteen distinct movement patterns (just discernible movements; startle; general movements; hiccup; breathing; isolated arm or leg movements; isolated retroflexion/rotation and anteflexion of the head; jaw movements; sucking and swallowing; hand-facecontact; stretch; yawn; rotation), closely resembling those observed in preterm and fullterm newborn infants, could be distinguished and a detailed description is presented. The first movements were observed at 7.5 weeks postmenstrual age. A scatter of two weeks was found for the ages at which frequently occurring movement patterns could be observed for the first time. By the age of 15 weeks all 16 movement patterns could be observed. There were no major changes between 8 and 20 weeks in the appearance of the different movements, which meant that they were easy to recognize at all ages studied. A systematic assessment of position and posture showed a preference for the supine position before 16 weeks, and for the lateral position after 16 weeks. There was no consistent intra-individual preference for position or posture. Two specific motor patterns could be identified as causing either somersault or rotation around the longitudinal axis. The number of changes in fetal position increases from 10 weeks onwards, reaches a peak at 13–15 weeks and decreases after 17 weeks.
Article
This research was designed to evaluate the circadian variation in the lipid content of the milk obtained from 10 lactating Mexican women as well as the effects of a meal eaten by the mother and of previous milk sampling on the milk volume and fat yield. In addition, predictions were made to determine the most appropriate sampling schedule to obtain a milk sample representative of 24-hour production. Every 4 h over a 24-hour period, the contents of the left breast of predominantly breast-feeding volunteers were completely extracted, using an Engell pump, and analysed for lipid content. In a separate experiment, 6 volunteers were sampled hourly from 9.00 to 13.00 h on 2 consecutive days, one after eating breakfast and the second while fasting. Significant circadian variations of volume (p < 0.05) and lipid yield (p < 0.001) were noted, peaking at 8.00-12.00 and 16.00-20.00 h, respectively. No effects of eating breakfast or of the volume and fat content of the preceding pumping on the actual volume or fat yield were found. In this population, sampling at 12.00, 20.00 and 24.00 h is the most representative of the 24-hour lipid yield, tending to overestimate it by 2.59 g/24 h with a predictive range of 97-124%.
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In the newborn, tryptophan (Trp) and its metabolites are essential to brain maturation and to the development of neurobehavioral regulations of food intake, satiation and sleep-wake-rhythm. Due to the high Trp concentration in human milk in relation to the total of neutral amino acids, the blood-brain transfer of tryptophan as a precursor of its metabolites serotonin and melatonin is optimal. In contrast, commercial infant formulas are lower in Trp and higher in neutral amino acid levels resulting in comparatively lower Trp serum concentrations. α-lactalbumin enriched, protein-reduced formulas adapted to 2.2% Trp were shown to be capable of producing Trp serum values that did not differ from those in breast-fed infants.
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A common disorder in children aged between 6 months and 5 years is childhood insomnia due to disorderly habits. The clinical characteristics of this condition are difficulty in going to sleep on their own and multiple nocturnal wakenings. It occurs in perfectly normal children who are seen to have difficulty in the normalization of their sleep-waking rhythm due to absence or weak application of external synchronizers. The only point on which we can act to enforce synchronization of the sleep-waking circadian rhythm is on the habits related to getting to sleep. To initiate this synchronization of sleep-waking rhythm, it is essential to create a ritual around the action of going to bed. The possibility of the child getting back to sleep during the many physiological wakenings he has during the night depends on this ritual. It is essential that the child be awake when he leaves the bedroom. The child must learn to go to sleep with external elements which are associated with sleep, and during the physiological wakenings during the night, he will reclaim the circumstances which he associates with sleep. If the child goes to sleep on his own, he will go back to sleep on his own when he wakes at night; but if he has gone to sleep in someone's arms or 'has been put to sleep' by rocking, he will want the arms or rocking again. Once the routine is completed, the parents will leave the room and should follow a pattern of waiting time, increasing his progressively, following techniques for the modification of conduct until the child manages to get to sleep on his own.
Article
There is considerable debate about the human lysine requirement and the consequent nutritional value of wheat protein. We used a novel [1-(13)C]leucine balance protocol to examine whether adaptive mechanisms to conserve lysine allow wheat to be utilized more efficiently than expected according to current estimates of lysine requirements and wheat utilization. Wheat and milk proteins were compared in 6 adults infused for 9 h with L-[1-(13)C]leucine in the postabsorptive state (0-3 h), who were fed half-hourly with low-protein (2% of energy, 3-6 h) and isoenergetic higher-protein (12-13% of energy, 6-9 h) meals providing maintenance energy intakes. From acute measurements of [1-(13)C]leucine balance, we predicted nitrogen balance, the metabolic demand for protein, the efficiency of postprandial protein utilization (PPU), and the requirements for wheat protein and lysine. Leucine balance was higher after the milk than after the wheat feeding because of the greater inhibition of proteolysis by milk. PPU, calculated as the ratio of Deltanitrogen balance to Deltanitrogen intake between the low-protein and higher-protein periods, was 0.68 +/- 0.06 for wheat and 1.00 +/- 0.09 for milk (P </= 0.001). The estimated average wheat protein requirement (0. 6/PPU) was 0.89 +/- 0.08 g*kg(-)(1)*d(-)(1), indicating a lysine requirement of 23.2 +/- 2.0 mg*kg(-)(1)*d(-)(1). The measured PPU for wheat, 0.68 +/- 0.06, was higher than the value calculated from wheat lysine intake and milk protein lysine deposition, 0.26 +/- 0. 02, and higher than predicted by most published estimates of lysine requirements, apart from a value of 19 mg/kg indicated by nitrogen balance studies. The results show that adaptive mechanisms of lysine conservation allow wheat protein to be utilized more efficiently than expected.
Article
Circadian rhythms are endogenously generated rhythms with a period length of about 24-hours. Evidence gathered over the past decade indicates that the circadian timing system develops prenatally, and the suprachiasmatic nuclei, the site of a circadian clock, is present by midgestation in human and nonhuman primates. Recent evidence also shows that the circadian system of primate infants is responsive to light at very premature stages and that low intensity lighting can regulate the developing clock. After birth, there is progressive maturation of the circadian system outputs, with pronounced rhythms in sleep-wake and hormone secretion generally developing after 2 months of age. With the continued elucidation of circadian system development and influences on human physiology and illness, it is anticipated that consideration of circadian biology will become an increasingly important component of neonatal care.